Datasets:

developerZoyal

/

full_drugs_data

like 0

{TEMOZOLOMIDE}

{'contraindications': '{"4 CONTRAINDICATIONS Temozolomide is contraindicated in patients with a history of serious hypersensitivity reactions to: temozolomide or any other ingredients in temozolomide capsules; and dacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide. Reactions to temozolomide have included anaphylaxis [see Adverse Reactions (6.2) ] . History of serious hypersensitivity to temozolomide or any other ingredients in temozolomide capsules and dacarbazine. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Pneumocystis Pneumonia [see Warnings and Precautions (5.3) ] Secondary Malignancies [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥20%) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥10%) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Glioblastoma The safety of temozolomide was evaluated in study MK-7365-051 [see Clinical Studies (14.1) ] . Severe or life-threatening adverse reactions occurred in 49% of patients treated with temozolomide; the most common were fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). The most common adverse reactions (≥20%) in patients treated with temozolomide were alopecia, fatigue, nausea, anorexia, headache, constipation, and vomiting. Table 3 summarizes the adverse reactions in MK-7365-051. Clinically relevant adverse reactions in <10% of patients are presented below: Central & Peripheral Nervous System: memory impairment, confusion Eye: vision blurred Gastrointestinal System: stomatitis, abdominal pain General: weakness, dizziness Immune System: allergic reaction Injury: radiation injury not otherwise specified Musculoskeletal System: arthralgia Platelet, Bleeding, & Clotting: thrombocytopenia Psychiatric: insomnia Respiratory System: coughing, dyspnea Special Senses Other: taste perversion Skin & Subcutaneous Tissue: dry skin, pruritus, erythema When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade 3 or Grade 4 platelet abnormalities including thrombocytopenic reactions were observed in 14% of patients. Newly Diagnosed Anaplastic Astrocytoma The safety of temozolomide for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma was derived from published literature [see Clinical Studies (14.2)] . The safety of temozolomide for the adjuvant treatment of patients with newly diagnosed anaplastic astrocytoma was consistent with the known safety profile of temozolomide. Refractory Anaplastic Astrocytoma The safety of temozolomide was evaluated in study MK-7365-006 [see Clinical Studies (14.2) ] . The most common adverse reactions (≥20%) were nausea, vomiting, headache, fatigue, constipation, and convulsions. Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in MK-7365-006. Clinically relevant adverse reactions in <10% of patients are presented below: Central and Peripheral Nervous System: paresthesia, somnolence, paresis, urinary incontinence, ataxia, dysphasia, convulsions local, gait abnormal, confusion Endocrine: adrenal hypercorticism Gastrointestinal System: abdominal pain, anorexia General: back pain Metabolic: weight increase Musculoskeletal System: myalgia Psychiatric: anxiety, depression Reproductive Disorders: breast pain female Respiratory System: upper respiratory tract infection, pharyngitis, sinusitis, coughing Skin & Appendages: rash, pruritus Urinary System: urinary tract infection, micturition increased frequency Vision: diplopia, vision abnormal* * This term includes blurred vision; visual deficit; vision changes; and vision troubles. Hematological Toxicities for Advanced Gliomas In clinical trial experience with 110 to 111 females and 169 to 174 males (depending on measurements), females experienced higher rates of Grade 4 neutropenia (ANC <0.5 x 10 9 /L) and thrombocytopenia (<20 x 10 9 /L) than males in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively). In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 10% (6/63) of patients >70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. temozolomide-table3 temozolomide-table4 temozolomide-table5 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of temozolomide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine: Diabetes insipidus."}', 'drug_interactions': None, 'indications_and_usage': '{"1 INDICATIONS AND USAGE Temozolomide is an alkylating drug indicated for the treatment of adults with: Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. ( 1.1 ) Anaplastic astrocytoma. ( 1.2 ) Adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma. ( 1.2 ) Treatment of adults with refractory anaplastic astrocytoma. ( 1.2 ) 1.1 Newly Diagnosed Glioblastoma Temozolomide capsules are indicated for the treatment of adults with newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment. 1.2 Anaplastic Astrocytoma Temozolomide capsules are indicated for the: adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma; treatment of adults with refractory anaplastic astrocytoma."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Myelosuppression: Monitor absolute neutrophil count (ANC) and platelet count prior to each cycle and during treatment. Geriatric patients and women have a higher risk of developing myelosuppression. ( 5.1 , 8.5 ) Hepatotoxicity: Fatal and severe hepatotoxicity have been reported. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of temozolomide. ( 5.2 ) Pneumocystis Pneumonia (PCP): Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP. ( 5.3 ) Secondary Malignancies: Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. ( 5.4 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms. ( 5.5 , 8.1 , 8.3 ) Exposure to Opened Capsules: Temozolomide capsules should not be opened, chewed, or dissolved but should be swallowed whole with a glass of water. ( 5.6 ) 5.1 Myelosuppression Myelosuppression, including pancytopenia, leukopenia, and anemia, some with fatal outcomes, have occurred with temozolomide [see Adverse Reactions (6.1, 6.2) ]. In MK-7365-006, myelosuppression usually occurred during the first few cycles of therapy and was generally not cumulative. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Approximately 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Obtain a complete blood count and monitor ANC and platelet counts before initiation of treatment and as clinically indicated during treatment. When temozolomide is used in combination with radiotherapy, obtain a complete blood count prior to initiation of treatment, weekly during treatment, and as clinically indicated [see Dosage and Administration (2.1 , 2.2 , 2.3) ]. For severe myelosuppression, withhold temozolomide and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.1 , 2.2 , 2.3) ]. 5.2 Hepatotoxicity Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide. 5.3 Pneumocystis Pneumonia Pneumocystis pneumonia (PCP) has been reported in patients receiving temozolomide. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens of temozolomide. For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue PCP prophylaxis in patients who experience lymphopenia, until resolution to Grade 1 or less [see Dosage and Administration (2.1) ]. Monitor all patients receiving temozolomide for the development of lymphopenia and PCP. 5.4 Secondary Malignancies The incidence of secondary malignancies is increased in patients treated with temozolomide-containing regimens. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, temozolomide can cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted in embryolethality and polymalformations at doses less than the maximum human dose based on body surface area. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose. Because of potential risk of genotoxic effects on sperm, advise male patients with female partners of reproductive potential to use condoms during treatment with temozolomide and for 3 months after the last dose. Advise male patients not to donate semen during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ]. 5.6 Exposure to Opened Capsules Advise patients not to open, chew or dissolve the contents of the temozolomide capsules. Swallow capsules whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membranes. In case of powder contact, wash affected area with water immediately [see Dosage and Administration (2.4) ] . If temozolomide capsules must be opened or the contents must be dissolved, this should be done by a professional trained in safe handling of hazardous drugs using appropriate equipment and safety procedures."}', 'overdosage': '{"10 OVERDOSAGE Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, monitor complete blood count and provide supportive measures as necessary."}', 'active_flag': 'Y', 'generic_name': '{TEMOZOLOMIDE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Inform patients that temozolomide capsules can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact their healthcare provider immediately for bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1) ]. Hepatotoxicity Advise patients of the increased risk of hepatotoxicity and to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity. Inform patients that they will have periodic liver enzyme tests during treatment and following the last dose of temozolomide capsules [see Warnings and Precautions (5.2) ] . Pneumocystis Pneumonia Advise patients of the increased risk of Pneumocystis pneumonia and to contact their healthcare provider immediately for new or worsening pulmonary symptoms. Inform patients that prophylaxis for Pneumocystis pneumonia may be needed [see Dosage and Administration (2.1) , Warnings and Precautions (5.3) ] . Secondary Malignancies Advise patients of the increased risk of myelodysplastic syndrome and secondary malignancies [see Warnings and Precautions (5.4) ] . Exposure to Opened Capsules Advise patient to not open, chew, or dissolve the capsules. If capsules are accidentally opened or damaged, advise patients to take rigorous precautions with capsule contents to avoid inhalation or contact with the skin or mucous membranes [see Warnings and Precautions (5.6) ]. In case of powder contact, wash the affected area with water immediately [see Dosage and Administration (2.4) ] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5) , Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose [see Use in Specific Populations (8.3) ] . Advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Advise male patients not to donate semen during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Lactation Advise women not to breastfeed during treatment with temozolomide and for 1 week after the last dose [see Use in Specific Populations (8.2) ]. Infertility Advise males of reproductive potential that temozolomide may impair fertility [see U se in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ]. Manufactured for: Rising Pharma Holdings, Inc. East Brunswick, NJ 08816 Made in India Code No.: TS/DRUGS/24/2015 Revised: 03/2024 PIR82120-02"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , temozolomide can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to temozolomide during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of temozolomide to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8 to 12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness of temozolomide have not been established in pediatric patients. Safety and effectiveness of temozolomide capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to 18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. In a second study conducted by the Children’s Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9). The adverse reaction profile in pediatric patients was similar to adults."}', 'geriatric_use': '{"8.5 Geriatric Use In MK-7365-051, 15% of patients with newly diagnosed glioblastoma were 65 years and older. This study did not include sufficient numbers of patients aged 65 years and older to determine differences in effectiveness from younger patients. No overall differences in safety were observed between patients ≥65 years and younger patients. The CATNON trial did not include sufficient numbers of patients aged 65 years and older to determine differences in safety or effectiveness when compared to younger patients. In MK-7365-006, 4% of patients with refractory anaplastic astrocytoma were 70 years and older. This study did not include sufficient numbers of patients aged 70 years and older to determine differences in effectiveness from younger patients. Patients 70 years and older had a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] . In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 10% (6/63) of patients >70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred."}'}

{CARBIDOPA,LEVODOPA}

{'contraindications': '{"CONTRAINDICATIONS Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with this combination product. Carbidopa and levodopa may be administered concomitantly with the manufacturer\'s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS , Drug Interactions). Carbidopa and levodopa is contraindicated in patients with known hypersensitivity to any component of this drug, and in patients with narrow-angle glaucoma."}', 'adverse_reactions': '{"ADVERSE REACTIONS The most common adverse reactions reported with carbidopa and levodopa have included dyskinesias, such as choreiform, dystonic, and other involuntary movements, and nausea. The following other adverse reactions have been reported with carbidopa and levodopa: Body as a Whole Chest pain, asthenia. Cardiovascular Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension, syncope, phlebitis, palpitation. Gastrointestinal Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations. Hematologic Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia. Hypersensitivity Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions). Musculoskeletal Back pain, shoulder pain, muscle cramps. Nervous System/Psychiatric Psychotic episodes including delusions, hallucinations, and paranoid ideation, bradykinetic episodes (\\"on-off\\" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal relationship with carbidopa and levodopa has not been established. Respiratory Dyspnea, upper respiratory infection. Skin Rash, increased sweating, alopecia, dark sweat. Urogenital Urinary tract infection, urinary frequency, dark urine. Laboratory Tests Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), LDH, bilirubin, BUN, Coombs test; elevated serum glucose; white blood cells, bacteria, and blood in the urine. Other adverse reactions that have been reported with levodopa alone and with various carbidopa and levodopa formulations, and may occur with this combination product are: Body as a Whole Abdominal pain and distress, fatigue. Cardiovascular Myocardial infarction. Gastrointestinal Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue, heartburn, hiccups. Metabolic Edema, weight gain, weight loss. Musculoskeletal Leg pain. Nervous System/Psychiatric Ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased tremor, numbness, muscle twitching, activation of latent Horner\'s syndrome, peripheral neuropathy. Respiratory Pharyngeal pain, cough. Skin Malignant melanoma, flushing. Special Senses Oculogyric crises, diplopia, blurred vision, dilated pupils. Urogenital Urinary retention, urinary incontinence, priapism. Miscellaneous Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation. Laboratory Tests Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid; protein and glucose in urine. To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Carbidopa and levodopa tablets are indicated in the treatment of Parkinson\'s disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Carbidopa allows patients treated for Parkinson\'s disease to use much lower doses of levodopa. Some patients who responded poorly to levodopa have improved on carbidopa and levodopa. This is most likely due to decreased peripheral decarboxylation of levodopa caused by administration of carbidopa rather than by a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa. Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Management of acute overdosage with carbidopa and levodopa is the same as management of acute overdosage with levodopa. Pyridoxine is not effective in reversing the actions of this product. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as carbidopa and levodopa tablets should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known. Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1,500 to 2,000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3,360 mg/kg."}', 'active_flag': 'Y', 'generic_name': '{"CARBIDOPA AND LEVODOPA"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS When carbidopa and levodopa tablets are to be given to patients who are being treated with levodopa, levodopa must be discontinued at least twelve hours before therapy with the combination product is started. In order to reduce adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION section before initiating therapy. The addition of carbidopa with levodopa in the form of this combination product reduces the peripheral effects (nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with carbidopa and levodopa than with levodopa alone. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Carbidopa and levodopa should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease. As with levodopa, care should be exercised in administering the combination product, to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care. As with levodopa, treatment with the combination product may increase the possibility of upper gastrointestinal hemorrhage in patients with a history of peptic ulcer. Falling Asleep During Activities of Daily Living and Somnolence Patients taking carbidopa and levodopa alone or with other dopaminergic drugs have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although many patients reported somnolence while on dopaminergic medications, there have been reports of road traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing preexisting somnolence, although some patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving or operating machines during treatment with carbidopa and levodopa. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with carbidopa and levodopa. Before initiating treatment with carbidopa and levodopa, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with carbidopa and levodopa such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing carbidopa and levodopa in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with carbidopa and levodopa continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Hyperpyrexia and Confusion Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as levodopa, carbidopa and levodopa, or carbidopa and levodopa extended release. Therefore, patients should be observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia. Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin have been reported. The early diagnosis of this condition is important for the appropriate management of these patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the clinical presentation includes both serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology. The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring and 2) treatment of any concomitant serious medical problems for which specific treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies."}', 'precautions': '{"PRECAUTIONS General As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are recommended during extended therapy. Patients with chronic wide-angle glaucoma may be treated cautiously with carbidopa and levodopa provided the intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular pressure during therapy. Dyskinesia Levodopa alone, as well as carbidopa and levodopa, is associated with dyskinesias. The occurrence of dyskinesias may require dosage reduction. Hallucinations/Psychotic-Like Behavior Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In general, hallucinations present shortly after the initiation of therapy and may be responsive to dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. Carbidopa and levodopa may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Ordinarily, patients with a major psychotic disorder should not be treated with carbidopa and levodopa, because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of carbidopa and levodopa. Impulse Control/Compulsive Behaviors Reports of patients taking dopaminergic medications (medications that increase central dopaminergic tone), suggest that patients may experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or the caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with carbidopa and levodopa. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking carbidopa and levodopa (see Information for Patients ). Melanoma Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using carbidopa and levodopa for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Information for Patients The patient should be informed that this combination product is an immediate-release formulation of carbidopa and levodopa that is designed to begin release of ingredients within 30 minutes. It is important that carbidopa and levodopa be taken at regular intervals according to the schedule outlined by the physician. The patient should be cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson medications, including other carbidopa and levodopa preparations, without first consulting the physician. Patients should be advised that sometimes a \'wearing-off\' effect may occur at the end of the dosing interval. The physician should be notified if such response poses a problem to lifestyle. Patients should be advised that occasionally, dark color (red, brown, or black) may appear in saliva, urine, or sweat after ingestion of carbidopa and levodopa. Although the color appears to be clinically insignificant, garments may become discolored. The patient should be advised that a change in diet to foods that are high in protein may delay the absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce the clinical effectiveness of the levodopa or carbidopa and levodopa therapy. Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some cases without awareness or warning signs, when they are taking dopaminergic agents, including levodopa. Patients should be advised to exercise caution while driving or operating machinery and that if they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities. (See WARNINGS , Falling Asleep During Activities of Daily Living and Somnolence . ) There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease, including carbidopa and levodopa. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with carbidopa and levodopa. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking carbidopa and levodopa. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking carbidopa and levodopa (See PRECAUTIONS , Impulse Control/Compulsive Behaviors ). Laboratory Tests Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase (LDH), and bilirubin. Abnormalities in blood urea nitrogen (BUN) and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during administration of this combination product than with levodopa. Carbidopa and levodopa may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. Cases of falsely diagnosed pheochromocytoma in patients on carbidopa and levodopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or carbidopa and levodopa therapy. Drug Interactions Caution should be exercised when the following drugs are administered concomitantly with carbidopa and levodopa. Symptomatic postural hypotension occurred when carbidopa and levodopa was added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with carbidopa and levodopa is started, dosage adjustment of the antihypertensive drug may be required. For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS . Concomitant therapy with selegiline and carbidopa and levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa and levodopa alone (see CONTRAINDICATIONS ). There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa and levodopa. Dopamine D 2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson\'s disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with carbidopa and levodopa should be carefully observed for loss of therapeutic response. Use of carbidopa and levodopa with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended. Carbidopa and levodopa and iron salts or multivitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa. Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties. Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year bioassay of carbidopa and levodopa, no evidence of carcinogenicity was found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa. In reproduction studies with carbidopa and levodopa, no effects on fertility were found in rats receiving doses of approximately two times the maximum daily human dose of carbidopa and four times the maximum daily human dose of levodopa. Pregnancy No teratogenic effects were observed in a study in mice receiving up to 20 times the maximum recommended human dose of carbidopa and levodopa. There was a decrease in the number of live pups delivered by rats receiving approximately two times the maximum recommended human dose of carbidopa and approximately five times the maximum recommended human dose of levodopa during organogenesis. Carbidopa and levodopa caused both visceral and skeletal malformations in rabbits at all doses and ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of carbidopa/levodopa. There are no adequate or well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Use of carbidopa and levodopa in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to mother and child. Nursing Mothers Levodopa has been detected in human milk. Caution should be exercised when carbidopa and levodopa is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients below the age of 18 is not recommended. Geriatric Use In the clinical efficacy trials for carbidopa and levodopa, almost half of the patients were older than 65, but few were older than 75. No overall meaningful differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions such as hallucinations cannot be ruled out. There is no specific dosing recommendation based upon clinical pharmacology data as carbidopa and levodopa is titrated as tolerated for clinical effect."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CALCIUM CARBONATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves • heartburn • acid indigestion • sour stomach • upset stomach associated with these symptoms"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CALCIUM CARBONATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Ask a doctor or pharmacist before use if you are presently taking a prescription drug. Antacids may interact with certain prescription drugs. When using this product • do not take more than 7 tablets in 24 hours • if pregnant do not take more than 5 tablets in 24 hours • do not use the maximum dosage for more than 2 weeks except under the advice and supervision of a doctor."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"TIMOLOL MALEATE"}

{'contraindications': '{"CONTRAINDICATIONS Preservative-free timolol maleate ophthalmic solution is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease ( see WARNINGS ) ; (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure ( see WARNINGS ) ; (7) cardiogenic shock; or (8) hypersensitivity to any component of this product."}', 'adverse_reactions': '{"ADVERSE REACTIONS The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients). The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations: BODY AS A WHOLE Headache, asthenia/fatigue, and chest pain. CARDIOVASCULAR Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud\'s phenomenon, and cold hands and feet. DIGESTIVE Nausea, diarrhea, dyspepsia, anorexia, and dry mouth. IMMUNOLOGIC Systemic lupus erythematosus. NERVOUS SYSTEM/PSYCHIATRIC Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss. SKIN Alopecia and psoriasiform rash or exacerbation of psoriasis. HYPERSENSITIVITY Signs and symptoms of systemic allergic reactions including anaphylaxis, angioedema, urticaria, and localized and generalized rash. RESPIRATORY Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections. ENDOCRINE Masked symptoms of hypoglycemia in diabetic patients ( see WARNINGS ) . SPECIAL SENSES Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, discharge (e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery ( see PRECAUTIONS , General ) ; and tinnitus. UROGENITAL Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie\'s disease. The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta blocking agents, and may be considered potential effects of ophthalmic timolol maleate: Allergic : Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole : Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular : Worsening of arterial insufficiency, vasodilatation; Digestive : Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic : Nonthrombocytopenic purpura, thrombocytopenic purpura, agranulocytosis; Endocrine : Hyperglycemia, hypoglycemia; Skin : Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal : Arthralgia; Nervous System/Psychiatric : Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory : Rales, bronchial obstruction; Urogenital : Urination difficulties. To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ."}', 'drug_interactions': '{"Drug Interactions Although timolol maleate ophthalmic solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate ophthalmic solution and epinephrine has been reported occasionally. Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and preservative-free timolol maleate ophthalmic solution should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. Calcium antagonists: Caution should be used in the co-administration of beta-adrenergic blocking agents, such as preservative-free timolol maleate ophthalmic solution, and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided. Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension. Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol. Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate. Injectable epinephrine: ( see PRECAUTIONS , General , Anaphylaxis )"}', 'indications_and_usage': '{"INDICATIONS AND USAGE Preservative-free timolol maleate ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Preservative-free timolol maleate ophthalmic solution may be used when a patient is sensitive to the preservative in timolol maleate ophthalmic solution, benzalkonium chloride, or when use of a preservative-free topical medication is advisable."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest ( see ADVERSE REACTIONS ) . Overdosage has been reported with timolol maleate tablets. A 30-year-old female ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block. An in vitro hemodialysis study, using 14 C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily."}', 'active_flag': 'Y', 'generic_name': '{"TIMOLOL MALEATE"}', 'route': '{OPHTHALMIC}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS As with many topically applied ophthalmic drugs, this drug is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate ( see CONTRAINDICATIONS ) . Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. In Patients without a History of Cardiac Failure continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, preservative-free timolol maleate ophthalmic solution should be discontinued. Obstructive Pulmonary Disease Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which timolol maleate ophthalmic solution is contraindicated ( see CONTRAINDICATIONS )) should, in general, not receive beta-blockers, including preservative-free timolol maleate ophthalmic solution. Major Surgery The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists. Diabetes Mellitus Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia. Thyrotoxicosis Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm."}', 'precautions': '{"PRECAUTIONS General Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with preservative-free timolol maleate ophthalmic solution, alternative therapy should be considered. Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol). Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil. Timolol maleate ophthalmic solution should not be used alone in the treatment of angle-closure glaucoma. Anaphylaxis: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions. Muscle weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. Information for Patients Patients should be instructed about the use of preservative-free timolol maleate ophthalmic solution. Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening and to discard the individual unit and any remaining contents immediately after use. Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product ( see CONTRAINDICATIONS ) . Drug Interactions Although timolol maleate ophthalmic solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate ophthalmic solution and epinephrine has been reported occasionally. Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and preservative-free timolol maleate ophthalmic solution should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. Calcium antagonists: Caution should be used in the co-administration of beta-adrenergic blocking agents, such as preservative-free timolol maleate ophthalmic solution, and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided. Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension. Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol. Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate. Injectable epinephrine: ( see PRECAUTIONS , General , Anaphylaxis ) Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose. In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000 times, respectively, the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin. Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test. Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose. Pregnancy: Teratogenic Effects: Teratogenicity studies with timolol in mice, rats and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women. Preservative-free timolol maleate ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of timolol maleate ophthalmic solution have been established when administered in pediatric patients aged 2 years and older. Use of timolol maleate ophthalmic solution in these children is supported by evidence from adequate and well-controlled studies in children and adults. Safety and efficacy in pediatric patients below the age of 2 years have not been established. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients."}', 'information_for_patients': '{"Information for Patients Patients should be instructed about the use of preservative-free timolol maleate ophthalmic solution. Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening and to discard the individual unit and any remaining contents immediately after use. Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product ( see CONTRAINDICATIONS ) ."}', 'pregnancy': '{"Pregnancy: Teratogenic Effects: Teratogenicity studies with timolol in mice, rats and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women. Preservative-free timolol maleate ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness of timolol maleate ophthalmic solution have been established when administered in pediatric patients aged 2 years and older. Use of timolol maleate ophthalmic solution in these children is supported by evidence from adequate and well-controlled studies in children and adults. Safety and efficacy in pediatric patients below the age of 2 years have not been established."}', 'geriatric_use': '{"Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients."}'}

{"NAPROXEN SODIUM"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves minor aches and pains due to: minor pain of arthritis muscular aches menstrual cramps toothache backache headache the common cold temporarily reduces fever"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"NAPROXEN SODIUM"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint vomit blood have bloody or black stools have stomach pain that does not get better you have symptoms of heart problems or stroke: chest pain trouble breathing weakness in one part or side of body slurred speech leg swelling pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days you have difficulty swallowing it feels like the pill is stuck in your throat redness or swelling is present in the painful area any new symptoms appear"}', 'do_not_use': '{"Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer right before or after heart surgery"}', 'when_using': '{"When using this product take with food or milk if stomach upset occurs"}', 'warnings': '{"Warnings Allergy alert: Naproxen sodium may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: hives facial swelling asthma (wheezing) shock skin reddening rash blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"NALOXONE HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Naloxone is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients in Naloxone."}', 'adverse_reactions': '{"ADVERSE REACTIONS Postoperative The following adverse events have been associated with the use of Naloxone in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of Naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults-Postoperative Opioid Depression ). Opioid Depression Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS ). Opioid Dependence Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but is not limited to, the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate, opioid withdrawal may also include: convulsions; excessive crying; hyperactive reflexes (see WARNINGS ). Adverse events associated with the postoperative use of Naloxone are listed by organ system and in decreasing order of frequency as follows: Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events. Gastrointestinal Disorders: vomiting, nausea Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion Psychiatric Disorders: agitation, hallucination, tremulousness Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating Vascular Disorders: hypertension, hypotension, hot flushes or flushing. See also PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults; Postoperative Opioid Depression ."}', 'drug_interactions': '{"Drug Interactions Large doses of Naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Naloxone is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone is also indicated for diagnosis of suspected or known acute opioid overdosage. Naloxone may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see CLINICAL PHARMACOLOGY; Adjunctive Use in Septic Shock )."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE There is limited clinical experience with Naloxone overdosage in humans. Adult Patients In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m 2 /min) of Naloxone followed immediately by 2 mg/kg/hr for 24 hours. Twenty- three patients experienced adverse events associated with Naloxone use, and Naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3). At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2-3 days. Pediatric Patients Up to 11 doses of 0.2 mg of Naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2-1/2 year-old child who inadvertently received a dose of 20 mg of Naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae. There is also a report of a 4-1/2 year-old child who received 11 doses during a 12-hour period, with no adverse sequelae. Patient Management Patients who experience a Naloxone overdose should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date patient management information."}', 'active_flag': 'Y', 'generic_name': '{"NALOXONE HYDROCHLORIDE"}', 'route': '{INTRAMUSCULAR,INTRAVENOUS,SUBCUTANEOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Drug Dependence Naloxone should be administered cautiously to persons including newborns of mothers who are known or suspected to be physically dependent on opioids. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes. Repeat Administration The patient who has satisfactorily responded to Naloxone should be kept under continued surveillance and repeated doses of Naloxone should be administered, as necessary, since the duration of action of some opioids may exceed that of Naloxone. Respiratory Depression due to Other Drugs Naloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated."}', 'precautions': '{"PRECAUTIONS General In addition to Naloxone, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of Naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults-Postoperative Opioid Depression ). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, Naloxone should be used with caution in patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of Naloxone is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. Drug Interactions Large doses of Naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals to assess the carcinogenic potential of Naloxone have not been conducted. Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to Naloxone. Use in Pregnancy Teratogenic Effects: Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to Naloxone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Naloxone should be used during pregnancy only if clearly needed. Non-teratogenic Effects: Risk-benefit must be considered before Naloxone is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur. Use in Labor and Delivery It is not known if Naloxone (naloxone hydrochloride injection, USP) affects the duration of labor and/or delivery. However, published reports indicated that administration of Naloxone during labor did not adversely affect maternal or neonatal status. Nursing Mothers It is not known whether Naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Naloxone is administered to a nursing woman. Pediatric Use Naloxone Hydrochloride Injection, USP may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to Naloxone, he/she must be carefully monitored for at least 24 hours as a relapse may occur as Naloxone is metabolized. When Naloxone is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer Naloxone directly to the neonate if needed after delivery. Naloxone has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of Naloxone in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures. Geriatric Use Clinical studies of Naloxone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Insufficiency/Failure The safety and effectiveness of Naloxone in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone is administered to this patient population. Liver Disease The safety and effectiveness of Naloxone in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone is administered to patients with liver disease."}', 'information_for_patients': None, 'pregnancy': '{"Use in Pregnancy Teratogenic Effects: Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to Naloxone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Naloxone should be used during pregnancy only if clearly needed. Non-teratogenic Effects: Risk-benefit must be considered before Naloxone is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur."}', 'pediatric_use': '{"Pediatric Use Naloxone Hydrochloride Injection, USP may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to Naloxone, he/she must be carefully monitored for at least 24 hours as a relapse may occur as Naloxone is metabolized. When Naloxone is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer Naloxone directly to the neonate if needed after delivery. Naloxone has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of Naloxone in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures."}', 'geriatric_use': '{"Geriatric Use Clinical studies of Naloxone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}'}

{DEXLANSOPRAZOLE}

{'contraindications': '{"4 CONTRAINDICATIONS Dexlansoprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any component of the formulation [see Description (11) ] . Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis and urticaria [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . PPIs, including dexlansoprazole delayed-release capsules, are contraindicated with rilpivirine-containing products [see Drug Interactions (7) ]. Patients with known hypersensitivity to any component of the formulation. ( 4 ) Patients receiving rilpivirine-containing products. ( 4 , 7 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions ( 5.2 )] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.3 )] Bone Fracture [see Warnings and Precautions ( 5.4 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.5 )] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.6 )] Cyanocobalamin (Vitamin B12) Deficiency [see Warnings and Precautions ( 5.7 )] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions ( 5.8 )] Fundic Gland Polyps [see Warnings and Precautions ( 5.11 )] Risk of Heart Valve Thickening in Pediatric Patients Less than Two Years of Age [see Warnings and Precautions ( 5.12 )] The most common adverse reactions are: Adults (≥2%): diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, and flatulence. ( 6.1 ) Patients 12 to 17 years of age (≥5%): headache, abdominal pain, diarrhea, nasopharyngitis, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The safety of dexlansoprazole was evaluated in 4,548 adult patients in controlled and single-arm clinical trials, including 863 patients treated for at least six months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% Other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on dexlansoprazole 30 mg capsules, 2,218 patients on dexlansoprazole 60 mg capsules, and 1,363 patients on lansoprazole 30 mg once daily. Common Adverse Reactions The most common adverse reactions (≥2%) that occurred at a higher incidence for dexlansoprazole capsules than placebo in the controlled studies are presented in Table 2 . Table 2: Common Adverse Reactions in Controlled Studies in Adults Adverse Reaction Placebo (N=896) % Dexlansoprazole capsules 30 mg (N=455) % Dexlansoprazole capsules 60 mg (N=2,218) % Dexlansoprazole capsules Total (N=2,621) % Lansoprazole 30 mg (N=1,363) % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4 4 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory Tract Infection 0.8 2.9 1.7 1.9 0.8 Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from dexlansoprazole was diarrhea (0.7%). Less Common Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial infarction, palpitation, tachycardia Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo Endocrine Disorders: goiter Eye Disorders: eye irritation, eye swelling Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly Immune System Disorders: hypersensitivity Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia Musculoskeletal and Connective Tissue Disorders : arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes Renal and Urinary Disorders: dysuria, micturition urgency Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnea, hiccups, hyperventilation, respiratory tract congestion, sore throat Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritus, rash, skin lesion, urticaria Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported in a long-term single-arm trial and were considered related to dexlansoprazole by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis. Pediatrics The safety of dexlansoprazole was evaluated in controlled and single-arm clinical trials including 166 pediatric patients, 12 to 17 years of age for the treatment of symptomatic non-erosive GERD, healing of EE, maintenance of healed EE and relief of heartburn [see Clinical Studies (14.4) ] . The adverse reaction profile was similar to that of adults. The most common adverse reactions that occurred in ≥5% of patients were headache, abdominal pain, diarrhea, nasopharyngitis and oropharyngeal pain. Other Adverse Reactions See the full prescribing information for lansoprazole for other adverse reactions not observed with dexlansoprazole. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of dexlansoprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders: deafness Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema, pancreatitis, fundic gland polyps General Disorders and Administration Site Conditions: facial edema Hepatobiliary Disorders: drug-induced hepatitis Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, SJS/TEN (some fatal), DRESS, AGEP Infections and Infestations: Clostridium difficile- associated diarrhea Metabolism and Nutrition Disorders: hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia Musculoskeletal System Disorders: bone fracture Nervous System Disorders: cerebrovascular accident, transient ischemic attack Renal and Urinary Disorders: acute renal failure Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leukocytoclastic vasculitis"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with dexlansoprazole and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 3: Clinically Relevant Interactions Affecting Drugs Coadministered with Dexlansoprazole and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with dexlansoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with dexlansoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with dexlansoprazole. Intervention: Rilpivirine-containing products : Concomitant use with dexlansoprazole is contraindicated [see Contraindications (4) ]. See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with dexlansoprazole. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.10) ]. Intervention: A temporary withdrawal of dexlansoprazole may be considered in some patients receiving high-dose methotrexate. Digoxin Clinical Impact: Potential for increased exposure of digoxin. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Dexlansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Coadministration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving dexlansoprazole and MMF. Use dexlansoprazole with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.2 )]. Intervention: Temporarily stop dexlansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention: Temporarily stop dexlansoprazole treatment at least 30 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2 )]. False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. Table 4: Clinically Relevant Interactions Affecting Dexlansoprazole When Coadministered with Other Drugs and Substances CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of dexlansoprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3 )]. Intervention: St. John’s Wort, rifampin : Avoid concomitant use with dexlansoprazole. Ritonavir-containing products : See prescribing information. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of dexlansoprazole is expected when used concomitantly with strong inhibitors [see Clinical Pharmacology ( 12.3 )]. Intervention: Voriconazole : See prescribing information. See full prescribing information for a list of clinically important drug interactions. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Dexlansoprazole is a proton pump inhibitor (PPI) indicated in patients 12 years of age and older for: Healing of all grades of erosive esophagitis (EE). ( 1.1 ) Maintenance of healed EE and relief of heartburn. ( 1.2 ) Treatment of symptomatic non-erosive gastroesophageal reflux disease (GERD). ( 1.3 ) 1.1 Healing of Erosive Esophagitis Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for healing of all grades of erosive esophagitis (EE) for up to eight weeks. 1.2 Maintenance of Healed Erosive Esophagitis and Relief of Heartburn Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older to maintain healing of EE and relief of heartburn for up to six months in adults and 16 weeks in patients 12 to 17 years of age. 1.3 Treatment of Symptomatic Non-Erosive Gastroesophageal Reflux Disease Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for four weeks."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Dexlansoprazole Delayed-Release Capsules, 60 mg contain FD&C Yellow # 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow # 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Gastric Malignancy : In adults, symptomatic response with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients. ( 5.2 ) Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.3 ) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. ( 5.4 ) Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue dexlansoprazole delayed-release capsules and refer to specialist for evaluation. ( 5.6 ) Cyanocobalamin (Vitamin B12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.7 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.8 ) Interactions with Investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. ( 5.9 , 7 ) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high-dose methotrexate administration, consider a temporary withdrawal of dexlansoprazole delayed-release capsules. ( 5.10 , 7 ) Fundic Gland Polyps : Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. ( 5.11 ) Risk of Heart Valve Thickening in Pediatric Patients Less than Two Years of Age : Dexlansoprazole is not recommended in pediatric patients less than 2 years of age. ( 5.12 , 8.4 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue dexlansoprazole and evaluate patients with suspected acute TIN [see Contraindications (4) ] . 5.3 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like dexlansoprazole may be associated with an increased risk of Clostridium difficile- associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 5.4 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the conditions being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) , Adverse Reactions (6.2) ]. 5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2) ] . Discontinue dexlansoprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI-associated SLE is usually milder than nondrug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving dexlansoprazole delayed-release capsules, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.7 Cyanocobalamin (Vitamin B12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with dexlansoprazole. 5.8 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ] . Consider monitoring magnesium and calcium levels prior to initiation of dexlansoprazole delayed-release capsules and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI. 5.9 Interactions with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop dexlansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7) , Clinical Pharmacology (12.2) ]. 5.10 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7) ]. 5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated. 5.12 Risk of Heart Valve Thickening in Pediatric Patients Less Than Two Years of Age Dexlansoprazole is not recommended in pediatric patients less than two years of age. Nonclinical studies in juvenile rats with lansoprazole have demonstrated an adverse effect of heart valve thickening. Dexlansoprazole is the R-enantiomer of lansoprazole [see Use in Specific Populations (8.4) ]."}', 'overdosage': '{"10 OVERDOSAGE There have been no reports of significant overdose with dexlansoprazole. Multiple doses of dexlansoprazole 120 mg and a single dose of dexlansoprazole 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of dexlansoprazole 60 mg. Nonserious adverse reactions observed with twice daily doses of dexlansoprazole 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. In the event of over-exposure, treatment should be symptomatic and supportive. If over-exposure occurs, call your poison control center at 1-800-222-1222 for current information on the management of poisoning or over-exposure."}', 'active_flag': 'Y', 'generic_name': '{DEXLANSOPRAZOLE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ). Adverse Reactions Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with: Hypersensitivity Reactions [see Contraindications (4) ] Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2) ] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.3) ] Bone Fracture [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6) ] Cyanocobalamin (Vitamin B12) Deficiency [see Warnings and Precautions (5.7) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8) ] Drug Interactions Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products [see Contraindications (4) ] or high-dose methotrexate [see Warnings and Precautions (5.10) ]. Pregnancy Advise a pregnant woman of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Administration Take without regard to food. Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose. Swallow whole; do not chew. Can be opened and sprinkled on applesauce for patients who have trouble swallowing the capsule. Alternatively, the capsule can be administered with water via oral syringe or NG tube, as described in the Instructions for Use."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no studies with dexlansoprazole use in pregnant women to inform a drug-associated risk. Dexlansoprazole is the R-enantiomer of lansoprazole, and published observational studies of lansoprazole use during pregnancy did not demonstrate an association of adverse pregnancy-related outcomes with lansoprazole ( see Data ). In animal reproduction studies, oral administration of lansoprazole to rats during organogenesis through lactation at 1.8 times the maximum recommended human dexlansoprazole dose produced reductions in the offspring in femur weight, femur length, crown-rump length and growth plate thickness (males only) on postnatal Day 21 ( see Data ). These effects were associated with reduction in body weight gain. Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Dexlansoprazole is the R-enantiomer of lansoprazole. Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs. There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, [95% Confidence Interval (CI) 0.25 to 4.21]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, [95% CI 0.86 to 1.45] and for spontaneous abortions OR=1.29, [95% CI 0.84 to 1.97]). Animal Data An embryo-fetal development study conducted in rabbits at oral dexlansoprazole doses up to 30 mg/kg/day (approximately nine times the maximum recommended human dexlansoprazole dose [60 mg/day] based on body surface area) during organogenesis showed no effects on fetuses due to dexlansoprazole. In addition, embryo-fetal development studies performed in rats with oral lansoprazole at doses up to 150 mg/kg/day (40 times the recommended human lansoprazole dose based on body surface area) during organogenesis and in rabbits with oral lansoprazole at doses up to 30 mg/kg/day (16 times the recommended human lansoprazole dose based on body surface area) during organogenesis revealed no effects on fetuses due to lansoprazole. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of 10 to 100 mg/kg/day (0.2 to 1.8 times the maximum recommended human dexlansoprazole dose of 60 mg based on dexlansoprazole AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation. Maternal effects observed at 100 mg/kg/day (1.8 times the maximum recommended human dexlansoprazole dose of 60 mg based on dexlansoprazole AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption. The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity. Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks. The effects on bone parameters were associated with reduction in body weight gain."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of dexlansoprazole have been established in pediatric patients 12 years to 17 years of age for the healing of all grades of EE, the maintenance of healed EE and relief of heartburn, and treatment of heartburn associated with symptomatic non-erosive GERD. Use of dexlansoprazole in this age group is supported by evidence from adequate and well-controlled studies of dexlansoprazole in adults with additional safety, efficacy and pharmacokinetic data in pediatric patients 12 to 17 years of age. The adverse reaction profile in patients 12 to 17 years of age was similar to adults [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . The safety and effectiveness of dexlansoprazole have not been established in pediatric patients less than 12 years of age. Dexlansoprazole is not recommended in pediatric patients less than two years of age [see Warnings and Precautions ( 5.12 )] . Nonclinical studies in juvenile rats treated with lansoprazole (the racemic mixture) have demonstrated adverse effects of heart valve thickening and bone changes at dexlansoprazole exposures which are expected to be similar to or higher than the dexlansoprazole exposure in pediatric patients one year to two years of age, as described below in Juvenile Animal Toxicity Data . The use of dexlansoprazole is not recommended for the treatment of symptomatic GERD in pediatric patients one month to less than one year of age because lansoprazole was not shown to be effective in a multicenter, double-blind controlled trial. Juvenile Animal Toxicity Data Heart Valve Thickening In two oral toxicity studies, thickening of the mitral heart valve occurred in juvenile rats treated with lansoprazole. Heart valve thickening was observed primarily with oral dosing initiated on postnatal Day 7 (age equivalent to neonatal humans) and postnatal Day 14 (human age equivalent of approximately one year) at doses of 250 mg/kg/day and higher (at postnatal Day 7 and postnatal Day 14 respectively, 2.5 and 1.8 times the expected dexlansoprazole exposure based on AUC in pediatric patients one year to two years of age). The treatment durations associated with heart valve thickening ranged from 5 days to 8 weeks. The findings reversed or trended towards reversibility after a 4-week drug-free recovery period. The incidence of heart valve thickening after initiation of dosing on postnatal Day 21 (human age equivalent of approximately two years) was limited to a single rat (1/24) in groups given 500 mg/kg/day for 4 or 8 weeks (2.1 times the expected dexlansoprazole exposure based on AUC in pediatric patients one year to two years of age). Based on the low incidence of heart valve thickening in 21-day old rats and the equivalent human age, the risk of heart valve injury does not appear to be relevant to patients two years of age and older. Bone Changes In an eight-week oral toxicity study of lansoprazole in juvenile rats with dosing initiated on postnatal Day 7, doses equal to or greater than 100 mg/kg/day (dexlansoprazole exposure based on AUC approximately equal to that in pediatric patients one year to two years of age) produced delayed growth, with impairment of weight gain observed as early as postnatal Day 10 (age equivalent to neonatal humans). At the end of treatment, the signs of impaired growth at 100 mg/kg/day and higher included reductions in body weight (14 to 44% compared to controls), absolute weight of multiple organs, femur weight, femur length and crown-rump length. Femoral growth plate thickness was reduced only in males and only at the 500 mg/kg/day dose. The effects related to delayed growth persisted through the end of the four-week recovery period. Longer term data were not collected."}', 'geriatric_use': '{"8.5 Geriatric Use Of the total number of patients (n=4,548) in clinical studies of dexlansoprazole, 11% of patients were aged 65 years and over, while 2% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology ( 12.3 )]."}'}

{TADALAFIL}

{'contraindications': '{"4 CONTRAINDICATIONS Administration of tadalafil to patients using any form of organic nitrate is contraindicated. Tadalafil was shown to potentiate the hypotensive effect of nitrates ( 4.1 ). History of known serious hypersensitivity reaction to Tadalafil or ADCIRCA ® ( 4.2 ). Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4.3 ). 4.1 Nitrates Administration of tadalafil to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology ( 12.2 )] . 4.2 Hypersensitivity Reactions Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil (Tadalafil tablets or ADCIRCA ® ). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions ( 6.2 )] . 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use Tadalafil in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including Tadalafil, may potentiate the hypotensive effects of GC stimulators."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse reactions (greater than or equal to 2%) include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and pain in limb ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of tadalafil tablets for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For tadalafil tablets for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively. Tadalafil tablets for Use as Needed for ED In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients. When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported ( see Table 1) for tadalafil tablets for use as needed: Table 1: Treatment-Emergent Adverse Reactions Reported by greater than or equal to 2% of Patients Treated with Tadalafil tablets (10 mg or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled Clinical Studies (Including a Study in Patients with Diabetes) for Tadalafil tablets for Use as Needed for ED a The term flushing includes: facial flushing and flushing Adverse Reaction Placebo (N=476) Tadalafil 5 mg (N=151) Tadalafil 10 mg (N=394) Tadalafil 20 mg (N=635) Headache 5% 11% 11% 15% Dyspepsia 1% 4% 8% 10% Back pain 3% 3% 5% 6% Myalgia 1% 1% 4% 3% Nasal congestion 1% 2% 3% 3% Flushing a 1% 2% 3% 3% Pain in limb 1% 1% 3% 3% Tadalafil tablets for Once Daily Use for ED In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8% in placebo-treated patients. The following adverse reactions were reported ( see Table 2) in clinical trials of 12 weeks duration: Table 2: Treatment-Emergent Adverse Reactions Reported by greater than or equal to 2% of Patients Treated with Tadalafil for Once Daily Use (2.5 mg or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes) for Tadalafil tablets for Once Daily Use for ED Adverse Reaction Placebo (N=248) Tadalafil 2.5 mg (N=196) Tadalafil 5 mg (N=304) Headache 5% 3% 6% Dyspepsia 2% 4% 5% Nasopharyngitis 4% 4% 3% Back pain 1% 3% 3% Upper respiratory tract infection 1% 3% 3% Flushing 1% 1% 3% Myalgia 1% 2% 2% Cough 0% 4% 2% Diarrhea 0% 1% 2% Nasal congestion 0% 2% 2% Pain in extremity 0% 1% 2% Urinary tract infection 0% 2% 0% Gastroesophageal reflux disease 0% 2% 1% Abdominal pain 0% 2% 1% The following adverse reactions were reported ( see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study: Table 3: Treatment-Emergent Adverse Reactions Reported by greater than or equal to 2% of Patients Treated with Tadalafil tablets for Once Daily Use (2.5 mg or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Tadalafil tablets for Once Daily Use for ED Adverse Reaction Placebo (N=94) Tadalafil 2.5 mg (N=96) Tadalafil 5 mg (N=97) Nasopharyngitis 5% 6% 6% Gastroenteritis 2% 3% 5% Back pain 3% 5% 2% Upper respiratory tract infection 0% 3% 4% Dyspepsia 1% 4% 1% Gastroesophageal reflux disease 0% 3% 2% Myalgia 2% 4% 1% Hypertension 0% 1% 3% Nasal congestion 0% 0% 4% Tadalafil tablets for Once Daily Use for BPH and for ED and BPH In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported ( see Table 4). Table 4: Treatment-Emergent Adverse Reactions Reported by greater than or equal to 1% of Patients Treated with Tadalafil tablets for Once Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo-Controlled Clinical Studies of 12 Weeks Treatment Duration, including Two Studies for Tadalafil tablets for Once Daily Use for BPH and One Study for ED and BPH Adverse Reaction Placebo (N=576) Tadalafil 5 mg (N=581) Headache 2.3% 4.1% Dyspepsia 0.2% 2.4% Back pain 1.4% 2.4% Nasopharyngitis 1.6% 2.1% Diarrhea 1.0% 1.4% Pain in extremity 0.0% 1.4% Myalgia 0.3% 1.2% Dizziness 0.5% 1.0% Additional, less frequent adverse reactions (less than 1%) reported in the controlled clinical trials of Tadalafil for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm. Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency (less than 5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with tadalafil for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for tadalafil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of tadalafil for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of less than 1% across all indications. Across placebo-controlled studies with tadalafil for use as needed for ED, diarrhea was reported more frequently inpatients 65 years of age and older who were treated with tadalafil (2.5% of patients) [see Use in Specific Populations ( 8.5 )] . Across all studies with any tadalafil dose, reports of changes in color vision were rare (less than 0.1% of patients). The following section identifies additional, less frequent events (less than 2%) reported in controlled clinical trials of tadalafil for once daily use or use as needed. A causal relationship of these events to tadalafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful: Body as a Whole — asthenia, face edema, fatigue, pain, peripheral edema Cardiovascular — angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia Digestive — abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage Musculoskeletal — arthralgia, neck pain Nervous — dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo Renal and Urinary — renal impairment Respiratory — dyspnea, epistaxis, pharyngitis Skin and Appendages — pruritus, rash, sweating Ophthalmologic — blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase, swelling of eyelids Otologic — sudden decrease or loss of hearing, tinnitus Urogenital — erection increased, spontaneous penile erection 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tadalafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Cardiovascular and Cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions ( 5.1 )] . Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis Nervous — migraine, seizure and seizure recurrence, transient global amnesia Ophthalmologic — visual field defect, retinal vein occlusion, retinal artery occlusion Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. [see Warnings and Precautions ( 5.4 )] . Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions ( 5.5 )] . Urogenital — priapism [see Warnings and Precautions ( 5.3 )]."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Tadalafil can potentiate the hypotensive effects of nitrates, alpha-blockers, antihypertensives or alcohol ( 7.1 ). CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase tadalafil exposure ( 2.7 , 5.10 , 7.2 ) requiring dose adjustment: Tadalafil for use as needed: no more than 10 mg every 72 hours Tadalafil for once daily use: dose not to exceed 2.5 mg CYP3A4 inducers (e.g. rifampin) decrease tadalafil exposure ( 7.2 ). 7.1 Potential for Pharmacodynamic Interactions with Tadalafil Nitrates — Administration of tadalafil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies tadalafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see Dosage and Administration ( 2.7 ), Contraindications ( 4.1 ), and Clinical Pharmacology ( 12.2 )] . Alpha-Blockers — Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin. [see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.6 ), and Clinical Pharmacology ( 12.2 )] . Antihypertensives — PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.2 )] . Alcohol — Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [see Warnings and Precautions ( 5.9 ) and Clinical Pharmacology ( 12.2 )] . 7.2 Potential for Other Drugs to Affect Tadalafil [See Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.10 )] . Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil. H2 Antagonists (e.g. Nizatidine ) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics. Cytochrome P450 Inhibitors — Tadalafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure. CYP3A4 (e.g., Ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone [see Dosage and Administration ( 2.7 )] . Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure. HIV Protease inhibitor — Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in C max , relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax , relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure [see Dosage and Administration ( 2.7 )] . Cytochrome P450 Inducers — Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure. CYP3A4 (e.g., Rifampin) — Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of tadalafil for once daily use; the magnitude of decreased efficacy is unknown. 7.3 Potential for Tadalafil to Affect Other Drugs Aspirin — Tadalafil did not potentiate the increase in bleeding time caused by aspirin. Cytochrome P450 Substrates — Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. CYP1A2 (e.g. Theophylline) — Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed. CYP2C9 (e.g. Warfarin) — Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin. CYP3A4 (e.g. Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin. P-glycoprotein (e.g. Digoxin ) — Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: erectile dysfunction (ED) ( 1.1 ) the signs and symptoms of benign prostatic hyperplasia (BPH) ( 1.2 ) ED and the signs and symptoms of BPH (ED/BPH) ( 1.3 ) If tadalafil is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks ( 1.4 ). 1.1 Erectile Dysfunction Tadalafil tablets, USP are indicated for the treatment of erectile dysfunction (ED). 1.2 Benign Prostatic Hyperplasia Tadalafil tablets, USP are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). 1.3 Erectile Dysfunction and Benign Prostatic Hyperplasia Tadalafil tablets, USP are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH). 1.4 Limitation of Use If tadalafil is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of tadalafil decreases from 4 weeks until 26 weeks, and the incremental benefit of tadalafil beyond 26 weeks is unknown [see Clinical Studies ( 14.3 )] ."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options. Before prescribing tadalafil tablets, it is important to note the following: Patients should not use tadalafil if sex is inadvisable due to cardiovascular status ( 5.1 ). Use of tadalafil with alpha-blockers, antihypertensives or substantial amounts of alcohol (greater than or equal to 5 units) may lead to hypotension ( 5.6 , 5.9 ). Tadalafil is not recommended in combination with alpha-blockers for the treatment of BPH because efficacy of the combination has not been adequately studied and because of the risk of blood pressure lowering. Caution is advised when tadalafil is used as a treatment for ED in men taking alpha-blockers. ( 2.7 , 5.6 , 7.1 , 12.2 ) Patients should seek emergency treatment if an erection lasts greater than 4 hours. Use tadalafil with caution in patients predisposed to priapism ( 5.3 ). Patients should stop tadalafil and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Tadalafil should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a “crowded” optic disc may also be at an increased risk of NAION ( 5.4 , 6.2 ). Patients should stop tadalafil and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5 ). Prior to initiating treatment with tadalafil for BPH, consideration should be given to other urological conditions that may cause similar symptoms ( 5.14 ). 5.1 Cardiovascular Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including tadalafil, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention. Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of tadalafil. In such a patient, who has taken tadalafil, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of tadalafil tablets before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking tadalafil tablets should seek immediate medical attention. [see Contraindications ( 4.1 ) and Patient Counseling Information ( 17.1 )] . Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors. The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for tadalafil, and therefore until further information is available, tadalafil is not recommended for the following groups of patients: myocardial infarction within the last 90 days unstable angina or angina occurring during sexual intercourse New York Heart Association Class 2 or greater heart failure in the last 6 months uncontrolled arrhythmias, hypotension (less than 90/50 mm Hg), or uncontrolled hypertension stroke within the last 6 months. As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects [see Clinical Pharmacology ( 12.2 )] . While this effect should not be of consequence in most patients, prior to prescribing tadalafil tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors. 5.2 Potential for Drug Interactions When Taking Tadalafil tablets for Once Daily Use Physicians should be aware that tadalafil tablets for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol [see Drug Interactions ( 7.1 , 7.2 , 7.3 ) ]. 5.3 Prolonged Erection There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease). 5.4 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged greater than or equal to 50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions ( 6.2 )] . Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including tadalafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including tadalafil, for this uncommon condition. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended. 5.5 Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including tadalafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1 , 6.2 )] . 5.6 Alpha-blockers and Antihypertensives Physicians should discuss with patients the potential for tadalafil to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] . Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] , which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following: ED • Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. • In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose. • In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. • Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other antihypertensive drugs. [see Dosage and Administration ( 2.7 ) and Drug Interactions ( 7.1 )] . BPH • The efficacy of the coadministration of an alpha-blocker and tadalafil for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of tadalafil and alpha-blockers is not recommended for the treatment of BPH. [see Dosage and Administration ( 2.7 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 .)] . • Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting tadalafil for once daily use for the treatment of BPH. 5.7 Renal Impairment Tadalafil tablets for Use as Needed Tadalafil should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of tadalafil in patients with creatinine clearance 30 mL/min to 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. [see Use in Specific Populations ( 8.7 )] . Tadalafil tablets for Once Daily Use ED Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil tablets for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations ( 8.7 )] . BPH and ED/BPH Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 mL/min to 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response [see Dosage and Administration ( 2.6 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )] . 5.8 Hepatic Impairment Tadalafil tablets for Use as Needed In patients with mild or moderate hepatic impairment, the dose of tadalafil tablets should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil in this group is not recommended [see Use in Specific Populations ( 8.6 )] . Tadalafil tablets for Once Daily Use Tadalafil tablets for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil in this group is not recommended [see Use in Specific Populations ( 8.6 )] . 5.9 Alcohol Patients should be made aware that both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Clinical Pharmacology ( 12.2 )] . 5.10 Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4) Tadalafil is metabolized predominantly by CYP3A4 in the liver. The dose of tadalafil tablets for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole [see Drug Interactions ( 7.2 )] . In patients taking potent inhibitors of CYP3A4 and tadalafil tablets for once daily use, the maximum recommended dose is 2.5 mg [see Dosage and Administration ( 2.7 )] . 5.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take tadalafil with other PDE5 inhibitors, including ADCIRCA. 5.12 Effects on Bleeding Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Tadalafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although tadalafil has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution. 5.13 Counseling Patients About Sexually Transmitted Diseases The use of tadalafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered. 5.14 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH Prior to initiating treatment with tadalafil for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist. 5.15 Risk of Allergic Reactions due to Tartrazine Tadalafil Tablets contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity."}', 'overdosage': '{"10 OVERDOSAGE Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination."}', 'active_flag': 'Y', 'generic_name': '{TADALAFIL}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION “See FDA-approved patient labeling (Patient Information)” 17.1 Nitrates Physicians should discuss with patients the contraindication of tadalafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of tadalafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke. Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of tadalafil. In such a patient, who has taken tadalafil, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking tadalafil should seek immediate medical attention [see Contraindications ( 4.1 ) and Warnings and Precautions ( 5.1 )] . 17.2 Guanylate Cyclase (GC) Stimulators Physicians should discuss with patients the contraindication of tadalafil with any use of a GC stimulator, such as riociguat, for pulmonary arterial hypertension. Patients should be counseled that the concomitant use of tadalafil with GC stimulators may cause blood pressure to drop to an unsafe level. 17.3 Cardiovascular Considerations Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Physicians should advise patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity and seek immediate medical attention [see Warnings and Precautions ( 5.1 )] . 17.4 Concomitant Use with Drugs Which Lower Blood Pressure Physicians should discuss with patients the potential for tadalafil to augment the blood-pressure-lowering effect of alpha-blockers, and antihypertensive medications [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )] . 17.5 Potential for Drug Interactions When Taking tadalafil tablets for Once Daily Use Physicians should discuss with patients the clinical implications of continuous exposure to tadalafil when prescribing tadalafil for once daily use, especially the potential for interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives and potent inhibitors of cytochrome P450 3A4) and with substantial consumption of alcohol. [see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 , 7.2 ), Clinical Pharmacology ( 12.2 ), and Clinical Studies (14.2)] . 17.6 Priapism There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention. 17.7 Sudden Loss of Vision Physicians should advise patients to stop use of all PDE5 inhibitors, including tadalafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including possible permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including tadalafil, for this uncommon condition [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2 )] . 17.8 Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including tadalafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1 , 6.2 )] . 17.9 Alcohol Patients should be made aware that both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )] . 17.10 Sexually Transmitted Disease The use of tadalafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered. 17.11 Recommended Administration Physicians should instruct patients on the appropriate administration of tadalafil to allow optimal use. For tadalafil for use as needed in men with ED, patients should be instructed to take one tablet at least 30 minutes before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 hours. For tadalafil for once daily use in men with ED or ED/BPH, patients should be instructed to take one tablet at approximately the same time every day without regard for the timing of sexual activity. Tadalafil is effective at improving erectile function over the course of therapy. For tadalafil for once daily use in men with BPH, patients should be instructed to take one tablet at approximately the same time every day. Revised: 05/2020 Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in INDIA."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Tadalafil is not indicated for use in females. There are no data with the use of tadalafil in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day (see Data). Data Animal Data Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In a prenatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance. In another rat prenatal and postnatal development study at doses of 60 mg/kg, 200 mg/kg, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats."}', 'pediatric_use': '{"8.4 Pediatric Use Tadalafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years have not been established. Juvenile Animal Study No adverse effects were observed in a study in which tadalafil was administered orally at doses of 60 mg/kg/day, 200 mg/kg/day, and 1000 mg/kg/day to juvenile rats on postnatal days 14 to 90. The highest plasma tadalafil exposures (AUC) achieved were approximately 10-fold that observed at the MRHD. Additional information describing a clinical study in which efficacy was not demonstrated is approved for Eli Lilly and Company’s CIALIS (tadalafil) tablets. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information."}', 'geriatric_use': '{"8.5 Geriatric Use Of the total number of subjects in ED clinical studies of tadalafil, approximately 19 percent were 65 and over, while approximately 2 percent were 75 and over. Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were 75 and over. In these clinical trials, no overall differences in efficacy or safety were observed between older (greater than 65 and greater than or equal to75 years of age) and younger subjects (less than or equal to 65 years of age). However, in placebo-controlled studies with tadalafil for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil (2.5% of patients) [see Adverse Reactions ( 6.1 )] . No dose adjustment is warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered. [see Clinical Pharmacology ( 12.3 )] ."}'}

{MINOXIDIL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use to regrow hair on the top of the scalp (vertex only, see pictures on side of carton)"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{MINOXIDIL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if chest pain, rapid heartbeat, faintness, or dizziness occurs sudden, unexplained weight gain occurs your hands or feet swell scalp irritation or redness occurs unwanted facial hair growth occurs you do not see hair regrowth in 4 months"}', 'do_not_use': '{"Do not use if you are a woman your amount of hair loss is different than that shown on the side of this carton or your hair loss is on the front of the scalp. Minoxidil topical solution 5% is not intended for frontal baldness or receding hairline. you have no family history of hair loss your hair loss is sudden and/or patchy you do not know the reason for your hair loss you are under 18 years of age. Do not use on babies and children. your scalp is red, inflamed, infected, irritated, or painful you use other medicines on the scalp"}', 'when_using': '{"When using this product do not apply on other parts of the body avoid contact with the eyes. In case of accidental contact, rinse eyes with large amounts of cool tap water. some people have experienced changes in hair color and/or texture it takes time to regrow hair. Results may occur at 2 months with twice a day usage. For some men, you may need to use this product for at least 4 months before you see results. the amount of hair regrowth is different for each person. This product will not work for all men."}', 'warnings': '{"Warnings For external use only. For use by men only. Flammable: Keep away from fire or flame Do not use if you are a woman your amount of hair loss is different than that shown on the side of this carton or your hair loss is on the front of the scalp. Minoxidil topical solution 5% is not intended for frontal baldness or receding hairline. you have no family history of hair loss your hair loss is sudden and/or patchy you do not know the reason for your hair loss you are under 18 years of age. Do not use on babies and children. your scalp is red, inflamed, infected, irritated, or painful you use other medicines on the scalp Ask a doctor before use if you have heart disease When using this product do not apply on other parts of the body avoid contact with the eyes. In case of accidental contact, rinse eyes with large amounts of cool tap water. some people have experienced changes in hair color and/or texture it takes time to regrow hair. Results may occur at 2 months with twice a day usage. For some men, you may need to use this product for at least 4 months before you see results. the amount of hair regrowth is different for each person. This product will not work for all men. Stop use and ask a doctor if chest pain, rapid heartbeat, faintness, or dizziness occurs sudden, unexplained weight gain occurs your hands or feet swell scalp irritation or redness occurs unwanted facial hair growth occurs you do not see hair regrowth in 4 months May be harmful if used when pregnant or breast-feeding. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ATAZANAVIR SULFATE"}

{'contraindications': '{"4 CONTRAINDICATIONS REYATAZ is contraindicated: • in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2) ] . • when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6). • when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6). Table 6 displays drugs that are contraindicated with REYATAZ. Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA ® for erectile dysfunction. Drug Class Drugs within class that are contraindicated with REYATAZ Alpha 1-adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin Antiarrhythmics Amiodarone (with ritonavir), quinidine (with ritonavir) Antimycobacterials Rifampin Antineoplastics Apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics Lurasidone (with ritonavir), pimozide Benzodiazepines Orally administered midazolam a , triazolam Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Motility Agent Cisapride Hepatitis C Direct-Acting Antivirals Elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort (Hypericum perforatum) Lipid-Modifying Agents: Lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor Sildenafil b when dosed as REVATIO® for the treatment of pulmonary arterial hypertension Protease Inhibitors Indinavir Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine • REYATAZ is contraindicated in patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4) • Coadministration with alfuzosin, amiodarone (if REYATAZ is coadministered with ritonavir), carbamazepine, quinidine (if REYATAZ is coadministered with ritonavir), triazolam, orally administered midazolam, ergot derivatives, rifampin, apalutamide, encorafenib, irinotecan, ivosidenib, lurasidone (if REYATAZ is coadministered with ritonavir), lovastatin, simvastatin, lomitapide, indinavir, cisapride, phenobarbital, phenytoin, pimozide, St. John’s wort, nevirapine, elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sildenafil when dosed as REVATIO ® . (4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • cardiac conduction abnormalities [see Warnings and Precautions (5.1) ] • rash [see Warnings and Precautions (5.2) ] • hyperbilirubinemia [see Warnings and Precautions (5.8) ] • chronic kidney disease [see Warnings and Precautions (5.5) ] • nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6) ] Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Treatment-Naive Adult Subjects The safety profile of REYATAZ in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received REYATAZ 300 mg with ritonavir 100 mg and 1089 subjects received REYATAZ 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive subjects receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively. Table 7: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, b Study AI424-138 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. 96 weeks c REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine d (n=441) 96 weeks c lopinavir/ritonavir d 400 mg / 100 mg (twice daily) and tenofovir DF/emtricitabine e (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% Skin and Appendages Rash 3% 2% Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, b Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Study AI424-034 Studies AI424-007, -008 64 weeks c REYATAZ 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) 120 weeks c,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% Adverse Reactions in Treatment-Experienced Adult Subjects The safety profile of REYATAZ in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced subjects receiving REYATAZ with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, b Study AI424-045 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. 48 weeks c REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI (n=118) Body as a Whole Fever 2% * Digestive System Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * Laboratory Abnormalities in Treatment-Naive Subjects The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively. Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, a Study AI424-138 a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. 96 weeks b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c 96 weeks b lopinavir/ritonavir 400 mg /1 00 mg c (twice daily) and tenofovir DF/emtricitabine d Variable Limit e (n=441) (n=437) Chemistry High SGOT/AST ≥5.1 × ULN 3% 1% SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, a Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Study AI424-034 Studies AI424-007, -008 64 weeks b REYATAZ 400 mg once daily and lamivudine / zidovudine e 64 weeks b efavirenz 600 mg once daily and lamivudine / zidovudine e 120 weeks b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limit d (n=404) (n=401) (n=279) (n=191) Chemistry High SGOT/AST ≥5.1 × ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 3 7% 9% 3% 7% Change in Lipids from Baseline in Treatment-Naive Subjects with HIV-1 Infection For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of subjects with LDL-cholesterol measured. f Fasting. REYATAZ with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL mg/dL Change d mg/dL Change d mg/dL mg/dL Change d mg/dL Change d (n=428 e ) (n=372 e ) (n=372 e ) (n=342 e ) (n=342 e ) (n=424 e ) (n=335 e ) (n=335 e ) (n=291 e ) (n=291 e ) LDL-Cholesterol f 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL-Cholesterol f 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol f 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides f 126 145 +15% 140 +13% 129 194 +52% 184 +50% Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-subject changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of subjects with LDL-cholesterol measured. f Fasting. REYATAZ a,b efavirenz b,c Baseline mg/dL (n=383 e ) Week 48 mg/dL (n=283 e ) Week 48 Change d (n=272 e ) Baseline mg/dL (n=378 e ) Week 48 mg/dL (n=264 e ) Week 48 Change d (n=253 e ) LDL-Cholesterol f 98 98 +1% 98 114 +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides f 138 124 −9% 129 168 +23% Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14. Table 14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045 a a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. 48 weeks b 48 weeks b REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI Variable Limit c (n=119) (n=118) Chemistry High SGOT/AST ≥5.1 × ULN 3% 3% SGPT/ALT ≥5.1 × ULN 4% 3% Total Bilirubin ≥2.6 × ULN 49% <1% Lipase ≥2.1 × ULN 5% 6% Creatine Kinase ≥5.1 × ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 3 2% 3% Neutrophils <750 cells/mm 3 7% 8% Change in Lipids from Baseline in Treatment-Experienced Subjects with HIV-1 Infection For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of subjects with LDL-cholesterol measured. f Fasting. REYATAZ with ritonavir a,b Lopinavir/ritonavir b,c Baseline mg/dL (n=111 e ) Week 48 mg/dL (n=75 e ) Week 48 Change d (n=74 e ) Baseline mg/dL (n=108 e ) Week 48 mg/dL (n=76 e ) Week 48 Change d (n=73 e ) LDL-Cholesterol f 108 98 −10% 104 103 +1% HDL-Cholesterol 40 39 −7% 39 41 +2% Total Cholesterol 188 170 −8% 181 187 +6% Triglycerides f 215 161 −4% 196 224 +30% Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Capsules The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric subjects were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of subjects. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 subjects weighing at least 5 kg to less than 35 kg, including 134 subjects exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric subjects with HIV-1 infection (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All subjects received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs). The safety profile of REYATAZ in pediatric subjects taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric subjects taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 subjects administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the subjects administered REYATAZ with ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered REYATAZ with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir. In Study AI424-045, 20 subjects administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 subjects treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the subjects administered REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the subjects administered REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 subjects treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the subjects treated with REYATAZ, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with REYATAZ, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [see Warnings and Precautions (5.8) ] . 6.2 Postmarketing Experience The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1) ] Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6) ] , cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9) ] Musculoskeletal System: arthralgia Renal System: nephrolithiasis [see Warnings and Precautions (5.6) ] , interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5) ] Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2) ] , pruritus, angioedema"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4 , 7 , 12.3) 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3) ] . The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. 7.2 Potential for Other Drugs to Affect REYATAZ Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect. Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H 2 -receptor antagonists are administered with REYATAZ [see Dosage and Administration ( 2.3 , 2.4 , 2.5 and 2.6 )] . 7.3 Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . b See Contraindications (4), Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily. HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF) ↓ atazanavir ↑ tenofovir When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, [ see Dosage and Administration (2.6) ] . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4) ] . Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ] . indinavir Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ] . ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) ] . glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) ] . voxilaprevir/sofosbuvir/velpatasvir ↑ voxilaprevir Coadministration with REYATAZ is not recommended. Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) ] . Antacids and buffered medications: ↓ atazanavir REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban REYATAZ with ritonavir ↑ rivaroxaban Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. REYATAZ ↑ rivaroxaban Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban. apixaban REYATAZ with ritonavir ↑ apixaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. REYATAZ ↑ apixaban Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ. Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. trazodone ↑ trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: carbamazepine ↓ atazanavir ↑ carbamazepine Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir. Antifungals: ketoconazole, itraconazole REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C max ). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir. voriconazole REYATAZ with ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day . If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day . Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterials: rifampin ↓ atazanavir Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ] . rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan ↑ irinotecan Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4) ] . apalutamide ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4) ] . ivosidenib ↓ atazanavir ↑ ivosidenib Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. encorafenib ↓ atazanavir ↑ encorafenib Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. Antiplatelets: ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. clopidogrel ↓ clopidogrel active metabolite Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: pimozide ↑ pimozide Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. lurasidone REYATAZ with ritonavir ↑ lurasidone REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. REYATAZ ↑ lurasidone REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. quetiapine ↑ quetiapine Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4) ]. parenterally administered midazolam b ↑ midazolam Coadministration with parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied. felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Corticosteroids: dexamethasone and other corticosteroids (all routes of administration) ↓ atazanavir ↑ corticosteroids Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. Endothelin receptor antagonists: bosentan REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan Coadministration of bosentan and REYATAZ without ritonavir is not recommended. For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine ↑ ergot derivatives Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4) ]. GI Motility Agents: cisapride ↑ cisapride Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix ↓ atazanavir ↑ elagolix Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response. Herbal Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4) ]. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) ]. atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4) ]. H 2 - Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H 2 -receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. • REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA. Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol ↑ norgestimate c ↑ ethinyl estradiol ↑ norethindrone d Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: fluticasone REYATAZ ↑ fluticasone Concomitant use of fluticasone propionate and REYATAZ without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. REYATAZ with ritonavir ↑ fluticasone With concomitant use of fluticasone propionate and REYATAZ with ritonavir, systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ] . Macrolide antibiotics: clarithromycin ↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied. Opioids: buprenorphine REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. REYATAZ ↓ atazanavir The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4) ] . The following dose adjustments are recommended for the use of ADCIRCA ® (tadalafil) with REYATAZ: Coadministration of ADCIRCA ® in patients on REYATAZ (with or without ritonavir): • For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA ® : • Avoid the use of ADCIRCA ® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA ® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA ® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS ® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. REYATAZ : Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended. 7.4 Drugs with No Observed Interactions with REYATAZ No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3) ] ."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE REYATAZ ® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. Limitations of Use: • REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4) ] . • Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4) ] . REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. (1)"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. (5.1 , 7.3 , 12.2 , 17) • Severe Skin Reactions: Discontinue if severe rash develops. (5.2 , 17) • Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.8) • Phenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3) • Hepatotoxicity: Patients with hepatitis B or C infection are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.8 , 5.4 , 8.8) • Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 infection treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of REYATAZ in patients with progressive renal disease. (5.5) • Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6) • The concomitant use of REYATAZ with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.7 , 7.3) • Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.9) , immune reconstitution syndrome (5.10) , and redistribution/accumulation of body fat (5.11) . • Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.12) 5.1 Cardiac Conduction Abnormalities REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some subjects. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10) ] . In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated subjects (n=920), 5.2% of lopinavir/ritonavir-treated subjects (n=252), 10.4% of nelfinavir-treated subjects (n=48), and 3.0% of efavirenz-treated subjects (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated subjects and 5% (6/116) of lopinavir/ritonavir-treated subjects who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), ECG monitoring should be considered in these patients [see Clinical Pharmacology (12.2) ] . 5.2 Severe Skin Reactions In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of subjects with HIV-1 infection treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions (6.1) ] . Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ [see Contraindications (4) and Adverse Reactions (6.1) ] . REYATAZ should be discontinued if severe rash develops. 5.3 Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine. 5.4 Hepatotoxicity Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , and Use in Specific Populations (8.8) ] . 5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered [see Dosage and Administration (2.2 and 2.7 ) and Adverse Reactions (6.2) ] . 5.6 Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 infection receiving REYATAZ therapy. Some patients required hospitalization for additional management, and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.2) ] . 5.7 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of REYATAZ with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving REYATAZ with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of REYATAZ with ritonavir, respectively. These interactions may lead to: • clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. • clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir. • loss of therapeutic effect (virologic response) of REYATAZ with ritonavir and possible development of resistance. See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7) ] . 5.8 Hyperbilirubinemia Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established [see Adverse Reactions (6.1) ] . 5.9 Diabetes Mellitus/Hyperglycemia New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 infection receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established [see Adverse Reactions (6.2) ] . 5.10 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.11 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.12 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established. 5.13 Resistance/Cross-Resistance Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors [see Microbiology (12.4) ] ."}', 'overdosage': '{"10 OVERDOSAGE Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy subjects without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 infection (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1 , 5.8) and Clinical Pharmacology (12.2) ] . Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine."}', 'active_flag': 'Y', 'generic_name': '{ATAZANAVIR}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). REYATAZ is not a cure for HIV-1 infection. Advise patients to remain under the care of a healthcare provider while using REYATAZ. Cardiac Conduction Abnormalities Inform patients that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Tell patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1) ] . Severe Skin Reaction Inform patients that there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Advise patients that if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, they must discontinue REYATAZ and seek medical evaluation immediately [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . Hyperbilirubinemia Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns [see Warnings and Precautions (5.8) ] . Patients with Phenylketonuria Advise caregivers of patients with phenylketonuria that REYATAZ oral powder contains phenylalanine [see Warnings and Precautions (5.3) ] . Chronic Kidney Disease Inform patients that treatment with REYATAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking REYATAZ [see Warnings and Precautions (5.5) ] . Nephrolithiasis and Cholelithiasis Inform patients that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management, and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events [see Warnings and Precautions (5.6) ] . Drug Interactions REYATAZ may lead to significant interaction with some drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort, to their healthcare provider prior to use [see Contraindications (4) , Warnings and Precautions (5.7) ] . Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.10) ] . Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.11) ] . Dosing Instructions Advise patients to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Advise patients that they should not alter the dose or discontinue therapy without consulting with their healthcare provider. Tell patients if a dose of REYATAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped the patient should not double the next dose. Pregnancy Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1) ] . Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk. REYATAZ can also be passed to the baby in breast milk, and it is not known whether it could harm the baby [see Use in Specific Populations (8.2) ] ."}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data ] . Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period • REYATAZ must be administered with ritonavir in pregnant patients. • For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions: • For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H 2 -receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H 2 -receptor antagonist and tenofovir DF in treatment-experienced pregnant patients. • No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ] . Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8) ] , including those who are pregnant [see Data ] . Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to REYATAZ in utero , should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data ] . Data Human Data In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1 infection, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1 infection, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level."}', 'pediatric_use': '{"8.4 Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Indications and Usage (1) ] . All REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5) ] . The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3) ] . The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.1) ] . See Dosage and Administration (2.4 , 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients."}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for C max and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}'}

{"OXYBUTYNIN CHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Oxybutynin chloride is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions. Oxybutynin chloride is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product."}', 'adverse_reactions': '{"ADVERSE REACTIONS The safety and efficacy of oxybutynin chloride was evaluated in a total of 199 patients in three clinical trials. These participants were treated with oxybutynin chloride 5 to 20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse events judged by investigators to be at least possibly related to treatment and reported by at least 5% of patients. Table 3 Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using Oxybutynin Chloride (5 to 20 mg/day) Body System Adverse Event Oxybutynin Chloride (5 to 20 mg/day) (n=199) Infections and Infestations Urinary tract infection 6.5% Psychiatric Disorders Insomnia Nervousness 5.5% 6.5% Nervous System Disorders Dizziness Somnolence Headache 16.6% 14.0% 7.5% Eye Disorders Blurred vision 9.6% Gastrointestinal Disorders Dry mouth Constipation Nausea Dyspepsia 71.4% 15.1% 11.6% 6.0% Renal and Urinary Disorders Urinary Hesitation Urinary Retention 8.5% 6.0% The most common adverse events reported by patients receiving oxybutynin chloride 5 to 20 mg/day were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose-related. In addition, the following adverse events were reported by 1 to < 5% of patients using oxybutynin chloride (5 to 20 mg/day) in all studies. Infections and Infestations: nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection; Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders: confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations, sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat, sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders: diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper, dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria, pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased, blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural Complications: fall. Postmarketing Surveillance Because postmarketing adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse events have been reported from worldwide postmarketing experience with oxybutynin chloride: Psychiatric Disorders: psychotic disorder, agitation, hallucination, memory impairment; Nervous System Disorders: convulsions; Eye Disorders: cycloplegia, mydriasis, glaucoma; Cardiac Disorders: tachycardia, QT interval prolongation; chest discomfort ; Gastrointestinal Disorders: decreased gastrointestinal motility; frequent bowel movements; Skin and Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary Disorders: impotence; Reproductive System and Breast Disorders: suppression of lactation; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; rare anaphylactic reactions requiring hospitalization for emergency treatment; Metabolism and Nutrition Disorders : anorexia; Respiratory, Thoracic and Mediastinal Disorders : dysphonia. To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"Drug Interactions The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Anticholinergic agents may also antagonize the effects of prokinetic agents, such as metoclopramide. Mean oxybutynin chloride plasma concentrations were approximately 3 to 4 fold higher when oxybutynin chloride was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., C max and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are coadministered."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Oxybutynin chloride tablets are indicated for the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence, dysuria)."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Treatment should be symptomatic and supportive. Activated charcoal as well as a cathartic may be administered. Overdosage with oxybutynin chloride has been associated with anticholinergic effects including central nervous system excitation (e.g., restlessness, tremor, irritability, convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Other symptoms may include hypotension or hypertension, respiratory failure, paralysis, and coma. Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in a 13 year old boy who experienced memory loss, and a 34 year old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients fully recovered with symptomatic treatment."}', 'active_flag': 'Y', 'generic_name': '{"OXYBUTYNIN CHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided."}', 'precautions': '{"PRECAUTIONS Central Nervous System Effects Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (see ADVERSE REACTIONS ). A variety of CNS anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. Oxybutynin chloride should be used with caution in patients with pre-existing dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms. Oxybutynin chloride should be used with caution in patients with Parkinson\'s disease due to the risk of aggravation of symptoms. General Oxybutynin chloride should be used with caution in the frail elderly, in patients with hepatic or renal impairment, and in patients with myasthenia gravis. Oxybutynin chloride may aggravate the symptoms of hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension, myasthenia gravis, and prostatic hypertrophy. Urinary Retention Oxybutynin chloride should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS ). Gastrointestinal Disorders Oxybutynin chloride should be used with caution in patients with autonomic neuropathy due to the risk of aggravation of symptoms of decreased gastrointestinal motility. Oxybutynin chloride should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS ). Administration of oxybutynin chloride to patients with ulcerative colitis may suppress intestinal motility to the point of producing a paralytic ileus and precipitate or aggravate toxic megacolon, a serious complication of the disease. Oxybutynin chloride, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, and intestinal atony. Oxybutynin chloride should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis. Information for Patients Patients should be informed that oxybutynin may produce angioedema that could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing. Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin chloride are administered in the presence of high environmental temperature. Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence), or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin. Drug Interactions The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Anticholinergic agents may also antagonize the effects of prokinetic agents, such as metoclopramide. Mean oxybutynin chloride plasma concentrations were approximately 3 to 4 fold higher when oxybutynin chloride was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., C max and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are coadministered. Carcinogenesis, Mutagenesis, Impairment of Fertility A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50 times the maximum human exposure, based on surface area. Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella typhimurium test systems. Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility. Pregnancy Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility or harm to the animal fetus. The safety of oxybutynin chloride administered to women who are or who may become pregnant has not been established. Therefore, oxybutynin chloride should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when oxybutynin chloride is administered to a nursing woman. Pediatric Use The safety and efficacy of oxybutynin chloride administration have been demonstrated for pediatric patients 5 years of age and older (see DOSAGE AND ADMINISTRATION ). The safety and efficacy of oxybutynin chloride tablets were studied in 30 children in a 24-week, open-label trial. Patients were aged 5 to 15 years, all had symptoms of detrusor overactivity in association with a neurological condition (e.g., spina bifida), all used clean intermittent catheterization, and all were current users of oxybutynin chloride. Study results demonstrated that the administration of oxybutynin chloride was associated with improvement in clinical and urodynamic parameters. At total daily doses ranging from 5 mg to 15 mg, treatment with oxybutynin chloride tablets was associated with an increase from baseline in mean urine volume per catheterization from 122 mL to 145 mL, an increase from baseline in mean urine volume after morning awakening from 148 mL to 168 mL, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 43% to 61%. Urodynamic results in these patients were consistent with the clinical results. Treatment with oxybutynin chloride tablets was associated with an increase from baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm H 2 O to 33 cm H 2 O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H 2 O) from 39% to 20%. As there is insufficient clinical data for pediatric populations under age 5, oxybutynin chloride is not recommended for this age group. Geriatric Use Clinical studies of oxybutynin chloride did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg given 2 or 3 times a day has been recommended for the frail elderly due to a prolongation of the elimination half-life from 2 to 3 hours to 5 hours. 2,3,4 In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}', 'information_for_patients': '{"Information for Patients Patients should be informed that oxybutynin may produce angioedema that could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing. Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin chloride are administered in the presence of high environmental temperature. Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence), or blurred vision, patients should be advised to exercise caution. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin."}', 'pregnancy': '{"Pregnancy Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility or harm to the animal fetus. The safety of oxybutynin chloride administered to women who are or who may become pregnant has not been established. Therefore, oxybutynin chloride should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards."}', 'pediatric_use': '{"Pediatric Use The safety and efficacy of oxybutynin chloride administration have been demonstrated for pediatric patients 5 years of age and older (see DOSAGE AND ADMINISTRATION ). The safety and efficacy of oxybutynin chloride tablets were studied in 30 children in a 24-week, open-label trial. Patients were aged 5 to 15 years, all had symptoms of detrusor overactivity in association with a neurological condition (e.g., spina bifida), all used clean intermittent catheterization, and all were current users of oxybutynin chloride. Study results demonstrated that the administration of oxybutynin chloride was associated with improvement in clinical and urodynamic parameters. At total daily doses ranging from 5 mg to 15 mg, treatment with oxybutynin chloride tablets was associated with an increase from baseline in mean urine volume per catheterization from 122 mL to 145 mL, an increase from baseline in mean urine volume after morning awakening from 148 mL to 168 mL, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 43% to 61%. Urodynamic results in these patients were consistent with the clinical results. Treatment with oxybutynin chloride tablets was associated with an increase from baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm H 2 O to 33 cm H 2 O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H 2 O) from 39% to 20%. As there is insufficient clinical data for pediatric populations under age 5, oxybutynin chloride is not recommended for this age group."}', 'geriatric_use': '{"Geriatric Use Clinical studies of oxybutynin chloride did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg given 2 or 3 times a day has been recommended for the frail elderly due to a prolongation of the elimination half-life from 2 to 3 hours to 5 hours. 2,3,4 In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}'}

{ASPIRIN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves minor aches and pains. Because of its delayed action, this product will not provide fast relief of headaches or other symptoms needing immediate relief. ask your doctor about other uses for enteric-coated 81 mg Aspirin"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ACETYLSALICYCLIC ACID"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. if you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better pain gets worse or lasts for more than 10 days fever gets worse or lasts for more than 3 days redness or swelling is present new symptoms occur ringing in the ears or loss of hearing occurs. These could be signs of a serious condition."}', 'do_not_use': '{"Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer if you have ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': None, 'warnings': '{"Warnings Reye’s syndrome : Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye’s syndrome, a rare but serious illness. Allergy alert : Aspirin may cause a severe allergic reaction, which may include: hives facial swelling shock asthma (wheezing) Stomach bleeding warning : This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, or kidney disease you are taking a diuretic you have asthma Ask a doctor or pharmacist before use if you are taking a prescription drug for gout diabetes arthritis Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. if you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better pain gets worse or lasts for more than 10 days fever gets worse or lasts for more than 3 days redness or swelling is present new symptoms occur ringing in the ears or loss of hearing occurs. These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ROPIVACAINE HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Ropivacaine Hydrochloride Injection, USP is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide-type. History of hypersensitivity to local anesthetics of the amide-type. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Reactions to ropivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation. The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine. The studies used a variety of premedications, sedatives, and surgical procedures of varying length. A total of 3,988 patients have been exposed to ropivacaine hydrochloride at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event. Because clinical trials are conducted under widely conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Incidence ≥ 5% For the indications of epidural administration in surgery, cesarean section, postoperative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥ 5% in all clinical studies (N=3988): hypotension (37%), nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8%), postoperative complications (7.1%), anemia (6.1%), paresthesia (5.6%), headache (5.1%), pruritus (5.1%), and back pain (5%). Incidence 1 to 5% Urinary retention, dizziness, rigors, hypertension, tachycardia, anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection. Incidence in Controlled Clinical Trials The reported adverse events are derived from controlled clinical studies with ropivacaine hydrochloride (concentrations ranged from 0.125% to 1% for ropivacaine hydrochloride and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Table 2 and Table 3 list adverse events (number and percentage) that occurred in at least 1% of ropivacaine hydrochloride-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with ropivacaine hydrochloride. Table 2 Adverse Events Reported in ≥1% of Adult Patients Receiving Regional or Local Anesthesia (Surgery, Labor, Cesarean Section, Postoperative Pain Management, Peripheral Nerve Block and Local Infiltration) Adverse Reaction Ropivacaine Hydrochloride Total N=1661 Bupivacaine Total N=1433 N % N % Hypotension 536 (32.3) 408 (28.5) Nausea 283 (17) 207 (14.4) Vomiting 117 (7) 88 (6.1) Bradycardia 96 (5.8) 73 (5.1) Headache 84 (5.1) 68 (4.7) Paresthesia 82 (4.9) 57 (4) Back pain 73 (4.4) 75 (5.2) Pain 71 (4.3) 71 (5) Pruritus 63 (3.8) 40 (2.8) Fever 61 (3.7) 37 (2.6) Dizziness 42 (2.5) 23 (1.6) Rigors (Chills) 42 (2.5) 24 (1.7) Postoperative complications 41 (2.5) 44 (3.1) Hypoesthesia 27 (1.6) 24 (1.7) Urinary retention 23 (1.4) 20 (1.4) Progression of labor poor/failed 23 (1.4) 22 (1.5) Anxiety 21 (1.3) 11 (0.8) Breast disorder, breast-feeding 21 (1.3) 12 (0.8) Rhinitis 18 (1.1) 13 (0.9) Table 3 Adverse Events Reported in ≥1% of Fetuses or Neonates of Mothers Who Received Regional Anesthesia (Cesarean Section and Labor Studies) Adverse Reaction Ropivacaine Hydrochloride Total N=639` Bupivacaine Total N=573 N % N % Fetal bradycardia 77 (12.1) 68 (11.9) Neonatal jaundice 49 (7.7) 47 (8.2) Neonatal complication-NOS 42 (6.6) 38 (6.6) Apgar score low 18 (2.8) 14 (2.4) Neonatal respiratory disorder 17 (2.7) 18 (3.1) Neonatal tachypnea 14 (2.2) 15 (2.6) Neonatal fever 13 (2) 14 (2.4) Fetal tachycardia 13 (2) 12 (2.1) Fetal distress 11 (1.7) 10 (1.7) Neonatal infection 10 (1.6) 8 (1.4) Neonatal hypoglycemia 8 (1.3) 16 (2.8) Incidence <1% The following adverse events were reported during the ropivacaine hydrochloride clinical program in more than one patient (N=3988), occurred at an overall incidence of <1%, and were considered relevant: Application Site Reactions – injection site pain Cardiovascular System – vasovagal reaction, syncope, postural hypotension, non-specific ECG abnormalities Female Reproductive – poor progression of labor, uterine atony Gastrointestinal System – fecal incontinence, tenesmus, neonatal vomiting General and Other Disorders – hypothermia, malaise, asthenia, accident and/or injury Hearing and Vestibular – tinnitus, hearing abnormalities Heart Rate and Rhythm – extrasystoles, non-specific arrhythmias, atrial fibrillation Liver and Biliary System – jaundice Metabolic Disorders – hypomagnesemia Musculoskeletal System – myalgia Myo/Endo/Pericardium – ST segment changes, myocardial infarction Nervous System – tremor, Horner’s syndrome, paresis, dyskinesia, neuropathy, vertigo, coma, convulsion, hypokinesia, hypotonia, ptosis, stupor Psychiatric Disorders – agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmares Respiratory System – bronchospasm, coughing Skin Disorders – rash, urticaria Urinary System Disorders – urinary incontinence, micturition disorder Vascular – deep vein thrombosis, phlebitis, pulmonary embolism Vision – vision abnormalities For the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of ropivacaine hydrochloride and bupivacaine. Table 4 is based on data from trials in the U.S. and other countries where ropivacaine hydrochloride was administered as an epidural anesthetic for surgery. Table 4 Common Events (Epidural Administration) Adverse Reaction Ropivacaine Bupivacaine 5 mg/mL Total N = 256 7.5 mg/mL Total N = 297 10 mg/mL Total N = 207 5 mg/mL Total N = 236 7.5 mg/mL Total N = 174 N (%) N (%) N (%) N (%) N (%) Hypotension 99 (38.7) 146 (49.2) 113 (54.6) 91 (38.6) 89 (51.1) Nausea 34 (13.3) 68 (22.9) 41 (17.4) 36 (20.7) Bradycardia 29 (11.3) 58 (19.5) 40 (19.3) 32 (13.6) 25 (14.4) Back pain 18 (7) 23 (7.7) 34 (16.4) 21 (8.9) 23 (13.2) Vomiting 18 (7) 33 (11.1) 23 (11.1) 19 (8.1) 14 (8) Headache 12 (4.7) 20 (6.7) 16 (7.7) 13 (5.5) 9 (5.2) Fever 8 (3.1) 5 (1.7) 18 (8.7) 11 (4.7) Chills 6 (2.3) 7 (2.4) 6 (2.9) 4 (1.7) 3 (1.7) Urinary retention 5 (2) 8 (2.7) 10 (4.8) 10 (4.2) Paresthesia 5 (2) 10 (3.4) 5 (2.4) 7 (3) Pruritus 14 (4.7) 3 (1.4) 7 (4) Using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in Table 5. In Table 6, the adverse events for ropivacaine are broken down by gender. Table 5 Effects of Age on Hypotension (Epidural Administration) Total N: Ropivacaine = 760, Bupivacaine = 410 Ropivacaine Bupivacaine Age 5 mg/mL 7.5 mg/mL 10 mg/mL 5 mg/mL 7.5 mg/mL <65 ≥65 N 68 31 (%) (32.2) (68.9) N 99 47 (%) (43.2) (69.1) N 87 26 (%) (51.5) (68.4) N 64 27 (%) (33.5) (60) N 73 16 (%) (48.3) (69.6) Table 6 Most Common Adverse Events by Gender (Epidural Administration) Total N: Females = 405, Males = 355 Adverse Reaction FEMALE MALE N (%) N (%) Hypotension Nausea Bradycardia Vomiting Back pain Headache Chills Fever Pruritus Pain Urinary retention Dizziness Hypoesthesia Paresthesia 220 119 65 59 41 33 18 16 16 12 11 9 8 8 (54.3) (29.4) (16) (14.6) (10.1) (8.1) (4.4) (4) (4) (3) (2.7) (2.2) (2) (2) 138 23 56 8 23 17 5 3 1 4 7 4 2 10 (38.9) (6.5) (15.8) (2.3) (6.5) (4.8) (1.4) (0.8) (0.3) (1.1) (2) (1.1) (0.6) (2.8) Systemic Reactions The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose-related and due to high plasma levels that may result from overdosage, rapid absorption from the injection site, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance. Epidural administration of ropivacaine hydrochloride has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to > 38.5°C. This occurred more frequently at doses of ropivacaine hydrochloride > 16 mg/h. Neurologic Reactions These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the route of administration and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. The incidence of adverse neurological reactions associated with the use of local anesthetics may be related to the total dose and concentration of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the drug. During lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally as well as the physiological and physical effects of a dural puncture. These observations may include spinal block of varying magnitude (including high or total spinal block), hypotension secondary to spinal block, urinary retention, loss of bladder and bowel control (fecal and urinary incontinence), and loss of perineal sensation and sexual function. Signs and symptoms of subarachnoid block typically start within 2 to 3 minutes of injection.Doses of 15 and 22.5 mg of ropivacaine hydrochloride resulted in sensory levels as high as T5 and T4, respectively. Analgesia started in the sacral dermatomes in 2 to 3 minutes and extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. Other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control; all of which may have slow, incomplete or no recovery. Headache, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported [see Dosage and Administration (2.1) ] . A high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia. Cardiovascular System Reactions High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and possibly cardiac arrest [see Warnings and Precautions (5.2) and Overdosage (10) ] . Allergic Reactions Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic [see Warnings and Precautions (5.1) ] . These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid symptomatology (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established. Most common adverse reactions (incidence ≥5%) are hypotension, nausea, vomiting, bradycardia, fever, pain, postoperative complications, anemia, paresthesia, headache, pruritus, and back pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1‑800‑438‑1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.4) ] : Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of ropivacaine, can interact with ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of ropivacaine. Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (e.g., amiodarone) have not been performed, but caution is advised [see Warnings and Precautions (5.13) ]. • Agents structurally related to amide-type local anesthetics: Concurrent use may cause additive effects. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Ropivacaine Hydrochloride Injection, USP is indicated for the production of local or regional anesthesia for surgery and for acute pain management. Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltration Acute Pain Management: epidural continuous infusion or intermittent bolus; e.g., postoperative or labor; local infiltration Ropivacaine hydrochloride is an amide local anesthetic indicated in adults for the production of local or regional anesthesia for surgery and for acute pain management. Surgical Anesthesia: epidural block for surgery including cesarean section; major nerve block; local infiltration. Acute Pain Management: epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Delay in proper management of dose-related toxicity, underventilation, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. ( 5.1 ) • In performing ropivacaine hydrochloride blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardia arrest. ( 5.2 ) • Intra-articular infusions of local anesthetics may cause chondrolysis. Ropivacaine hydrochloride is not approved for this use. ( 5.3 ) • Signs of methemoglobinemia may occur. ( 5.4 ) 5.1 General Warnings and Precautions Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an IV line inserted. All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Adverse Reactions (6) and Overdosage (10.1) ] . Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. The safe and effective use of local anesthetics depends on proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use [see Adverse Reactions (6) ] . The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse events. Injections should be made slowly and incrementally, with frequent aspirations before and during the injection to avoid intravascular injection. When a continuous catheter technique is used, syringe aspirations should also be performed before and during each supplemental injection. During the administration of epidural anesthesia, it is recommended that a test dose of a local anesthetic with a fast onset be administered initially and that the patient be monitored for central nervous system and cardiovascular toxicity, as well as for signs of unintended intrathecal administration before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions, which contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Administration of higher than recommended doses of ropivacaine hydrochloride to achieve greater motor blockade or increased duration of sensory blockade may result in cardiovascular depression, particularly in the event of inadvertent intravascular injection. Tolerance to elevated blood levels varies with the physical condition of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical condition. Local anesthetics should also be used with caution in patients with hypotension, hypovolemia or heart block. Solutions of ropivacaine hydrochloride should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine. It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. 5.2 Unintended Intravenous Injection In performing ropivacaine hydrochloride blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of ropivacaine hydrochloride for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. Ropivacaine hydrochloride should be administered in incremental doses. It is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously. 5.3 Intra-Articular Infusions and Risk of Chondrolysis Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno‑humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. 5.4 Risk of Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue ropivacaine hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.5 Central Nervous System Toxicity Careful and constant monitoring of cardiovascular and respiratory vital signs (adequacy of ventilation) and the patient\'s state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, incoherent speech, light-headedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. 5.6 Epidural Anesthesia A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of ropivacaine hydrochloride at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved. During epidural administration, ropivacaine hydrochloride should be administered in incremental doses of 3 to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and the effects monitored before the full dose is given. When clinical conditions permit, the test dose should contain an appropriate dose of epinephrine to serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient \\"epinephrine response\\" within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart should be continuously monitored for a heart rate increase. Patients on beta‑blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a rise in systolic blood pressure. A test dose of a short-acting amide anesthetic such as lidocaine is recommended to detect an unintentional intrathecal administration. This will be manifested within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects. 5.7 Use in Brachial Plexus Block Ropivacaine plasma concentrations may approach the threshold for central nervous system toxicity after the administration of 300 mg of ropivacaine for brachial plexus block. Caution should be exercised when using the 300 mg dose [see Overdosage (10) ] . The dose for a major nerve block must be adjusted according to the site of administration and patient status. Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used. 5.8 Use in Peripheral Nerve Block Major peripheral nerve blocks may result in the administration of a large volume of local anesthetic in highly vascularized areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations. 5.9 Use in Head and Neck Area Small doses of local anesthetics injected into the head and neck area may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2) ] . 5.10 Use in Ophthalmic Surgery The use of ropivacaine hydrochloride in retrobulbar blocks for ophthalmic surgery has not been studied. Until appropriate experience is gained, the use of ropivacaine hydrochloride for such surgery is not recommended. 5.11 Hepatic Disease Because amide-type local anesthetics such as ropivacaine are metabolized by the liver, these drugs, especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. 5.12 Cardiovascular Impairment Local anesthetics should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. 5.13 Risk of Additive Effects Ropivacaine hydrochloride should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive [see Drug Interactions (7) ]. Patients treated with class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive [see Drug Interactions (7) ]. 5.14 Malignant Hyperthermia Many drugs used during the conduct of anesthesia are considered potential triggering agents for malignant hyperthermia (MH). Amide-type local anesthetics are not known to trigger this reaction. However, since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for MH management should be available."}', 'overdosage': '{"10 OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered, or large doses administered, during therapeutic use of local anesthetics or to unintended subarachnoid or intravascular injection of local anesthetic solution [see Adverse Reactions (6) and Warnings and Precautions (5.1 , 5.2 , 5.6 )]. 10.1 Treatment Therapy with ropivacaine should be discontinued at the first sign of toxicity. No specific information is available for the treatment of toxicity with ropivacaine; therefore, treatment should be symptomatic and supportive. The first consideration is prevention, best accomplished by incremental injection of ropivacaine, careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic and during continuous infusion. At the first sign of change in mental status, oxygen should be administered. The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Circulation should be assisted as necessary. This may prevent convulsions if they have not already occurred. If necessary, use drugs to control convulsions. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome. The mean dosages of ropivacaine producing seizures, after intravenous infusion in dogs, non-pregnant and pregnant sheep were 4.9, 6.1 and 5.9 mg/kg, respectively. These doses were associated with peak arterial total plasma concentrations of 11.4, 4.3 and 5 mcg/mL, respectively. In human volunteers given intravenous ropivacaine, the mean (min-max) maximum tolerated total and free arterial plasma concentrations were 4.3 (3.4 to 5.3) and 0.6 (0.3 to 0.9) mcg/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted. Clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. If difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated, endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of non-pregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the fetus may improve the response to resuscitative efforts."}', 'active_flag': 'Y', 'generic_name': '{"ROPIVACAINE HYDROCHLORIDE"}', 'route': '{EPIDURAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients and Caregivers When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity in the anesthetized part of the body following proper administration of lumbar epidural anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the ropivacaine package insert. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about Ropivacaine hydrochloride injection please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA LAB-1390-3.0 Logo"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no available human data on use of ropivacaine injection in pregnant women to evaluate a drug‑associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone, and cardiac function (see Clinical Considerations ) . No teratogenicity was observed at doses up to 0.3 times the maximum recommended human dose of 770 mg/24 hours for epidural use, and equal to the MRHD of 250 mg for nerve block use, based on body surface area (BSA) comparisons and a 60 kg human weight (see Animal Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Labor or Delivery Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity [see Clinical Pharmacology (12) ] . The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal Adverse Reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient\'s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Data Animal Data No malformations were reported in embryo-fetal development toxicity studies conducted in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6 to 18, rabbits received daily subcutaneous doses of ropivacaine at 1.3, 4.2, or 13 mg/kg/day (equivalent to 0.03, 0.10, and 0.33 times the maximum recommended human dose (MRHD) of 770 mg/24 hours, respectively, and 0.10, 0.32, and 1.0 times the MRHD of 250 mg for nerve block use, respectively based on body surface area (BSA) comparisons and a 60 kg human weight). Rats received daily subcutaneous doses of 5.3, 11, and 26 mg/kg/day (equivalent to 0.07, 0.14, and 0.33 times the MRHD for epidural use, respectively, and 0.21, 0.43, and 1.0 times the MRHD for nerve block use, respectively, based on BSA comparisons) during GD 6 to 15. No treatment-related effects on late fetal development, parturition, litter size, lactation, neonatal viability, or growth of the offspring were reported in a prenatal and postnatal reproductive and development toxicity study; however functional endpoints were not evaluated. Female rats were dosed daily subcutaneously from GD 15 to Lactation Day 20 at doses of 5.3, 11, and 26 mg/kg/day (equivalent to 0.07, 0.1, and 0.3 times the MRHD for epidural use, respectively, and 0.21, 0.43, and 1.0 times the MRHD for nerve block use, respectively), with maternal toxicity exhibited at the high dose. No adverse effects in physical developmental milestones or in behavioral tests were reported in a 2‑generational reproduction study, in which rats received daily subcutaneous doses of 6.3, 12, and 23 mg/kg/day (equivalent to 0.08, 0.15, and 0.29 times the MRHD for epidural use, respectively, and 0.24, 0.45, and 0.88 times the MRHD for nerve block use, respectively, based on BSA comparisons) for 9 weeks before mating and during mating for males, and for 2 weeks before mating and during mating, pregnancy, and lactation, up to day 42 post coitus for females. Significant pup loss was observed in the high dose group during the first 3 days postpartum, from a few hours up to 3 days after delivery compared to the control group, which was considered secondary to impaired maternal care due to maternal toxicity. No differences were observed in litter parameters, or fertility, mean gestation time, or number of live births were observed between the control (saline) and treatment groups [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1) ] ."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and efficacy of ropivacaine in pediatric patients have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use Of the 2,978 subjects that were administered ropivacaine injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older which includes 127 patients (4%) 75 years of age and over. Ropivacaine injection was found to be safe and effective in the patients in these studies. Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3) ] ."}'}

{"CETIRIZINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: runny nose sneezing itchy, watery eyes itching of the nose or throat"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CETIRIZINE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away."}', 'do_not_use': '{"Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine."}', 'when_using': '{"When using this product drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness be careful when driving a motor vehicle or operating machinery"}', 'warnings': '{"Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding: if breast-feeding: not recommended if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{KETOCONAZOLE}

{'contraindications': '{"CONTRAINDICATIONS Ketoconazole Cream, 2% is contraindicated in persons who have shown hypersensitivity to the active or excipient ingredients of this formulation."}', 'adverse_reactions': '{"ADVERSE REACTIONS During clinical trials 45 (5%) of 905 patients treated with Ketoconazole Cream, 2% and 5 (2.4%) of 208 patients treated with placebo reported side effects consisting mainly of severe irritation, pruritus and stinging. One of the patients treated with ketoconazole cream developed a painful allergic reaction. In worldwide postmarketing experience, rare reports of contact dermatitis have been associated with ketoconazole cream or one of its excipients, namely sodium sulfite or propylene glycol. To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Ketoconazole Cream, 2% is indicated for the topical treatment of tinea corporis, tinea cruris and tinea pedis caused by Trichophyton rubrum , T. mentagrophytes and Epidermophyton floccosum ; in the treatment of tinea (pityriasis) versicolor caused by Malassezia furfur (Pityrosporum orbiculare) ; and in the treatment of cutaneous candidiasis caused by Candida spp . and in the treatment of seborrheic dermatitis."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"KETOCONAZOLE CREAM, 2%"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Ketoconazole Cream, 2% is not for ophthalmic use. Ketoconazole Cream, 2% contains sodium sulfite anhydrous, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people."}', 'precautions': '{"PRECAUTIONS General If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued. Hepatitis (1:10,000 reported incidence) and, at high doses, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with orally administered ketoconazole; these effects have not been seen with topical ketoconazole. Carcinogenesis, Mutagenesis, Impairment of Fertility A long-term feeding study in Swiss Albino mice and in Wistar rats showed no evidence of oncogenic activity. The dominant lethal mutation test in male and female mice revealed that single oral doses of ketoconazole as high as 80 mg/kg produced no mutation in any stage of germ cell development. The Ames\' Salmonella microsomal activator assay was also negative. Pregnancy Teratogenic effects Pregnancy Category C Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given orally in the diet at 80 mg/kg/day, (10 times the maximum recommended human oral dose). However, these effects may be related to maternal toxicity, which was seen at this and higher dose levels. There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether Ketoconazole Cream, 2% administered topically could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy Teratogenic effects Pregnancy Category C Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when given orally in the diet at 80 mg/kg/day, (10 times the maximum recommended human oral dose). However, these effects may be related to maternal toxicity, which was seen at this and higher dose levels. There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness in children have not been established."}', 'geriatric_use': None}

{"SULFACETAMIDE SODIUM"}

{'contraindications': '{"Contraindications: Sulfacetamide Sodium Ophthalmic Solution is contraindicated in individuals who have a hypersensitivity to sulfonamides or to any ingredient of the preparation."}', 'adverse_reactions': '{"ADVERSE REACTIONS: Bacterial and fungal corneal ulcers have developed during treatment with sulfonamide ophthalmic preparations. The most frequently reported reactions are local irritation, stinging and burning. Less commonly reported reactions include non-specific conjunctivitis, conjunctival hyperemia, secondary infections and allergic reactions. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias (See WARNINGS )."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE: Sulfacetamide Sodium Ophthalmic Solution USP, 10% is indicated for the treatment of conjunctivitis and other superficial ocular infections due to susceptible microorganisms, and as an adjunctive in systemic sulfonamide therapy of trachoma: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), Haemophilus influenzae, Klebsiella species, and Enterobacter species. Topically applied sulfonamides do not provide adequate coverage against Neisseria species, Serratia marcescens and Pseudomonas aeruginosa . A significant percentage of staphylococcal isolates are completely resistant to sulfa drugs."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"SULFACETAMIDE SODIUM"}', 'route': '{OPHTHALMIC}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS: FOR TOPICAL EYE USE ONLY - NOT FOR INJECTION. FATALITIES HAVE OCCURRED, ALTHOUGH RARELY, DUE TO SEVERE REACTIONS TO SULFONAMIDES INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS. Sensitizations may recur when a sulfonamide is readministered, irrespective of the route of administration. Sensitivity reactions have been reported in individuals with no prior history of sulfonamide hypersensitivity. At the first sign of hypersensitivity, skin rash or other serious reaction, discontinue use of this preparation."}', 'precautions': '{"PRECAUTIONS: General: Prolonged use of topical antibacterial agents may give rise to overgrowth of nonsusceptible organisms including fungi. Bacterial resistance to sulfonamides may also develop. The effectiveness of sulfonamides may be reduced by the para-aminobenzoic acid present in purulent exudates. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration, and cross-sensitivity between different sulfonamides may occur. At the first sign of hypersensitivity, increase in purulent discharge, or aggravation of inflammation or pain, the patient should discontinue use of the medication and consult a physician (See WARNINGS ). Information for Patients: To avoid contamination, do not touch tip of container to the eye, eyelid or any surface. Drug Interactions: Sulfacetamide preparations are incompatible with silver preparations. Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been conducted in animals or in humans to evaluate the possibility of these effects with ocularly administered sulfacetamide. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides, and long-term oral administration of sulfonamides has resulted in thyroid malignancies in these animals. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with sulfonamide ophthalmic preparations. Kernicterus may occur in the newborn as a result of treatment of a pregnant woman at term with orally administered sulfonamides. There are no adequate and well controlled studies of sulfonamide ophthalmic preparations in pregnant women and it is not known whether topically applied sulfonamides can cause fetal harm when administered to a pregnant woman. This product should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Systematically administered sulfonamides are capable of producing kernicterus in infants of lactating women. Because of the potential for the development of kernicterus in neonates, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in children below the age of two months have not been established. ADVERSE REACTIONS: Bacterial and fungal corneal ulcers have developed during treatment with sulfonamide ophthalmic preparations. The most frequently reported reactions are local irritation, stinging and burning. Less commonly reported reactions include non-specific conjunctivitis, conjunctival hyperemia, secondary infections and allergic reactions. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias (See WARNINGS )."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{EPINEPHRINE}

{'contraindications': '{"4 CONTRAINDICATIONS None. None. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse reactions to systemically administered epinephrine are headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; peripheral coldness; nausea/vomiting; and/or respiratory difficulties. Arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact BPI Labs, LLC at (727) 471-0850 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions associated with Epinephrine Infusion (for Hypotension associated with Septic Shock) The following adverse reactions associated with the infusion of epinephrine were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Cardiovascular disorders: tachycardia, supraventricular tachycardia, ventricular arrhythmias, myocardial ischemia, myocardial infarction, limb ischemia, pulmonary edema Gastrointestinal disorders: Nausea, vomiting General disorders and administrative site conditions: Chest pain, extravasation, Metabolic: hypoglycemia, hyperglycemia, insulin resistance, hypokalemia, lactic acidosis Nervous system disorders: Headache, nervousness, paresthesia, tremor, stroke, central nervous system bleeding Psychiatric disorders: Excitability Renal disorders: Renal insufficiency Respiratory: Pulmonary edema, rales Skin and subcutaneous tissue disorders: Diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation 6.2 Adverse Reactions associated with Intramuscular or Subcutaneous Use (for Anaphylaxis) Common adverse reactions to systemically administered epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with heart disease, hypertension, or hyperthyroidism [see Warnings and Precautions (5.9) ]. Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below by body system: Cardiovascular: angina, arrhythmias, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, and ventricular ectopy. Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.6) ]. Arrhythmias, including fatal ventricular fibrillation, have occurred, particularly in patients with underlying organic heart disease or patients receiving drugs that sensitize the heart to arrhythmias [see Warnings and Precautions (5.6) ]. Rapid rises in blood pressure associated with epinephrine use have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see Warnings and Precautions (5.6) ]. Respiratory: respiratory difficulties. Neurological: dizziness, disorientation, excitability, headache, impaired memory, lightheadedness, nervousness, panic, psychomotor agitation, sleepiness, tingling, tremor, and weakness. Psychiatric: anxiety, apprehensiveness, restlessness. Gastrointestinal: nausea, vomiting. Skin: sweating. Other: Patients with Parkinson’s disease may experience psychomotor agitation or a temporary worsening of symptoms [see Warnings and Precautions (5.9) ]. Diabetic patients may experience transient increases in blood sugar [see Warnings and Precautions (5.9) ]. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.3) ]. Adverse events experienced as a result of an injection into these areas include increased heart rate, local reactions including injection site pallor, coldness, hypoesthesia, and tissue loss, or injury at the injection site resulting in bruising, bleeding, discoloration, erythema, and skeletal injury. Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.3) ]. Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection in the thigh [see Warnings and Precautions (5.8) ]. 6.3 Adverse Reactions Associated with Intraocular Use (for Mydriasis) Epinephrine products containing sodium bisulfite have been associated with corneal endothelial damage when used in the eye at undiluted concentrations (1 mg/mL). Although this Epinephrine product contains no sulfites or preservatives, warning is still advised [see Warnings and Precautions (5.7) ]. To report SUSPECTED ADVERSE REACTIONS, contact BPI Labs LLC at (727) 471-0850 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Drugs antagonizing pressor effects of epinephrine α-blockers, such as phentolamine Vasodilators, such as nitrates Diuretics Antihypertensives Ergot alkaloids Drugs potentiating pressor effects of epinephrine Sympathomimetics β-blockers, such as propranolol Tricyclic anti-depressants Monoamine oxidase (MAO) inhibitors Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone Clonidine Doxapram Oxytocin Drugs potentiating arrhythmogenic effects of epinephrine. Patients who are concomitantly receiving any of the following drugs should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.6) and Adverse Reactions (6) ]. β-blockers, such as propranolol Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane Antihistamines Thyroid hormones Diuretics Cardiac glycosides, such as digitalis glycosides Quinidine Drugs potentiating hypokalemic effects of epinephrine Potassium depleting diuretics Corticosteroids Theophylline Epinephrine should not be used to counteract circulatory collapse or hypotension caused by phenothiazines, as a reversal of the pressor effects of epinephrine may result in further lowering of blood pressure. Epinephrine may antagonize the neuronal blockade produced by guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the latter. Drugs that counter the pressor effects of epinephrine include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives and ergot alkaloids. ( 7 ) Drugs that potentiate the effects of epinephrine include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin, levothyroxine sodium, and certain antihistamines. ( 7 ) Drugs that increase the arrhythmogenic potential of epinephrine include beta blockers, cyclopropane and halogenated hydrocarbon anesthetics, quinidine, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. Observe for development of cardiac arrhythmias. ( 7 ) Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of epinephrine. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Epinephrine is a non-selective alpha and beta adrenergic agonist indicated: To increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. ( 1.1 ) For emergency treatment of allergic reactions (Type 1), including anaphylaxis. ( 1.2 ) For induction and maintenance of mydriasis during intraocular surgery. ( 1.3 ) 1.1 Hypotension associated with Septic Shock Epinephrine Injection USP, 1 mg/mL is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. 1.2 Anaphylaxis Emergency treatment of allergic reactions (Type I), including anaphylaxis, which may result from allergic reactions to insect stings, biting insects, foods, drugs, sera, diagnostic testing substances and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The signs and symptoms associated with anaphylaxis include flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with hypotension, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, airway swelling, laryngospasm, bronchospasm, pruritus, urticaria or angioedema, swelling of the eyelids, lips, and tongue. 1.3 Induction and Maintenance of Mydriasis during Intraocular Surgery Induction and maintenance of mydriasis during intraocular surgery."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Monitor patient for acute severe hypertension. ( 5.1 ) Avoid extravasation into tissues, which can cause local necrosis. ( 5.2 ) Do not inject into buttocks, digits, hands, or feet. ( 5.3 ) Potential for pulmonary edema, which may be fatal. ( 5.4 ) May constrict renal blood vessels and decrease urine formation. ( 5.5 ) May induce potentially serious cardiac arrhythmias or aggravate angina pectoris, particularly in patients with underlying heart disease. ( 5.6 ) Rare cases of serious skin and soft tissue infections have been reported following epinephrine injection. Advise patients to seek medical care if they develop signs or symptoms of infection. ( 5.8 ) Patients with hyperthyroidism, Parkinson\'s disease, diabetes, and pheochromocytoma are at greater risk of having adverse reactions when used intravenously, intramuscularly, or subcutaneously. ( 5.9 ) 5.1 Hypertension When Epinephrine Injection is administered intravenously, titrate the infusion while monitoring vital signs. Invasive arterial blood pressure monitoring and central venous pressure monitoring are recommended. Because of varying response to epinephrine, dangerously high blood pressure may occur. Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may experience severe, prolonged hypertension when given epinephrine. 5.2 Extravasation and Tissue Necrosis with Intravenous Infusion When Epinephrine Injection is administered intravenously, the infusion site should be checked frequently for free flow. Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. Blanching along the course of the infused vein, sometimes without obvious extravasation, may be attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage. This also may progress on rare occasions to superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. Antidote for Extravasation Ischemia: To prevent sloughing and necrosis in areas in which extravasation has taken place, infiltrate the area with 10 mL to 15 mL of saline solution containing from 5 mg to 10 mg of phentolamine , an adrenergic blocking agent. Use a syringe with a fine hypodermic needle, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. 5.3 Incorrect Locations of Injection for Anaphylaxis When Epinephrine Injection is used for the treatment of anaphylaxis, the most appropriate location for administration is into the anterolateral aspect of the thigh (vastus lateralis muscle) because of its location, size, and available blood flow. Injection into (or near) smaller muscles, such as in the deltoid, is not recommended due to possible differences in absorption associated with this use. Do not administer repeated injections of epinephrine at the same site, as the resulting vasoconstriction may cause tissue necrosis. Do not inject into buttock. Injection into the buttock may not provide effective treatment of anaphylaxis and has been associated with the development of Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk. Do not inject into digits, hands, or feet. Epinephrine is a strong vasoconstrictor. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area and has been associated with tissue necrosis. 5.4 Pulmonary Edema When Epinephrine Injection is administered intravenously, there is risk of pulmonary edema because of the peripheral constriction and cardiac stimulation produced. Treatment of pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. 5.5 Renal Impairment Intravenously administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation. 5.6 Cardiac Arrhythmias and Ischemia Epinephrine may induce cardiac arrhythmias and angina pectoris in patients, especially patients suffering from coronary artery disease, organic heart disease, cerebrovascular disease, hypertension, or patients who are receiving drugs that sensitize the myocardium [see Adverse Reactions (6) and Drug Interactions (7)]. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug (such as propranolol). 5.7 Injury with Undiluted Intraocular Solution Epinephrine must be diluted before intraocular use. Other epinephrine products that contain sodium bisulfite have been associated with corneal endothelial damage when used in the eye at undiluted concentrations (1 mg/mL). Although this Epinephrine product contains no sulfites or preservatives, warning is still advised [see Dosage and Administration (2.4) ]. 5.8 Serious Infections at the Injection Site Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Clostridium spores can be present on the skin and introduced into the deep tissue with subcutaneous or intramuscular injection. While cleansing with alcohol may reduce presence of bacteria on the skin, alcohol cleansing does not kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject Epinephrine Injection into the buttock [see Warnings and Precautions (5.3) ]. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site. 5.9 Other Disease Interactions Epinephrine should be administered with caution to patients with hyperthyroidism, Parkinson’s disease, diabetes mellitus, pheochromocytoma, elderly individuals, and pregnant women. Patients with Parkinson’s disease may experience psychomotor agitation or notice a temporary worsening of symptoms. Diabetic patients may experience transient increases in blood sugar. Despite these concerns, the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation."}', 'overdosage': '{"10 OVERDOSAGE Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Epinephrine overdosage may also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Myocardial ischemia and infarction, cardiomyopathy, extreme pallor and coldness of the skin, metabolic acidosis due to elevated blood lactic acid levels, and renal insufficiency and failure have also been reported. Epinephrine is rapidly inactivated in the body and treatment following overdose is primarily supportive. Treatment of pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug (such as propranolol). If necessary, pressor effects may be counteracted by rapidly acting vasodilators (such as nitrites) or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug."}', 'active_flag': 'Y', 'generic_name': '{EPINEPHRINE}', 'route': '{INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise patients or their caregivers about common adverse reactions associated with the use of epinephrine, including an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially with rest, quiet and recumbent positioning. Warn patients with a good response to initial treatment about the possibility of recurrence of anaphylaxis symptoms and instruct patients to obtain medical attention if symptoms return. Advise patients with diabetes that they may develop increased blood glucose levels following epinephrine administration. Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site [see Warnings and Precautions (5.8) ] ."}', 'pregnancy': '{"8.1 Pregnancy Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Epinephrine crosses the placenta. Epinephrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (fetal anoxia, spontaneous abortion, or both). Epinephrine is teratogenic in rabbits, mice, and hamsters dosed during organogenesis. Epinephrine has been shown to have teratogenic effects (including gastroschisis and embryonic lethality) when administered subcutaneous in rabbits at approximately 15 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days). In mice, teratogenic effects (including embryonic lethality) were observed at approximately 3 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). In hamsters, teratogenic effects were observed at approximately 2 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day for 4 days)."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been established. Clinical use data support weight-based dosing for treatment of anaphylaxis in pediatric patients, and other reported clinical experience with the use of epinephrine suggests that the adverse reactions seen in children are similar in nature and extent to those both expected and reported in adults. The safety and effectiveness of epinephrine (at a dilution of 1:100,000 to 1:400,000) for induction and maintenance of mydriasis during intraocular surgery have been established in pediatric patients. Use of epinephrine for induction and maintenance of mydriasis during intraocular surgery in pediatric patients is supported by adequate and well controlled studies in adults and uncontrolled studies in pediatric patients."}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of epinephrine for the treatment of hypotension associated with septic shock did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Therefore, for the treatment of anaphylaxis, consider starting with a lower dose to take into account potential concomitant disease or other drug therapy. For induction and maintenance of mydriasis during intraocular surgery, no overall differences have been observed between elderly and other patients."}'}

{"BOS TAURUS EYE","LARIX DECIDUA RESIN","SILICON DIOXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Directions: FOR ORAL USE ONLY."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CHRYSOLITH RETINA"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings: Claims based on traditional homeopathic practice, not accepted medical evidence. Not FDA evaluated. Contains sugar. Diabetics and persons intolerant of sucrose (sugar): Consult a doctor before use. Do not use if allergic to any ingredient. Consult a doctor before use for serious conditions or if conditions worsen or persist. If pregnant or nursing, consult a doctor before use. Do not use if safety seal is broken or missing."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"TROLAMINE SALICYLATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves minor pain associated with: • arthritis • simple backache • muscle strains • sprains • bruises"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"TROLAMINE SALICYLATE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • condition worsens • symptoms persist for more than 7 days or clear up and occur again within a few days • redness is present • irritation develops"}', 'do_not_use': None, 'when_using': '{"When using this product • use only as directed • do not bandage tightly or use with a heating pad • avoid contact with the eyes or mucous membranes • do not apply to wounds or damaged skin"}', 'warnings': '{"Warnings For external use only Allergy alert: If prone to allergic reaction from aspirin or salicylates, consult a doctor before use. When using this product • use only as directed • do not bandage tightly or use with a heating pad • avoid contact with the eyes or mucous membranes • do not apply to wounds or damaged skin Stop use and ask a doctor if • condition worsens • symptoms persist for more than 7 days or clear up and occur again within a few days • redness is present • irritation develops If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222)"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{METHIMAZOLE}

{'contraindications': '{"CONTRAINDICATIONS Methimazole tablets are contraindicated in the presence of hypersensitivity to the drug or any of the other product components."}', 'adverse_reactions': '{"ADVERSE REACTIONS Major adverse reactions (which occur with much less frequency than the minor adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia, thrombocytopenia, and aplastic anemia), drug fever, a lupus-like syndrome, insulin autoimmune syndrome (which can result in hypoglycemic coma), hepatitis (jaundice may persist for several weeks after discontinuation of the drug), periarteritis, and hypoprothrombinemia. Nephritis occurs very rarely. There have been postmarketing case reports of acute pancreatitis. There are reports of a vasculitis, often associated with the presence of anti-neutrophilic cytoplasmic antibodies (ANCA), resulting in severe complications (see WARNINGS). Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy. To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"Drug Interactions Anticoagulants (oral): Due to potential inhibition of vitamin K activity by methimazole, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures. ß-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Methimazole tablets are indicated: In patients with Graves\' disease with hyperthyroidism or toxic multinodular goiter for whom surgery or radioactive iodine therapy is not an appropriate treatment option. To ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Signs and Symptoms Symptoms may include nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, and edema. Aplastic anemia (pancytopenia) or agranulocytosis may be manifested in hours to days. Less frequent events are hepatitis, nephrotic syndrome, exfoliative dermatitis, neuropathies, and CNS stimulation or depression. No information is available on the median lethal dose of the drug or the concentration of methimazole in biologic fluids associated with toxicity and/or death. Treatment To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient\'s medical status."}', 'active_flag': 'Y', 'generic_name': '{METHIMAZOLE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS First Trimester Use of Methimazole and Congenital Malformations Methimazole crosses the placental membranes and can cause fetal harm, when administered in the first trimester of pregnancy. Rare instances of congenital defects, including aplasia cutis, craniofacial malformations (facial dysmorphism; choanal atresia), gastrointestinal malformations (esophageal atresia with or without tracheoesophageal fistula), omphalocele and abnormalities of the omphalomesenteric duct have occurred in infants born to mothers who received methimazole tablets in the first trimester of pregnancy. If methimazole tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. Because of the risk for congenital malformations associated with use of methimazole tablets in the first trimester of pregnancy, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. If methimazole tablets are used, the lowest possible dose to control the maternal disease should be given. Agranulocytosis Agranulocytosis is potentially a life-threatening adverse reaction of methimazole therapy. Patients should be instructed to immediately report to their physicians any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis or aplastic anemia (pancytopenia), and the patient\'s bone marrow indices should be monitored. Liver Toxicity Although there have been reports of hepatotoxicity (including acute liver failure) associated with methimazole, the risk of hepatotoxicity appears to be less with methimazole than with propylthiouracil, especially in the pediatric population. Symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc.) should prompt evaluation of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST). Drug treatment should be discontinued promptly in the event of clinically significant evidence of liver abnormality including hepatic transaminase values exceeding 3 times the upper limit of normal. Hypothyroidism Methimazole can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, methimazole can cause fetal goiter and cretinism when administered to a pregnant woman. For this reason, it is important that a sufficient, but not excessive, dose be given during pregnancy (see PRECAUTIONS, Pregnancy). Vasculitis Cases of vasculitis resulting in severe complications have been reported in patients receiving methimazole therapy. These cases of vasculitis include: leukocytoclastic cutaneous vasculitis, acute kidney injury and glomerulonephritis, alveolar/pulmonary hemorrhage, CNS vasculitis, and neuropathy. Most cases were associated with anti-neutrophilic cytoplasmic antibodies (ANCA)-positive vasculitis. In some cases, vasculitis resolved/improved with drug discontinuation; however, more severe cases required treatment with additional measures including corticosteroids, immunosuppressant therapy, and plasmapheresis. If vasculitis is suspected, discontinue therapy and initiate appropriate intervention."}', 'precautions': '{"PRECAUTIONS General Patients who receive methimazole should be under close surveillance and should be cautioned to report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white-blood-cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis. Information for Patients Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy. Inform patients that cases of vasculitis resulting in severe complications have occurred with methimazole tablets. Inform patients to promptly report symptoms that may be associated with vasculitis including new rash, hematuria or decreased urine output, dyspnea or hemoptysis (see WARNINGS and ADVERSE REACTIONS). Laboratory Tests Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time should be monitored during therapy with the drug, especially before surgical procedures. Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of a rising serum TSH indicates that a lower maintenance dose of methimazole tablets should be employed. Drug Interactions Anticoagulants (oral): Due to potential inhibition of vitamin K activity by methimazole, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures. ß-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2 year study, rats were given methimazole at doses of 0.5, 3, and 18 mg/kg/day. These doses were 0.3, 2, and 12 times the 15 mg/day maximum human maintenance dose (when calculated on the basis of surface area). Thyroid hyperplasia, adenoma, and carcinoma developed in rats at the two higher doses. The clinical significance of these findings is unclear. Pregnancy See WARNINGS If methimazole tablets are used during the first trimester of pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. In pregnant women with untreated or inadequately treated Graves\' disease, there is an increased risk of adverse events of maternal heart failure, spontaneous abortion, preterm birth, stillbirth and fetal or neonatal hyperthyroidism. Because methimazole crosses placental membranes and can induce goiter and cretinism in the developing fetus, hyperthyroidism should be closely monitored in pregnant women and treatment adjusted such that a sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction of dosage may be possible. In some instances, anti-thyroid therapy can be discontinued several weeks or months before delivery. Due to the rare occurrence of congenital malformations associated with methimazole use, it may be appropriate to use an alternative anti-thyroid medication in pregnant women requiring treatment for hyperthyroidism particularly in the first trimester of pregnancy during organogenesis. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters. Nursing Mothers Methimazole is present in breast milk. However, several studies found no effect on clinical status in nursing infants of mothers taking methimazole. A long-term study of 139 thyrotoxic lactating mothers and their infants failed to demonstrate toxicity in infants who are nursed by mothers receiving treatment with methimazole. Monitor thyroid function at frequent (weekly or biweekly) intervals. Pediatric Use Because of postmarketing reports of severe liver injury in pediatric patient treated with propylthiouracil, methimazole is the preferred choice when an antithyroid drug is required for a pediatric patient (see DOSAGE AND ADMINISTRATION)."}', 'information_for_patients': '{"Information for Patients Patients should be advised that if they become pregnant or intend to become pregnant while taking an antithyroid drug, they should contact their physician immediately about their therapy. Inform patients that cases of vasculitis resulting in severe complications have occurred with methimazole tablets. Inform patients to promptly report symptoms that may be associated with vasculitis including new rash, hematuria or decreased urine output, dyspnea or hemoptysis (see WARNINGS and ADVERSE REACTIONS)."}', 'pregnancy': '{"Pregnancy See WARNINGS If methimazole tablets are used during the first trimester of pregnancy or if the patient becomes pregnant while taking this drug, the patient should be warned of the potential hazard to the fetus. In pregnant women with untreated or inadequately treated Graves\' disease, there is an increased risk of adverse events of maternal heart failure, spontaneous abortion, preterm birth, stillbirth and fetal or neonatal hyperthyroidism. Because methimazole crosses placental membranes and can induce goiter and cretinism in the developing fetus, hyperthyroidism should be closely monitored in pregnant women and treatment adjusted such that a sufficient, but not excessive, dose be given during pregnancy. In many pregnant women, the thyroid dysfunction diminishes as the pregnancy proceeds; consequently, a reduction of dosage may be possible. In some instances, anti-thyroid therapy can be discontinued several weeks or months before delivery. Due to the rare occurrence of congenital malformations associated with methimazole use, it may be appropriate to use an alternative anti-thyroid medication in pregnant women requiring treatment for hyperthyroidism particularly in the first trimester of pregnancy during organogenesis. Given the potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity), it may be preferable to switch from propylthiouracil to methimazole for the second and third trimesters."}', 'pediatric_use': '{"Pediatric Use Because of postmarketing reports of severe liver injury in pediatric patient treated with propylthiouracil, methimazole is the preferred choice when an antithyroid drug is required for a pediatric patient (see DOSAGE AND ADMINISTRATION)."}', 'geriatric_use': None}

{"TIMOLOL MALEATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Timolol GFS is contraindicated in patients with: • bronchial asthma • history of bronchial asthma • severe chronic obstructive pulmonary disease • sinus bradycardia • second or third degree atrioventricular block • overt cardiac failure • cardiogenic shock • hypersensitivity to any component of this product. • Bronchial asthma (or history of) ( 4 ) • Severe chronic obstructive pulmonary disease ( 4 ) • Sinus bradycardia ( 4 ) • Second or third degree atrioventricular block ( 4 ) • Overt cardiac failure ( 4 ) • Cardiogenic shock ( 4 ) • Hypersensitivity to any component of this product ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse reactions (1% to 5%) occur upon instillation and include transient blurred vision, burning, and stinging ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials with Timolol GFS, transient blurred vision upon instillation of the drop was reported in approximately one in three patients. The frequency of patients reporting burning and stinging upon instillation was approximately one in eight patients which was comparable to that observed for TIMOPTIC*. Adverse reactions reported in 1% to 5% of patients were: Ocular: Blepharitis, conjunctivitis, crusting, discomfort, foreign body sensation, hyperemia, pruritus and tearing; Systemic: Headache, hypertension, and upper respiratory infections. In a 3-month, double-masked, active-controlled, multicenter study in pediatric patients, the adverse reactions profile of Timolol GFS 0.25% and 0.5% was comparable to that seen in adult patients. 6.2 Additional Potential Adverse Reactions Associated with Timolol Maleate The following additional adverse experiences have been reported with the ocular administration of this or other timolol maleate formulations: BODY AS A WHOLE Asthenia/fatigue and chest pain. CARDIOVASCULAR Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, dizziness, edema, claudication, Raynaud\'s phenomenon, and cold hands and feet. DIGESTIVE Nausea, diarrhea, dyspepsia, anorexia, and dry mouth. IMMUNOLOGIC Systemic lupus erythematosus. NERVOUS SYSTEM/PSYCHIATRIC Increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including confusion, hallucinations, anxiety, depression, disorientation, nervousness, and memory loss. SKIN Alopecia and psoriasiform rash or exacerbation of psoriasis. HYPERSENSITIVITY Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria and localized and generalized rash. RESPIRATORY Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, and cough. ENDOCRINE Masked symptoms of hypoglycemia in diabetic patients [see Warnings and Precautions (5.5) ] . SPECIAL SENSES Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery [see Warnings and Precautions (5.9 )] ; and tinnitus. UROGENITAL Retroperitoneal fibrosis, decreased libido, impotence and Peyronie\'s disease."}', 'drug_interactions': '{"7 DRUG INTERACTIONS • Oral beta-adrenergic receptor inhibitors may have additive effects ( 7.1 ) • Digitalis and calcium antagonists may have additive effects ( 7.2 ) • Catecholamine-depleting drugs may have additive effects ( 7.3 ) • Quinidine may have additive effects ( 7.4 ) 7.1 Oral Beta-Adrenergic Receptor Inhibitors Patients who are receiving a beta-adrenergic receptor inhibiting agent orally and Timolol GFS should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. Patients should not usually receive two topical ophthalmic beta-adrenergic receptor inhibiting agents concurrently. 7.2 Digitalis and Calcium Antagonists The concomitant use of beta-adrenergic receptor inhibiting agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. Caution should be used in the co-administration of beta-adrenergic receptor inhibitors, such as Timolol GFS, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or hypotension. In patients with impaired cardiac function, co-administration should be avoided. 7.3 Catecholamine-Depleting Drugs Close observation of the patient is recommended when a beta receptor inhibitor is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension. 7.4 Quinidine Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6. 7.5 Clonidine Oral beta-adrenergic receptor inhibiting agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate. 7.6 Injectable Epinephrine Patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions. [See Warnings and Precautions (5.11) ]"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Timolol GFS 0.25% and 0.5% are indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Timolol GFS is a beta adrenergic blocker indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma ( 1 )."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration ( 5.1 ). • Beta-adrenergic receptor inhibitors may mask signs and symptoms of hypoglycemia and should be administered with caution in diabetic patients subject to hypoglycemia ( 5.5 ). • Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism ( 5.6 ). 5.1 Systemic Absorption As with many topically applied ophthalmic drugs, Timolol GFS is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and death due to cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate [see Contraindications (4) ]. 5.2 Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. In patients without a history of cardiac failure, continued depression of the myocardium with beta-adrenergic receptor inhibitors over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Timolol GFS should be discontinued. 5.3 Bronchospasm and Obstructive Pulmonary Disease Bronchospasm may occur. Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which Timolol GFS is contraindicated [see Contraindications (4) ] ) should, in general, not receive beta-adrenergic receptor inhibitors, including Timolol GFS. 5.4 Surgical Anesthesia The necessity or desirability of withdrawal of beta-adrenergic receptor inhibitors prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor inhibitors have experienced protracted, severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. In patients undergoing elective surgery, consider gradual withdrawal of beta-adrenergic receptor inhibitors. If necessary during surgery, the effects of beta-adrenergic receptor inhibitors may be reversed by sufficient doses of adrenergic agonists. 5.5 Diabetes Mellitus Beta-adrenergic receptor inhibitors should be administered with caution in diabetic patients subject to hypoglycemia who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia. 5.6 Thyrotoxicosis Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic receptor inhibitors that might precipitate a thyroid storm. 5.7 Cerebrovascular Insufficiency Because of potential effects of beta-adrenergic receptor inhibitors on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol GFS, alternative therapy should be considered. 5.8 Bacterial Keratitis Bacterial keratitis may occur with use of multiple dose containers of topical ophthalmic products when these containers are inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Instruct patients on appropriate instillation techniques [see Patient Counseling Information (17) ]. 5.9 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant (e.g., timolol) therapy. 5.10 Angle-Closure Glaucoma In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This may require constricting the pupil. Timolol GFS has little or no effect on the pupil and should not be used alone in the treatment of angle-closure glaucoma. 5.11 Atopy/Anaphylaxis While taking beta receptor inhibitors, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions. 5.12 Muscle Weakness Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms."}', 'overdosage': '{"10 OVERDOSAGE No data are available with regard to human overdose with, or accidental oral ingestion of Timolol GFS. There have been reports of inadvertent overdose with Timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic receptor inhibitors such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest [see also Adverse Reactions (6) ]. Overdosage has been reported with timolol maleate tablets. A 30-year old female ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block. An in vitro hemodialysis study, using 14 C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily."}', 'active_flag': 'Y', 'generic_name': '{"TIMOLOL MALEATE"}', 'route': '{OPHTHALMIC}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION How to Use the Timolol GFS solution? The bottle is designed to assure the delivery of a precise dose of medication. Before using your bottle, read the complete instructions carefully. 1. If you use other topically applied ophthalmic medications, they should be administered at least 10 minutes before Timolol GFS. 2. Wash hands before each use. 3. Before using the medication for the first time, be sure the Safety Seal on the bottle is unbroken. 4. Tear off the Safety Seal to break the seal. 5. Before each use, shake once and remove the screw cap. 6. Invert the bottle and hold the bottle between your thumb and middle finger, with the tips of the fingers pointing towards you. 7. Tilt your head back and position the bottle above the affected eye. DO NOT TOUCH THE EYE WITH THE TIP OF THE DROPPER. 8. With the opposite hand, place a finger under the eye. Gently pull down until a \\"V\\" pocket is made between your eye and lower lid. 9. With the hand holding the bottle, place your index finger on the bottom of the bottle. Push the bottom of the bottle to dispense one drop of medication. DO NOT SQUEEZE THE SIDES OF THE BOTTLE. 10. Repeat 6, 7, 8, and 9 with other eye if instructed to do so. 11. Replace screw cap by turning until firmly touching the bottle. Avoiding Contamination of the Product Instruct patients to avoid allowing the tip of the dispensing container to contact the eye(s) or surrounding structures. Advise patients that ocular solutions, if handled improperly, could become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye(s) and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions (5.8) ]. When to Seek Physician Advice Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician\'s advice concerning the continued use of the present multidose container. Administration Instructions Instruct patients to invert the closed container and shake once before each use. It is not necessary to shake the container more than once. Instruct patients requiring concomitant topical ophthalmic medications to administer these at least 10 minutes before instilling Timolol GFS. Asthma, COPD, Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Advise patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure to not use Timolol GFS [see Contraindications (4) ]. Temporary Blurred Vision Advise patients that transient blurred vision or visual disturbance, generally lasting from 30 seconds to 5 minutes, following instillation may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle. *TIMOPTIC is a Registered trademark of Merck & Co., Inc. Manufactured by: Alcon Laboratories, Inc. Fort Worth, Texas 76134 for Sandoz Inc. Princeton, NJ 08540 300066885-0524 bottle eye"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with timolol maleate to inform a drug-associated risk. Administration of oral timolol maleate to pregnant mice, rats and rabbits did not produce teratogenicity at clinically relevant systemic exposures (see Data). Because animal reproductive studies are not always predictive of human response, Timolol GFS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and IOP-lowering effect of Timolol GFS 0.25% and 0.5% have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-controlled trial."}', 'geriatric_use': '{"8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients."}'}

{"CALCIUM CARBONATE",FAMOTIDINE,"MAGNESIUM HYDROXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use relieves heartburn associated with acid indigestion and sour stomach"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"FAMOTIDINE, CALCIUM CARBONATE, MAGNESIUM HYDROXIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • your heartburn continues or worsens • you need to take this product for more than 14 days"}', 'do_not_use': '{"Do not use • if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor. • with other acid reducers"}', 'when_using': None, 'warnings': '{"Warnings Allergy alert: Do not use if you are allergic to famotidine or other acid reducers Do not use • if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor. • with other acid reducers Ask a doctor before use if you have • had heartburn over 3 months. This may be a sign of a more serious condition. • heartburn with lightheadedness, sweating, or dizziness • chest pain or shoulder pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness • frequent chest pain • frequent wheezing, particularly with heartburn • unexplained weight loss • nausea or vomiting • stomach pain • kidney disease Ask a doctor or pharmacist before use if you are taking a prescription drug. Antacids and acid reducers may interact with certain prescription drugs. Stop use and ask a doctor if • your heartburn continues or worsens • you need to take this product for more than 14 days If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BENZALKONIUM CHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Thoroughly wipe hands with wipe. Discard properly. Not flushable. Be sure to close lid to keep wipes moist."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZALKONIUM CHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"For external use only. Flammable. Keep away from heat or flame. Do not use in children less than 2 months of age on open skin wounds When using this product keep out of eyes, ears, and mouth. In case of contact with eyes, rinse thoroughly with water. Stop use and ask a doctor if irritation or rash occurs. These may be signs of a serious condition. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ROSUVASTATIN CALCIUM"}

{'contraindications': '{"4 CONTRAINDICATIONS Rosuvastatin tablets is contraindicated in the following conditions: • Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus,urticaria, and angioedema have been reported with rosuvastatin tablets [ see Adverse Reactions (6.1) ]. • Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [ see Warnings and Precautions ( 5.3 ) ]. • Pregnancy [see Use in Specific Populations (8.1, 8.3 )] • Lactation. Limited data indicate that rosuvastatin tablets is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin tablets treatment should not breastfeed their infants [see Use in Specific Populations (8.2) ]. • Known hypersensitivity to product components ( 4 ) • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 ) • Pregnancy ( 4 , 8.1 , 8.3) • Lactation ( 4 , 8.2)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [ see Warnings and Precautions ( 5.1 )] • Liver enzyme abnormalities [ see Warnings and Precautions ( 5.3 )] Most frequent adverse reactions (rate ≥2%) are headache, myalgia, abdominal pain, asthenia, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In the rosuvastatin tablets controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: • myalgia • abdominal pain • nausea The most commonly reported adverse reactions (incidence ≥ 2%) in the rosuvastatin tablets controlled clinical trial database of 5394 patients were: • headache • myalgia • abdominal pain • asthenia • nausea Adverse reactions reported in ≥2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks. Table 1. Adverse Reactions1 Reported in ≥ 2% of Patients Treated with rosuvastatin tablets and > Placebo in Placebo–Controlled Trials (% of Patients) Adverse Reactions Rosuvastatin tablets 5 mg N=291 Rosuvastatin tablets 10 mg N=283 Rosuvastatin tablets 20 mg N=64 Rosuvastatin tablets 40 mg N=106 Total rosuvastatin tablets 5 mg to 40 mg N=744 Placebo N=382 Headache 5.5 4.9 3.1 8.5 5.5 5.0 Nausea 3.8 3.5 6.3 0 3.4 3.1 Myalgia 3.1 2.1 6.3 1.9 2.8 1.3 Asthenia 2.4 3.2 4.7 0.9 2.7 2.6 Constipation 2.1 2.1 4.7 2.8 2.4 2.4 1 Adverse reactions by COSTART preferred term. Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria,and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [ see Warnings and Precautions ( 5.5 ) ]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In a clinical trial, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin tablets versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased,headache, and nausea. Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2. Table 2. Adverse Reactions 1 Reported in ≥ 2% of Patients Treated with rosuvastatin tablets and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin tablets 40 mg N=700 Placebo N=281 Myalgia 12.7 12.1 Arthralgia 10.1 7.1 Headache 6.4 5.3 Dizziness 4.0 2.8 Increased CPK 2.6 0.7 Abdominal pain 2.4 1.8 ALT >3x ULN 2 2.2 0.7 1 Adverse reactions by MedDRA preferred term. 2 Frequency recorded as abnormal laboratory value. In a clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively,discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation. There was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin treated versus placebo-treated patients [ see Warnings and Precautions ( 5.6 ) ]. Adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 3. Table 3. Adverse Reactions 1 Reported in ≥ 2% of Patients Treated with rosuvastatin tablets and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin tablets 20 mg N=8901 Placebo N=8901 Myalgia 7.6 6.6 Arthralgia 3.8 3.2 Constipation 3.3 3.0 Diabetes mellitus 2.8 2.3 Nausea 2.4 2.3 1 Treatment-emergent adverse reactions by MedDRA preferred term. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin tablets: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares),peripheral neuropathy,interstitial lung disease and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [ see Warnings and Precautions ( 5.2 ) ]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment and confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks)."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Combination of sofosbuvir/velpatasvir/voxilaprevir or ledipasvir/sofosbuvir: Combination increases rosuvastatin tablets exposure. Use with rosuvastatin tablets is not recommended. ( 2.4 , 5.1 , 7.3 , 12.3 ) Cyclosporine and darolutamide : Combination increases rosuvastatin tablets exposure. Limit rosuvastatin tablets dose to 5 mg once daily. ( 2. 4, 5.1 , 7.1 , 7.4 , 12.3 ) Gemfibrozil : Combination should be avoided. If used together, limit rosuvastatin tablets dose to 10 mg once daily. (2.4, 5.1 , 7.2 ) Atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir: Combination increases rosuvastatin tablets exposure. Limit rosuvastatin tablets dose to 10 mg once daily. ( 2.4 , 5.1 , 7.3 , 12.3 ) Regorafenib: Combination increases rosuvastatin exposure. Limit rosuvastatin tablets dose to 10 mg once daily.( 2.4 , 5.1 , 7.5 ) Coumarin anticoagulants : Combination prolongs INR. Achieve stable INR prior to starting rosuvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of rosuvastatin tablets therapy. ( 5.4 , 7.6 ) Concomitant lipid-lowering therapies : Use with fibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with rosuvastatin tablets. ( 5.1 , 7.7 , 7.8 ) 7.1 Cyclosporine Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of rosuvastatin tablets should not exceed 5 mg once daily [ see Dosage and Administration (2.4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ]. 7.2 Gemfibrozil Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis,combination therapy with rosuvastatin tablets and gemfibrozil should be avoided. If used together, the dose of rosuvastatin tablets should not exceed 10 mg once daily [ see Clinical Pharmacology (12.3) ]. 7.3 Anti-viral Medications Coadministration of rosuvastatin with certain anti-viral drugs has differing effects on rosuvastatin exposure and may increase risk of myopathy. The combination of sofosbuvir/velpatasvir/voxilaprevir which are anti-Hepatitis C virus (anti-HCV) drugs, increases rosuvastatin exposure. Similarly, the combination of ledipasvir/sofosbuvir may significantly increase rosuvastatin exposure. For these combinations of anti-HCV drugs, concomitant use with rosuvastatin tablets is not recommended. Simeprevir and combinations of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir which are anti-HCV drugs, increase rosuvastatin exposure. Combinations of atazanavir/ritonavir and lopinavir/ritonavir, which are anti-HIV-1 drugs, increase rosuvastatin exposure [see Table 4 – Clinical Pharmacology ( 12.3 )] . For these anti-viral drugs, the dose of rosuvastatin tablets should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure. No dose adjustment is needed for concomitant use with these combinations [see Dosage and Administration ( 2.4 ) , Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . 7.4 Darolutamide Darolutamide increased rosuvastatin exposure more than 5 fold. Therefore, in patients taking darolutamide, the dose of rosuvastatin tablets should not exceed 5 mg once daily [see Dosage and Administration ( 2.4 ) , Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . 7.5 Regorafenib Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. If used together, the dose of rosuvastatin tablets should not exceed 10 mg once daily [see Dosage and Administration ( 2.4 ) , Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. 7.6 Coumarin Anticoagulants Rosuvastatin tablets significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin tablets. In patients taking coumarin anticoagulants and rosuvastatin tablets concomitantly, INR should be determined before starting rosuvastatin tablets and frequently enough during early therapy to ensure that no significant alteration of INR occurs [ see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 ) ]. 7.7 Niacin The risk of skeletal muscle effects may be enhanced when rosuvastatin tablets is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin tablets [ see Warnings and Precautions (5.1) ]. 7.8 Fenofibrate When rosuvastatin tablets was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with rosuvastatin tablets [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.9 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with HMG–CoA reductase inhibitors, including rosuvastatin,coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin tablets with colchicine [ see Warnings and Precautions (5.1) ]."}', 'indications_and_usage': '{"1 INDICATIONS & USAGE Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Rosuvastatin tablets is an HMG Co-A reductase inhibitor indicated for: adult patients with hypertriglyceridemia as an adjunct to diet ( 1. 3) adult patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet ( 1. 4) adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total-C, and ApoB ( 1. 5)Limitations of use ( 1. 8): Rosuvastatin tablets has not been studied in Fredrickson Type I and V dyslipidemias. 1.3 Hypertriglyceridemia Rosuvastatin tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). 1.5 Adult Patients with Homozygous Familial Hypercholesterolemia Rosuvastatin tablets are indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL–C, Total–C, and ApoB in adult patients with homozygous familial hypercholesterolemia. 1.8 Limitations of Use Rosuvastatin tablets has not been studied in Fredrickson Type I and V dyslipidemias."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis) : Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, darolutamide, regorafenib, certain anti-viral medicines or their combinations. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue rosuvastatin tablets if signs or symptoms appear. ( 5.1 , 7.4 , 7.5 , 7.7 , 7.8 ) • Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. ( 5.2 ) • Liver enzyme abnormalities : Persistent elevations in hepatic transaminases can occur. Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3 ) 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin tablets. These risks can occur at any dose level, but are increased at the highest dose (40 mg). Rosuvastatin tablets should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with rosuvastatin tablets may be increased with concurrent administration of gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir) [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )] . Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin tablets with colchicine [see Drug Interactions ( 7.9 )] . Rosuvastatin tablets therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin tablets therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin tablets. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM. 5.3 Liver Enzyme Abnormalities It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin tablets, and if signs or symptoms of liver injury occur. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG–CoA reductase inhibitors, including rosuvastatin tablets. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin tablets therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin tablets versus 0.5% of patients treated with placebo. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin tablets, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin tablets. Rosuvastatin tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [ see Clinical Pharmacology ( 12.3 )]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin tablets [ see Contraindications ( 4 ) ]. 5.4 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin tablets because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin tablets concomitantly, INR should be determined before starting rosuvastatin tablets and frequently enough during early therapy to ensure that no significant alteration of INR occurs [ see Drug Interactions ( 7.6 )] 5.5 Proteinuria and Hematuria In the rosuvastatin tablets clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin tablets treated patients. These findings were more frequent in patients taking rosuvastatin tablets 40 mg, when compared to lower doses of rosuvastatin tablets or comparator HMG–CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin tablets therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing. 5.6 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG–CoA reductase inhibitors, including rosuvastatin tablets. Based on clinical trial data with rosuvastatin tablets, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [ see Adverse Reactions ( 6.1 ) ]. Although clinical studies have shown that rosuvastatin tablets alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin tablets is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine."}', 'overdosage': '{"10 OVERDOSAGE There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin."}', 'active_flag': 'Y', 'generic_name': '{"ROSUVASTATIN CALCIUM"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients should be instructed not to take 2 doses of rosuvastatin tablets within 12 hours of each other. Skeletal Muscle Effects Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin tablets. Concomitant Use of Antacids When taking rosuvastatin tablets with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin tablets administration. Embryofetal Toxicity Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy. [see Contraindications (4) and Use in Specific Populations ( 8.1 , 8.3 )]. Lactation Advise women not to breastfeed during treatment with rosuvastatin tablets [see Contraindications (4) and Use in Specific Populations (8.2) ]. Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin tablets and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin tablets should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Manufactured by: Alkem Laboratories Ltd., INDIA. Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: November, 2021 PT2180-07"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Rosuvastatin tablets is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin tablets during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin tablets may cause fetal harm when administered to pregnant women. rosuvastatin tablets should be discontinued as soon as pregnancy is recognized [see Contraindications (4) ] . Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively). In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Animal Data Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18. Rosuvastatin administration did not indicate a teratogenic effect in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body surface area, respectively). In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC). In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area). In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area)."}', 'pediatric_use': '{"8.4 Pediatric Use Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information."}', 'geriatric_use': '{"8.5 Geriatric Use Of the 10,275 patients in clinical studies with rosuvastatin tablets, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are at higher risk of myopathy and rosuvastatin tablets should be prescribed with caution in the elderly [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]."}'}

{"FLUTICASONE PROPIONATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Fluticasone propionate nasal spray is contraindicated in patients with hypersensitivity to any of its ingredients [see Warnings and Precautions (5.3) , Description (11)] . Hypersensitivity to any ingredient. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Systemic and local corticosteroid use may result in the following: • Epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, and impaired wound healing [see Warnings and Precautions (5.1)] • Glaucoma and cataracts [see Warnings and Precautions (5.2)] • Immunosuppression [see Warnings and Precautions (5.4)] • Hypercorticism and adrenal suppression [see Warnings and Precautions (5.5)] • Effect on growth [see Warnings and Precautions (5.7)] The most common adverse reactions (>3%) are headache, pharyngitis, epistaxis, nasal burning/nasal irritation, nausea/vomiting, asthma symptoms, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In controlled US clinical trials, more than 3,300 subjects with allergic and nonallergic rhinitis received treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical trials have been primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were reported with approximately the same frequency by subjects treated with placebo. Less than 2% of subjects in clinical trials discontinued because of adverse reactions; this rate was similar for vehicle placebo and active comparators. The safety data described below are based on 7 placebo-controlled clinical trials in subjects with allergic rhinitis. The 7 trials included 536 subjects (57 girls and 108 boys aged 4 to 11 years, 137 female and 234 male adolescents and adults) treated with fluticasone propionate nasal spray 200 mcg once daily over 2 to 4 weeks and 2 placebo-controlled clinical trials which included 246 subjects (119 female and 127 male adolescents and adults) treated with fluticasone propionate nasal spray 200 mcg once daily over 6 months (Table 1). Also included in Table 1 are adverse reactions from 2 trials in which 167 children (45 girls and 122 boys aged 4 to 11 years) were treated with fluticasone propionate nasal spray 100 mcg once daily for 2 to 4 weeks. Table 1: Adverse Reactions with Fluticasone Propionate Nasal Spray with >3% Incidence and More Common than Placebo in Subjects ≥ 4 Years with Allergic Rhinitis Adverse Reaction Fluticasone Propionate 100 mcg Once Daily (N = 167) % Fluticasone Propionate 200 mcg Once Daily (N = 782) % Placebo (N = 758) % Headache 6.6 16.1 14.6 Pharyngitis 6 7.8 7.2 Epistaxis 6 6.9 5.4 Nasal Burning/Nasal Irritation 2.4 3.2 2.6 Nausea/Vomiting 4.8 2.6 2 Asthma Symptoms 7.2 3.3 2.9 Cough 3.6 3.8 2.8 Other adverse reactions with fluticasone propionate nasal spray observed with an incidence less than or equal to 3% but greater than or equal to 1% and more common than with placebo included: blood in nasal mucus, runny nose, abdominal pain, diarrhea, fever, flu-like symptoms, aches and pains, dizziness, and bronchitis. 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following adverse events have been identified during postapproval use of intranasal fluticasone propionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate or a combination of these factors. General Disorders and Administration Site Conditions : Hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions, which in rare instances were severe. Ear and Labyrinth Disorders : Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes. Eye Disorders : Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and cataracts. Cases of growth suppression have been reported for intranasal corticosteroids, including fluticasone propionate nasal spray [see Warnings and Precautions (5.7)] ."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid effects. ( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, nefazodone, voriconazole) with fluticasone propionate nasal spray is not recommended because increased systemic corticosteroid adverse effects may occur. Ritonavir : A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate products, including fluticasone propionate nasal spray, with ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole : Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Fluticasone propionate nasal spray is indicated for the management of the nasal symptoms of perennial nonallergic rhinitis in adults and pediatric patients aged 4 years and older. Fluticasone propionate nasal spray is a corticosteroid indicated for the management of the nasal symptoms of perennial nonallergic rhinitis in adult and pediatric patients aged 4 years and older. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, and impaired wound healing. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma. ( 5.1 ) • Glaucoma and cataracts: Consider referral to an ophthalmologist in patients who develop ocular symptoms or use fluticasone propionate nasal spray long-term. ( 5.2 ) • Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, and rash) have been reported after administration of fluticasone propionate nasal spray. Discontinue fluticasone propionate nasal spray if such reactions occur. ( 5.3 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.4 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue fluticasone propionate nasal spray slowly. ( 5.5 ) • Monitor growth of pediatric patients. ( 5.7 ) 5.1 Local Nasal Effects Epistaxis : In clinical trials of 2 to 26 weeks’ duration, epistaxis was observed more frequently in subjects treated with fluticasone propionate nasal spray than those who received placebo [see Adverse Reactions (6.1)] . Nasal Ulceration : Postmarketing cases of nasal ulceration have been reported in patients treated with fluticasone propionate nasal spray [see Adverse Reactions (6.2)] . Candida Infection : In clinical trials with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of fluticasone propionate nasal spray. Patients using fluticasone propionate nasal spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Nasal Septal Perforation : Postmarketing cases of nasal septal perforation have been reported in patients treated with fluticasone propionate nasal spray [see Adverse Reactions (6.2)] . Impaired Wound Healing : Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid using fluticasone propionate nasal spray until healing has occurred. 5.2 Glaucoma and Cataracts Use of intranasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use fluticasone propionate nasal spray long-term . 5.3 Hypersensitivity Reactions including Anaphylaxis Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, and rash) have been reported after administration of fluticasone propionate nasal spray. Discontinue fluticasone propionate nasal spray if such reactions occur [see Contraindications (4)] . Rarely, immediate hypersensitivity reactions may occur after the administration of fluticasone propionate nasal spray. 5.4 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the complete prescribing information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered. Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.5 Hypercorticism and Adrenal Suppression When intranasal corticosteroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of fluticasone propionate nasal spray should be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid therapy. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression). Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. 5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, nefazodone, voriconazole) with fluticasone propionate nasal spray is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] . 5.7 Effect on Growth Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients [see Use in Specific Populations (8.4)]. Monitor the growth routinely of pediatric patients receiving fluticasone propionate nasal spray. To minimize the systemic effects of intranasal corticosteroids, including fluticasone propionate nasal spray, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2), Use in Specific Populations (8.4)]."}', 'overdosage': '{"10 OVERDOSAGE Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days was administered to healthy human volunteers. Adverse events reported with fluticasone propionate were similar to placebo, and no clinically significant abnormalities in laboratory safety tests were observed. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. Acute overdosage with this dosage form is unlikely since one bottle of fluticasone propionate nasal spray contains approximately 8 mg of fluticasone propionate."}', 'active_flag': 'Y', 'generic_name': '{"FLUTICASONE PROPIONATE"}', 'route': '{NASAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Local Nasal Effects : Inform patients that treatment with fluticasone propionate nasal spray may lead to adverse reactions, which include epistaxis and nasal ulceration. Candida infection may also occur with treatment with fluticasone propionate nasal spray. In addition, fluticasone propionate nasal spray has been associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use fluticasone propionate nasal spray until healing has occurred [see Warnings and Precautions (5.1)] . Glaucoma and Cataracts : Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Advise patients to notify their healthcare providers if a change in vision is noted while using fluticasone propionate nasal spray [see Warnings and Precautions (5.2)] . Hypersensitivity Reactions, including Anaphylaxis : Inform patients that hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, contact dermatitis, and rash, may occur after administration of fluticasone propionate nasal spray. If such reactions occur, patients should discontinue use of fluticasone propionate nasal spray [see Warnings and Precautions (5.3)]. Immunosuppression : Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and if they are exposed to consult their healthcare provider without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex [see Warnings and Precautions (5.4)] . Reduced Growth Velocity : Advise parents that fluticasone propionate nasal spray may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.7), Pediatric Use (8.4)] . Use Daily for Best Effect : Inform patients that they should use fluticasone propionate nasal spray on a regular basis. Fluticasone propionate nasal spray, like other corticosteroids, does not have an immediate effect on rhinitis symptoms. Maximum benefit may not be reached for several days. Patients should not increase the prescribed dosage but should contact their healthcare providers if symptoms do not improve or if the condition worsens. Keep Spray Out of Eyes and Mouth : Inform patients to avoid spraying fluticasone propionate nasal spray in their eyes and mouth. Distr. by: West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724 10002064/10 Revised December 2019","Patient Information Fluticasone Propionate Nasal Spray USP, 50 mcg (floo tik’ a sone proe’ pee oh nate) What is fluticasone propionate nasal spray? Fluticasone propionate nasal spray is a prescription medicine used to treat non-allergy nasal symptoms such as runny nose, stuffy nose, sneezing, and nasal itching in adults and children aged 4 years and older. It is not known if fluticasone propionate nasal spray is safe and effective in children younger than 4 years of age. Do not use fluticasone propionate nasal spray if you are allergic to fluticasone propionate or any of the ingredients in fluticasone propionate nasal spray. See “What are the ingredients in fluticasone propionate nasal spray?” below for a complete list of ingredients. Before using fluticasone propionate nasal spray, tell your healthcare provider about all of your medical conditions, including if you: • have or have had nasal sores, nasal surgery, or nasal injury. • have or have had eye problems, such as glaucoma or cataracts. • have an immune system problem. • have any type of viral, bacterial, or fungal infection. • are exposed to chickenpox or measles. • are pregnant or planning to become pregnant. It is not known if fluticasone propionate nasal spray may harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if fluticasone propionate nasal spray passes into your breast milk and if it can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Fluticasone propionate nasal spray and certain other medicines may interact with each other. This may cause serious side effects. Especially, tell your healthcare provider if you take antifungal or anti-HIV medicines. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use fluticasone propionate nasal spray? Read the step-by-step instructions for using fluticasone propionate nasal spray at the end of this Patient Information. • Fluticasone propionate nasal spray is for use in your nose only. Do not spray it in your eyes or mouth. • Children should use fluticasone propionate nasal spray with an adult’s help, as instructed by the child’s healthcare provider. • Use fluticasone propionate nasal spray exactly as your healthcare provider tells you. Do not use fluticasone propionate nasal spray more often than prescribed. • Fluticasone propionate nasal spray may take several days of regular use for your rhinitis symptoms to get better. If your symptoms do not improve or get worse, call your healthcare provider. • You will get the best results if you keep using fluticasone propionate nasal spray regularly each day without missing a dose. After you begin to feel better, your healthcare provider may decrease your dose. Do not stop using fluticasone propionate nasal spray unless your healthcare provider tells you to do so. What are the possible side effects of fluticasone propionate nasal spray? Fluticasone propionate nasal spray may cause serious side effects, including: • nose problems. Nose problems may include: • nose bleeds. • sores (ulcers) in your nose. • a certain fungal infection in your nose, mouth, or throat (thrush). • hole in the cartilage of your nose (nasal septal perforation). Symptoms of nasal septal perforation may include: • crusting in the nose • nose bleeds • runny nose • whistling sound when you breathe • slow wound healing. You should not use fluticasone propionate nasal spray until your nose has healed if you have a sore in your nose, have had surgery on your nose, or if your nose has been injured. • glaucoma and cataracts. Using nasal and inhaled corticosteroid medicines may result in you developing glaucoma and/or cataracts. Your healthcare provider may have you see an eye doctor (ophthalmologist) if you develop eye symptoms or use fluticasone propionate nasal spray for long periods of time. Tell your healthcare provider if you have any changes in your eye sight while using fluticasone propionate nasal spray. • serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following signs of a serious allergic reaction: • rash • hives • swelling of your face, mouth, and tongue • breathing problems • weakened immune system and increased chance of getting infections (immunosuppression). Taking medicines that weaken your immune system makes you more likely to get infections and can make certain infections worse. These infections may include tuberculosis (TB), ocular herpes simplex infections, and infections caused by fungi, bacteria, viruses, and parasites. Avoid contact with people who have a contagious disease such as chickenpox or measles while using fluticasone propionate nasal spray. If you come in contact with someone who has chickenpox or measles call your healthcare provider right away. Symptoms of an infection may include: • fever • feeling tired • pain • nausea • aches • vomiting • chills • lowered steroid hormone levels (adrenal insufficiency). Adrenal insufficiency happens when your adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines (such as prednisone) and start taking medicine containing an inhaled steroid (such as fluticasone propionate nasal spray). Symptoms of adrenal insufficiency may include: • feeling tired • lack of energy • weakness • nausea and vomiting • low blood pressure • slowed growth in children. A child’s growth should be checked often. The most common side effects of fluticasone propionate nasal spray include: • headache • nausea and vomiting • sore throat • trouble breathing • nose bleeds • cough • nose burning or itching These are not all the possible side effects with fluticasone propionate nasal spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store Fluticasone Propionate Nasal Spray? • Store fluticasone propionate nasal spray between 39° and 86°F (4° and 30°C). Keep fluticasone propionate nasal spray and all medicines out of the reach of children. General information about the safe and effective use of fluticasone propionate nasal spray. Medicines are sometimes prescribed for purposes not mentioned in a Patient Information leaflet. Do not use fluticasone propionate nasal spray for a condition for which it was not prescribed. Do not give your fluticasone propionate nasal spray to other people, even if they have the same condition that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about fluticasone propionate nasal spray that was written for healthcare professionals. What are the ingredients in fluticasone propionate nasal spray USP? Active ingredient: fluticasone propionate USP. Inactive ingredients: 0.02% w/w benzalkonium chloride, dextrose, microcrystalline cellulose and carboxymethylcellulose sodium, 0.25% w/w phenylethyl alcohol and polysorbate 80. For more information about fluticasone propionate nasal spray, call 1-800-962-8364. Distr. by: West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724 10002064/10 Revised December 2019"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are insufficient data on the use of fluticasone propionate nasal spray in pregnant women to inform a drug-associated risk. In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, were observed in rats, mice, and rabbits with subcutaneously administered maternal toxic doses of fluticasone propionate 5 times, equivalent to, and less than the maximum recommended human daily intranasal dose (MRHDID) on a mcg/m 2 basis, respectively. ( See Animal Data. ) However, fluticasone propionate administered via nose-only inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose equivalent to the MRHDID on a mcg/m 2 basis. ( See Animal Data. ) Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data : Following inhaled administration, fluticasone propionate was detected in the neonatal cord blood after delivery. Animal Data: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 5 times the MRHDID of 200 mcg/day (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed at approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.3 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the nose-only inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal nose-only inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.25 times the MRHDID (on a mcg/m 2 basis with a maternal nose-only inhalation dose of 5.5 mcg/kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.06 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose 0.39 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.01 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 2 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day)."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of fluticasone propionate nasal spray in children aged 4 years and older have been established [ see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) ]. Six hundred fifty (650) subjects aged 4 to 11 years and 440 subjects aged 12 to 17 years were studied in US clinical trials with fluticasone propionate nasal spray. The safety and effectiveness of fluticasone propionate nasal spray in children younger than 4 years have not been established. Effects on Growth: Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including fluticasone propionate nasal spray, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of intranasal corticosteroids, including fluticasone propionate nasal spray, each patient’s dosage should be titrated to the lowest dosage that effectively controls his/her symptoms. A 1-year placebo-controlled trial was conducted in 150 pediatric subjects (aged 3 to 9 years) to assess the effect of fluticasone propionate nasal spray (single daily dose of 200 mcg) on growth velocity. From the primary population receiving fluticasone propionate nasal spray (n=56) and placebo (n=52), the point estimate for growth velocity with fluticasone propionate nasal spray was 0.14 cm/year lower than placebo (95% CI:-0.54, 0.27 cm/year). Thus, no statistically significant effect on growth was noted compared with placebo. No evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as assessed by 12-hour urinary cortisol excretion and dual-energy x-ray absorptiometry, respectively. The potential for fluticasone propionate nasal spray to cause growth suppression in susceptible patients or when given at higher than recommended dosages cannot be ruled out."}', 'geriatric_use': '{"8.5 Geriatric Use A limited number of subjects aged 65 years and older (n=129) or 75 years and older (n=11) have been treated with fluticasone propionate nasal spray in clinical trials. While the number of subjects is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}'}

{"SILDENAFIL CITRATE"}

{'contraindications': '{"4. CONTRAINDICATIONS Use with organic nitrates or riociguat ( 4 ) History of hypersensitivity reaction to sildenafil or any component of the tablet ( 4 ) Sildenafil tablets are contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.2) ]. Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil."}', 'adverse_reactions': '{"6. ADVERSE REACTIONS Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 888-413-0949 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse events are discussed elsewhere in the labeling: Mortality with pediatric use [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] Hypotension [see Warnings and Precautions (5.2) ] Vision loss [see Warnings and Precautions (5.5) ] Hearing loss [see Warnings and Precautions (5.6) ] Priapism [see Warnings and Precautions (5.8) ] Vaso-occlusive crisis [see Warnings and Precautions (5.9) ] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data of sildenafil tablets in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil tablets-treated patients with PAH, WHO Group I. [see Clinical Studies (14) ]. The overall frequency of discontinuation in sildenafil tablets-treated patients on 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil tablets-treated patients (20 mg three times a day) and were more frequent in sildenafil tablets-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil tablets-Treated Patients than Placebo-Treated Patients and Incidence ≥ 3% in Sildenafil tablets-Treated Patients) Placebo, % (n = 70) Sildenafil 20 mg three times a day, % (n = 69) Placebo-Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil tablets 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil tablets doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil tablets versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil tablets (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil tablets + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14) ]. Table 2. Adverse Reactions (%) in patients with PAH in Study 2(incidence in Sildenafil tablets + Epoprostenol group at least 6% greater than Epoprostenol group) ^includes peripheral edema Sildenafil tablets + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil tablets + Epoprostenol) minus Epoprostenol Headache 57 34 23 Edema^ 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient\'s underlying cardiovascular disease, or to a combination of these or other factors. Nervous system Seizure, seizure recurrence Ophthalmologic NAION [see Warnings and Precautions (5.5) and Patient Counseling Information (17) ]."}', 'drug_interactions': '{"7. DRUG INTERACTIONS Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. ( 7 ) Use with ritonavir and other potent CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. ( 5.7 ). Nitrates Concomitant use of sildenafil tablets with nitrates in any form is contraindicated [see Contraindications (4) ]. Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil tablets with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3) ]. Other drugs that reduce blood pressure Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil tablets [see Warnings and Precautions (5.2) ]."}', 'indications_and_usage': '{"1. INDICATIONS AND USAGE Sildenafil tablets are phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). ( 1 ) Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. ( 1 , 14 ) Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when Sildenafil tablets were added to background epoprostenol therapy [see Clinical Studies (14) ]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14) ]."}', 'warnings_and_cautions': '{"5. WARNINGS AND PRECAUTIONS Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. ( 5.1 ) Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.2 ) Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. ( 5.3 ) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.5 , 5.6 ) Pulmonary hypertension secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. ( 5.9 ) 5.1 Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil tablets dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil tablets, particularly chronic use, is not recommended in children. [see Use in Specific Populations (8.4) ]. 5.2 Hypotension Sildenafil tablets has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil tablets, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil tablets. 5.3 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil tablets to patients with veno-occlusive disease, administration of sildenafil tablets to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil tablets are administered, consider the possibility of associated PVOD. 5.4 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil tablets with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil tablets 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil tablets-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil tablets is unknown in patients with bleeding disorders or active peptic ulceration. 5.5 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (\\"crowded disc\\"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [see Adverse Reactions (6.2) ]. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil tablets. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil tablets with caution in these patients. 5.6 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil tablets. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Sildenafil tablets, to the patient\'s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil tablets. 5.7 Combination with other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA ® ;. The safety and efficacy of combinations of sildenafil tablets with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors. 5.8 Priapism Use sildenafil tablets with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie\'s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil tablets than by those randomized to placebo. The effectiveness and safety of sildenafil tablets in the treatment of PAH secondary to sickle cell anemia has not been established."}', 'overdosage': '{"10. OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine."}', 'active_flag': 'Y', 'generic_name': '{SILDENAFIL}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information ). Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets. These events may be accompanied by tinnitus and dizziness."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (See Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)."}', 'pediatric_use': '{"8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil tablets, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil tablets on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil tablets did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil tablets remained on his/her dose of sildenafil tablets or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil tablets. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Tablets Dose During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil tablets doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil tablets, particularly chronic use, is not recommended in children. Graph"}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of sildenafil tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ]."}'}

{"DULOXETINE HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with Duloxetine delayed-release capsules or within 5 days of stopping treatment with Duloxetine delayed-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of Duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated [see Dosage and Administration (2.8) and Warnings and Precautions (5.4) ]. Starting Duloxetine delayed-release capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.9) and Warnings and Precautions (5.4) ]. Concomitant use of an MAOI antidepressant with Duloxetine delayed-release capsules is contraindicated Use of Duloxetine delayed-release capsules within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid- or intravenous methylene blue-treated patients, initiation of Duloxetine delayed-release capsules is contraindicated ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3) ] Serotonin Syndrome [see Warnings and Precautions (5.4) ] Increased Risk of Bleeding [see Warnings and Precautions (5.5) ] Severe Skin Reactions [see Warnings and Precautions (5.6) ] Discontinuation Syndrome [see Warnings and Precautions (5.7) ] Activation of Mania/Hypomania [see Warnings and Precautions (5.8) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Increases in Blood Pressure [see Warnings and Precautions (5.11) ] Clinically Important Drug Interactions [see Warnings and Precautions (5.12) ] Hyponatremia [see Warnings and Precautions (5.13) ] Urinary Hesitation and Retention [see Warnings and Precautions (5.15) ] Sexual Dysfunction [see Warnings and Precautions (5.16) ] Most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients): ( 6.1 ) Adults : nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis Pediatric Patients : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received Duloxetine delayed-release capsules dosages of a total of 60 to 120 mg per day [see Clinical Studies (14) ] . The data below do not include results of the trial that evaluated the efficacy of Duloxetine delayed-release capsules for the treatment of GAD in patients ≥65 years old (Study GAD-5) [see Clinical Studies (14.3) ] ; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population. Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8.4% (319/3779) of duloxetine-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (Duloxetine 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo-treated patients). Generalized Anxiety Disorder Approximately 13.7% (139/1018) of the duloxetine-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3.3%, placebo 0.4%), and dizziness (Duloxetine 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain Approximately 12.9% (117/906) of the duloxetine-treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3.5%, placebo 0.7%), dizziness (Duloxetine 1.2%, placebo 0.4%), and somnolence (Duloxetine 1.1%, placebo 0%). Fibromyalgia Approximately 17.5% (227/1294) of the duloxetine-treated patients in 3- to 6-month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 2.0%, placebo 0.5%), headache (Duloxetine 1.2%, placebo 0.3%), somnolence (Duloxetine 1.1%, placebo 0%), and fatigue (Duloxetine 1.1%, placebo 0.1%). Chronic Pain due to Osteoarthritis Approximately 15.7% (79/503) of the duloxetine-treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 2.2%, placebo 1%). Chronic Low Back Pain Approximately 16.5% (99/600) of the duloxetine-treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3%, placebo 0.7%), and somnolence (Duloxetine 1%, placebo 0%). Most Common Adverse Reactions in Adult Trials The most commonly observed adverse reactions in Duloxetine delayed-release capsules-treated patients (as defined above) were: Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. The most commonly observed adverse reactions in Duloxetine delayed-release capsules-treated patients in all the pooled adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of duloxetine-treated patients and with an incidence greater than placebo-treated patients. Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations Includes adults with MDD, GAD, DPNP, FM, and chronic musculoskeletal pain. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N=8100) Placebo (N=5655) Nausea Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. 23 8 Headache 14 12 Dry mouth 13 5 Somnolence Also includes hypersomnia and sedation. 10 3 Fatigue Also includes asthenia. , 9 5 Insomnia Also includes initial insomnia, middle insomnia, and early morning awakening. 9 5 Constipation 9 4 Dizziness 9 5 Diarrhea 9 6 Decreased appetite 7 2 Hyperhidrosis 6 1 Abdominal pain Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. 5 4 Adverse Reactions in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of duloxetine-treated patients and with an incidence greater than placebo-treated patients. Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. , For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years. System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N=4797) Placebo (N=3303) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. 23 8 Dry mouth 14 6 Constipation 9 4 Diarrhea 9 6 Abdominal pain Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue Includes asthenia. 9 5 Metabolism and Nutrition Disorders Decreased appetite 6 2 Nervous System Disorders Headache 14 14 Dizziness 9 5 Somnolence Includes hypersomnia and sedation. 9 3 Tremor 3 1 Psychiatric Disorders Insomnia Includes initial insomnia, middle insomnia, and early morning awakening. 9 5 Agitation Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayed 2 1 Libido decreased Includes loss of libido. 3 1 Orgasm abnormal Includes anorgasmia. 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials Table 4 displays the incidence of adverse reactions that occurred in 2% or more of Duloxetine delayed-release capsules-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients. Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N=3303) Placebo (N=2352) Gastrointestinal Disorders Nausea 23 7 Dry Mouth Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. 11 3 Constipation 10 3 Diarrhea 9 5 Abdominal Pain Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness and gastrointestinal pain. 5 4 Vomiting 3 2 Dyspepsia 2 1 General Disorders and Administration Site Conditions Fatigue Includes asthenia. 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decreased Appetite 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain Includes myalgia and neck pain. 3 3 Muscle Spasms 2 2 Nervous System Disorders Headache 13 8 Somnolence , Includes hypersomnia and sedation. 11 3 Dizziness 9 5 Paraesthesia Includes hypoaesthesia, facial hypoaesthesia, genital hypoaesthesia and oral paraesthesia. 2 2 Tremor 2 <1 Psychiatric Disorders Insomnia , Includes initial insomnia, middle insomnia, and early morning awakening. 10 5 Agitation Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. 3 1 Reproductive System and Breast Disorders Erectile Dysfunction 4 <1 Ejaculation Disorder Includes ejaculation failure. 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing Includes hot flush. 3 1 Blood pressure increased Includes increased diastolic blood pressure, increased systolic blood pressure, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension. 2 1 Effects on Male and Female Sexual Function in Adults with MDD Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials (Studies MDD-1, MDD-2, MDD-3, and MDD-4) [see Clinical Studies (14.2) ]. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. In these trials, Duloxetine delayed-release capsules-treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5 ). Duloxetine delayed-release capsules- treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in Duloxetine delayed-release capsules-treated patients. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials Male Patients n=Number of patients with non-missing change score for ASEX total. Female Patients Duloxetine delayed-release capsules (n=175) Placebo (n=83) Duloxetine delayed-release capsules (n=241) Placebo (n=126) ASEX Total (Items 1-5) 0.56 p=0.013 versus placebo. -1.07 -1.15 -1.07 Item 1- Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 - Arousal 0.01 -0.26 -0.21 -0.18 Item 3 - Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 - Ease of reaching orgasm 0.40 p<0.001 versus placebo. -0.24 -0.09 -0.13 Item 5 - Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3 , 5.11) ]. Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). Laboratory Changes in Adults Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2) ]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Duloxetine delayed-release capsules-treated patients compared to placebo-treated patients. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine in Adults Following is a list of adverse reactions reported by patients treated with duloxetine in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine. Of these, 27% (9337) took duloxetine for at least 6 months, and 12% (4317) took duloxetine at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy. Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders — Infrequent: hypothyroidism. Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment. Gastrointestinal Disorders — Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer. General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance. Infections and Infestations — Infrequent: gastroenteritis and laryngitis. Investigations — Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders — Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia. Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders — Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria. Psychiatric Disorders — Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide. Renal and Urinary Disorders — Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder. Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness. Skin and Subcutaneous Tissue Disorders — Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis. Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients Pediatric Clinical Trial Database The data described below reflect exposure to duloxetine (N=567) in pediatric patients aged 7 to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo- controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91). Duloxetine delayed-release capsules are not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4) ] . Of the duloxetine-treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 to 120 mg of Duloxetine delayed-release capsules per day during placebo-controlled acute treatment studies. In the pediatric MDD, GAD, and fibromyalgia trials up to 40 weeks long, there were 988 duloxetine-treated pediatric patients aged 7 to 17 years of age (most patients received 30-120 mg per day) – 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female. Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions (≥5% in duloxetine-treated patients and at least twice the incidence of placebo- treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea. Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD The adverse reaction profile observed in clinical trials in pediatric patients aged 7 to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials. The most common (≥5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness. Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with Duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo. Duloxetine delayed-release capsules are not approved in the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4) ]. Table 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in Three 10-week Pediatric Placebo-Controlled Trials in MDD and GAD Duloxetine delayed-release capsules are not approved for the treatment of pediatric MDD [see Use in Specific Populations (8.4) ]. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. System Organ Class / Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine delayed-release capsules (N=476) Placebo (N=362) Gastrointestinal Disorders Nausea 18 8 Abdominal Pain Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. 13 10 Vomiting 9 4 Diarrhea 6 3 Dry Mouth 2 1 General Disorders and Administration Site Conditions Fatigue Also includes asthenia. 7 5 Investigations Decreased Weight Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 Duloxetine delayed-release capsules; N=354 Placebo). 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence Also includes hypersomnia and sedation. 11 6 Dizziness 8 4 Psychiatric Disorders Insomnia Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain 4 2 Cough 3 1 Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (Duloxetine delayed-release capsules is not approved to treat pediatric patients with MDD). The most commonly reported symptoms following discontinuation of Duloxetine delayed-release capsules in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7) ]. Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Duloxetine delayed-release capsules-treated pediatric patients in clinical trials experienced a 0.1 kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the Duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, Duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, Duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to 17 years of age). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients 7 to 11 years of age and increase of 0.3% in patients 12 to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with Duloxetine delayed-release capsules [see Use in Specific Populations (8.4) ]. Adverse Reactions in Pediatric Patients Aged 13 to 17 Years Old with Fibromyalgia Table 7 provides the incidence of adverse reactions in a fibromyalgia pediatric placebo-controlled trial (Study FM-4) that occurred in greater than 5% of patients treated with Duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo [see Clinical Studies (14.5) ]. Table 7: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in a 13-week Placebo-Controlled Trial in Pediatric Patients 13 to 17 Years Old with Fibromyalgia (Study FM-4) The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. Duloxetine delayed-release capsules (N=91) Placebo (N=93) Nausea 25% 15% Decreased appetite 15% 3% Vomiting 15% 5% Decreased weight Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=89 Duloxetine delayed-release capsules; N=92 Placebo). 15% 5% Headache 14% 11% Nasopharyngitis 9% 2% Somnolence 9% 3% Upper respiratory tract infection 7% 2% Viral gastroenteritis 5% 0% Fatigue 5% 2% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Duloxetine delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to Duloxetine delayed-release capsules therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potent inhibitors of CYP1A2 should be avoided ( 7.1 ) Potent inhibitors of CYP2D6 may increase Duloxetine delayed-release capsules concentrations ( 7.2 ) Duloxetine delayed-release capsules is a moderate inhibitor of CYP2D6 ( 7.9 ) 7.1 Inhibitors of CYP1A2 When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the C max was increased about 2.5-fold, and duloxetine t 1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions (5.12) ]. 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions (5.12) ]. 7.3 Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and C max. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with Duloxetine delayed-release capsules 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC τ,ss , C max,ss or t max,ss ) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when Duloxetine delayed-release capsules are initiated or discontinued [see Warnings and Precautions (5.5) ]. 7.5 Lorazepam Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. 7.6 Temazepam Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 7.7 Drugs that Affect Gastric Acidity Duloxetine delayed-release capsules have an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Duloxetine delayed-release capsules, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine delayed-release capsules in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co- administration of Duloxetine delayed-release capsules with aluminum- and magnesium-containing antacids (51 mEq) or Duloxetine delayed-release capsules with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions (5.14) ]. 7.8 Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily). 7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions (5.12) ]. 7.10 Drugs Metabolized by CYP2C9 Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drug Interactions (7.4) ]. 7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. 7.12 Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. 7.13 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration (2.9 , 2.10) , Contraindications (4) , and Warnings and Precautions (5.4) ]. 7.14 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John\'s Wort) with Duloxetine delayed-release capsules increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Duloxetine delayed-release capsules and/or concomitant serotonergic drugs [see Warnings and Precautions (5.4) ]. 7.15 Alcohol When Duloxetine delayed-release capsules and ethanol were administered several hours apart so that peak concentrations of each would coincide, Duloxetine delayed-release capsules did not increase the impairment of mental and motor skills caused by alcohol. In the Duloxetine delayed-release capsules clinical trials database, three Duloxetine delayed-release capsules-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions (5.2 , 5.12) ]. 7.16 CNS Drugs [See Warnings and Precautions (5.12) ]. 7.17 Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of Duloxetine delayed-release capsules to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions (7.4) ]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Duloxetine delayed-release capsules is indicated for the treatment of: Major depressive disorder in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain in adults Fibromyalgia in adults and pediatric patients 13 years of age and older Chronic musculoskeletal pain in adults Duloxetine delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of the following conditions: Major depressive disorder (MDD) in adults ( 1 ) Generalized anxiety disorder (GAD) in adults and pediatric patients 7 years of age and older ( 1 ) Diabetic peripheral neuropathic pain (DPNP) in adults ( 1 ) Fibromyalgia (FM) in adults and pediatric patients 13 years of age and older ( 1 ) Chronic musculoskeletal pain in adults ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Hepatic failure, sometimes fatal, has been reported. Discontinue Duloxetine delayed-release capsules in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Avoid use in patients with substantial alcohol use or evidence of chronic liver disease ( 5.2 ) Orthostatic Hypotension, Falls and Syncope : Consider dosage reduction or discontinuation if these events occur ( 5.3 ) Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue Duloxetine delayed-release capsules and serotonergic agents ( 5.4 ) Increased Risk of Bleeding : May increase the risk of bleeding events. Concomitant use of antiplatelet drugs and anticoagulants may increase this risk ( 5.5 , 7.4 , 8.1 ) Severe Skin Reactions : Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur; Discontinue at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified ( 5.6 ) Activation of Mania or Hypomania : Prior to initiating, screen patients for personal or family history of bipolar disorder, mania, or hypomania ( 5.8 ) Angle-Closure Glaucoma : Has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.9 ) Seizures : Prescribe with care in patients with a history of seizure disorder ( 5.10 ) Blood Pressure Increases : Monitor blood pressure prior to initiating treatment and periodically throughout treatment ( 5.11 ) Inhibitors of CYP1A2 or Thioridazine : Avoid co-administration with Duloxetine delayed-release capsules ( 5.12 ) Hyponatremia : Can occur in association with SIADH; consider discontinuation ( 5.13 ) Glucose Control in Diabetes : In DPNP patients, increases in fasting blood glucose, and HbA 1c have been observed ( 5.14 ) Conditions that Slow Gastric Emptying : Use cautiously in these patients ( 5.14 ) Sexual Dysfunction : Duloxetine delayed-release capsules may cause symptoms of sexual dysfunction ( 5.16 ) 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric Duloxetine delayed-release capsules trials. There were suicides in the adult Duloxetine delayed-release capsules trials, but the number was not sufficient to reach any conclusion about Duloxetine delayed-release capsules effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient\'s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.8) and Warnings and Precautions (5.7) ] for descriptions of the risks of discontinuation of Duloxetine delayed-release capsules. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Duloxetine delayed-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Duloxetine delayed-release capsules are not approved for use in treating bipolar depression. 5.2 Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in patients treated with Duloxetine delayed-release capsules. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine delayed-release capsules should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Duloxetine delayed-release capsules increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of Duloxetine delayed-release capsules-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the ULN occurred in 1.25% (144/11,496) of Duloxetine delayed-release capsules-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo- controlled studies using a fixed dose design, there was evidence of a Duloxetine delayed-release capsules dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively. Because it is possible that Duloxetine delayed-release capsules and alcohol may interact to cause liver injury or that Duloxetine delayed-release capsules may aggravate pre-existing liver disease, Duloxetine delayed-release capsules should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.3 Orthostatic Hypotension, Falls and Syncope Orthostatic hypotension, falls, and syncope have been reported in patients treated with the recommended Duloxetine delayed-release capsules dosages. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during Duloxetine delayed-release capsules treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure (BP) as well as other factors that may increase the underlying risk of falls. In an analysis of patients from all placebo-controlled trials, patients treated with Duloxetine delayed-release capsules reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in BP. The risk of BP decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions (5.12) and Drug Interactions (7.1) ] and in patients taking Duloxetine delayed-release capsules at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of Duloxetine delayed-release capsules in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during duloxetine therapy. Risk of falling also appeared to be proportional to a patient\'s underlying risk for falls and appeared to increase steadily with age. As geriatric patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including fractures and hospitalizations have been reported with duloxetine use [see Adverse Reactions (6.1) ]. 5.4 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Duloxetine delayed-release capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John\'s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs, [see Contraindications (4) , Drug Interactions (7.13) ]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Duloxetine delayed-release capsules with MAOIs is contraindicated. In addition, do not initiate Duloxetine delayed-release capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Duloxetine delayed-release capsules, discontinue Duloxetine delayed-release capsules before initiating treatment with the MAOI [see Contraindications (4) and Drug Interactions (7.13) ]. Monitor all patients taking Duloxetine delayed-release capsules for the emergence of serotonin syndrome. Discontinue treatment with Duloxetine delayed-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Duloxetine delayed-release capsules with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Duloxetine delayed-release capsules, may increase the risk of bleeding events. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking Duloxetine delayed-release capsules. Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti- coagulants may add to this risk. Inform patients about the risk of increased bleeding associated with the concomitant use of Duloxetine delayed-release capsules and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.4) ]. 5.6 Severe Skin Reactions Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Duloxetine delayed-release capsules. The reporting rate of SJS associated with Duloxetine delayed-release capsules use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting. Duloxetine delayed-release capsules should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. 5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking Duloxetine delayed-release capsules. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in Duloxetine delayed-release capsules-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Duloxetine delayed-release capsules. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.8) ]. 5.8 Activation of Mania/Hypomania In adult placebo-controlled trials in patients with MDD, activation of mania or hypomania was reported in 0.1% (4/3779) of duloxetine-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Duloxetine delayed-release capsules should be used cautiously in patients with a history of mania. 5.9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including duloxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.10 Seizures Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with duloxetine and 0.01% (1/9513) of patients treated with placebo. Duloxetine delayed-release capsules should be prescribed with care in patients with a history of a seizure disorder. 5.11 Increases in Blood Pressure In adult placebo-controlled clinical trials across the approved adult populations from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily (approximately 3.3 times the maximum recommended dosage). At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions (6.1) ]. 5.12 Clinically Important Drug Interactions Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potential for Other Drugs to Affect Duloxetine delayed-release capsules CYP1A2 Inhibitors — Co-administration of Duloxetine delayed-release capsules with potent CYP1A2 inhibitors should be avoided [see Drug Interactions (7.1) ] . CYP2D6 Inhibitors — Because CYP2D6 is involved in Duloxetine delayed-release capsules metabolism, concomitant use of Duloxetine delayed-release capsules with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see Drug Interactions (7.2) ] . Potential for Duloxetine delayed-release capsules to Affect Other Drugs Drugs Metabolized by CYP2D6 — Co-administration of Duloxetine delayed-release capsules with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloxetine delayed-release capsules. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine delayed-release capsules and thioridazine should not be co-administered [see Drug Interactions (7.9) ] . Other Clinically Important Drug Interactions Alcohol — Use of Duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine delayed-release capsules should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.15) ] . CNS Acting Drugs — Given the primary CNS effects of Duloxetine delayed-release capsules, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Warnings and Precautions (5.12) and Drug Interactions (7.16) ] . 5.13 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Duloxetine delayed-release capsules. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported with Duloxetine delayed-release capsules use and appeared to be reversible when Duloxetine delayed-release capsules were discontinued. Geriatric patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5) ] . Discontinuation of Duloxetine delayed-release capsules should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.14 Use in Patients with Concomitant Illness Clinical experience with Duloxetine delayed-release capsules in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Duloxetine delayed-release capsules\' enteric coating. In extremely acidic conditions, Duloxetine delayed-release capsules, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine delayed-release capsules in patients with conditions that may slow gastric emptying (e.g., some diabetics). Duloxetine delayed-release capsules have not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product\'s premarketing testing. Hepatic Impairment Avoid use in patients with chronic liver disease or cirrhosis [see Dosage and Administration (2.7) , Warnings and Precautions (5.2) , and Use in Specific Populations (8.9) ]. Severe Renal Impairment Avoid use in patients with severe renal impairment, GFR <30 mL/minute. Increased plasma concentration of Duloxetine delayed-release capsules, and especially of its metabolites, occurred in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.7) and Use in Specific Populations (8.10) ]. Glycemic Control in Patients with Diabetes As observed in DPNP trials, Duloxetine delayed-release capsules treatment worsened glycemic control in some patients with diabetes. In three clinical trials of Duloxetine delayed-release capsules for the management of neuropathic pain associated with diabetic peripheral neuropathy [see Clinical Studies (14.4) ] , the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A 1c (HbA 1c ) was 7.8%. In the 12-week acute treatment phase of these studies, Duloxetine delayed-release capsules was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Duloxetine delayed-release capsules group and decreased by 11.5 mg/dL in the routine care group. HbA 1c increased by 0.5% in the Duloxetine delayed-release capsules group and by 0.2% in the routine care group. 5.15 Urinary Hesitation and Retention Duloxetine delayed-release capsules are in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine delayed-release capsules, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed. 5.16 Sexual Dysfunction Use of SNRIs, including Duloxetine delayed-release capsules, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1) ] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of Duloxetine delayed-release capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment."}', 'overdosage': '{"10 OVERDOSAGE 10.1 Signs and Symptoms In postmarketing experience, fatal outcomes have been reported for acute duloxetine overdoses, primarily with mixed overdoses, but also with duloxetine only, including 1000 mg of duloxetine (approximately 8.3 times the maximum recommended dosage). Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. 10.2 Management of Overdose There is no specific antidote to a Duloxetine delayed-release capsules overdosage, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose with Duloxetine delayed-release capsules, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Induction of emesis is not recommended. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease duloxetine AUC and C max by an average of one-third, although some patients had a limited effect of activated charcoal. Due to the large volume of distribution of duloxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who overdose with Duloxetine delayed-release capsules and tricyclic antidepressants. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions (5.4) and Drug Interactions (7) ]. Consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of overdosage."}', 'active_flag': 'Y', 'generic_name': '{"DULOXETINE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors — Advise patients, their families, and their caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider [see Boxed Warning and Warnings and Precautions (5.1) ]. Administration — Advise patients to swallow Duloxetine delayed-release capsules whole and to not chew, crush, or open the capsule (do not sprinkle contents on food or mixed with liquids) because these actions might affect the enteric coating. Hepatotoxicity — Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with Duloxetine delayed-release capsules. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking Duloxetine delayed-release capsules, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of Duloxetine delayed-release capsules with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions (5.2) ]. Alcohol — Although Duloxetine delayed-release capsules does not increase the impairment of mental and motor skills caused by alcohol, use of Duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions (5.2) and Drug Interactions (7.15) ]. Orthostatic Hypotension, Falls and Syncope — Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of Duloxetine delayed-release capsules [see Warnings and Precautions (5.3) ]. Serotonin Syndrome — Caution patients about the risk of serotonin syndrome with the concomitant use of Duloxetine delayed-release capsules and other serotonergic agents including triptans, tricyclic antidepressants, opioids, lithium, buspirone, tryptophan, amphetamines, and St. John\'s Wort [see Contraindications (4) , Warnings and Precautions (5.4) , and Drug Interactions (7.14) ]. Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms . Increased Risk of Bleeding — Caution patients about the concomitant use of Duloxetine delayed-release capsules and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1) ]. Severe Skin Reactions — Caution patients that Duloxetine delayed-release capsules may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions (5.6) ]. Discontinuation of Treatment — Instruct patients that discontinuation of Duloxetine delayed-release capsules may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking Duloxetine delayed-release capsules without consulting their healthcare provider [see Warnings and Precautions (5.7) ]. Activation of Mania or Hypomania — Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with Duloxetine delayed-release capsules. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability [see Warnings and Precautions (5.8) ]. Angle-Closure Glaucoma — Advise patients that taking Duloxetine delayed-release capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.9) ]. Seizures — Advise patients to inform their healthcare provider if they have a history of seizure disorder [see Warnings and Precautions (5.10) ]. Effects on Blood Pressure — Caution patients that Duloxetine delayed-release capsules may cause an increase in blood pressure [see Warnings and Precautions (5.11) ]. Concomitant Medications — Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [see Dosage and Administration (2.9 , 2.10) , Contraindications (4) , Warnings and Precautions (5.4 , 5.12) , and Drug Interactions (7) ]. Hyponatremia — Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including Duloxetine delayed-release capsules. Advise patients of the signs and symptoms of hyponatremia [see Warnings and Precautions (5.13) ]. Concomitant Illnesses — Advise patients to inform their healthcare provider about all of their medical conditions [see Warnings and Precautions (5.14) ]. Urinary Hesitation and Retention — Duloxetine delayed-release capsules are in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.15) ]. Sexual Dysfunction — Advise patients that use of Duloxetine delayed-release capsules may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.16) ]. Pregnancy Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Duloxetine delayed-release capsules. Advise pregnant women or patients who intend to become pregnant that Duloxetine delayed-release capsules may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Advise pregnant women that there is a risk of relapse with discontinuation of antidepressants. Lactation — Advise breastfeeding women using Duloxetine delayed-release capsules to monitor infants for sedation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2) ]. Interference with Psychomotor Performance — Duloxetine delayed-release capsules may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that Duloxetine delayed-release capsules therapy does not affect their ability to engage in such activities."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes (see Data ) . There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including Duloxetine delayed-release capsules, during pregnancy (see Clinical Considerations ). In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m 2 basis. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors. Maternal Adverse Reactions Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5) ]. Fetal/Neonatal Adverse Reaction Neonates exposed to Duloxetine delayed-release capsules and other SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.4) ]. Data Human Data Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08-2.18). The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. Animal Data In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 basis]. However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of Duloxetine delayed-release capsules have been established for treatment of generalized anxiety disorder (GAD) in patients 7 to 17 years of age and for treatment of juvenile fibromyalgia syndrome in patients 13 to 17 years of age. The safety and effectiveness of Duloxetine delayed-release capsules have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain. Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes [see Warnings and Precautions (5.1) ] . Perform regular monitoring of weight and growth in pediatric patients treated with Duloxetine delayed-release capsules [see Adverse Reactions (6.1) ]. Generalized Anxiety Disorder Use of Duloxetine delayed-release capsules for the treatment of GAD in patients 7 to 17 years of age is supported by one 10-week, placebo- controlled trial (GAD-6). The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age (53% were 12 to 17 years of age). Duloxetine delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies (14.3) ]. The safety and effectiveness of Duloxetine delayed-release capsules for the treatment of GAD in pediatric patients less than 7 years of age have not been established. Fibromyalgia Use of Duloxetine delayed-release capsules for treatment of fibromyalgia in patients 13 to 17 years of age is supported by a 13-week placebo- controlled trial in 184 patients with juvenile fibromyalgia syndrome (Study FM-4). Duloxetine delayed-release capsules showed improvement over placebo on the primary endpoint, change from baseline to end-of-treatment on the Brief Pain Inventory (BPI) – Modified Short Form: Adolescent Version 24-hour average pain severity rating [see Clinical Studies (14.5) ] . The safety and effectiveness of Duloxetine delayed-release capsules for the treatment of fibromyalgia in patients less than 13 years of age have not been established. Major Depressive Disorder The safety and effectiveness of Duloxetine delayed-release capsules have not been established in pediatric patients for the treatment of MDD. Efficacy of Duloxetine delayed-release capsules was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 to 17 years old with MDD (MDD-6 and MDD-7). Neither Duloxetine delayed-release capsules nor an active control (approved for treatment of pediatric MDD) was superior to placebo. The most frequently observed adverse reactions in the MDD pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Juvenile Animal Toxicology Data Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child)."}', 'geriatric_use': '{"8.5 Geriatric Use Geriatric Exposure in Premarketing Clinical Trials of Duloxetine delayed-release capsules Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over. Of the 1,041 patients in CLBP trials, 21% (221) were 65 years of age or over. Of the 487 patients in OA trials, 41% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out. SSRIs and SNRIs, including Duloxetine delayed-release capsules have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.13) ]. In an analysis of data from all placebo-controlled-trials, Duloxetine delayed-release capsules-treated patients reported a higher rate of falls compared to placebo-treated patients. The increased risk appears to be proportional to a patient\'s underlying risk for falls. Underlying risk appears to increase steadily with age. As geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during Duloxetine delayed-release capsules treatment is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported with Duloxetine delayed-release capsules use [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ]. The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the C max , but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the adult patient is not necessary."}'}

{MENTHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses For the temporarily relief of minor aches and pains of muscles and joints associated with: Arthritis Simple backache Strains Bruises Sprains"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{L-MENTHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only Do not use on wounds or damaged skin if you are allergic to any ingredients of this product with a heating pad with, or at the same time as, other external analgesic products When using this product do not use otherwise than directed avoid contact with eyes, mucous membranes or rashes do not bandage tightly Ask a doctor before use if you are prone to allergic reaction from aspirin or salicylates Stop use and ask a doctor if rash, itching, or excessive skin irritation develops conditions worsen symptoms persist for more than 7 days symptoms clear up and occur again within a few days If pregnant or breast-feeding, ask a health professional before use."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"MIDAZOLAM HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Injectable midazolam hydrochloride is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam hydrochloride; patients with glaucoma have not been studied. Midazolam hydrochloride is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form. Midazolam hydrochloride is contraindicated for use in premature infants because the formulation contains benzyl alcohol (see WARNINGS and PRECAUTIONS, Pediatric Use )."}', 'adverse_reactions': '{"ADVERSE REACTIONS See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam hydrochloride is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures). Adults The following additional adverse reactions were reported after intramuscular administration: headache (1.3%) Local effects at IM Injection site pain (3.7%) induration (0.5%) redness (0.5%) muscle stiffness (0.3%) Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION ). The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%) Local effects at the IV site nausea (2.8%) tenderness (5.6%) vomiting (2.6%) pain during injection (5.0%) coughing (1.3%) redness (2.6%) “oversedation” (1.6%) induration (1.7%) headache (1.5%) phlebitis (0.4%) drowsiness (1.2%) Pediatric Patients The following adverse events related to the use of IV midazolam hydrochloride in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent. Neonates For information concerning hypotensive episodes and seizures following the administration of midazolam hydrochloride to neonates (see Boxed WARNING , CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). Other adverse experiences, observed mainly following IV injection as a single sedative/anxiolytic/amnesia agent and occurring at an incidence of 1.0% in adult and pediatric patients, are as follows: Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea Cardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm Gastrointestinal: Acid taste, excessive salivation, retching CNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia Special Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness Integumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site Hypersensitivity: Allergic reactions including anaphylactoid reactions, hives, rash, pruritus Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma To report SUSPECTED ADVERSE REACTIONS, contact Belcher Pharmaceuticals, LLC at 1-727-471 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ."}', 'drug_interactions': '{"Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation. Other CNS Depressants The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION ). Other Drug Interactions Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of oral midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled. Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam. The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine. In a placebo-controlled study where saquinavir or placebo was administered orally as a 1200 mg dose, three times a day, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled. A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam hydrochloride for premedication in adults. The intravenous administration of midazolam hydrochloride decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam hydrochloride administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam hydrochloride does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Midazolam Injection is indicated: • intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; • intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; • intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); • continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS : Abuse, Misuse, and Addiction ). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting a poison center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations."}', 'active_flag': 'Y', 'generic_name': '{"MIDAZOLAM HYDROCHLORIDE"}', 'route': '{INTRAMUSCULAR,INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Personnel and Equipment for Monitoring and Resuscitation Prior to the intravenous administration of midazolam hydrochloride in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means readily available (e.g., pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam can depress respiration (see CLINICAL PHARMACOLOGY ), especially when used concomitantly with opioid agonists and other sedatives (see DOSAGE AND ADMINISTRATION ), it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population (see DOSAGE AND ADMINISTRATION for complete information). Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS, Drug Interactions ). Risk of Respiratory Adverse Events Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic. Individualization of Dosage Midazolam hydrochloride must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression (see DOSAGE AND ADMINISTRATION for complete information). Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam hydrochloride; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam hydrochloride and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients. Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. Debilitation and Comorbid Considerations Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam hydrochloride. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY ). Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam hydrochloride is recommended, and the possibility of profound and/or prolonged effect should be considered. Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. Risk of Intra-Arterial Injection There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided. The safety and efficacy of midazolam following non-intravenous and non-intramuscular routes of administration have not been established. Midazolam hydrochloride should only be administered intramuscularly or intravenously. Return to Full Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY ) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until 1 full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation. Neonatal Sedation and Withdrawal Syndrome Use of midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy ). Monitor neonates exposed to midazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam during pregnancy for signs of withdrawal; manage these neonates accordingly. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam hydrochloride for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS, Pediatric Use ). Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans (see PRECAUTIONS, Pregnancy and Pediatric Use and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks."}', 'precautions': '{"PRECAUTIONS General Intravenous doses of midazolam hydrochloride should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION ). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia. The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam hydrochloride to the patient\'s underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam hydrochloride and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see Boxed WARNING , WARNINGS and DOSAGE AND ADMINISTRATION ). Practitioners administering midazolam hydrochloride must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal (see DRUG ABUSE AND DEPENDENCE ). Information for Patients To assure safe and effective use of benzodiazepines, the following information and instructions should be communicated to the patient when appropriate: 1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication and antibiotics, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment. 2. Inform your physician if you are pregnant or are planning to become pregnant. 3. Inform your physician if you are nursing. 4. Patients should be informed of the pharmacological effects of midazolam, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received injectable midazolam hydrochloride, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. 5. Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal following abrupt discontinuation. 6. Effect of anesthetic and sedation drugs on early brain development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs. Pregnancy Advise pregnant females that use of midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ). Instruct patients to inform their healthcare provider if they are pregnant. Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see PRECAUTIONS, Nursing Mothers ). Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation. Other CNS Depressants The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION ). Other Drug Interactions Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of oral midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled. Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam. The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine. In a placebo-controlled study where saquinavir or placebo was administered orally as a 1200 mg dose, three times a day, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled. A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam hydrochloride for premedication in adults. The intravenous administration of midazolam hydrochloride decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam hydrochloride administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam hydrochloride does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam. Drug/Laboratory Test Interactions Midazolam has not been shown to interfere with results obtained in clinical laboratory tests. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 1, 9 and 80 mg/kg/day. In female mice in the highest dose group there was a marked increase in the incidence of hepatic tumors. In high-dose male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of midazolam maleate (4 times a human induction dose of 0.35 mg/kg based on body surface area comparison) do not increase the incidence of tumors. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be of single or several doses. Mutagenesis Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice. Impairment of Fertility Male rats were treated orally with 1, 4, or 16 mg/kg midazolam beginning 62 days prior to mating with female rats treated with the same doses for 14 days prior to mating to Gestation Day 13 or Lactation Day 21. The high dose produced an equivalent exposure (AUC) as 4 mg/kg intravenous midazolam (1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparison). There were no adverse effects on either male or female fertility noted. Pregnancy Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome , and Clinical Considerations ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to midazolam injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia. The high dose produced a 5% decrease in maternal body weight gain compared to control. Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity. Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control. There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use , and Animal Toxicology and/or Pharmacology ). Nursing Mothers Risk Summary There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. Based on data from published studies, midazolam is present in human milk in low levels ( see Data ). There are no data on the effects of midazolam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother\'s clinical need for midazolam injection and any potential adverse effects on the breastfed infant from midazolam injection or from the underlying maternal condition. Clinical Considerations Infants exposed to midazolam injection through breast milk should be monitored for sedation, poor feeding and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant. Pediatric Use The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single dose intramuscular administration, intravenously by intermittent injections and continuous infusion have been established in pediatric and neonatal patients. For specific safety monitoring and dosage guidelines (see Boxed WARNING , CLINICAL PHARMACOLOGY , INDICATIONS AND USAGE , WARNINGS , PRECAUTIONS , ADVERSE REACTIONS , OVERDOSAGE and DOSAGE AND ADMINISTRATION ). UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The healthcare practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. Midazolam hydrochloride should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly, with concomitant use of fentanyl. Midazolam contain benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages greater than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Animal Data Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as midazolam injection, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS, Pediatric Neurotoxicity , PRECAUTIONS, Pregnancy, and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). Geriatric Use Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Intravenous and intramuscular doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION ) and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of IM and IV midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION ). Specific dosing and monitoring guidelines for geriatric patients are provided in the DOSAGE AND ADMINISTRATION section for premedicated patients for sedation/anxiolysis/amnesia following IV and IM administration, for induction of anesthesia following IV administration and for continuous infusion."}', 'information_for_patients': '{"Information for Patients To assure safe and effective use of benzodiazepines, the following information and instructions should be communicated to the patient when appropriate: 1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication and antibiotics, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment. 2. Inform your physician if you are pregnant or are planning to become pregnant. 3. Inform your physician if you are nursing. 4. Patients should be informed of the pharmacological effects of midazolam, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received injectable midazolam hydrochloride, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. 5. Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal following abrupt discontinuation. 6. Effect of anesthetic and sedation drugs on early brain development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs. Pregnancy Advise pregnant females that use of midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ). Instruct patients to inform their healthcare provider if they are pregnant. Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see PRECAUTIONS, Nursing Mothers )."}', 'pregnancy': '{"Pregnancy Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome , and Clinical Considerations ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to midazolam injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ). Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia. The high dose produced a 5% decrease in maternal body weight gain compared to control. Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity. Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control. There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use , and Animal Toxicology and/or Pharmacology )."}', 'pediatric_use': '{"Pediatric Use The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single dose intramuscular administration, intravenously by intermittent injections and continuous infusion have been established in pediatric and neonatal patients. For specific safety monitoring and dosage guidelines (see Boxed WARNING , CLINICAL PHARMACOLOGY , INDICATIONS AND USAGE , WARNINGS , PRECAUTIONS , ADVERSE REACTIONS , OVERDOSAGE and DOSAGE AND ADMINISTRATION ). UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The healthcare practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. Midazolam hydrochloride should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly, with concomitant use of fentanyl. Midazolam contain benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages greater than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. Animal Data Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as midazolam injection, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data (see WARNINGS, Pediatric Neurotoxicity , PRECAUTIONS, Pregnancy, and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY )."}', 'geriatric_use': '{"Geriatric Use Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Intravenous and intramuscular doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION ) and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of IM and IV midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION ). Specific dosing and monitoring guidelines for geriatric patients are provided in the DOSAGE AND ADMINISTRATION section for premedicated patients for sedation/anxiolysis/amnesia following IV and IM administration, for induction of anesthesia following IV administration and for continuous infusion."}'}

{DUTASTERIDE}

{'contraindications': '{"4 CONTRAINDICATIONS Dutasteride capsules are contraindicated for use in: • Pregnancy. In animal reproduction and developmental toxicity studies, dutasteride inhibited development of male fetus external genitalia. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. • Women of childbearing potential [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. • Pediatric patients [see Use in Specific Populations (8.4) ]. • Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or other 5 alpha-reductase inhibitors [see Adverse Reactions (6.2) ]. Pregnancy and women of childbearing potential. ( 4 , 5.4 , 8.1 ) Pediatric patients. ( 4 ) Patients with previously demonstrated, clinically significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride capsules or other 5 alpha-reductase inhibitors. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The most common adverse reactions, reported in ≥1% of subjects treated with dutasteride capsules and more commonly than in subjects treated with placebo, are impotence, decreased libido, ejaculation disorders, and breast disorders. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact PuraCap Pharmaceuticals, LLC at 1-855-215-8180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice. From clinical trials with DUTASTERIDE as monotherapy or in combination with tamsulosin: • The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy. • Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%). • In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%). Monotherapy Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of dutasteride in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were Caucasian. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo. Table 1. Adverse Reactions Reported in ≥1% of Subjects Over a 24-Month Period and More Frequently in the Group Receiving Dutasteride Capsules Than the Placebo Group (Randomized, Double-Blind, Placebo-Controlled Trials Pooled) by Time of Onset Adverse Reaction Adverse Reaction Time of Onset Months 0-6 Months 7-12 Months 13-18 Months 19-24 Dutasteride capsules (n) (n = 2,167) (n = 1,901) (n = 1,725) (n = 1,605) Placebo (n) (n = 2,158) (n = 1,922) (n = 1,714) (n = 1,555) Impotencea Dutasteride capsules 4.7% 1.4% 1.0% 0.8% Placebo 1.7% 1.5% 0.5% 0.9% Decreased libido a Dutasteride capsules 3.0% 0.7% 0.3% 0.3% Placebo 1.4% 0.6% 0.2% 0.1% Ejaculation disorders a Dutasteride capsules 1.4% 0.5% 0.5% 0.1% Placebo 0.5% 0.3% 0.1% 0.0% Breast disorders b Dutasteride capsules 0.5% 0.8% 1.1% 0.6% Placebo 0.2% 0.3% 0.3% 0.1% a These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. b Includes breast tenderness and breast enlargement. Long-Term Treatment (Up to 4 Years): High-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (N = 4,126) or 0.5-mg daily doses of dutasteride capsules (N = 4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving dutasteride capsules (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.3) , Warnings and Precautions (5.2) ]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR ® ), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride capsules. Reproductive and Breast Disorders: In the 3 pivotal placebo-controlled BPH trials with dutasteride capsules, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial. The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown. Combination With Alpha-Blocker Therapy (CombAT): Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg dutasteride capsules, 0.4-mg tamsulosin, or combination therapy (0.5-mg dutasteride capsules plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride capsules; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were Caucasian. Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride capsules or tamsulosin. Table 2. Adverse Reactions Reported Over a 48-Month Period in ≥1% of Subjects and More Frequently in the Coadministration Therapy Group Than the Groups Receiving Monotherapy With Dustateride Capsules or Tamsulosin (CombAT) by Time of Onset Adverse Reaction Adverse Reaction Time of Onset Year 1 Months 0-6 Months 7-12 Year 2 Years 3 Year 4 Combination a (n = 1,610) (n = 1,527) (n = 1,428) (n = 1,283) (n = 1,200) Dutasteride capsules (n = 1,623) (n = 1,548) (n = 1,464) (n = 1,325) (n = 1,200) Tamsulosin (n = 1,611) (n = 1,545) (n = 1,468) (n = 1,281) (n = 1,112) Ejaculation disorders b,c Combination 7.8% 1.6% 1.0% 0.5% <0.1% Dutasteride capsules 1.0% 0.5% 0.5% 0.2% 0.3% Tamsulosin 2.2% 0.5% 0.5% 0.2% 0.3% Impotence c,d Combination 5.4% 1.1% 1.8% 0.9% 0.4% Dutasteride capsules 4.0% 1.1% 1.6% 0.6% 0.3% Tamsulosin 2.6% 0.8% 1.0% 0.6% 1.1% Decreased libido c,e Combination 4.5% 0.9% 0.8% 0.2% 0.0% Dutasteride capsules 3.1% 0.7% 1.0% 0.2% 0.0% Tamsulosin 2.0% 0.6% 0.7% 0.2% <0.1% Breast disorders f Combination 1.1% 1.1% 0.8% 0.9% 0.6% Dutasteride capsules 0.9% 0.9% 1.2% 0.5% 0.7% Tamsulosin 0.4% 0.4% 0.4% 0.2% 0.0% Dizziness Combination 1.1% 0.4% 0.1% <0.1% 0.2% Dutasteride capsules 0.5% 0.3% 0.1% <0.1% <0.1% Tamsulosin 0.9% 0.5% 0.4% <0.1% 0.0% a Combination = Dutasteride capsules 0.5 mg once daily plus tamsulosin 0.4 mg once daily. b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. c These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. d Includes erectile dysfunction and disturbance in sexual arousal. e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling. Cardiac Failure: In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride capsules, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%).Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride capsules in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride capsules was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had co-morbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride capsules, alone or in combination with tamsulosin, and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dutasteride capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to dutasteride. Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema. Neoplasms: Male breast cancer. Psychiatric Disorders: Depressed mood. Reproductive System and Breast Disorders: Testicular pain and testicular swelling."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Use with caution in patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir). ( 7 ) 7.1 Cytochrome P450 3A Inhibitors Dutasteride is extensively metabolized in humans by the CYP3A4 and CYP3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride capsules to patients taking potent, chronic CYP3A4 enzyme inhibitors (e.g., ritonavir) [see Clinical Pharmacology (12.3) ]. 7.2 Alpha Adrenergic Antagonists The administration of dutasteride capsules in combination with tamsulosin or terazosin has no effect on the steady-state pharmacokinetics of either alpha-adrenergic antagonist. The effect of administration of tamsulosin or terazosin on dutasteride pharmacokinetic parameters has not been evaluated. 7.3 Calcium Channel Antagonists Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended [see Clinical Pharmacology (12.3) ]. 7.4 Cholestyramine Administration of a single 5-mg dose of dutasteride capsules followed 1 hour later by 12 g of cholestyramine does not affect the relative bioavailability of dutasteride [see Clinical Pharmacology (12.3) ]. 7.5 Digoxin Dutasteride capsules do not alter the steady-state pharmacokinetics of digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks [see Clinical Pharmacology (12.3) ]. 7.6 Warfarin Concomitant administration of dutasteride capsules 0.5 mg/day for 3 weeks with warfarin does not alter the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time [see Clinical Pharmacology (12.3) ]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Dutasteride capsules is a 5 alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: ( 1.1 ) • improve symptoms, • reduce the risk of acute urinary retention, and • reduce the risk of the need for BPH-related surgery. Dutasteride capsules in combination with the alpha adrenergic antagonist, tamsulosin, is indicated for the treatment of symptomatic BPH in men with an enlarged prostate. (1.2) Limitations of Use: Dutasteride capsules is not approved for the prevention of prostate cancer. (1.3) 1.1 Monotherapy Dutasteride capsules are indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: • improve symptoms, • reduce the risk of acute urinary retention (AUR), and • reduce the risk of the need for BPH-related surgery. 1.2 Combination with Alpha-adrenergic Antagonist Dutasteride capsules in combination with the alpha-adrenergic antagonist, tamsulosin, is indicated for the treatment of symptomatic BPH in men with an enlarged prostate. 1.3 Limitations of Use Dutasteride capsules are not approved for the prevention of prostate cancer."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Dutasteride capsules reduce serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on dutasteride capsules may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. ( 5.1 ) • Dutasteride capsules may increase the risk of high-grade prostate cancer. ( 5.2 , 6.1 ) • Prior to initiating treatment with dutasteride capsules, consideration should be given to other urological conditions that may cause similar symptoms. ( 5.3 ) • Women who are pregnant or could become pregnant should not handle dutasteride capsules due to potential risk to a male fetus. ( 5.4 , 8.1 ) • Patients should not donate blood until 6 months after their last dose of dutasteride capsules. (5.5) 5.1 Effects on Prostate-specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results. To interpret an isolated PSA value in a man treated with dutasteride for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary. Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy. 5.2 Increased Risk of High-grade Prostate Cancer In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) [see Indications and Usage (1.3) , Adverse Reactions (6.1) ]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR ® ), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). 5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established. 5.3 Evaluation for Other Urological Diseases Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist. 5.4 Exposure of Women—Risk to Male Fetus Dutasteride Capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who could become pregnant comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Use in Specific Populations (8.1) ]. 5.5 Blood Donation Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient. 5.6 Effect on Semen Characteristics The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known."}', 'overdosage': '{"10 OVERDOSAGE In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage, symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration."}', 'active_flag': 'Y', 'generic_name': '{DUTASTERIDE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). 17.1 PSA Monitoring Physicians should inform patients that dutasteride capsules reduce serum PSA levels by approximately 50% within 3 to 6 months of therapy, although it may vary for each individual. For patients undergoing PSA screening, increases in PSA levels while on treatment with dutasteride capsules may signal the presence of prostate cancer and should be evaluated by a healthcare provider [see Warnings and Precautions (5.1) ]. 17.2 Increased Risk of High-Grade Prostate Cancer Physicians should inform patients that there was an increase in high-grade prostate cancer in men treated with 5 alpha-reductase inhibitors (which are indicated for BPH treatment), including dutasteride capsules, compared with those treated with placebo in trials looking at the use of these drugs to reduce the risk of prostate cancer [see Indications and Usage (1.3) , Warnings and Precautions (5.2) , Adverse Reactions (6.1) ]. 17.3 Exposure of Women - Risk to Male Fetus Physicians should inform patients that dutasteride capsules should not be handled by a woman who is pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a pregnant woman or woman of childbearing potential comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. 17.4 Blood Donation Physicians should inform men treated with dutasteride capsules that they should not donate blood until at least 6 months following their last dose to prevent pregnant women from receiving dutasteride through blood transfusion [see Warnings and Precautions (5.5) ]. Serum levels of dutasteride are detectable for 4 to 6 months after treatment ends [see Clinical Pharmacology (12.3) ]. Manufactured by: Humanwell PuraCap Pharmaceutical Wuhan, Hubei 430206, China"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Category X. Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy. Dutasteride are a 5 alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus. Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to DHT by 5 alpha-reductase inhibitors. These results are similar to observations in male infants with genetic 5 alpha-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or could become pregnant should not handle dutasteride capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4) ]. Dutasteride is secreted into semen. The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman’s dutasteride concentration would be about 0.0175 ng/mL. This concentration is more than 100 times less than concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption. In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) of 0.5 mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day), nipple development, hypospadias, and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30 mg/kg/day). An increase in stillborn pups was observed at 111 times the MRHD, and reduced fetal body weight was observed at doses of about 15 times the MRHD (animal dose of 2.5 mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses about 56 times the MRHD (animal dose of 12.5 mg/kg/day). In a rabbit embryo-fetal study, doses 28- to 93-fold the MRHD (animal doses of 30, 100, and 200 mg/kg/day) were administered orally during the period of major organogenesis (gestation days 7 to 29) to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at 0.3- to 53-fold the expected clinical exposure (animal doses of 0.05, 0.4, 3.0, and 30 mg/kg/day) also produced evidence of feminization of the genitalia in male fetuses at all doses. In an oral pre- and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of male offspring occurred at 14- to 90-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). At 0.05-fold the expected clinical exposure (animal dose of 0.05 mg/kg/day), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Animal doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and a decrease in prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day. In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. Dutasteride was administered on gestation days 20 to 100 at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). The development of male external genitalia of monkey offspring was not adversely affected. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested in monkeys. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. (These calculations are based on blood levels of parent drug which are achieved at 32 to 186 times the daily doses administered to pregnant monkeys on a ng/kg basis). Dutasteride is highly bound to proteins in human semen (greater than 96%), potentially reducing the amount of dutasteride available for vaginal absorption. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites. Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state."}', 'pediatric_use': '{"8.4 Pediatric Use Dutasteride is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use Of 2,167 male subjects treated with dutasteride capsules in 3 clinical trials, 60% were aged 65 years and older and 15% were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ]."}'}

{NICOTINE}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use • reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"NICOTINE POLACRILEX"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash)"}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase blood pressure. • stomach ulcer or diabetes • history of seizures Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth, teeth or jaw problems occur • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222)."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{BENZOCAINE}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"\u200bUse For oral mucosal use only, as directed by dentist. For the temporary relief of pain due to minor dental procedures"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{BENZOCAINE}', 'route': '{DENTAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"\u200b \u200bWarnings Methemoglobinemia warning: Use of this product may cause methemoglobinemia, a serious condition that must be treated promptly because it reduces the amount of oxygen carried in the blood. This can occur even if you have used this product before. Stop use and seek immediate medical attention if you or a child in your care develops: pale, gray or blue colored skin (cyanosis) headache rapid heart rate shortness of breath dizziness or lightheadedness fatigue or lack of energy Allergy Alert: Do not use on patients with a history of allergies to local anesthetics such as procaine, butacaine, benzocaine or other \\"caine\\" anesthetics. Do not use for more than 7 days unless directed by a physician. If sore mouth symptoms do not improve in 7 days; irritation, pain, or redness persists or worsens; or if swelling, rash or fever develops, see your physician promptly. for teething in children under 2 years of age When using this product Avoid contact with eyes. If contact occurs, flush with water. Do not exceed recommended dosage. If more than used for pain is accidentally swallowed, get medical help or contact a Poison Control Center right away. If pregnant or breast feeding, ask a physician before use."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{MELOXICAM}

{'contraindications': '{"4 CONTRAINDICATIONS Meloxicam oral suspension is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [see Warnings and Precautions (5.7 , 5.9) ] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7 , 5.8) ] In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ] Known hypersensitivity to meloxicam or any components of the drug product ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Boxed Warning and Warnings and Precautions (5.1) ] GI Bleeding, Ulceration, and Perforation [see Boxed Warning and Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and Precautions (5.4) ] Heart Failure and Edema [see Warnings and Precautions (5.5) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6) ] Anaphylactic Reactions [see Warnings and Precautions (5.7) ] Serious Skin Reactions [see Warnings and Precautions (5.9) ] Hematologic Toxicity [see Warnings and Precautions (5.12) ] Most common (≥5% and greater than placebo) adverse events in adults are diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms ( 6.1 ) Adverse events observed in pediatric studies were similar in nature to the adult clinical trial experience ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Emerald Therapeutics, LLC at (800) 970-1991 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Osteoarthritis and Rheumatoid Arthritis The meloxicam Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with meloxicam 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo- and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials. A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of meloxicam with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of meloxicam with placebo. Table 1a depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in a 12-week placebo-and active-controlled osteoarthritis trial. Table 1b depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in two 12-week placebo-controlled rheumatoid arthritis trials. Table 1a Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in a 12-Week Osteoarthritis Placebo-and Active-Controlled Trial Placebo Meloxicam 7.5 mg daily Meloxicam 15 mg daily Diclofenac 100 mg daily No. of Patients 157 154 156 153 Gastrointestinal 17.2 20.1 17.3 28.1 Abdominal pain 2.5 1.9 2.6 1.3 Diarrhea 3.8 7.8 3.2 9.2 Dyspepsia 4.5 4.5 4.5 6.5 Flatulence 4.5 3.2 3.2 3.9 Nausea 3.2 3.9 3.8 7.2 Body as a Whole Accident household 1.9 4.5 3.2 2.6 Edema WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2.5 1.9 4.5 3.3 Fall 0.6 2.6 0.0 1.3 Influenza-like symptoms 5.1 4.5 5.8 2.6 Central and Peripheral Nervous System Dizziness 3.2 2.6 3.8 2.0 Headache 10.2 7.8 8.3 5.9 Respiratory Pharyngitis 1.3 0.6 3.2 1.3 Upper respiratory tract infection 1.9 3.2 1.9 3.3 Skin Rash WHO preferred terms rash, rash erythematous, and rash maculo-papular combined. 2.5 2.6 0.6 2.0 Table 1b Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in Two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials Placebo Meloxicam 7.5 mg daily Meloxicam 15 mg daily No. of Patients 469 481 477 Gastrointestinal Disorders 14.1 18.9 16.8 Abdominal pain NOS MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS 0.6 2.9 2.3 Dyspeptic signs and symptoms MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-pathogen unspecified (laryngitis NOS, pharyngitis NOS, sinusitis NOS), joint related signs and symptoms (arthralgia, arthralgia aggravated, joint crepitation, joint effusion, joint swelling) 3.8 5.8 4.0 Nausea 2.6 3.3 3.8 General Disorders and Administration Site Conditions Influenza-like illness 2.1 2.9 2.3 Infection and Infestations Upper respiratory tract infections-pathogen class unspecified 4.1 7.0 6.5 Musculoskeletal and Connective Tissue Disorders Joint related signs and symptoms 1.9 1.5 2.3 Nervous System Disorders Headaches NOS 6.4 6.4 5.5 Skin and Subcutaneous Tissue Disorders Rash NOS 1.7 1.0 2.1 The adverse events that occurred with meloxicam oral suspension in ≥2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2. Table 2 Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials 4 to 6 Weeks Controlled Trials 6 Month Controlled Trials Meloxicam 7.5 mg daily Meloxicam 15 mg daily Meloxicam 7.5 mg daily Meloxicam 15 mg daily No. of Patients 8955 256 169 306 Gastrointestinal 11.8 18.0 26.6 24.2 Abdominal pain 2.7 2.3 4.7 2.9 Constipation 0.8 1.2 1.8 2.6 Diarrhea 1.9 2.7 5.9 2.6 Dyspepsia 3.8 7.4 8.9 9.5 Flatulence 0.5 0.4 3.0 2.6 Nausea 2.4 4.7 4.7 7.2 Vomiting 0.6 0.8 1.8 2.6 Body as a Whole Accident household 0.0 0.0 0.6 2.9 Edema WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 0.6 2.0 2.4 1.6 Pain 0.9 2.0 3.6 5.2 Central and Peripheral Nervous System Dizziness 1.1 1.6 2.4 2.6 Headache 2.4 2.7 3.6 2.6 Hematologic Anemia 0.1 0.0 4.1 2.9 Musculoskeletal Arthralgia 0.5 0.0 5.3 1.3 Back pain 0.5 0.4 3.0 0.7 Psychiatric Insomnia 0.4 0.0 3.6 1.6 Respiratory Coughing 0.2 0.8 2.4 1.0 Upper respiratory tract infection 0.2 0.0 8.3 7.5 Skin Pruritus 0.4 1.2 2.4 0.0 Rash WHO preferred terms rash, rash erythematous, and rash maculo-papular combined 0.3 1.2 3.0 1.3 Urinary Micturition frequency 0.1 0.4 2.4 1.3 Urinary tract infection 0.3 0.4 4.7 6.9 Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of meloxicam oral suspension should not exceed 15 mg. Pediatrics Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis (JRA) Three hundred and eighty-seven patients with pauciarticular and polyarticular course JRA were exposed to meloxicam with doses ranging from 0.125 to 0.375 mg/kg per day in three clinical trials. These studies consisted of two 12-week multicenter, double-blind, randomized trials (one with a 12-week open-label extension and one with a 40-week extension) and one 1-year open-label PK study. The adverse events observed in these pediatric studies with meloxicam were similar in nature to the adult clinical trial experience, although there were differences in frequency. In particular, the following most common adverse events, abdominal pain, vomiting, diarrhea, headache, and pyrexia, were more common in the pediatric than in the adult trials. Rash was reported in seven (<2%) patients receiving meloxicam. No unexpected adverse events were identified during the course of the trials. The adverse events did not demonstrate an age or gender-specific subgroup effect. The following is a list of adverse drug reactions occurring in <2% of patients receiving meloxicam in clinical trials involving approximately 16,200 patients. Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis Central and Peripheral Nervous System convulsions, paresthesia, tremor, vertigo Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative Heart Rate and Rhythm arrhythmia, palpitation, tachycardia Hematologic leukopenia, purpura, thrombocytopenia Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis Metabolic and Nutritional dehydration Psychiatric abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence Respiratory asthma, bronchospasm, dyspnea Skin and Appendages alopecia, angioedema, bullous eruption, photosensitivity reaction, pruritus, sweating increased, urticaria Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus Urinary System albuminuria, BUN increased, creatinine increased, hematuria, renal failure 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of meloxicam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide post marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome; toxic epidermal necrolysis, and infertility female."}', 'drug_interactions': '{"7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. See also Warnings and Precautions (5.2 , 5.6 , 5.12) and Clinical Pharmacology (12.3) . Table 3 Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of meloxicam oral suspension with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. Intervention: Concomitant use of meloxicam oral suspension and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12) ]. Meloxicam oral suspension is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of meloxicam oral suspension and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam oral suspension and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention: During concomitant use of meloxicam oral suspension with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ]. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3) ]. Intervention: During concomitant use of meloxicam oral suspension and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of meloxicam oral suspension and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of meloxicam and cyclosporine may increase cyclosporine\'s nephrotoxicity. Intervention: During concomitant use of meloxicam oral suspension and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ]. Intervention: The concomitant use of meloxicam oral suspension with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of meloxicam oral suspension and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. Sodium Polystyrene Sulfonate Clinical Impact: Cases of intestinal necrosis (possibly fatal) have been described in patients who received concomitant sorbitol and sodium polystyrene sulfonate. Due to the presence of sorbitol in meloxicam oral suspension, use with sodium polystyrene sulfonate is not recommended. Intervention: The concomitant use of meloxicam oral suspension with sodium polystyrene sulfonate is not recommended. Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking meloxicam oral suspension with drugs that interfere with hemostasis. Concomitant use of meloxicam oral suspension and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARBs) or Beta-Blockers: Concomitant use with meloxicam oral suspension may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs: Concomitant use with meloxicam oral suspension in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7 ) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Meloxicam oral suspension is a non-steroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) ( 1.1 ) Rheumatoid Arthritis (RA) ( 1.2 ) Juvenile Rheumatoid Arthritis (JRA) in patients 2 years of age or older ( 1.3 ) 1.1 Osteoarthritis (OA) Meloxicam oral suspension is indicated for relief of the signs and symptoms of osteoarthritis [see Clinical Studies (14.1) ]. 1.2 Rheumatoid Arthritis (RA) Meloxicam oral suspension is indicated for relief of the signs and symptoms of rheumatoid arthritis [see Clinical Studies (14.1) ]. 1.3 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course Meloxicam oral suspension is indicated for relief of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older [see Clinical Studies (14.2) ]."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema: Avoid use of meloxicam oral suspension in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of meloxicam oral suspension in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity: Meloxicam oral suspension is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions: Discontinue meloxicam oral suspension at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically ( 5.10 ) Fetal Toxicity: Limit use of NSAIDs, including meloxicam oral suspension, between about 20 to 30 weeks in pregnacy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of fetal ductus arteriosus ( 5.11 , 8.1 ) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of meloxicam oral suspension in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meloxicam oral suspension is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue meloxicam oral suspension until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7) ]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and \\"flu-like\\" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam oral suspension immediately, and perform a clinical evaluation of the patient [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 5.4 Hypertension NSAIDs, including meloxicam oral suspension, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7) ]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists\' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7) ]. Avoid the use of meloxicam oral suspension in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam oral suspension is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs, including meloxicam oral suspension, has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of meloxicam oral suspension may hasten the progression of renal dysfunction in patients with preexisting renal disease. Because some meloxicam oral suspension metabolites are excreted by the kidney, monitor patients for signs of worsening renal function. Correct volume status in dehydrated or hypovolemic patients prior to initiating meloxicam oral suspension. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of meloxicam oral suspension [see Drug Interactions (7) ]. No information is available from controlled clinical studies regarding the use of meloxicam oral suspension in patients with advanced renal disease. Avoid the use of meloxicam oral suspension in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If meloxicam oral suspensionis used in patients with advanced renal disease, monitor patients for signs of worsening renal function [see Clinical Pharmacology (12.3) ]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8) ]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam oral suspension is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4) ]. When meloxicam oral suspension is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam oral suspension at the first appearance of skin rash or any other sign of hypersensitivity. meloxicam oral suspension is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam oral suspension. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meloxicam oral suspension and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including meloxicam oral suspension, in pregnant women at about 30 weeks gestation and later. NSAIDs, including meloxicam oral suspension, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including meloxicam oral suspension, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meloxicam oral suspension use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam oral suspension treatment extends beyond 48 hours. Discontinue meloxicam oral suspension if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1) ] . 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with meloxicam oral suspension has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam oral suspension, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7) ]. 5.13 Masking of Inflammation and Fever The pharmacological activity of meloxicam oral suspension in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2 , 5.3 , 5.6) ]."}', 'overdosage': '{"10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.6) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. There is limited experience with meloxicam overdosage. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage. For additional information about overdosage treatment, call a poison control center (1-800-222-1222)."}', 'active_flag': 'Y', 'generic_name': '{MELOXICAM}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families or their caregivers of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately [see Warnings and Precautions (5.1) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and \\"flu-like\\" symptoms). If these occur, instruct patients to stop meloxicam oral suspension and seek immediate medical therapy [see Warnings and Precautions (5.3) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7) ]. Serious Skin Reactions, including DRESS Advise patients to stop taking meloxicam oral suspension immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9) , (5.10) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including meloxicam oral suspension, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3) ]. Fetal Toxicity Inform pregnant women to avoid use of meloxicam oral suspension and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meloxicam oral suspension is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1) ] . Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of meloxicam oral suspension with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Alert patients that NSAIDs may be present in \\"over the counter\\" medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with meloxicam oral suspension until they talk to their healthcare provider [see Drug Interactions (7) ]."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam oral suspension, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of meloxicam oral suspension use between about 20 and 30 weeks of gestation, and avoid meloxicam oral suspension use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations , Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam oral suspension, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65- and 6.5-times the maximum recommended human dose (MRHD) of meloxicam oral suspension. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times MRHD of meloxicam. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the MRHD [see Data ] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam oral suspension, can cause premature closure of the fetal ductus arteriosus (see Data ) . Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam oral suspension treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam oral suspension and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of meloxicam oral suspension during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the fullterm infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the MRHD of 15 mg of meloxicam based on BSA comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65- and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison)."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [see Dosage and Administration (2.3) , Adverse Reactions (6.1) and Clinical Studies (14.2) ]."}', 'geriatric_use': '{"8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.6 , 5.14) ]."}'}

{"MEPIVACAINE HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Mepivacaine is contraindicated in patients with a known hypersensitivity to amide-type local anesthetics."}', 'adverse_reactions': '{"ADVERSE REACTIONS Reactions to Mepivacaine are characteristic of those associated with other amide-type local anesthetics. Systemic adverse reactions involving the central nervous system and the cardiovascular system usually result from high plasma levels (which may be due to excessive dosage, rapid absorption, inadvertent intravascular injection, or slow metabolic degradation), injection technique, or volume of injection. A small number of reactions may result from hypersensitivity, idiosyncrasy or diminished tolerance to normal dosage on the part of the patient. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of mepivacaine, with slow, incomplete, or no recovery. These post-marketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches. Reactions involving the central nervous system are characterized by excitation and/or depression. Nervousness, dizziness, blurred vision, or tremors may occur followed by drowsiness, convulsions, unconsciousness, and possible respiratory arrest. Since excitement may be transient or absent, the first manifestations may be drowsiness merging into unconsciousness and respiratory arrest. Cardiovascular reactions are depressant. They may be the result of direct drug effect or more commonly in dental practice, the result of vasovagal reaction, particularly if the patient is in the sitting position. Failure to recognize premonitory signs such as sweating, feeling of faintness, changes in pulse or sensorium may result in progressive cerebral hypoxia and seizure or serious cardiovascular catastrophe. Management consists of placing the patient in the recumbent position and administration of oxygen. Vasoactive drugs such as Ephedrine or Methoxamine may be administered intravenously. Allergic reactions are rare and may occur as a result of sensitivity to the local anesthetic and are characterized by cutaneous lesions of delayed onset or urticaria, edema and other manifestations of allergy. The detection of sensitivity by skin testing is of limited value. As with other local anesthetics, anaphylactoid reactions to Mepivacaine have occurred rarely. The reaction may be abrupt and severe and is not usually dose related. Localized puffiness and swelling may occur."}', 'drug_interactions': '{"Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Levonordefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient\'s cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient\'s prior experience with Mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as Mepivacaine. Since Mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Mepivacaine is indicated for production of local anesthesia for dental procedures by infiltration or nerve block in adults and pediatric patients."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Treatment of a patient with toxic manifestations consists of assuring and maintaining a patent airway and supporting ventilation (respiration) as required. This usually will be sufficient in the management of most reactions. Should a convulsion persist despite ventilatory therapy, small increments of anticonvulsive agents may be given intravenously, such as benzodiazephine (e.g., diazepam) or ultrashort-acting barbiturates (e.g., thiopental or thiamylal) or short-acting barbiturates (e.g., pentobarbital or secobarbital). Cardiovascular depression may require circulatory assistance with intravenous fluids and/or vasopressor (e.g., Ephedrine) as dictated by the clinical situation. Allergic reactions should be managed by conventional means. IV and SC LD 50 \'s in mice for Mepivacaine Hydrochloride 3% are 33 and 258 mg/kg, respectively. The acute IV and SC LD 50 \'s in mice for Mepivacaine Hydrochloride 2% with Levonordefrin 1:20,000 are 30 and 184 mg/kg, respectively."}', 'active_flag': 'Y', 'generic_name': '{"MEPIVACAINE HYDROCHLORIDE"}', 'route': '{SUBMUCOSAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS RESUSCITATIVE EQUIPMENT AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE. (See ADVERSE REACTIONS). Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in the absence of a history of hypersensitivity. Fatalities may occur with use of local anesthetics in the head and neck region as the result of retrograde arterial flow to vital CNS areas even when maximum recommended doses are observed. The practitioner should be alert to early evidence of alteration in sensorium or vital signs. The solution which contains a vasoconstrictor (Mepivacaine HCl 2% (20 mg/mL)) should be used with extreme caution for patients whose medical history and physical evaluation suggest the existence of hypertension, arteriosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis and diabetes, etc. The solution which contains a vasoconstrictor (Mepivacaine HCl 2% (20 mg/mL)) also contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and lifethreatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. Mepivacaine HCl 3% (30 mg/mL) is SULFITE FREE. Mepivacaine, along with other local anesthetics, is capable of producing methemoglobinemia. The clinical signs of methemoglobinemia are cyanosis of the nail beds and lips, fatigue and weakness. If methemoglobinemia does not respond to administration of oxygen, administration of methylene blue intravenously 1-2 mg/kg body weight over a 5 minute period is recommended. The American Heart Association has made the following recommendations regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: “Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used.” (Kaplan, EL, editor: Cardiovascular disease in dental practice, Dallas 1986, American Heart Association.) Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use; MEPIVACAINE, along with other local anesthetics, is capable of producing this condition. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by cyanosis of the skin, nail beds and lips, and/or abnormal coloration of the blood, fatigue and weakness. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue MEPIVACAINE and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. If methemoglobinemia does not respond to administration of oxygen, a more severe clinical presentation may require treatment with methylene blue exchange transfusion, or hyperbaric oxygen."}', 'precautions': '{"PRECAUTIONS The safety and effectiveness of Mepivacaine depend upon proper dosage, correct technique, adequate precautions, and readiness for emergencies. The lowest dose that results in effective anesthesia should be used to avoid high plasma levels and possible adverse effects. Injection of repeated doses of Mepivacaine may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or due to slower metabolic degradation than normal. Tolerance varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their weight and physical status. Mepivacaine should be used with caution in patients with a history of severe disturbances of cardiac rhythm or heart block. INJECTIONS SHOULD ALWAYS BE MADE SLOWLY WITH ASPIRATION TO AVOID INTRAVASCULAR INJECTION AND THEREFORE SYSTEMIC REACTION TO BOTH LOCAL ANESTHETIC AND VASOCONSTRICTOR. If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents, like sedatives, are central nervous system depressants which in combination may have an additive effect. Young children should be given minimal doses of each agent. Changes in sensorium such as excitation, disorientation or drowsiness may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of Mepivacaine. Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. Information for Patients/Patient Counseling Information: The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue. Clinically Significant Drug Interactions The administration of local anesthetic solutions containing vasopressors, such as Levonordefrin, Epinephrine or Norepinephrine, to patients receiving tricyclic antidepressants or monoamine oxidase inhibitors may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of Epinephrine. Solutions containing a vasoconstrictor should be used cautiously in the presence of disease which may adversely affect the patient\'s cardiovascular system. Serious cardiac arrhythmias may occur if preparations containing a vasoconstrictor are employed in patients during or following the administration of potent inhalation anesthetics. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: EXAMPLES OF DRUGS ASSOCIATED WITH METHEMOGLOBINEMIA: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprus-side, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hy-droxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine MEPIVACAINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH KNOWN DRUG ALLERGIES AND SENSITIVITIES. A thorough history of the patient\'s prior experience with Mepivacaine or other local anesthetics as well as concomitant or recent drug use should be taken (see CONTRAINDICATIONS ). Patients allergic to methylparaben or para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as Mepivacaine. Since Mepivacaine is metabolized in the liver and excreted by the kidneys, it should be used cautiously in patients with liver and renal disease. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of Mepivacaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. Pregnancy Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when this solution is administered to a nursing woman. Pediatric Use Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': '{"Information for Patients/Patient Counseling Information: The patient should be cautioned against loss of sensation and possibility of biting trauma should the patient attempt to eat or chew gum prior to return of sensation. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue."}', 'pregnancy': '{"Pregnancy Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with this solution. It is also not known whether this solution can cause fetal harm when administered to a pregnant woman or can effect reproductive capacity. This solution should be given to a pregnant woman only if clearly needed."}', 'pediatric_use': '{"Pediatric Use Great care must be exercised in adhering to safe concentrations and dosages for pedodontic administration (see DOSAGE AND ADMINISTRATION )."}', 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"USE Decrease bacteria on hands"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ALCOHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if irritation and redness develops and persists."}', 'do_not_use': '{"When using this product avoid contact with eyes; in case of contact, flush eyes with water."}', 'when_using': None, 'warnings': '{"Warnings Flammable-keep product awau from fire or flame. Waring - Choking Hazard S mall parts. Not for children under 3 years. When using this product avoid contact with eyes; in case of contact, flush eyes with water. Stop use and ask a doctor if irritation and redness develops and persists. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use For rinse free hand cleaning to remove 99.9% bacteria on skin."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ALCOHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': '{"When using this product Avoid contact with eyes. In case of eye contact, rinse with water."}', 'warnings': '{"Warnings For external use only. Flammable Keep away from fire or flame. When using this product Avoid contact with eyes. In case of eye contact, rinse with water. Keep out of reach of children & pets. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"MICONAZOLE NITRATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses • treats vaginal yeast infections • relieves external itching and irritation due to a vaginal yeast infection"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"MICONAZOLE NITRATE"}', 'route': '{VAGINAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • symptoms do not get better in 3 days • symptoms last more than 7 days • you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge"}', 'do_not_use': '{"Do not use if you have never had a vaginal yeast infection diagnosed by a doctor"}', 'when_using': '{"When using this product • do not use tampons, douches, spermicides or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs). • do not have vaginal intercourse • mild increase in vaginal burning, itching or irritation may occur • if you do not get complete relief ask a doctor before using another product"}', 'warnings': '{"Warnings For vaginal use only Do not use if you have never had a vaginal yeast infection diagnosed by a doctor Ask a doctor before use if you have • vaginal itching and discomfort for the first time • lower abdominal, back or shoulder pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge. You may have a more serious condition. • vaginal yeast infections often (such as once a month or 3 in 6 months). You could be pregnant or have a serious underlying medical cause for your symptoms, including diabetes or a weakened immune system. • been exposed to the human immunodeficiency virus (HIV) that causes AIDS Ask a doctor or pharmacist before use if you are taking the prescription blood thinning medicine warfarin, because bleeding or bruising may occur When using this product • do not use tampons, douches, spermicides or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs). • do not have vaginal intercourse • mild increase in vaginal burning, itching or irritation may occur • if you do not get complete relief ask a doctor before using another product Stop use and ask a doctor if • symptoms do not get better in 3 days • symptoms last more than 7 days • you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away (1-800-222-1222)."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DEXTROMETHORPHAN HYDROBROMIDE",GUAIFENESIN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses ■ Temporarily relieves cough due to minor throat and bronchial irritation as may occur with a common cold ■ Helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus ■ Helps make coughs more productive."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"DEXTROMETHORPHAN HYDROBROMIDE / GUAIFENESIN"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask doctor if ■ symptoms are accompanied by fever, rash or persistent headache ■ cough persists for more than 1 week or tends to recur. A persistent cough may be a sign of a serious condition."}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Do not use ■ if you are now taking a prescription monoamine oxidase (inhiMor~MAIO) (Certain drugs for depression, psychiatric or emotional conditioners or Parkinson\'s disease)or for 2 weeks after stopping MAIO drug, If you do not know if your prescription drug contains an MAIO, ask your doctor or pharmacist before using this product."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{TETRABENAZINE}

{'contraindications': '{"4 CONTRAINDICATIONS Tetrabenazine tablets are contraindicated in patients: • Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.1) ] . • With hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . • Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablets should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3) ] . • Taking reserpine. At least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets [see Drug Interactions (7.2) ] . • Taking deutetrabenazine or valbenazine [see Drug Interactions (7.7) ]. • Actively suicidal, or who have depression which is untreated or undertreated (4 , 5.1) • Hepatic impairment (4 , 8.6 , 12.3) • Taking monoamine oxidase inhibitors (MAOIs) or reserpine (4 , 7.2 , 7.3) • Taking deutetrabenazine or valbenazine (4 , 7.7)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Depression and Suicidality [see Warnings and Precautions (5.1) ] • Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4) ] • Akathisia, Restlessness, and Agitation [see Warnings and Precautions (5.5) ] • Parkinsonism [see Warnings and Precautions (5.6) ] • Sedation and Somnolence [see Warnings and Precautions (5.7) ] • QTc Prolongation [see Warnings and Precautions (5.8) ] • Hypotension and Orthostatic Hypotension [see Warnings and Precautions (5.9) ] • Hyperprolactinemia [see Warnings and Precautions (5.10) ] • Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.11) ] Most common adverse reactions (greater than 10% and at least 5% greater than placebo) were: sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During its development, tetrabenazine tablets was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine tablets varied greatly, and included single-dose and multiple-dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients. In a randomized, 12-week, placebo-controlled clinical trial of HD patients, adverse reactions were more common in the tetrabenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received tetrabenazine tablets experienced one or more adverse reactions at any time during the study. The most common adverse reactions (over 10%, and at least 5% greater than placebo) were sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, and nausea. Adverse Reactions Occurring in ≥4% of Patients The number and percentage of the most common adverse reactions that occurred at any time during the study in ≥4% of tetrabenazine tablets-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1. Table 1: Adverse Reactions in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington\'s Disease Adverse Reaction Tetrabenazine Tablets N=54 % Placebo N=30 % Sedation/somnolence 31 3 Insomnia 22 0 Fatigue 22 13 Depression 19 0 Akathisia 19 0 Anxiety/anxiety aggravated 15 3 Fall 15 13 Nausea 13 7 Upper respiratory tract infection 11 7 Irritability 9 3 Balance difficulty 9 0 Parkinsonism/bradykinesia 9 0 Vomiting 6 3 Laceration (head) 6 0 Ecchymosis 6 0 Decreased appetite 4 0 Obsessive reaction 4 0 Dizziness 4 0 Dysarthria 4 0 Unsteady gait 4 0 Headache 4 3 Shortness of breath 4 0 Bronchitis 4 0 Dysuria 4 0 Dose escalation was discontinued or dosage of study drug was reduced because of one or more adverse reactions in 28 of 54 (52%) patients randomized to tetrabenazine tablets. These adverse reactions consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AR and are, therefore, counted more than once. Adverse Reactions Due to Extrapyramidal Symptoms Table 2 describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at a greater frequency in tetrabenazine tablets-treated patients compared to placebo- treated patients. Table 2: Adverse Reactions Due to Extrapyramidal Symptoms in a 12-Week, Double- Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease Tetrabenazine Tablets n = 54 % Placebo n = 30 % Akathisia* 19 0 Extrapyramidal event† 15 0 Any extrapyramidal event 33 0 *Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. † Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia. Patients may have had events in more than one category. Dysphagia Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of tetrabenazine tablets-treated patients and 3% of placebo-treated patients. In 48-week and 80-week, open-label studies, dysphagia was observed in 10% and 8% of tetrabenazine tablets-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tetrabenazine tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorders: tremor Psychiatric disorders: confusion, worsening aggression Respiratory, thoracic and mediastinal disorders: pneumonia Skin and subcutaneous tissue disorders: hyperhidrosis, skin rash"}', 'drug_interactions': '{"7 DRUG INTERACTIONS 7.1 Strong CYP2D6 Inhibitors In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in tetrabenazine dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of tetrabenazine tablets. The daily dose of tetrabenazine tablets should not exceed 50 mg per day and the maximum single dose of tetrabenazine tablets should not exceed 25 mg in patients taking strong CYP2D6 inhibitors [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 7.2 Reserpine Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. Prescribers should wait for chorea to re-emerge before administering tetrabenazine tablets to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets. Tetrabenazine tablets and reserpine should not be used concomitantly [see Contraindications (4) ] . 7.3 Monoamine Oxidase Inhibitors (MAOIs) Tetrabenazine tablets are contraindicated in patients taking MAOIs. Tetrabenazine tablets should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4) ] . 7.4 Alcohol or Other Sedation Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions (5.7) ]. 7.5 Drugs That Cause QTc Prolongation Tetrabenazine tablets causes a small prolongation of QTc (about 8 msec), concomitant use with other drugs that are known to cause QTc prolongation should be avoided, these including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetrabenazine should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain conditions may increase the risk for torsade de pointes or sudden death such as (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval [see Warnings and Precautions (5.8) , Clinical Pharmacology (12.2) ] . 7.6 Neuroleptic Drugs The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of tetrabenazine tablets and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) [see Warnings and Precautions (5.4 , 5.5 , 5.6) ]. 7.7 Concomitant Deutetrabenazine or Valbenazine Tetrabenazine tablets are contraindicated in patients currently taking deutetrabenazine or valbenazine."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Tetrabenazine tablets are indicated for the treatment of chorea associated with Huntington’s disease. Tetrabenazine tablets are a vesicular monoamine transporter 2 (VMAT) inhibitor indicated for the treatment of chorea associated with Huntington’s disease. (1)"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity. (5.2) • Do not exceed 50 mg per day and the maximum single dose should not exceed 25 mg if administered in conjunction with a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine). (5.3 , 7.1) • Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs. (5.4 , 7.6) • Restlessness, agitation, akathisia and parkinsonism: Reduce dose or discontinue if occurs. (5.5 , 5.6) • Sedation/Somnolence: May impair patient’s ability to drive or operate complex machinery (5.7) • QTc prolongation: Not recommended in combination with other drugs that prolong QTc (5.8) 5.1 Depression and Suicidality Patients with Huntington’s disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine increases the risk for suicidality in patients with HD. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease, 10 of 54 patients (19%) treated with tetrabenazine tablets were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received tetrabenazine tablets for up to 48 weeks; in the second study, 75 patients received tetrabenazine tablets for up to 80 weeks), the rate of depression/worsening depression was 35%. In all of the HD chorea studies of tetrabenazine (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation. When considering the use of tetrabenazine tablets, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with tetrabenazine tablets should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine tablets. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with tetrabenazine tablets, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately. 5.2 Clinical Worsening and Adverse Effects Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, tetrabenazine tablets was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown. Prescribers should periodically re-evaluate the need for tetrabenazine tablets in their patients by assessing the effect on chorea and possible adverse effects, including depression and suicidality, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness, and disability. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for tetrabenazine tablets. 5.3 Laboratory Tests Before prescribing a daily dose of tetrabenazine tablets that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of tetrabenazine tablets. Patients who are PMs of tetrabenazine tablets will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient’s CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg [see Dosage and Administration (2.2) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine tablets and other drugs that reduce dopaminergic transmission [see Drug Interactions (7.6) ] . Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection), and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include (1) immediate discontinuation of tetrabenazine tablets; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. Recurrence of NMS has been reported with resumption of drug therapy. If treatment with tetrabenazine tablets is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5 Akathisia, Restlessness, and Agitation Tetrabenazine tablets may increase the risk of akathisia, restlessness, and agitation. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine tablets-treated patients and 0% of placebo-treated patients. In an 80-week, open-label study, akathisia was observed in 20% of tetrabenazine tablets-treated patients. Patients receiving tetrabenazine tablets should be monitored for the presence of akathisia. Patients receiving tetrabenazine tablets should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine tablets dose should be reduced; however, some patients may require discontinuation of therapy. 5.6 Parkinsonism Tetrabenazine tablets can cause parkinsonism. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15% of tetrabenazine tablets-treated patients compared to 0% of placebo-treated patients. In 48-week and 80-week, open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of tetrabenazine tablets-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between this drug-induced adverse reaction and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease. If a patient develops parkinsonism during treatment with tetrabenazine tablets, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary. 5.7 Sedation and Somnolence Sedation is the most common dose-limiting adverse reaction of tetrabenazine tablets. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence occurred in 17/54 (31%) of tetrabenazine tablets-treated patients and in 1 (3%) of placebo-treated patient. Sedation was the reason upward titration of tetrabenazine tablets was stopped and/or the dose of tetrabenazine tablets was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of tetrabenazine tablets resulted in decreased sedation. In 48-week and 80-week, open-label studies, sedation/somnolence occurred in 17% and 57% of tetrabenazine-treated patients, respectively. In some patients, sedation occurred at doses that were lower than recommended doses. Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine and know how the drug affects them. 5.8 QTc Prolongation Tetrabenazine tablets causes a small increase (about 8 msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases [see Clinical Pharmacology (12.2) ] . The use of tetrabenazine tablets should be avoided in combination with other drugs that are known to prolong QTc, including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval [see Drug Interactions (7.5) ] . Tetrabenazine tablets should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval [see Clinical Pharmacology (12.2) ] . 5.9 Hypotension and Orthostatic Hypotension Tetrabenazine tablets induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope, and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of tetrabenazine tablets-treated patients (vs. none on placebo) in the 12-week, controlled trial; however, blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension. 5.10 Hyperprolactinemia Tetrabenazine tablets elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin‑ dependent in vitro , a factor of potential importance if tetrabenazine tablets is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the tetrabenazine tablets development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine tablets. 5.11 Binding to Melanin-Containing Tissues Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine tablets may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species, such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure. The clinical relevance of tetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects [see Clinical Pharmacology (12.2) ] ."}', 'overdosage': '{"10 OVERDOSAGE Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with tetrabenazine tablets have been reported in the literature. The dose of tetrabenazine tablets in these patients ranged from 100 mg to 1 g. Adverse reactions associated with tetrabenazine tablets overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose."}', 'active_flag': 'Y', 'generic_name': '{TETRABENAZINE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Suicidality Inform patients and their families that tetrabenazine tablets may increase the risk of suicidal thinking and behaviors. Counsel patients and their families to remain alert to the emergence of suicidal ideation and to report it immediately to the patient’s physician [see Contraindications (4) , Warnings and Precautions (5.1) ] . Risk of Depression Inform patients and their families that tetrabenazine tablets may cause depression or may worsen pre‑ existing depression. Encourage patients and their families to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and to report such symptoms promptly to the patient’s physician [see Contraindications (4) , Warnings and Precautions (5.1) ] . Dosing of Tetrabenazine Tablets Inform patients and their families that the dose of tetrabenazine tablets will be increased slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician, and the tetrabenazine tablets dose may need to be reduced or discontinued [see Dosage and Administration (2.2) ] . Risk of Sedation and Somnolence Inform patients that tetrabenazine tablets may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to tetrabenazine tablets, they should be careful doing activities that require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions (5.7) ] . Interaction with Alcohol Advise patients and their families that alcohol may potentiate the sedation induced by tetrabenazine tablets [see Drug Interactions (7.4) ] . Usage in Pregnancy Advise patients and their families to notify the physician if the patient becomes pregnant or intends to become pregnant during tetrabenazine tablets therapy, or is breastfeeding or intending to breastfeed an infant during therapy [see Use in Specific Populations (8.1) ] . Manufactured by: Piramal Pharma Limited, Plot No. 67-70 Sector 2, Pithampur-454775, Dist. Dhar (Madhya Pradesh), INDIA Mfg Lic. No.: 25/10/92 Distributed by: Slate Run Pharmaceuticals, LLC. Columbus, Ohio 43215 Product of India Revised 10/2020 20768371 EM15633/a"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of tetrabenazine tablets in pregnant women. Administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality. Administration of a major human metabolite of tetrabenazine to rats during pregnancy or during pregnancy and lactation produced adverse effects on the developing fetus and offspring (increased mortality, decreased growth, and neurobehavioral and reproductive impairment). The adverse developmental effects of tetrabenazine and a major human metabolite of tetrabenazine in rats occurred at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Tetrabenazine had no clear effects on embryofetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [MRHD] of 100 mg per day on a mg/m 2 basis). Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m 2 basis). When tetrabenazine (5, 15, and 30 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. A no-effect dose for pre- and postnatal developmental toxicity in rats was not identified. The lowest dose tested (5 mg/kg/day) was less than the MRHD on a mg/m 2 basis. Because rats dosed orally with tetrabenazine do not produce 9-desmethyl-β-DHTBZ, a major human metabolite of tetrabenazine, the metabolite was directly administered to pregnant and lactating rats. Oral administration of 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. The no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (AUC) of 9-desmethyl-β-DHTBZ in pregnant rats lower than that in humans at the MRHD."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects."}'}

{ADENINE,"ANHYDROUS CITRIC ACID","DEXTROSE MONOHYDRATE","SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE","TRISODIUM CITRATE DIHYDRATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ANTICOAGULANT CITRATE PHOSPHATE DEXTROSE ADENINE"}', 'route': '{INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"TRIAMCINOLONE ACETONIDE"}

{'contraindications': '{"CONTRAINDICATIONS Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparations."}', 'adverse_reactions': '{"ADVERSE REACTIONS The following local adverse reactions are reported infrequently with topical corticosteroids, but may occur more frequently with the use of occlusive dressings (reactions are listed in an approximate decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Triamcinolone acetonide cream, 0.1% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS, General )."}', 'active_flag': 'Y', 'generic_name': '{"TRIAMCINOLONE ACETONIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': '{"PRECAUTIONS General Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing\'s syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients receiving a large dose of any potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, substitute a less potent steroid, or use a sequential approach when utilizing the occlusive technique. Recovery of HPA axis function and thermal homeostasis are generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids. Occasionally, a patient may develop a sensitivity reaction to a particular occlusive dressing material or adhesive and a substitute material may be necessary. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS, Pediatric Use ). If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted. In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled. These preparations are not for ophthalmic use. Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for dermatologic use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory Tests A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA axis suppression. Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity with prednisolone and hydrocortisone showed negative results. Pregnancy Teratogenic Effects Category C Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time. Nursing Mothers It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing\'s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing\'s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children."}', 'information_for_patients': '{"Information for the Patient Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for dermatologic use only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician. 4. Patients should report any signs of local adverse reactions especially under occlusive dressing. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings."}', 'pregnancy': '{"Pregnancy Teratogenic Effects Category C Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time."}', 'pediatric_use': '{"Pediatric Use Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing\'s syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushing\'s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children."}', 'geriatric_use': None}

{"BETAMETHASONE DIPROPIONATE",CLOTRIMAZOLE}

{'contraindications': '{"CONTRAINDICATIONS Clotrimazole and betamethasone dipropionate cream is contraindicated in patients who are sensitive to clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or to any ingredient in these preparations."}', 'adverse_reactions': '{"ADVERSE REACTIONS Adverse reactions reported for clotrimazole and betamethasone dipropionate cream in clinical trials were paresthesia in 1 . 9% of patients, and rash, edema, and secondary infection, each in less than 1% of patients. The following local adverse reactions have been reported with topical corticosteroids and may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria, capillary fragility (ecchymoses), and sensitization (local reactions upon repeated application of product). In the pediatric population, reported adverse events for clotrimazole and betamethasone dipropionate cream include growth retardation, benign intracranial hypertension, Cushing’s syndrome (HPA axis suppression), and local cutaneous reactions, including skin atrophy. Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients. Adverse reactions reported with the use of clotrimazole are as follows: erythema, stinging, blistering, peeling, edema, pruritus, urticaria and general irritation of the skin."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Clotrimazole and Betamethasone Dipropionate Cream is indicated in patients 17 years and older for the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris and tinea corporis due to Epidermophyton floccosum , Trichophyton mentagrophytes , and Trichophyton rubrum . Effective treatment without the risks associated with topical corticosteroid use may be obtained using a topical antifungal agent that does not contain a corticosteroid, especially for noninflammatory tinea infections. The efficacy of clotrimazole and betamethasone dipropionate cream for the treatment of infections caused by zoophilic dermatophytes (e.g., Microsporum canis ) has not been established. Several cases of treatment failure of clotrimazole and betamethasone dipropionate cream in the treatment of infections caused by Microsporum canis have been reported"}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Amounts greater than 45 g/week of clotrimazole and betamethasone dipropionate cream should not be used. Acute overdosage with topical application of clotrimazole and betamethasone dipropionate cream is unlikely and would not be expected to lead to a life-threatening situation. Clotrimazole and betamethasone dipropionate cream should not be used for longer than the prescribed time period. Topically applied corticosteroids, such as the one contained in clotrimazole and betamethasone dipropionate cream, can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS )."}', 'active_flag': 'Y', 'generic_name': '{"CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': '{"PRECAUTIONS General Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment. Conditions which augment systemic absorption include use over large surface areas, prolonged use, and use under occlusive dressings. Use of more than one corticosteroid-containing product at the same time may increase total systemic glucocorticoid exposure. Patients applying clotrimazole and betamethasone dipropionate cream to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA-axis suppression. This may be done by using the ACTH stimulation, morning plasma cortisol, and urinary-free cortisol tests. If HPA-axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA-axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. In a small study, clotrimazole and betamethasone dipropionate cream was applied using large dosages, 7 g daily for 14 days (BID) to the crural area of normal adult subjects. Three of the eight normal subjects on whom clotrimazole and betamethasone dipropionate cream was applied exhibited low morning plasma cortisol levels during treatment. One of these subjects had an abnormal Cortrosyn test. The effect on morning plasma cortisol was transient and subjects recovered one week after discontinuing dosing. In addition, two separate studies in pediatric patients demonstrated adrenal suppression as determined by cosyntropin testing (see PRECAUTIONS – Pediatric Use section). Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS – Pediatric Use section). If irritation develops, clotrimazole and betamethasone dipropionate cream should be discontinued and appropriate therapy instituted. THE SAFETY OF CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM HAS NOT BEEN DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN OBSERVED IN PATIENTS TREATED WITH CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM FOR DIAPER DERMATITIS. THE USE OF CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM IN THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED. Information for Patients Patients using clotrimazole and betamethasone dipropionate cream should receive the following information and instructions: • The medication is to be used as directed by the physician and is not recommended for use longer than the prescribed time period. It is for external use only. Avoid contact with the eyes, the mouth, or intravaginally. • This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify the physician if there is no improvement after 1 week of treatment for tinea cruris or tinea corporis, or after 2 weeks for tinea pedis. • This medication should only be used for the disorder for which it was prescribed. • Other corticosteroid-containing products should not be used with clotrimazole and betamethasone dipropionate without first talking with your physician. • The treated skin area should not be bandaged, covered, or wrapped so as to be occluded (see DOSAGE AND ADMINISTRATION ). • Any signs of local adverse reactions should be reported to your physician. • Patients should avoid sources of infection or reinfection. • When using clotrimazole and betamethasone dipropionate cream in the groin area, patients should use the medication for two weeks only, and apply the cream sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after two weeks. • The safety of clotrimazole and betamethasone dipropionate cream has not been demonstrated in the treatment of diaper dermatitis. Adverse events consistent with corticosteroid use have been observed in patients treated with clotrimazole and betamethasone dipropionate cream for diaper dermatitis. The use of clotrimazole and betamethasone dipropionate cream in the treatment of diaper dermatitis is not recommended. Laboratory Tests If there is a lack of response to clotrimazole and betamethasone dipropionate cream, appropriate confirmation of the diagnosis, including possible mycological studies, is indicated before instituting another course of therapy. The following tests may be helpful in evaluating HPA-axis suppression due to the corticosteroid components: Carcinogenesis, Mutagenesis, Impairment of Fertility There are no adequate laboratory animal studies with either the combination of clotrimazole and betamethasone dipropionate or with either component individually to evaluate carcinogenesis. Betamethasone was negative in the bacterial mutagenicity assay ( Salmonella typhimurium and Escherichia coli) and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay. This pattern of response is similar to that of dexamethasone and hydrocortisone. Reproductive studies with betamethasone dipropionate carried out in rabbits at doses of 1 . 0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the intramuscular route indicated no impairment of fertility except for dose-related increases in fetal resorption rates in both species. These doses are approximately 5- and 38-fold the maximum human dose based on body surface areas, respectively. In a combined study of the effects of clotrimazole on fertility, teratogenicity, and postnatal development, male and female rats were dosed orally (diet admixture) with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum dose in a 60 kg adult based on body surface area) from 10 weeks prior to mating until 4 weeks postpartum. No adverse effects on the duration of estrous cycle, fertility, or duration of pregnancy were noted. Pregnancy Teratogenic Effects Pregnancy Category C: There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels. Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure. No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation days 6-15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights) and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or fetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks. Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18-55 times the maximum human dose). Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0 . 05 mg/kg. This dose is approximately one-fifth the maximum human dose. The abnormalities observed included umbilical hernias, cephalocele and cleft palates. Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. There are no adequate and well-controlled studies in pregnant women of the teratogenic effects of topically applied corticosteroids. Therefore, clotrimazole and betamethasone dipropionate cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroids production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when clotrimazole and betamethasone dipropionate cream is administered to a nursing woman. Pediatric Use Adverse events consistent with corticosteroid use have been observed in patients under 12 years of age treated with clotrimazole and betamethasone dipropionate cream. In open-label studies, 17 of 43 (39 . 5%) evaluable pediatric patients (aged 12 to 16 years old) using clotrimazole and betamethasone dipropionate cream for treatment of tinea pedis demonstrated adrenal suppression as determined by cosyntropin testing. In another open-label study, 8 of 17 (47 . 1%) evaluable pediatric patients (aged 12 to 16 years old) using clotrimazole and betamethasone dipropionate cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing. THE USE OF CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM IN THE TREATMENT OF PATIENTS UNDER 17 YEARS OF AGE OR PATIENTS WITH DIAPER DERMATITIS IS NOT RECOMMENDED. Because of higher ratio of skin surface area to body mass, pediatric patients under the age of 12 years are at a higher risk with clotrimazole and betamethasone dipropionate cream. The studies described above suggest that pediatric patients under the age of 17 years may also have this risk. They are at increased risk of developing Cushing’s syndrome while on treatment and adrenal insufficiency after withdrawal of treatment. Adverse effects, including striae and growth retardation, have been reported with inappropriate use of clotrimazole and betamethasone dipropionate cream in infants and children (see PRECAUTIONS and ADVERSE REACTIONS ). Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. Geriatric Use Clinical studies of clotrimazole and betamethasone dipropionate cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post market adverse event reporting for clotrimazole and betamethasone dipropionate cream in patients aged 65 and above includes reports of skin atrophy and rare reports of skin ulceration. Caution should be exercised with the use of these corticosteroid containing topical products on thinning skin. THE USE OF CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM UNDER OCCLUSION, SUCH AS IN DIAPER DERMATITIS, IS NOT RECOMMENDED."}', 'information_for_patients': '{"Information for Patients Patients using clotrimazole and betamethasone dipropionate cream should receive the following information and instructions: • The medication is to be used as directed by the physician and is not recommended for use longer than the prescribed time period. It is for external use only. Avoid contact with the eyes, the mouth, or intravaginally. • This medication is to be used for the full prescribed treatment time, even though the symptoms may have improved. Notify the physician if there is no improvement after 1 week of treatment for tinea cruris or tinea corporis, or after 2 weeks for tinea pedis. • This medication should only be used for the disorder for which it was prescribed. • Other corticosteroid-containing products should not be used with clotrimazole and betamethasone dipropionate without first talking with your physician. • The treated skin area should not be bandaged, covered, or wrapped so as to be occluded (see DOSAGE AND ADMINISTRATION ). • Any signs of local adverse reactions should be reported to your physician. • Patients should avoid sources of infection or reinfection. • When using clotrimazole and betamethasone dipropionate cream in the groin area, patients should use the medication for two weeks only, and apply the cream sparingly. Patients should wear loose-fitting clothing. Notify the physician if the condition persists after two weeks. • The safety of clotrimazole and betamethasone dipropionate cream has not been demonstrated in the treatment of diaper dermatitis. Adverse events consistent with corticosteroid use have been observed in patients treated with clotrimazole and betamethasone dipropionate cream for diaper dermatitis. The use of clotrimazole and betamethasone dipropionate cream in the treatment of diaper dermatitis is not recommended."}', 'pregnancy': '{"Pregnancy Teratogenic Effects Pregnancy Category C: There have been no teratogenic studies performed in animals or humans with the combination of clotrimazole and betamethasone dipropionate. Corticosteroids are generally teratogenic in laboratory animals when administered at relatively low dosage levels. Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole exposure. No increase in fetal malformations was noted in pregnant rats receiving oral (gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation days 6-15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased resorptions), fetotoxic (reduced fetal weights) and maternally toxic (reduced body weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the maximum human dose) was maternally lethal, and therefore fetuses were not evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the maximum human dose) had no adverse effects on dams or fetuses. However, in the combined fertility, teratogenicity, and postnatal development study described above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain and reduced numbers of offspring reared to 4 weeks. Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the maximum human dose) were not teratogenic in mice. No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120, or 180 mg/kg/day (18-55 times the maximum human dose). Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0 . 05 mg/kg. This dose is approximately one-fifth the maximum human dose. The abnormalities observed included umbilical hernias, cephalocele and cleft palates. Betamethasone dipropionate has not been tested for teratogenic potential by the dermal route of administration. Some corticosteroids have been shown to be teratogenic after dermal application to laboratory animals. There are no adequate and well-controlled studies in pregnant women of the teratogenic effects of topically applied corticosteroids. Therefore, clotrimazole and betamethasone dipropionate cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"Pediatric Use Adverse events consistent with corticosteroid use have been observed in patients under 12 years of age treated with clotrimazole and betamethasone dipropionate cream. In open-label studies, 17 of 43 (39 . 5%) evaluable pediatric patients (aged 12 to 16 years old) using clotrimazole and betamethasone dipropionate cream for treatment of tinea pedis demonstrated adrenal suppression as determined by cosyntropin testing. In another open-label study, 8 of 17 (47 . 1%) evaluable pediatric patients (aged 12 to 16 years old) using clotrimazole and betamethasone dipropionate cream for treatment of tinea cruris demonstrated adrenal suppression as determined by cosyntropin testing. THE USE OF CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM IN THE TREATMENT OF PATIENTS UNDER 17 YEARS OF AGE OR PATIENTS WITH DIAPER DERMATITIS IS NOT RECOMMENDED. Because of higher ratio of skin surface area to body mass, pediatric patients under the age of 12 years are at a higher risk with clotrimazole and betamethasone dipropionate cream. The studies described above suggest that pediatric patients under the age of 17 years may also have this risk. They are at increased risk of developing Cushing’s syndrome while on treatment and adrenal insufficiency after withdrawal of treatment. Adverse effects, including striae and growth retardation, have been reported with inappropriate use of clotrimazole and betamethasone dipropionate cream in infants and children (see PRECAUTIONS and ADVERSE REACTIONS ). Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema."}', 'geriatric_use': '{"Geriatric Use Clinical studies of clotrimazole and betamethasone dipropionate cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post market adverse event reporting for clotrimazole and betamethasone dipropionate cream in patients aged 65 and above includes reports of skin atrophy and rare reports of skin ulceration. Caution should be exercised with the use of these corticosteroid containing topical products on thinning skin. THE USE OF CLOTRIMAZOLE AND BETAMETHASONE DIPROPIONATE CREAM UNDER OCCLUSION, SUCH AS IN DIAPER DERMATITIS, IS NOT RECOMMENDED."}'}

{"HYDROXYZINE PAMOATE"}

{'contraindications': '{"CONTRAINDICATIONS Hydroxyzine, when administered to the pregnant mouse, rat, and rabbit, induced fetal abnormalities in the rat and mouse at doses substantially above the human therapeutic range. Clinical data in human beings are inadequate to establish safety in early pregnancy. Until such data are available, hydroxyzine is contraindicated in early pregnancy. Hydroxyzine is contraindicated in patients with a prolonged QT interval. Hydroxyzine pamoate is contraindicated for patients who have shown a previous hypersensitivity to any component of this medication. Hydroxyzine is contraindicated in patients with known hypersensitivity to hydroxyzine products, and in patients with known hypersensitivity to cetirizine hydrochloride or levocetrizine hydrochloride."}', 'adverse_reactions': '{"ADVERSE REACTIONS Side effects reported with the administration of hydroxyzine pamoate are usually mild and transitory in nature. Skin and Appendages: Oral hydroxyzine hydrochloride is associated with Acute Generalized Exanthematous Pustulosis (AGEP) and fixed drug eruptions in post-marketing reports. Anticholinergic: Dry mouth. Central Nervous System: Drowsiness is usually transitory and may disappear in a few days of continued therapy or upon reduction of the dose. Involuntary motor activity, including rare instances of tremor and convulsions, has been reported, usually with doses considerably higher than those recommended. Clinically significant respiratory depression has not been reported at recommended doses. Cardiac System: QT prolongation,Torsade de Pointes. In post-marketing experience, the following additional undesirable effects have been reported: Body as a Whole: allergic reaction, Nervous System: headache, Psychiatric: hallucination, Skin and Appendages: pruritus, rash, urticaria. To report SUSPECTED ADVERSE EVENTS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS For symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested. Useful in the management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus. As a sedative when used as premedication and following general anesthesia, Hydroxyzine may potentiate meperidine (Demerol ® ) and barbiturates , so their use in pre-anesthetic adjunctive therapy should be modified on an individual basis. Atropine and other belladonna alkaloids are not affected by the drug. Hydroxyzine is not known to interfere with the action of digitalis in any way and it may be used concurrently with this agent. The effectiveness of hydroxyzine as an antianxiety agent for long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should reassess periodically the usefulness of the drug for the individual patient."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE The most common manifestation of overdosage of hydroxyzine pamoate is hypersedation. Other reported signs and symptoms were convulsions, stupor, nausea and vomiting. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting has not occurred spontaneously, it should be induced. Immediate gastric lavage is also recommended. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Hypotension, though unlikely, may be controlled with intravenous fluids and vasopressors ( do not use epinephrine as hydroxyzine counteracts its pressor action. ) Caffeine and Sodium Benzoate Injection, USP, may be used to counteract central nervous system depressant effects. Hydroxyzine overdose may cause QT prolongation and Torsade de Pointes. ECG monitoring is recommended in cases of hydroxyzine overdose. There is no specific antidote. It is doubtful that hemodialysis would be of any value in the treatment of overdosage with hydroxyzine. However, if other agents such as barbiturates have been ingested concomitantly, hemo-dialysis may be indicated. There is no practical method to quantitate hydroxyzine in body fluids or tissue after its ingestion or administration."}', 'active_flag': 'Y', 'generic_name': '{"HYDROXYZINE PAMOATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Nursing Mothers It is not known whether this drug is excreted in human milk. Since many drugs are so excreted, hydroxyzine should not be given to nursing mothers."}', 'precautions': '{"PRECAUTIONS THE POTENTIATING ACTION OF HYDROXYZINE MUST BE CONSIDERED WHEN THE DRUG IS USED IN CONJUNCTION WITH CENTRAL NERVOUS SYSTEM DEPRESSANTS SUCH AS NARCOTICS, NON-NARCOTIC ANALGESICS AND BARBITURATES. Therefore, when central nervous system depressants are administered concomitantly with hydroxyzine, their dosage should be reduced. Since drowsiness may occur with use of the drug, patients should be warned of this possibility and cautioned against driving a car or operating dangerous machinery while taking hydroxyzine pamoate. Patients should be advised against the simultaneous use of other CNS depressant drugs, and cautioned that the effect of alcohol may be increased. QT Prolongation/Torsade de Pointes (TdP): Cases of QT prolongation and Torsade de Pointes have been reported during post-marketing use of hydroxyzine. The majority of reports occurred in patients with other risk factors for QT prolongation/TdP (pre-existing heart disease, electrolyte imbalances or concomitant arrhythmogenic drug use). Therefore, hydroxyzine should be used with caution in patients with risk factors for QT prolongation, congenital long QT syndrome, a family history of long QT syndrome, other conditions that predispose to QT prolongation and ventricular arrhythmia, as well as recent myocardial infarction, uncompensated heart failure, and bradyarrhythmias. Caution is recommended during the concomitant use of drugs known to prolong the QT interval. These include Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmics, certain antipsychotics (e.g., ziprasidone, iloperidone, clozapine, quetiapine, chlorpromazine), certain antidepressants (e.g., citalopram, fluoxetine), certain antibiotics (e.g., azithromycin, erythromycin, clarithromycin, gatifloxacin, moxifloxacin); and others (e.g., pentamidine, methadone, ondansetron, droperidol). Acute Generalized Exanthematous Pustulosis (AGEP): Hydroxyzine may rarely cause acute generalized exanthematous pustulosis (AGEP), a serious skin reaction characterized by fever and numerous small, superficial, non-follicular, sterile pustules, arising within large areas of edematous erythema. Inform patients about the signs of AGEP, and discontinue hydroxyzine at the first appearance of a skin rash, worsening of pre-existing skin reactions which hydroxyzine may be used to treat, or any other sign of hypersensitivity. If signs or symptoms suggest AGEP, use of hydroxyzine should not be resumed and alternative therapy should be considered. Avoid cetirizine or levocetirizine in patients who have experienced AGEP or other hypersensitivity reactions with hydroxyzine, due to the risk of cross-sensitivity. Geriatric Use A determination has not been made whether controlled clinical studies of hydroxyzine pamoate included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. The extent of renal excretion of hydroxyzine pamoate has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of hydroxyzine pamoate and observed closely."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ACETAMINOPHEN,"HYDROCODONE BITARTRATE"}

{'contraindications': '{"CONTRAINDICATIONS Hydrocodone Bitartrate and Acetaminophen Tablets are contraindicated in patients with: Significant respiratory depression [see WARNINGS ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see WARNINGS ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see WARNINGS ] Hypersensitivity to hydrocodone or acetaminophen (e.g., anaphylaxis) [see WARNINGS , ADVERSE REACTIONS ]"}', 'adverse_reactions': '{"ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of Hydrocodone and Acetaminophen Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting. Other adverse reactions include: Central Nervous System Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychological dependence, mood changes. Gastrointestinal System Constipation. Genitourinary System Ureteral spasm, spasm of vesical sphincters, and urinary retention. Special Senses Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose. Dermatological Skin rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic reactions. Hematological Thrombocytopenia, agranulocytosis. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Acetaminophen Tablets. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY ]. To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc., at (732) 940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch"}', 'drug_interactions': '{"Drug Interactions Inhibitors of CYP3A4 and CYP2D6 The concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of the hydrocodone from Hydrocodone Bitartrate and Acetaminophen Tablets, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Acetaminophen Tablets is achieved [see WARNINGS ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Acetaminophen Tablets. If concomitant use is necessary, consider dosage reduction of Hydrocodone Bitartrate and Acetaminophen Tablets until stable drug effects are achieved. Follow patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Hydrocodone Bitartrate and Acetaminophen Tablets dosage until stable drug effects are achieved. Follow for signs or symptoms of opioid withdrawal. Inducers of CYP3A4 The concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see WARNINGS ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see CLINICAL PHARMACOLOGY ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If concomitant use is necessary, consider increasing the Hydrocodone Bitartrate and Acetaminophen Tablets dosage until stable drug effects are achieved. Follow the patient for signs and symptoms of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Hydrocodone Bitartrate and Acetaminophen Tablets dosage reduction and follow for signs of respiratory depression. Benzodiazepines and Other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome [see PRECAUTIONS; Information for Patients ]. If concomitant use is warranted, carefully follow the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and acetaminophen tablets if serotonin syndrome is suspected. Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS ]. The use of Hydrocodone Bitartrate and Acetaminophen Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of Hydrocodone Bitartrate and Acetaminophen Tablets and/or precipitate withdrawal symptoms. Advise patient to avoid concomitant use of these drugs. Muscle Relaxants Hydrocodone Bitartrate and Acetaminophen Tablets may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. If concomitant use is warranted, follow patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. If concomitant use is warranted, follow patients for signs and symptoms of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Acetaminophen Tablets are used concomitantly with anticholinergic drugs."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Hydrocodone Bitartrate and Acetaminophen Tablets are indicated for the management of pain severe enough to require opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses [see WARNINGS ], reserve Hydrocodone Bitartrate and Acetaminophen Tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia"}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen. Clinical Presentation Acute overdosage with Hydrocodone Bitartrate and Acetaminophen Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Acetaminophen Dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect of acetaminophen overdosage. Renal tubular necrosis, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment of Overdose Hydrocodone In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone in Hydrocodone Bitartrate and Acetaminophen Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist. Acetaminophen Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication."}', 'active_flag': 'Y', 'generic_name': '{"HYDROCODONE BITARTRATE AND ACETAMINOPHEN"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Addiction, Abuse, and Misuse Hydrocodone Bitartrate and Acetaminophen Tablets contains hydrocodone, a Schedule II controlled substance. As an opioid, Hydrocodone Bitartrate and Acetaminophen Tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydrocodone Bitartrate and Acetaminophen Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydrocodone Bitartrate and Acetaminophen Tablets, and monitor all patients receiving Hydrocodone Bitartrate and Acetaminophen Tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hydrocodone Bitartrate and Acetaminophen Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Hydrocodone Bitartrate and Acetaminophen Tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydrocodone Bitartrate and Acetaminophen Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS; Information for Patients ]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG . Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydrocodone Bitartrate and Acetaminophen Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Hydrocodone Bitartrate and Acetaminophen Tablets. To reduce the risk of respiratory depression, proper dosing and titration of Hydrocodone Bitartrate and Acetaminophen Tablets are essential [see DOSAGE AND ADMINISTRATION ]. Overestimating the Hydrocodone Bitartrate and Acetaminophen Tablets dosage when converting patients from another opioid product can result in a fatal overdose. Accidental ingestion of even one dose of Hydrocodone Bitartrate and Acetaminophen Tablets, especially by children, can result in respiratory depression and death due to an overdose of Hydrocodone Bitartrate and Acetaminophen Tablets. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS, Information for Patients/Caregivers ]. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION ] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Hydrocodone Bitartrate and Acetaminophen Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see PRECAUTIONS, Information for Patients/Caregivers ]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see WARNINGS, Addiction, Abuse, and Misuse , Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ; PRECAUTIONS, Information for Patients/Caregivers ]. Neonatal Opioid Withdrawal Syndrome Prolonged use of Hydrocodone Bitartrate and Acetaminophen Tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients, Pregnancy]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of Hydrocodone Bitartrate and Acetaminophen Tablets and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see WARNINGS ], particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Acetaminophen Tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Hydrocodone Bitartrate and Acetaminophen Tablets-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions. When adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Hydrocodone Bitartrate and Acetaminophen Tablets-treated patients, follow patients at frequent intervals and consider dosage reduction of Hydrocodone Bitartrate and Acetaminophen Tablets until stable drug effects are achieved [see PRECAUTIONS; Drug Interactions ]. Concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using Hydrocodone Bitartrate and Acetaminophen Tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, follow patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see PRECAUTIONS; Drug Interactions ]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see PRECAUTIONS; Drug Interactions ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ]. Advise both patients and caregivers about the risks of respiratory depression and sedation when Hydrocodone Bitartrate and Acetaminophen Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see PRECAUTIONS: Drug Interactions , Information for Patients ]. Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Hydrocodone Bitartrate and Acetaminophen Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Hydrocodone Bitartrate and Acetaminophen Tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hydrocodone Bitartrate and Acetaminophen Tablets [see WARNINGS; Life-Threatening Respiratory Depression ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS; Life-Threatening Respiratory Depression ]. Follow such patients closely, particularly when initiating and titrating Hydrocodone Bitartrate and Acetaminophen Tablets and when Hydrocodone Bitartrate and Acetaminophen Tablets is given concomitantly with other drugs that depress respiration [see WARNINGS; Life-Threatening Respiratory Depression ]. Alternatively, consider the use of non-opioid analgesics in these patients. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension Hydrocodone Bitartrate and Acetaminophen Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS; Drug Interactions ]. Follow these patients for signs of hypotension after initiating or titrating the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets. In patients with circulatory shock Hydrocodone Bitartrate and Acetaminophen Tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate and Acetaminophen Tablets with circulatory shock. Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Hydrocodone Bitartrate and Acetaminophen Tablets immediately and seek medical care if they experience these symptoms. Do not prescribe Hydrocodone Bitartrate and Acetaminophen Tablets for patients with acetaminophen allergy [see PRECAUTIONS; Information for Patients ]. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hydrocodone Bitartrate and Acetaminophen Tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Follow such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hydrocodone Bitartrate and Acetaminophen Tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydrocodone Bitartrate and Acetaminophen Tablets in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions Hydrocodone Bitartrate and Acetaminophen Tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The administration of Hydrocodone Bitartrate and Acetaminophen Tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in Hydrocodone Bitartrate and Acetaminophen Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Follow patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate and acetaminophen tablet therapy. Withdrawal Do not abruptly discontinue Hydrocodone Bitartrate and Acetaminophen Tablets in a patient physically dependent on opioids. When discontinuing Hydrocodone Bitartrate and Acetaminophen Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of Hydrocodone Bitartrate and Acetaminophen Tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION , DRUG ABUSE AND DEPENDENCE ]. Additionally, avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydrocodone Bitartrate and Acetaminophen Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see PRECAUTIONS/Drug Interactions ].","Addiction, Abuse, and Misuse Hydrocodone Bitartrate and Acetaminophen Tablets contains hydrocodone, a Schedule II controlled substance. As an opioid, Hydrocodone Bitartrate and Acetaminophen Tablets exposes users to the risks of addiction, abuse, and misuse [see DRUG ABUSE AND DEPENDENCE ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydrocodone Bitartrate and Acetaminophen Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydrocodone Bitartrate and Acetaminophen Tablets, and monitor all patients receiving Hydrocodone Bitartrate and Acetaminophen Tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hydrocodone Bitartrate and Acetaminophen Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Hydrocodone Bitartrate and Acetaminophen Tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS, Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION, Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose ]. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydrocodone Bitartrate and Acetaminophen Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PRECAUTIONS; Information for Patients ]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.","Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see OVERDOSAGE ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydrocodone Bitartrate and Acetaminophen Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Hydrocodone Bitartrate and Acetaminophen Tablets. To reduce the risk of respiratory depression, proper dosing and titration of Hydrocodone Bitartrate and Acetaminophen Tablets are essential [see DOSAGE AND ADMINISTRATION ]. Overestimating the Hydrocodone Bitartrate and Acetaminophen Tablets dosage when converting patients from another opioid product can result in a fatal overdose. Accidental ingestion of even one dose of Hydrocodone Bitartrate and Acetaminophen Tablets, especially by children, can result in respiratory depression and death due to an overdose of Hydrocodone Bitartrate and Acetaminophen Tablets. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see PRECAUTIONS, Information for Patients/Caregivers ]. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see DOSAGE AND ADMINISTRATION ] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Hydrocodone Bitartrate and Acetaminophen Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see PRECAUTIONS, Information for Patients/Caregivers ]. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see WARNINGS, Addiction, Abuse, and Misuse , Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants ; PRECAUTIONS, Information for Patients/Caregivers ].","Neonatal Opioid Withdrawal Syndrome Prolonged use of Hydrocodone Bitartrate and Acetaminophen Tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see PRECAUTIONS; Information for Patients, Pregnancy].","Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Hydrocodone Bitartrate and Acetaminophen Tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Hydrocodone Bitartrate and Acetaminophen Tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hydrocodone Bitartrate and Acetaminophen Tablets [see WARNINGS; Life-Threatening Respiratory Depression ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see WARNINGS; Life-Threatening Respiratory Depression ]. Follow such patients closely, particularly when initiating and titrating Hydrocodone Bitartrate and Acetaminophen Tablets and when Hydrocodone Bitartrate and Acetaminophen Tablets is given concomitantly with other drugs that depress respiration [see WARNINGS; Life-Threatening Respiratory Depression ]. Alternatively, consider the use of non-opioid analgesics in these patients.","Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.","Severe Hypotension Hydrocodone Bitartrate and Acetaminophen Tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see PRECAUTIONS; Drug Interactions ]. Follow these patients for signs of hypotension after initiating or titrating the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets. In patients with circulatory shock Hydrocodone Bitartrate and Acetaminophen Tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of Hydrocodone Bitartrate and Acetaminophen Tablets with circulatory shock.","Hepatotoxicity Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.","Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.","Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Hydrocodone Bitartrate and Acetaminophen Tablets immediately and seek medical care if they experience these symptoms. Do not prescribe Hydrocodone Bitartrate and Acetaminophen Tablets for patients with acetaminophen allergy [see PRECAUTIONS; Information for Patients ].","Withdrawal Do not abruptly discontinue Hydrocodone Bitartrate and Acetaminophen Tablets in a patient physically dependent on opioids. When discontinuing Hydrocodone Bitartrate and Acetaminophen Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of Hydrocodone Bitartrate and Acetaminophen Tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see DOSAGE AND ADMINISTRATION , DRUG ABUSE AND DEPENDENCE ]. Additionally, avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydrocodone Bitartrate and Acetaminophen Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see PRECAUTIONS/Drug Interactions ]."}', 'precautions': '{"PRECAUTIONS Risks of Driving and Operating Machinery Hydrocodone Bitartrate and Acetaminophen Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hydrocodone Bitartrate and Acetaminophen Tablets and know how they will react to the medication [see PRECAUTIONS; Information for Patients /Caregivers]. Information for Patients/Caregivers Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Hydrocodone Bitartrate and Acetaminophen Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see WARNINGS , DRUG ABUSE AND DEPENDENCE ]. Inform patients that leaving Hydrocodone Bitartrate and Acetaminophen Tablets unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Hydrocodone Bitartrate and Acetaminophen Tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Addiction, Abuse, and Misuse Inform patients that the use of Hydrocodone Bitartrate and Acetaminophen Tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS ]. Instruct patients not to share Hydrocodone Bitartrate and Acetaminophen Tablets with others and to take steps to protect Hydrocodone Bitartrate and Acetaminophen Tablets from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydrocodone Bitartrate and Acetaminophen Tablets or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see WARNINGS, Life Threatening Respiratory Depression ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Hydrocodone Bitartrate and Acetaminophen Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see WARNINGS, Life-Threatening Respiratory Depression ; DOSAGE AND ADMINISTRATION ]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see OVERDOSAGE ]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS ]. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Hydrocodone Bitartrate and Acetaminophen Tablets are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS , PRECAUTIONS; Drug Interactions ]. Serotonin Syndrome Inform patients that Hydrocodone Bitartrate and Acetaminophen Tablets could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions ]. Monoamine Oxidase Inhibitor (MAOI) Interaction Inform patients to avoid taking Hydrocodone and Acetaminophen Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydrocodone and Acetaminophen Tablets [see PRECAUTIONS; Drug Interactions ]. Adrenal Insufficiency Inform patients that Hydrocodone Bitartrate and Acetaminophen Tablets opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS ]. Important Administration Instructions Instruct patients how to properly take Hydrocodone Bitartrate and Acetaminophen Tablets [see DOSAGE AND ADMINISTRATION , WARNINGS ]. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Hydrocodone Bitartrate and Acetaminophen Tablets without first discussing a tapering plan with the prescriber [see DOSAGE AND ADMINISTRATION ] . Maximum Daily Dose of Acetaminophen Inform patients not to take more than 4,000 milligrams of acetaminophen per day. Advise patients to call their prescriber if they take more than the recommended dose. Hypotension Inform patients that Hydrocodone Bitartrate and Acetaminophen Tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Acetaminophen Tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS , ADVERSE REACTIONS ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of Hydrocodone Bitartrate and Acetaminophen Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS , PRECAUTIONS; Pregnancy ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that Hydrocodone Bitartrate and Acetaminophen Tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy ]. Lactation Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers ]. Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS ]. Driving or Operating Heavy Machinery Inform patients that Hydrocodone Bitartrate and Acetaminophen Tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS ]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY ]. Laboratory Tests In patients with severe hepatic or renal disease, effects of therapy should be followed with serial liver and/or renal function tests. Drug Interactions Inhibitors of CYP3A4 and CYP2D6 The concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of the hydrocodone from Hydrocodone Bitartrate and Acetaminophen Tablets, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Acetaminophen Tablets is achieved [see WARNINGS ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Acetaminophen Tablets. If concomitant use is necessary, consider dosage reduction of Hydrocodone Bitartrate and Acetaminophen Tablets until stable drug effects are achieved. Follow patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Hydrocodone Bitartrate and Acetaminophen Tablets dosage until stable drug effects are achieved. Follow for signs or symptoms of opioid withdrawal. Inducers of CYP3A4 The concomitant use of Hydrocodone Bitartrate and Acetaminophen Tablets and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see WARNINGS ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see CLINICAL PHARMACOLOGY ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If concomitant use is necessary, consider increasing the Hydrocodone Bitartrate and Acetaminophen Tablets dosage until stable drug effects are achieved. Follow the patient for signs and symptoms of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Hydrocodone Bitartrate and Acetaminophen Tablets dosage reduction and follow for signs of respiratory depression. Benzodiazepines and Other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome [see PRECAUTIONS; Information for Patients ]. If concomitant use is warranted, carefully follow the patient, particularly during treatment initiation and dose adjustment. Discontinue hydrocodone bitartrate and acetaminophen tablets if serotonin syndrome is suspected. Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS ]. The use of Hydrocodone Bitartrate and Acetaminophen Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of Hydrocodone Bitartrate and Acetaminophen Tablets and/or precipitate withdrawal symptoms. Advise patient to avoid concomitant use of these drugs. Muscle Relaxants Hydrocodone Bitartrate and Acetaminophen Tablets may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. If concomitant use is warranted, follow patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. If concomitant use is warranted, follow patients for signs and symptoms of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Acetaminophen Tablets are used concomitantly with anticholinergic drugs. Drug/Laboratory Test Interactions Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies to evaluate the carcinogenic potential of the combination of Hydrocodone Bitartrate and Acetaminophen Tablets have not been conducted. Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6,000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 0.7 times or mice at up to 1.2 to 1.4 times the MHDD, based on a body surface area comparison. Mutagenesis In the published literature, acetaminophen has been reported to be clastogenic when administered at 1,500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body surface area comparison), suggesting a threshold effect. Impairment of Fertility In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.78 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known. Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS ]. Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Hydrocodone Bitartrate and Acetaminophen Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydrocodone Bitartrate and Acetaminophen Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Hydrocodone Bitartrate and Acetaminophen Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Nursing Mothers Hydrocodone is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Hydrocodone Bitartrate and Acetaminophen Tablets and any potential adverse effects on the breastfed infant from Hydrocodone Bitartrate and Acetaminophen Tablets or from the underlying maternal condition. Infants exposed to Hydrocodone Bitartrate and Acetaminophen Tablets through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Pediatric Use Safety and effectiveness of Hydrocodone Bitartrate and Acetaminophen Tablets in pediatric patients have not been established. Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to Hydrocodone Bitartrate and Acetaminophen Tablets. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression [see WARNINGS ]. Hydrocodone and acetaminophen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Hepatic Impairment Patients with hepatic impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose of Hydrocodone Bitartrate and Acetaminophen Tablets in patients with hepatic impairment and follow closely for adverse events such as respiratory depression and sedation. Renal Impairment Patients with renal impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose Hydrocodone Bitartrate and Acetaminophen Tablets in patients with renal impairment and follow closely for adverse events such as respiratory depression and sedation."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Hydrocodone Bitartrate and Acetaminophen Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS ]."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness of Hydrocodone Bitartrate and Acetaminophen Tablets in pediatric patients have not been established."}', 'geriatric_use': '{"Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to Hydrocodone Bitartrate and Acetaminophen Tablets. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydrocodone Bitartrate and Acetaminophen Tablets slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression [see WARNINGS ]. Hydrocodone and acetaminophen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function."}'}

{"LEVOTHYROXINE SODIUM"}

{'contraindications': '{"4 CONTRAINDICATIONS Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal insufficiency [see Warnings and Precautions (5.4)] . Uncorrected adrenal insufficiency. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5), Overdosage (10)] . They include the following: General: fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia Musculoskeletal: tremors, muscle weakness, muscle spasm Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, heart failure, angina, myocardial infarction, cardiac arrest Respiratory: dyspnea Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests Dermatologic: hair loss, flushing, rash Endocrine: decreased bone mineral density Reproductive: menstrual irregularities, impaired fertility Seizures have been reported rarely with the institution of levothyroxine therapy. Adverse Reactions in Pediatric Patients Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants who have not undergone complete closure of the fontanelles, and in premature closure of the epiphyses in pediatric patients still experiencing growth with resultant compromised adult height. Hypersensitivity Reactions Hypersensitivity reactions to inactive ingredients have occurred in patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to levothyroxine itself is not known to occur. Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"7 DRUG INTERACTIONS See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium tablets. ( 7 ) 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to levothyroxine sodium tablets (Tables 5 to 8). Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism) Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Drug or Drug Class Effect Phosphate Binders (e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum) Phosphate binders may bind to levothyroxine. Administer levothyroxine sodium tablets at least 4 hours apart from these agents. Orlistat Monitor patients treated concomitantly with orlistat and levothyroxine sodium tablets for changes in thyroid function. Bile Acid Sequestrants (e.g., colesevelam, cholestyramine, colestipol) Ion Exchange Resins (e.g., Kayexalate) Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine sodium tablets at least 4 hours prior to these drugs or monitor TSH levels. Proton Pump Inhibitors Sucralfate Antacids (e.g., aluminum & magnesium hydroxides, simethicone) Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately. Table 6. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) Drug or Drug Class Effect Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen These drugs may increase serum thyroxine-binding globulin (TBG) concentration. Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid These drugs may decrease serum TBG concentration. Potential impact (below): Administration of these agents with levothyroxine sodium tablets results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. Salicylates (> 2 g/day) Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs -Fenamates These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. Table 7. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine sodium tablets requirements. Drug or Drug Class Effect Phenobarbital Rifampin Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5\'-diphospho-glucuronosyltransferase (UGT) and leads to lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. Table 8. Drugs That May Decrease Conversion of T4 to T3 Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. Drug or Drug Class Effect Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day) In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. Glucocorticoids (e.g., Dexamethasone ≥ 4 mg/day) Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). Other drugs: Amiodarone Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. 7.2 Antidiabetic Therapy Addition of levothyroxine sodium tablets therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued [see Warnings and Precautions (5.5)] . 7.3 Oral Anticoagulants Levothyroxine sodium tablet increases the response to oral anticoagulant therapy. Therefore, a decrease in the dose of anticoagulant may be warranted with correction of the hypothyroid state or when the levothyroxine sodium tablets dose is increased. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments. 7.4 Digitalis Glycosides Levothyroxine sodium tablets may reduce the therapeutic effects of digitalis glycosides. Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, necessitating an increase in the dose of digitalis glycosides. 7.5 Antidepressant Therapy Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and levothyroxine sodium tablets may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and central nervous system stimulation. Levothyroxine sodium tablets may accelerate the onset of action of tricyclics. Administration of sertraline in patients stabilized on levothyroxine sodium tablets may result in increased levothyroxine sodium tablets requirements. 7.6 Ketamine Concurrent use of ketamine and levothyroxine sodium tablets may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 7.7 Sympathomimetics Concurrent use of sympathomimetics and levothyroxine sodium tablets may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. 7.8 Tyrosine-Kinase Inhibitors Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients. 7.9 Drug-Food Interactions Consumption of certain foods may affect levothyroxine sodium tablets absorption thereby necessitating adjustments in dosing [see Dosage and Administration (2.1)] . Soybean flour, cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of levothyroxine sodium tablets from the gastrointestinal tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability. 7.10 Drug-Laboratory Test Interactions Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG deficiency approximating 1 in 9000."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Hypothyroidism Levothyroxine sodium tablets are indicated in adult and pediatric patients, including neonates, as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression Levothyroxine sodium tablets are indicated in adult and pediatric patients, including neonates, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Limitations of Use Levothyroxine sodium tablets are not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and overtreatment with levothyroxine sodium tablets may induce hyperthyroidism [see Warnings and Precautions ( 5.1 )] . Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. Levothyroxine sodium tablet is a L-thyroxine (T4) indicated in adult and pediatric patients, including neonates, for: Hypothyroidism: As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. ( 1 ) Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. ( 1 ) Limitations of Use Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient patients. Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Serious risks related to overtreatment or undertreatment with levothyroxine sodium tablet Titrate the dose of levothyroxine sodium tablet carefully and monitor response to titration. ( 5.1 ). Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease Initiate levothyroxine sodium tablet at less than the full replacement dose because of the increased risk of cardiac adverse reactions, including atrial fibrillation. (( 2.3 , 5.2 , 8.5 ) Myxedema coma Do not use oral thyroid hormone drug products to treat myxedema coma. ( 5.3 ) Acute adrenal crisis in patients with concomitant adrenal insufficiency Treat with replacement glucocorticoids prior to initiation of levothyroxine sodium tablet treatment. ( 5.4 ) Worsening of diabetic control Therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing thyroid hormone therapy. ( 5.5 ) Decreased bone mineral density associated with thyroid hormone over-replacement Over-replacement can increase bone resorption and decrease bone mineral density. Give the lowest effective dose. ( 5.6 ) 5.1 Serious Risks Related to Overtreatment or Undertreatment with Levothyroxine sodium tablets Levothyroxine sodium tablet has a narrow therapeutic index. Overtreatment or undertreatment with Levothyroxine sodium tablets may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients. In pediatric patients with congenital and acquired hypothyroidism, undertreatment may adversely affect cognitive development and linear growth, and overtreatment is associated with craniosynostosis and acceleration of bone age [see Use in Specific Populations (8.4)] . Titrate the dose of Levothyroxine sodium tablets carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)] . Consider the potential for food or drug interactions and adjust the administration or dosage of Levothyroxine sodium tablets as needed [see Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3)] . 5.2 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate levothyroxine sodium tablets therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease [see Dosage and Administration (2.3), Use in Specific Populations (8.5)] . Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive levothyroxine sodium tablets therapy. Monitor patients receiving concomitant levothyroxine sodium tablets and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the levothyroxine sodium tablets dose or withhold for one week and restart at a lower dose. 5.3 Myxedema Coma Myxedema coma is a life-threatening emergency characterized by poor circulation and hypometabolism and may result in unpredictable absorption of levothyroxine sodium from the gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to treat myxedema coma. Administer thyroid hormone products formulated for intravenous administration to treat myxedema coma. 5.4 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with levothyroxine sodium tablets [see Contraindications (4)] . 5.5 Worsening of Diabetic Control Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing, or discontinuing levothyroxine sodium tablets [see Drug Interactions (7.2)] . 5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. Administer the minimum dose of levothyroxine sodium tablets that achieves the desired clinical and biochemical response to mitigate this risk"}', 'overdosage': '{"10 OVERDOSAGE The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions (5) and Adverse Reactions (6)] . In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures occurred in a 3-year old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium. Reduce the levothyroxine sodium tablets dosage or discontinue temporarily if signs or symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient\'s medical status. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org."}', 'active_flag': 'Y', 'generic_name': '{"LEVOTHYROXINE SODIUM"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Inform the patient of the following information to aid in the safe and effective use of levothyroxine sodium tablets: Dosing and Administration Instruct patients to take levothyroxine sodium tablets only as directed by their healthcare provider. Instruct patients to take levothyroxine sodium tablets as a single dose, preferably on an empty stomach, one-half to one hour before breakfast. Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine. Instruct patients not to take levothyroxine sodium tablets within 4 hours of these agents. Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are thinking of becoming pregnant while taking levothyroxine sodium tablets. Important Information Inform patients that it may take several weeks before they notice an improvement in symptoms. Inform patients that the levothyroxine in levothyroxine sodium tablet is intended to replace a hormone that is normally produced by the thyroid gland. Generally, replacement therapy is to be taken for life. Inform patients that levothyroxine sodium tablets should not be used as a primary or adjunctive therapy in a weight control program. Instruct patients to notify their healthcare provider if they are taking any other medications, including prescription and over-the-counter preparations. Instruct patients to notify their physician of any other medical conditions they may have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland problems, as the dose of medications used to control these other conditions may need to be adjusted while they are taking levothyroxine sodium tablets. If they have diabetes, instruct patients to monitor their blood and/or urinary glucose levels as directed by their physician and immediately report any changes to their physician. If patients are taking anticoagulants, their clotting status should be checked frequently. Instruct patients to notify their physician or dentist that they are taking levothyroxine sodium tablets prior to any surgery. Adverse Reactions Instruct patients to notify their healthcare provider if they experience any of the following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual periods, hives or skin rash, or any other unusual medical event. Inform patients that partial hair loss may occur rarely during the first few months of levothyroxine sodium tablets therapy, but this is usually temporary. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Pithampur (M.P.) - 454 775 INDIA Revised: September 2023 ID#: 274663"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary The clinical experience, including data from postmarketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine sodium tablets dosage adjusted during pregnancy ( see Clinical Considerations) . Animal reproductive studies have not been conducted with levothyroxine sodium. Levothyroxine sodium tablets should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development. Dose Adjustments During Pregnancy and the Postpartum Period Pregnancy may increase levothyroxine sodium tablets requirements. Serum TSH levels should be monitored and the levothyroxine sodium tablets dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the levothyroxine sodium tablets dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and Administration (2.3)] ."}', 'pediatric_use': '{"8.4 Pediatric Use Levothyroxine Sodium Tablets is indicated in patients from birth to less than 17 years of age: As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. As an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation. Therefore, initiate levothyroxine sodium tablets therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. [see Warnings and Precautions (5.1)] . Closely monitor infants during the first 2 weeks of levothyroxine sodium tablets therapy for cardiac overload and arrhythmias."}', 'geriatric_use': '{"8.5 Geriatric Use Because of the increased prevalence of cardiovascular disease among the elderly, initiate levothyroxine sodium tablets at less than the full replacement dose [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)] . Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly."}'}

{"SERTRALINE HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Sertraline hydrochloride tablets are contraindicated in patients: Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [See Warnings and Precautions (5.2) , Drug Interactions (7.1) ] . Taking pimozide [See Drug Interactions (7.1) ] . With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema) [See Adverse Reactions (6.1 , 6.2) ]. Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 , 7.1 ) Concomitant use of pimozide ( 4 , 7.1 ) Known hypersensitivity to sertraline or excipients ( 4 , 5.4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information: Hypersensitivity reactions to sertraline [See Contraindications (4) ] QTc prolongation and ventricular arrhythmias when taken with pimozide [See Contraindications (4) , Clinical Pharmacology (12.2) ] Suicidal thoughts and behaviors [See Warnings and Precautions (5.1) ] Serotonin syndrome [See Contraindications (4) , Warnings and Precautions (5.2) , Drug Interactions (7.1) ] Increased risk of bleeding [See Warnings and Precautions (5.3) ] Activation of mania/hypomania [See Warnings and Precautions (5.4) ] Discontinuation syndrome [See Warnings and Precautions (5.5) ] Seizures [See Warnings and Precautions (5.6) ] Angle-closure glaucoma [See Warnings and Precautions (5.7) ] Hyponatremia [See Warnings and Precautions (5.8) ] Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled MDD, OCD, PD, PTSD, SAD and PMDD clinical trials were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below are from randomized, double-blind, placebo-controlled trials of sertraline hydrochloride (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to sertraline hydrochloride for 8 to 12 weeks represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males. The most common adverse reactions (≥5% and twice placebo) in all pooled placebo-controlled clinical trials of all sertraline hydrochloride-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 3). The following are the most common adverse reactions in trials of sertraline hydrochloride (≥5% and twice placebo) by indication that were not mentioned previously. MDD: somnolence; OCD: insomnia, agitation; PD: constipation, agitation; PTSD: fatigue; PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain; SAD: insomnia, dizziness, fatigue, dry mouth, malaise. Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD* Sertraline hydrochloride (N=3066) Placebo (N=2293) Cardiac disorders Palpitations 4% 2% Eye disorders Visual impairment 4% 2% Gastrointestinal Disorders Nausea 26% 12% Diarrhea/Loose Stools 20% 10% Dry mouth 14% 9% Dyspepsia 8% 4% Constipation 6% 4% Vomiting 4% 1% General disorders and administration site conditions Fatigue 12% 8% Metabolism and nutrition disorders Decreased appetite 7% 2% Nervous system disorders Dizziness 12% 8% Somnolence 11% 6% Tremor 9% 2% Psychiatric Disorders Insomnia 20% 13% Agitation 8% 5% Libido Decreased 6% 2% Reproductive system and breast disorders Ejaculation failure (1) 8% 1% Erectile dysfunction (1) 4% 1% Ejaculation disorder (1) 3% 0% Male sexual dysfunction (1) 2% 0% Skin and subcutaneous tissue disorders Hyperhidrosis 7% 3% (1) Denominator used was for male patients only (n=1316 sertraline hydrochloride; n=973 placebo). * Adverse reactions that occurred greater than 2% in sertraline hydrochloride-treated patients and at least 2% greater in sertraline hydrochloride-treated patients than placebo-treated patients. Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical Trials In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received sertraline hydrochloride discontinued treatment due to an adverse reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the following were the common adverse reactions leading to discontinuation in sertraline hydrochloride-treated patients: MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%). MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting. OCD: somnolence. PD: nervousness and somnolence. Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of sertraline hydrochloride-treated patients and twice placebo from pooled placebo-controlled trials. For men and all indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido. Table 4: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women from Sertraline Hydrochloride Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD Sertraline Hydrochloride Placebo Men only (N=1316) (N=973) Ejaculation failure 8% 1% Libido decreased 7% 2% Erectile dysfunction 4% 1% Ejaculation disorder 3% 0% Male sexual dysfunction 2% 0% Women only (N=1750) (N=1320) Libido decreased 4% 2% Adverse Reactions in Pediatric Patients In 281 pediatric patients treated with sertraline hydrochloride in placebo-controlled studies, the overall profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that do not appear in Table 3 (most common adverse reactions in adults) yet were reported in at least 2% of pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and anxiety. Other Adverse Reactions Observed During the Premarketing Evaluation of Sertraline Hydrochloride Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with sertraline hydrochloride were: Cardiac disorders – tachycardia Ear and labyrinth disorders – tinnitus Endocrine disorders - hypothyroidism Eye disorders -mydriasis, blurred vision Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia Hepatobiliary disorders - elevated liver enzymes Immune system disorders - anaphylaxis Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetite Musculoskeletal and connective tissue disorders - arthralgia, muscle spasms, tightness, or twitching Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncope Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination Renal and urinary disorders - hematuria Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura; erythematous, follicular, or maculopapular rash; urticaria Vascular disorders - hemorrhage, hypertension, vasodilation 6.2 Post-marketing Experience The following adverse reactions have been identified during postapproval use of sertraline hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Bleeding or clotting disorders - increased coagulation times (altered platelet function) Cardiac disorders – AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes) [See Clinical Pharmacology (12.2) ] Endocrine disorders -gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH Eye disorders - blindness, optic neuritis, cataract Hepatobiliary disorders – severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitis Hemic and lymphatic disorders – agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness Immune system disorders - angioedema Metabolism and nutrition disorders – hyponatremia, hyperglycemia Musculoskeletal and connective tissue disorders – rhabdomyolysis, trismus Nervous system disorders -serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis Psychiatric disorders – psychosis, enuresis, paroniria Renal and urinary disorders - acute renal failure Respiratory, thoracic and mediastinal disorders - pulmonary hypertension Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Protein-bound drugs: Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs (e.g., warfarin) as warranted. ( 7.1 , 12.3 ) CYP2D6 substrates: Reduce dosage of drugs metabolized by CYP2D6 ( 7.1 , 12.3 ) 7.1 Clinically Significant Drug Interactions Table 5 includes clinically significant drug interactions with sertraline hydrochloride [See Clinical Pharmacology (12.3) ] . Table 5: Clinically-Significant Drug Interactions with Sertraline Hydrochloride Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. Intervention: Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5) , Contraindications (4) , Warnings and Precautions (5.2) ]. Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Pimozide Clinical Impact: Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. Intervention: Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4) ]. Other Serotonergic Drugs Clinical Impact: The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2) ]. Examples: other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3) ]. Examples: aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact: Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3) ] . Intervention: Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. Examples: warfarin Drugs Metabolized by CYP2D6 Clinical Impact: Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3) ] . The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention: Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. Examples: propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine Phenytoin Clinical Impact: Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations. Intervention: Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. Examples: phenytoin, fosphenytoin Drugs that Prolong the QTc Interval Clinical Impact: The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval [See Warnings and Precautions (5.10) , Clinical Pharmacology (12.2) ] . Intervention: Pimozide is contraindicated for use with sertraline. Avoid the concomitant use of drugs known to prolong the QTc interval. Examples: Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). 7.2 Drugs Having No Clinically Important Interactions with Sertraline Hydrochloride Based on pharmacokinetic studies, no dosage adjustment of sertraline hydrochloride is necessary when used in combination with cimetidine. Additionally, no dosage adjustment is required for diazepam, lithium, atenolol, tolbutamide, digoxin, and drugs metabolized by CYP3A4, when sertraline hydrochloride is administered concomitantly [See Clinical Pharmacology (12.3) ] . 7.3 False-Positive Screening Tests for Benzodiazepines False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline hydrochloride. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of sertraline hydrochloride. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Sertraline hydrochloride tablets are indicated for the treatment of the following [See Clinical Studies (14) ] : Major depressive disorder (MDD) Obsessive-compulsive disorder (OCD) Panic disorder (PD) Posttraumatic stress disorder (PTSD) Social anxiety disorder (SAD) Premenstrual dysphoric disorder (PMDD) Sertraline is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of ( 1 ): Major depressive disorder (MDD) Obsessive-compulsive disorder (OCD) Panic disorder (PD) Post-traumatic stress disorder (PTSD) Social anxiety disorder (SAD) Premenstrual dysphoric disorder (PMDD)"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue sertraline hydrochloride tablets and initiate supportive treatment. ( 5.2 ) Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk. ( 5.3 ) Activation of Mania/Hypomania: Screen patients for bipolar disorder. ( 5.4 ) Seizures: Use with caution in patients with seizure disorders. ( 5.6 ) Angle Closure Glaucoma: Avoid use of antidepressants, including sertraline hydrochloride tablets, in patients with untreated anatomically narrow angles. ( 5.7 ) QTc Prolongation: Sertraline hydrochloride tablets should be used with caution in patients with risk factors for QTc prolongation. ( 5.10 ) 5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing sertraline hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including sertraline hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [See Contraindications (4) , Drug Interactions (7.1) ]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of sertraline hydrochloride tablets with MAOIs is contraindicated. In addition, do not initiate sertraline hydrochloride tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking sertraline hydrochloride tablets, discontinue sertraline hydrochloride tablets before initiating treatment with the MAOI [See Contraindications (4) , Drug Interactions (7.1) ]. Monitor all patients taking sertraline hydrochloride tablets for the emergence of serotonin syndrome. Discontinue treatment with sertraline hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of sertraline hydrochloride tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including sertraline hydrochloride, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. 5.4 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with sertraline hydrochloride tablets or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with sertraline hydrochloride. Prior to initiating treatment with sertraline hydrochloride tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.5 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.6) ]. 5.6 Seizures Sertraline hydrochloride has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Sertraline hydrochloride tablets should be prescribed with caution in patients with a seizure disorder. 5.7 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including sertraline hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including sertraline hydrochloride, in patients with untreated anatomically narrow angles. 5.8 Hyponatremia Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including sertraline hydrochloride. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue sertraline hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [See Use in Specific Populations (8.5) ] . 5.9 False-Positive Effects on Screening Tests for Benzodiazepines False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline hydrochloride. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of sertraline hydrochloride. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish sertraline hydrochloride from benzodiazepines [See Drug Interactions (7.3) ] . 5.10 QTc Prolongation During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP) have been reported. Most reports were confounded by other risk factors. In a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects, there was a positive relationship between the length of the rate-adjusted QTc interval and serum sertraline concentration. Therefore, sertraline hydrochloride should be used with caution in patients with risk factors for QTc prolongation [See Drug Interactions (7.1) , Clinical Pharmacology (12.2) ] ."}', 'overdosage': '{"10 OVERDOSAGE Human Experience The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. No cases of fatal overdosage with only sertraline have been reported. Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QTc-interval prolongation, Torsade de Pointes, serotonin syndrome, stupor, and syncope [See Clinical Pharmacology (12.2) ]. Overdose Management No specific antidotes for sertraline hydrochloride are known. Contact Poison Control (1-800-222-1222) for latest recommendations."}', 'active_flag': 'Y', 'generic_name': '{"SERTRALINE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [See Boxed Warning and Warnings and Precautions (5.1) ] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of sertraline hydrochloride tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [See Warnings and Precautions (5.2) , Drug Interactions (7.1) ] . Increased Risk of Bleeding Inform patients about the concomitant use of sertraline hydrochloride tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [See Warnings and Precautions (5.3) ]. Activation of Mania/Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [See Warnings and Precautions (5.4) ] . Discontinuation Syndrome Advise patients not to abruptly discontinue sertraline hydrochloride tablets and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when sertraline hydrochloride tablets are discontinued [See Warnings and Precautions (5.5) ]. Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [See Adverse Reactions (6.2) ] . Pregnancy Inform pregnant women that sertraline hydrochloride tablets may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN) [See Use in Specific Populations (8.1) ] . ® The brands listed are trademarks of their respective owners. Manufactured For: Accord Healthcare, Inc., 1009 Slater Road, Suite 210-B, Durham, NC 27703, USA. Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad-380 054, India. 10 0223 4 6004614 Issued October 2020"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive [See Data] . There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including sertraline hydrochloride, during the third trimester of pregnancy [See Clinical Considerations]. Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m 2 basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD [See Data] . The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing sertraline hydrochloride tablets. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk A prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal adverse reactions Exposure to SSRIs and SNRIs, including sertraline hydrochloride in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). When treating a pregnant woman with sertraline hydrochloride during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to sertraline hydrochloride in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data]. Data Human Data Third Trimester Exposure Neonates exposed to sertraline hydrochloride and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [See Warnings and Precautions (5.2) ] . Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997 to 2005 found a PPHN risk ratio of 2.4 (95% CI 1.2 to 4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2 to 8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”. First Trimester Exposure The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88 to 1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70 to 1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations. Animal Data Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis in adolescents. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the MRHD on a mg/m 2 basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m 2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (0.8 times the MRHD on a mg/m 2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m 2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and efficacy of sertraline hydrochloride have been established in the treatment of OCD in pediatric patients aged 6 to 17 [See Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.2) ] . Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established. Safety and effectiveness have not been established in pediatric patients for indications other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the data were not sufficient to support an indication for use in pediatric patients. Monitoring Pediatric Patients Treated with Sertraline Hydrochloride Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases [See Boxed Warning , Warnings and Precautions (5.1) ] . Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as sertraline hydrochloride . Weight Loss in Studies in Pediatric Patients with MDD In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50 mg to 200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between sertraline hydrochloride and placebo of roughly 1 kg, for both children (ages 6 to 11) and adolescents (ages 12 to 17), in both age groups representing a slight weight loss for the sertraline hydrochloride group compared to a slight gain for the placebo group. For children, about 7% of the sertraline hydrochloride-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of sertraline hydrochloride-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients. A subset of patients who completed the randomized controlled trials in patients with MDD (sertraline hydrochloride n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of sertraline hydrochloride treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of sertraline hydrochloride on the growth, development, and maturation in pediatric patients. Juvenile Animal Data A study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females. In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug –free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6 to 17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day)."}', 'geriatric_use': '{"8.5 Geriatric Use Of the total number of patients in clinical studies of sertraline hydrochloride in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In 354 geriatric subjects treated with sertraline hydrochloride in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3 [See Adverse Reactions (6.1) ], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients. SNRIs and SSRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [See Warnings and Precautions (5.8) ] ."}'}

{"PROPRANOLOL HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride."}', 'adverse_reactions': '{"ADVERSE REACTIONS The following adverse events were observed and have been reported in patients using propranolol. Cardiovascular Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type. Central Nervous System Light-headedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related. Gastrointestinal Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. Allergic Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. Respiratory Bronchospasm. Hematologic Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Autoimmune Systemic lupus erythematosus (SLE). Skin and mucous membranes Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol. Genitourinary Male impotence; Peyronie’s disease. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM ). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following co-administration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Hypertension Propranolol hydrochloride tablets are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride is not indicated in the management of hypertensive emergencies. Angina Pectoris Due to Coronary Atherosclerosis Propranolol hydrochloride tablets are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Atrial Fibrillation Propranolol hydrochloride tablets are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Myocardial Infarction Propranolol is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Migraine Propranolol is indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use. Essential Tremor Propranolol is indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol causes a reduction in the tremor amplitude, but not in the tremor frequency. Propranolol is not indicated for the treatment of tremor associated with Parkinsonism. Hypertrophic Subaortic Stenosis Propranolol improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis. Pheochromocytoma Propranolol is indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration. Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50 mcg/kg to 150 mcg/kg intravenously followed by continuous drip of 1 mg/hour to 5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm."}', 'active_flag': 'Y', 'generic_name': '{"PROPRANOLOL HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications. Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS ). Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS ). Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients without a History of Heart Failure, Continued use of beta blockers can, in some cases, lead to cardiac failure. Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T 4 and reverse T 3 and decreasing T 3 . Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol. Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure."}', 'precautions': '{"PRECAUTIONS General Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol is not indicated for the treatment of hypertensive emergencies. Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen. Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM ). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following co-administration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol. Carcinogenesis, Mutagenesis, Impairment of Fertility In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol hydrochloride in bacteria ( S . typhimurium strain TA 1538). Pregnancy In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing woman. Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients. Geriatric Use Clinical studies of propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients."}', 'geriatric_use': None}

{FLUOROURACIL}

{'contraindications': '{"CONTRAINDICATIONS Fluorouracil Cream may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women with either the topical or the parenteral forms of fluorouracil. One birth defect (cleft lip and palate) has been reported in the newborn of a patient using Fluorouracil Cream as recommended. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when Fluorouracil Cream was applied to mucous membrane areas. Multiple birth defects have been reported in a fetus of a patient treated with intravenous fluorouracil. Animal reproduction studies have not been conducted with Fluorouracil Cream. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose; however, the amount of fluorouracil absorbed systemically after topical administration to actinic keratoses is minimal (see CLINICAL PHARMACOLOGY ). Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on Day 10 or 12 of gestation. Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between Days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg/kg given to hamsters between Days 8 and 11 of gestation were teratogenic and/or embryotoxic (i.e., resulted in increased resorptions or embryolethality). In monkeys, divided doses of 40 mg/kg given between Days 20 and 24 of gestation were not teratogenic. Doses higher than 40 mg/kg resulted in abortion. Fluorouracil Cream should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities. Fluorouracil Cream is contraindicated in women who are or may become pregnant during therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus. Fluorouracil Cream is also contraindicated in patients with known hypersensitivity to any of its components."}', 'adverse_reactions': '{"ADVERSE REACTIONS The most frequent adverse reactions to Fluorouracil Cream occur locally and are often related to an extension of the pharmacological activity of the drug. These include burning, crusting, allergic contact dermatitis, pruritus, scarring, rash, soreness, and ulceration. Ulcerations, other local reactions, cases of miscarriage, and a birth defect (ventricular septal defect) have been reported when Fluorouracil Cream was applied to mucous membrane areas. Leukocytosis is the most frequent hematological side effect. Although a causal relationship is remote, other adverse reactions which have been reported infrequently are: Central Nervous System: Emotional upset, insomnia, irritability. Gastrointestinal: Medicinal taste, stomatitis. Hematological: Eosinophilia, thrombocytopenia, toxic granulation. Integumentary: Alopecia, blistering, bullous pemphigoid, discomfort, ichthyosis, scaling, suppuration, swelling, telangiectasia, tenderness, urticaria, skin rash. Special Senses: Conjunctival reaction, corneal reaction, lacrimation, nasal irritation. Miscellaneous: Herpes simplex. To report SUSPECTED ADVERSE REACTIONS contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.FDA.gov/medwatch."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Fluorouracil Cream is recommended for the topical treatment of multiple actinic or solar keratoses. In the 5% strength, it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established. The diagnosis should be established prior to treatment, since this method has not been proven effective in other types of basal cell carcinomas. With isolated, easily accessible basal cell carcinomas, surgery is preferred since success with such lesions is almost 100%. The success rate with Fluorouracil Cream is approximately 93%, based on 113 lesions in 54 patients. Eighty-eight lesions treated with the cream produced 7 failures."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE There have been no reports of overdosage with Fluorouracil Cream. The oral LD 50 for the 5% topical cream was 234 mg/kg in rats and 39 mg/kg in dogs. These doses represented 11.7 and 1.95 mg/kg of fluorouracil, respectively. The topical application of the 5% cream to rats yielded an LD 50 of greater than 500 mg/kg."}', 'active_flag': 'Y', 'generic_name': '{FLUOROURACIL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Application to mucous membranes should be avoided due to the possibility of local inflammation and ulceration. Additionally, cases of miscarriage and a birth defect (ventricular septal defect) have been reported when Fluorouracil Cream was applied to mucous membrane areas during pregnancy. Occlusion of the skin with resultant hydration has been shown to increase percutaneous penetration of several topical preparations. If any occlusive dressing is used in treatment of basal cell carcinoma, there may be an increase in the severity of inflammatory reactions in the adjacent normal skin. A porous gauze dressing may be applied for cosmetic reasons without increase in reaction. Exposure to ultraviolet rays should be minimized during and immediately following treatment with Fluorouracil Cream because the intensity of the reaction may be increased. Patients should discontinue therapy with Fluorouracil Cream if symptoms of DPD enzyme deficiency develop (see CONTRAINDICATIONS ). Rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration of fluorouracil in patients with DPD enzyme deficiency. One case of life-threatening systemic toxicity has been reported with the topical use of Fluorouracil Cream in a patient with DPD enzyme deficiency. Symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, inflammation of the esophagus, stomach, and small bowel. Although this case was observed with 5% fluorouracil cream, it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil."}', 'precautions': '{"PRECAUTIONS General There is a possibility of increased absorption through ulcerated or inflamed skin. Information for Patients Patients should be forewarned that the reaction in the treated areas may be unsightly during therapy and, usually, for several weeks following cessation of therapy. Patients should be instructed to avoid exposure to ultraviolet rays during and immediately following treatment with Fluorouracil Cream because the intensity of the reaction may be increased. If Fluorouracil Cream is applied with the fingers, the hands should be washed immediately afterward. Fluorouracil Cream should not be applied on the eyelids or directly into the eyes, nose or mouth because irritation may occur. Fluorouracil, including Fluorouracil Cream may be fatal if ingested by pets. Avoid allowing pets to contact the Fluorouracil Cream container or the skin where Fluorouracil Cream has been applied. Store Fluorouracil Cream out of reach of pets. Safely discard or clean any cloth or applicator that may retain Fluorouracil Cream and avoid leaving any residues of Fluorouracil Cream on your hands, clothing, carpeting or furniture. Laboratory Tests Solar keratoses which do not respond should be biopsied to confirm the diagnosis. Follow-up biopsies should be performed as indicated in the management of superficial basal cell carcinoma. Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil. Studies with the active ingredient of Fluorouracil Cream, 5-fluorouracil, have shown positive effects in in vitro tests for mutagenicity and on impairment of fertility. 5-Fluorouracil was positive in three in vitro cell neoplastic transformation assays. In the C3H/10T ½ clone 8 mouse embryo cell system, the resulting morphologically transformed cells formed tumors when inoculated into immunosuppressed syngeneic mice. While no evidence for mutagenic activity was observed in the Ames test (three studies), fluorouracil has been shown to be mutagenic in the survival count rec-assay with Bacillus subtilis and in the Drosophila wing-hair spot test. Fluorouracil produced petite mutations in Saccharomyces cerevisiae and was positive in the micronucleus test (bone marrow cells of male mice). Fluorouracil was clastogenic in vitro (i.e., chromatid gaps, breaks and exchanges) in Chinese hamster fibroblasts at concentrations of 1.0 and 2.0 mcg/mL and has been shown to increase sister chromatid exchange in vitro in human lymphocytes. In addition, 5-fluorouracil has been reported to produce an increase in numerical and structural chromosome aberrations in peripheral lymphocytes of patients treated with this product. Doses of 125 to 250 mg/kg, administered intraperitoneally, have been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. Spermatogonial differentiation was also inhibited by fluorouracil, resulting in transient infertility. However, in studies with a strain of mouse which is sensitive to the induction of sperm head abnormalities after exposure to a range of chemical mutagens and carcinogens, fluorouracil was inactive at oral doses of 5 to 80 mg/kg/day. In female rats, fluorouracil administered intraperitoneally at doses of 25 and 50 mg/kg during the preovulatory phase of oogenesis significantly reduced the incidence of fertile matings, delayed the development of preimplantation and postimplantation embryos, increased the incidence of preimplantation lethality and induced chromosomal anomalies in these embryos. Single-dose intravenous and intraperitoneal injections of 5-fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes (at 500 mg/kg) and to produce abnormalities in spermatids (at 50 mg/kg) in mice. Pregnancy See CONTRAINDICATIONS . Nursing Mothers It is not known whether Fluorouracil Cream is excreted in human milk. Because there is some systemic absorption of fluorouracil after topical administration (see CLINICAL PHARMACOLOGY ), because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue use of the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established."}', 'information_for_patients': '{"Information for Patients Patients should be forewarned that the reaction in the treated areas may be unsightly during therapy and, usually, for several weeks following cessation of therapy. Patients should be instructed to avoid exposure to ultraviolet rays during and immediately following treatment with Fluorouracil Cream because the intensity of the reaction may be increased. If Fluorouracil Cream is applied with the fingers, the hands should be washed immediately afterward. Fluorouracil Cream should not be applied on the eyelids or directly into the eyes, nose or mouth because irritation may occur. Fluorouracil, including Fluorouracil Cream may be fatal if ingested by pets. Avoid allowing pets to contact the Fluorouracil Cream container or the skin where Fluorouracil Cream has been applied. Store Fluorouracil Cream out of reach of pets. Safely discard or clean any cloth or applicator that may retain Fluorouracil Cream and avoid leaving any residues of Fluorouracil Cream on your hands, clothing, carpeting or furniture."}', 'pregnancy': '{"Pregnancy See CONTRAINDICATIONS ."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness in children have not been established."}', 'geriatric_use': None}

{"ROSUVASTATIN CALCIUM"}

{'contraindications': '{"4 CONTRAINDICATIONS Rosuvastatin calcium is contraindicated in the following conditions: Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with rosuvastatin calcium [see Adverse Reactions (6.1) ]. Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.3)]. Pregnancy [see Use in Specific Populations (8.1 , 8.3 )] . Lactation. Limited data indicate that rosuvastatin calcium is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require rosuvastatin calcium treatment should not breastfeed their infants [see Use in Specific Populations (8.2) ] . Known hypersensitivity to product components ( 4 ) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 ) Preganancy ( 4 , 8.1 , 8.3 ) Lactation ( 4 , 8.2 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy (including myositis) [see Warnings and Precautions (5.1)] Liver enzyme abnormalities [see Warnings and Precautions (5.3)] Most frequent adverse reactions (rate ≥2%) are headache, myalgia, abdominal pain, asthenia, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In the rosuvastatin calcium controlled clinical trials database (placebo or active-controlled) of 5394 patients with a mean treatment duration of 15 weeks, 1.4% of patients discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia abdominal pain nausea The most commonly reported adverse reactions (incidence ≥ 2%) in the rosuvastatin calcium controlled clinical trial database of 5394 patients were: headache myalgia abdominal pain asthenia nausea Adverse reactions reported in ≥ 2% of patients in placebo-controlled clinical studies and at a rate greater than placebo are shown in Table 1. These studies had a treatment duration of up to 12 weeks. Table 1. Adverse Reactions1 Reported in ≥2% of Patients Treated with Rosuvastatin Calcium and > Placebo in Placebo-Controlled Trials (% of Patients) Adverse Reactions Rosuvastatin calcium 5 mg N=291 Rosuvastatin calcium 10 mg N=283 Rosuvastatin calcium 20 mg N=64 Rosuvastatin calcium 40 mg N=106 Total Rosuvastatin calcium 5 mg to 40 mg N=744 Placebo N=382 Headache 5.5 4.9 3.1 8.5 5.5 5 Nausea 3.8 3.5 6.3 0 3.4 3.1 Myalgia 3.1 2.1 6.3 1.9 2.8 1.3 Asthenia 2.4 3.2 4.7 0.9 2.7 2.6 Constipation 2.1 2.1 4.7 2.8 2.4 2.4 1 Adverse reactions by COSTART preferred term. Other adverse reactions reported in clinical studies were abdominal pain, dizziness, hypersensitivity (including rash, pruritus, urticaria, and angioedema) and pancreatitis. The following laboratory abnormalities have also been reported: dipstick-positive proteinuria and microscopic hematuria [see Warnings and Precautions (5.5 )]; elevated creatine phosphokinase, transaminases, glucose, glutamyl transpeptidase, alkaline phosphatase, and bilirubin; and thyroid function abnormalities. In a clinical trial, involving 981 participants treated with rosuvastatin 40 mg (n=700) or placebo (n=281) with a mean treatment duration of 1.7 years, 5.6% of subjects treated with rosuvastatin calcium versus 2.8% of placebo-treated subjects discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: myalgia, hepatic enzyme increased, headache, and nausea. Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 2. Table 2. Adverse Reactions 1 Reported in ≥ 2% of Patients Treated with Rosuvastatin calcium and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin calcium 40 mg N=700 Placebo N=281 Myalgia 12.7 12.1 Arthralgia 10.1 7.1 Headache 6.4 5.3 Dizziness 4.0 2.8 Increased CPK 2.6 0.7 Abdominal pain 2.4 1.8 ALT > 3x ULN 2 2.2 0.7 1 Adverse reactions by MedDRA preferred term. 2 Frequency recorded as abnormal laboratory value. In a clinical trial, 17,802 participants were treated with rosuvastatin 20 mg (n=8901) or placebo (n=8901) for a mean duration of 2 years. A higher percentage of rosuvastatin-treated patients versus placebo-treated patients, 6.6% and 6.2%, respectively, discontinued study medication due to an adverse event, irrespective of treatment causality. Myalgia was the most common adverse reaction that led to treatment discontinuation. There was a significantly higher frequency of diabetes mellitus reported in patients taking rosuvastatin (2.8%) versus patients taking placebo (2.3%). Mean HbA1c was significantly increased by 0.1% in rosuvastatin-treated patients compared to placebo-treated patients. The number of patients with a HbA1c > 6.5% at the end of the trial was significantly higher in rosuvastatin-treated versus placebo-treated patients [see Warnings and Precautions (5.6) ] Adverse reactions reported in ≥ 2% of patients and at a rate greater than placebo are shown in Table 3. Table 3. Adverse Reactions 1 Reported in ≥ 2% of Patients Treated with Rosuvastatin calcium and > Placebo in a Trial (% of Patients) Adverse Reactions Rosuvastatin calcium 20 mg N=8901 Placebo N=8901 Myalgia 7.6 6.6 Arthralgia 3.8 3.2 Constipation 3.3 3.0 Diabetes mellitus 2.8 2.3 Nausea 2.4 2.3 1 Treatment-emergent adverse reactions by MedDRA preferred term. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of rosuvastatin calcium: arthralgia, fatal and non-fatal hepatic failure, hepatitis, jaundice, thrombocytopenia, depression, sleep disorders (including insomnia and nightmares), peripheral neuropathy, interstitial lung disease, and gynecomastia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.2)]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, and confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks)."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Combination of sofosbuvir/velpatasvir/voxilaprevir or ledipasvir/sofosbuvir: Combination increases rosuvastatin exposure. Use with rosuvastatin calcium is not recommended. ( 2.4 , 5.1 , 7.3 , 12.3 ) Cyclosporine and darolutamide: Combination increases rosuvastatin exposure. Limit rosuvastatin calcium dose to 5 mg once daily. ( 2.4 , 5.1 , 7.1 , 7.4 , 12.3 ) Gemfibrozil: Combination should be avoided. If used together, limit rosuvastatin calcium dose to 10 mg once daily.( 2.4 , 5.1 , 7.2 ) Atazanavir/ritonavir, lopinavir/ritonavir, simeprevir or combination of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir: Combination increases rosuvastatin exposure. Limit rosuvastatin calcium dose to 10 mg once daily. ( 2.4 , 5.1 , 7.3 , 12.3 ) Regorafenib: Combination increases rosuvastatin exposure. Limit rosuvastatin calcium dose to 10 mg once daily. ( 2.4 , 5.1 , 7.5 ) Coumarin anticoagulants: Combination prolongs INR. Achieve stable INR prior to starting rosuvastatin calcium. Monitor INR frequently until stable upon initiation or alteration of rosuvastatin calcium therapy. ( 5.4 , 7.6 ) Concomitant lipid-lowering therapies: Use with fibrates or lipid- modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with rosuvastatin calcium. ( 5.1 , 7.7 7.8 ) 7.1 Cyclosporine Cyclosporine increased rosuvastatin exposure and may result in increased risk of myopathy. Therefore, in patients taking cyclosporine, the dose of rosuvastatin calcium should not exceed 5 mg once daily [see Dosage and Administration (2.4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. 7.2 Gemfibrozil Gemfibrozil significantly increased rosuvastatin exposure. Due to an observed increased risk of myopathy/rhabdomyolysis, combination therapy with rosuvastatin calcium and gemfibrozil should be avoided. If used together, the dose of rosuvastatin calcium should not exceed 10 mg once daily [see Clinical Pharmacology (12.3) ]. 7.3 Anti-viral Medications Coadministration of rosuvastatin with certain anti-viral drugs has differing effects on rosuvastatin exposure and may increase risk of myopathy. The combination of sofosbuvir/velpatasvir/voxilaprevir which are anti-Hepatitis C virus (anti-HCV) drugs, increases rosuvastatin exposure. Similarly, the combination of ledipasvir/sofosbuvir may significantly increase rosuvastatin exposure. For these combinations of anti-HCV drugs, concomitant use with rosuvastatin calcium is not recommended. Simeprevir and combinations of dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir which are anti-HCV drugs, increase rosuvastatin exposure. Combinations of atazanavir/ritonavir and lopinavir/ritonavir, which are anti-HIV-1 drugs, increase rosuvastatin exposure [see Table 4 – Clinical Pharmacology (12.3)]. For these anti-viral drugs, the dose of rosuvastatin calcium should not exceed 10 mg once daily. The combinations of fosamprenavir/ritonavir or tipranavir/ritonavir, which are anti-HIV-1 drugs, produce little or no change in rosuvastatin exposure. No dose adjustment is needed for concomitant use with these combinations [ see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.4 Darolutamide Darolutamide increased rosuvastatin exposure more than 5 fold. Therefore, in patients taking darolutamide, the dose of rosuvastatin calcium should not exceed 5 mg once daily [ see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.5 Regorafenib Regorafenib increased rosuvastatin exposure and may increase the risk of myopathy. If used together, the dose of rosuvastatin calcium should not exceed 10 mg once daily [ see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.6 Coumarin Anticoagulants Rosuvastatin calcium significantly increased INR in patients receiving coumarin anticoagulants. Therefore, caution should be exercised when coumarin anticoagulants are given in conjunction with rosuvastatin calcium. In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium and frequently enough during early therapy to ensure that no significant alteration of INR occurs [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 7.7 Niacin The risk of skeletal muscle effects may be enhanced when rosuvastatin calcium is used in combination with lipid- modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with rosuvastatin calcium [ see Warnings and Precautions (5.1)]. 7.8 Fenofibrate When rosuvastatin calcium was coadministered with fenofibrate, no clinically significant increase in the AUC of rosuvastatin or fenofibrate was observed. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concomitant use of fenofibrates, caution should be used when prescribing fenofibrates with rosuvastatin calcium [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 7.9 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin calcium with colchicine [see Warnings and Precautions (5.1)]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Rosuvastatin tablets are an HMG Co-A reductase inhibitor indicated for: adult patients with hypertriglyceridemia as an adjunct to diet ( 1.3 ) adult patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia) as an adjunct to diet ( 1.4 ) adult patients with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C, total-C, and ApoB ( 1.5 ) Limitations of use ( 1.8 ): Rosuvastatin tablets has not been studied in Fredrickson Type I and V dyslipidemias. 1.3 Hypertriglyceridemia Rosuvastatin tablets are indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.4 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) Rosuvastatin tablets are indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). 1.5 Adult Patients with Homozygous Familial Hypercholesterolemia Rosuvastatin tablets are indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia. 1.8 Limitations of Use Rosuvastatin tablets have not been studied in Fredrickson Type I and V dyslipidemias."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with use of 40 mg dose, advanced age (≥65), hypothyroidism, renal impairment, and combination use with cyclosporine, darolutamide, regorafenib, certain anti-viral medicines or their combinations. Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue rosuvastatin calcium tablets if signs or symptoms appear. ( 5.1 , 7.4, 7.5 , 7.7,7.8) Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement elevations in with immunosuppressive agents. ( 5.2 ) Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Perform liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3) 5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including rosuvastatin tablets. These risks can occur at any dose level, but are increased at the highest dose (40 mg). Rosuvastatin calcium should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment). The risk of myopathy during treatment with ros uvastatin calcium may be increased with concurrent administration of gemfibrozil, some other lipid-lowering therapies (other fibrates or niacin), cyclosporine, darolutamide, regorafenib, atazanavir/ritonavir, lopinavir/ritonavir,simeprevir or combination of sofosbuvir/velpatasvir/voxilaprevir, dasabuvir/ombitasvir/paritaprevir/ritonavir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, all combinations with ledipasvir (including ledipasvir/sofosbuvir) [see Dosage and Administration (2) and Drug Interactions (7)]. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors, including rosuvastatin, coadministered with colchicine, and caution should be exercised when prescribing rosuvastatin calcium with colchicine [see Drug Interactions (7.9) ]. Rosuvastatin calcium therapy should be discontinued if markedly elevated creatine kinase levels occur or myopathy is diagnosed or suspected. Rosuvastatin calcium therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing rosuvastatin calcium. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM. 5.3 Liver Enzyme Abnormalities It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin calcium, and if signs or symptoms of liver injury occur. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy. There were two cases of jaundice, for which a relationship to rosuvastatin calcium therapy could not be determined, which resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease in these trials. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to > 3 times the upper limit of normal occurred in 1.1% of patients taking rosuvastatin calcium versus 0.5% of patients treated with placebo. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including rosuvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with rosuvastatin calcium, promptly interrupt therapy. If an alternate etiology is not found, do not restart rosuvastatin calcium. Rosuvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase elevations, is a contraindication to the use of rosuvastatin calcium [ see Contraindications (4) ]. 5.4 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with rosuvastatin calcium because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and rosuvastatin calcium concomitantly, INR should be determined before starting rosuvastatin calcium and frequently enough during early therapy to ensure that no significant alteration of INR occurs [ see Drug Interactions (7.6)] 5.5 Proteinuria and Hematuria In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin calcium treated patients. These findings were more frequent in patients taking rosuvastatin calcium 40 mg, when compared to lower doses of rosuvastatin calcium or comparator HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin calcium therapy with unexplained persistent proteinuria and/or hematuria during routine urinalysis testing. 5.6 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including rosuvastatin calcium. Based on clinical trial data with rosuvastatin calcium, in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus [see Adverse Reactions (6.1)]. Although clinical studies have shown that rosuvastatin calcium alone does not reduce basal plasma cortisol concentration or impair adrenal reserve, caution should be exercised if rosuvastatin calcium is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and cimetidine."}', 'overdosage': '{"10 OVERDOSAGE There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin."}', 'active_flag': 'Y', 'generic_name': '{"ROSUVASTATIN CALCIUM"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients should be instructed not to take 2 doses of rosuvastatin tablets within 12 hours of each other. Skeletal Muscle Effects Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing rosuvastatin tablets. Concomitant Use of Antacids When taking rosuvastatin tablets with an aluminum and magnesium hydroxide combination antacid, the antacid should be taken at least 2 hours after rosuvastatin tablets administration. Embryofetal Toxicity Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy. [see Contraindications (4) and Use in Specific Populations (8.1 , 8.3 )]. Lactation Advise women not to breastfeed during treatment with rosuvastatin calcium [see Contraindications (4) and Use in Specific Populations (8.2) ]. Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of rosuvastatin tablets and if signs or symptoms of liver injury occur. All patients treated with rosuvastatin tablets should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854-3714 Issued on: February 2021"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Rosuvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with rosuvastatin calcium during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, rosuvastatin calcium may cause fetal harm when administered to pregnant women. Rosuvastatin calcium should be discontinued as soon as pregnancy is recognized [ see Contraindications (4)] . Limited published data on the use of rosuvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, there were no adverse developmental effects with oral administration of rosuvastatin during organogenesis at systemic exposures equivalent to a maximum recommended human dose (MRHD) of 40 mg/day in rats or rabbits (based on AUC and body surface area, respectively). In rats and rabbits, decreased pup/fetal survival occurred at 12 times and equivalent, respectively, to the MRHD of 40 mg/day [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Limited published data on rosuvastatin have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Animal Data Rosuvastatin crosses the placenta in rats and rabbits and is found in fetal tissue and amniotic fluid at 3% and 20%, respectively, of the maternal plasma concentration following a single 25 mg/kg oral gavage dose on gestation day 16 in rats. A higher fetal tissue distribution (25% maternal plasma concentration) was observed in rabbits after a single oral gavage dose of 1 mg/kg on gestation day 18. Rosuvastatin administration did not indicate a teratogenic effect in rats at ≤25 mg/kg/day or in rabbits ≤3 mg/kg/day (doses equivalent to the MRHD of 40 mg/day based on AUC and body surface area, respectively). In female rats given 5, 15 and 50 mg/kg/day before mating and continuing through to gestation day 7 resulted in decreased fetal body weight (female pups) and delayed ossification at 50 mg/kg/day (10 times the human exposure at the MRHD dose of 40 mg/day based on AUC). In pregnant rats given 2, 10 and 50 mg/kg/day of rosuvastatin from gestation day 7 through lactation day 21 (weaning), decreased pup survival occurred at 50 mg/kg/day (dose equivalent to 12 times the MRHD of 40 mg/day based body surface area). In pregnant rabbits given 0.3, 1, and 3 mg/kg/day of rosuvastatin from gestation day 6 to day 18, decreased fetal viability and maternal mortality was observed at 3 mg/kg/day (dose equivalent to the MRHD of 40 mg/day based on body surface area)."}', 'pediatric_use': '{"8.4 Pediatric Use Pediatric use information for patients 7 to 17 years of age is approved for AstraZeneca’s CRESTOR (rosuvastatin calcium) tablets. However, due to AstraZeneca’s marketing exclusivity rights, this drug product is not labeled with that pediatric information."}', 'geriatric_use': '{"8.5 Geriatric Use Of the 10,275 patients in clinical studies with rosuvastatin calcium, 3159 (31%) were 65 years and older, and 698 (6.8%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are at higher risk of myopathy and rosuvastatin calcium should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]."}'}

{"TROLAMINE SALICYLATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Adults and children 12 years of age : apply generously to the affected area, massage into painful area until thoroughly absorbed into the skin, repeat as necessary, but not more than 3 to 4 times daily. Children under 12 years of age : ask a doctor."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"TROLAMIN SALICYLATE 10%"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"For external use only . Allergy Alert: if prone to allergic reaction from aspirin or salicylates, consult a doctor before use. When using this product use only as directed, avoid taking a bath or shower within 1 hour before or after applying, do not bandage or use with a heating pad, avoid contact with eyes or mucous membranes, do not apply to wounds or damaged skin. Stop use and ask a doctor if condition worsens or symptoms persist for more than 7 days, if symptoms clear up and occur again within a few days, or if irritation develops."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ACETAMINOPHEN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Temporarily: • reduces fever • relieves minor aches and pains due to: • the common cold • flu • headache • sore throat • toothache"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ACETAMINOPHEN 160MG/5ML"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': '{"Do not use • with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist • If your child is allergic to acetaminophen or any of the inactive ingredients in this product"}', 'when_using': None, 'warnings': '{"Warnings Liver Warning : This product contains acetaminophen. Severe liver damage may occur if your child takes • more than 5 doses in 24 hours, which is the maximum daily amount for this product • With other drugs containing acetaminophen Allergy alert: acetaminophen may cause severe skin reactions. Symptoms may include: • skin reddening • blisters • rash. If a skin reaction occurs, stop use and seek medical help right away. Sore throat warning: If sore throat is severe, persists for more than 2 days, is accompanied or followed by fever, headache, rash, nausea, or vomiting consult a doctor promptly. Ask a doctor before use if your child has liver disease Ask a doctor or pharmacist before use if your child is taking the blood thinning drug warfarin. Stop use and ask a doctor if • pain gets worse or lasts more than 5 days • fever gets worse or lasts more than 3 days • new symptoms occur • redness or swelling is present. These could be signs of a serious condition. Keep out of reach of children In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Prompt medical attention is critical even if you do not notice any signs or symptoms. Do not use • with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist • If your child is allergic to acetaminophen or any of the inactive ingredients in this product"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BENZALKONIUM CHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses: For hand washing to decrease bacteria on the skin. Recommended for repeated use."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZALKONIUM CHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours."}', 'do_not_use': None, 'when_using': '{"When using this product avoid contact with eyes. In case of eye contact, flush with water."}', 'warnings': '{"Warnings: For external use only When using this product avoid contact with eyes. In case of eye contact, flush with water. Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"PHENYLEPHRINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses • temporarily relieves nasal congestion due to: • common cold • hay fever • upper respiratory allergies"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"PHENYLEPHRINE HYDROCHLORIDE"}', 'route': '{NASAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist"}', 'do_not_use': None, 'when_using': '{"When using this product • do not use more than directed • do not use for more than 3 days. Frequent or prolonged use may cause nasal congestion to come back or get worse. • use only as directed • temporary discomfort such as burning, stinging, sneezing or an increase in nasal discharge may occur • use of this container by more than one person may spread infection"}', 'warnings': '{"Warnings Ask a doctor before use if you have • heart disease • diabetes • thyroid disease • high blood pressure • trouble urinating due to an enlarged prostate gland When using this product • do not use more than directed • do not use for more than 3 days. Frequent or prolonged use may cause nasal congestion to come back or get worse. • use only as directed • temporary discomfort such as burning, stinging, sneezing or an increase in nasal discharge may occur • use of this container by more than one person may spread infection Stop use and ask a doctor if symptoms persist If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. (1-800-222-1222)"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{CEPHALEXIN}

{'contraindications': '{"4 CONTRAINDICATIONS Cephalexin is contraindicated in patients with known hypersensitivity to cephalexin or other members of the cephalosporin class of antibacterial drugs. Patients with known hypersensitivity to cephalexin or other members of the cephalosporin class of antibacterial drugs. (4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious events are described in greater detail in the Warning and Precautions section: Hypersensitivity reactions [ see Warning and Precautions ( 5.1 ) ] Clostridium difficile-associated diarrhea [ see Warnings and Precautions ( 5.2 ) ] Direct Coombs’ Test Seroconversion [ see Warnings and Precautions ( 5.3 ) ] Seizure Potential [ see Warnings and Precautions ( 5.4 ) ] Effect on Prothrombin Activity [ see Warnings and Precautions ( 5.5 ) ] Development of Drug-Resistant Bacteria [ see Warnings and Precautions ( 5.6 ) ] The most common adverse reactions associated with cephalexin include diarrhea, nausea, vomiting, dyspepsia and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice In clinical trials, the most frequent adverse reaction was diarrhea. Nausea and vomiting, dyspepsia, gastritis, and abdominal pain have also occurred. As with penicillins and other cephalosporins, transient hepatitis and cholestatic jaundice have been reported. Other reactions have included hypersensitivity reactions, genital and anal pruritus, genital candidiasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Reversible interstitial nephritis has been reported. Eosinophilia, neutropenia, thrombocytopenia, hemolytic anemia, and slight elevations in aspartate transaminase (AST) and alanine transaminase (ALT) have been reported. In addition to the adverse reactions listed above that have been observed in patients treated with cephalexin, the following adverse reactions and other altered laboratory tests have been reported for cephalosporin class antibacterial drugs: Other Adverse Reactions: Fever, colitis, aplastic anemia, hemorrhage, renal dysfunction, and toxic nephropathy. Altered Laboratory Tests: Prolonged prothrombin time, increased blood urea nitrogen (BUN), increased creatinine, elevated alkaline phosphatase, elevated bilirubin, elevated lactate dehydrogenase (LDH), pancytopenia, leukopenia, and agranulocytosis."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Metformin: increased metformin concentrations. Monitor for hypoglycemia. ( 7.1 ) Probenecid- The renal excretion of cephalexin is inhibited by probenecid. Co-administration of probenecid with cephalexin is not recommended. ( 7.2 ) Administration of cephalexin may result in a false-positive reaction glucose in the urine. ( 7.3 ) 7.1 Metformin Administration of cephalexin with metformin results in increased plasma metformin concentrations and decreased renal clearance of metformin. Careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin and metformin [ see Clinical Pharmacology ( 12.3 )] 7.2 Probenecid The renal excretion of cephalexin is inhibited by probenecid. Co-administration of probenecid with cephalexin is not recommended. 7.3 Interaction with Laboratory or Diagnostic Testing A false-positive reaction may occur when testing for the presence of glucose in the urine using Benedict’s solution or Fehling’s solution."}', 'indications_and_usage': '{"1 INDICATIONS & USAGE Cephalexin is a cephalosporin antibacterial drug indicated for the treatment of the following infections caused by susceptible isolates of designated bacteria: Respiratory tract infection ( 1.1 ) Otitis media ( 1.2 ) Skin and skin structure infections ( 1.3 ) Bone infections (1.4) Genitourinary tract infections ( 1.5 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin and other antibacterial drugs, Cephalexin should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. (1.6) 1.1 Respiratory Tract Infections Cephalexin is indicated for the treatment of respiratory tract infections caused by susceptible isolates of Streptococcus pneumoniae and Streptococcus pyogenes. 1.2 Otitis Media Cephalexin is indicated for the treatment of otitis media caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxella catarrhalis. 1.3 Skin and Skin Structure Infections Cephalexin is indicated for the treatment of skin and skin structure infections caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus and Streptococcus pyogenes. 1.4 Bone Infections Cephalexin is indicated for the treatment of bone infections caused by susceptible isolates of Staphylococcus aureus and Proteus mirabilis. 1.5 Genitourinary Tract Infections Cephalexin is indicated for the treatment of genitourinary tract infections, including acute prostatitis, caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin and other antibacterial drugs, Cephalexin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information is available, this information should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Serious hypersensitivity (anaphylactic) reactions : Prior to use, inquire regarding history of hypersensitivity to beta-lactam antibacterial drugs. Discontinue the drug if signs or symptoms of an allergic reaction occur and institute supportive measures. ( 5.1 ) Clostridium difficile-associated diarrhea (CDAD ): Evaluate if diarrhea occurs. ( 5.2 ) Direct Coomb’s Test Seroconversion : If anemia develops during or after cephalexin therapy, evaluate for drug-induced hemolytic anemia. ( 5.3 ) Seizure Potential : Use lower dose in patients with renal impairment. ( 5.4 ) 5.1 Hypersensitivity Reactions Allergic reactions in the form of rash, urticaria, angioedema, anaphylaxis, erythema multiforme, Stevens- Johnson syndrome, or toxic epidermal necrolysis have been reported with the use of cephalexin. Before therapy with cephalexin is instituted, inquire whether the patient has a history of hypersensitivity reactions to cephalexin, cephalosporins, penicillins, or other drugs. Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cephalexin occurs, discontinue the drug and institute appropriate treatment. 5.2 Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cephalexin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Direct Coombs’ Test Seroconversion Positive direct Coombs’ tests have been reported during treatment with the cephalosporin antibacterial drugs including cephalexin. Acute intravascular hemolysis induced by cephalexin therapy has been reported. If anemia develops during or after cephalexin therapy, perform a diagnostic work-up for drug-induced hemolytic anemia, discontinue cephalexin and institute appropriate therapy. 5.4 Seizure Potential Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures occur, discontinue cephalexin. Anticonvulsant therapy can be given if clinically indicated. 5.5 Prolonged Prothrombin Time Cephalosporins may be associated with prolonged prothrombin time. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antibacterial therapy, and patients receiving anticoagulant therapy. Monitor prothrombin time in patients at risk and manage as indicated. 5.6 Development of Drug-Resistant Bacteria Prescribing cephalexin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of cephalexin may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken."}', 'overdosage': '{"10 OVERDOSAGE Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria. In the event of an overdose, institute general supportive measures. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin."}', 'active_flag': 'Y', 'generic_name': '{CEPHALEXIN}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Allergic Reactions Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask the patient about any previous hypersensitivity reactions to cephalexin, other beta-lactams (including cephalosporins) or other allergens ( 5.1 ) Diarrhea Advise patients that diarrhea is a common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, advise patients to contact their healthcare provider Antibacterial Resistance Counsel patients that antibacterial drugs including cephalexin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cephalexin is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cephalexin or other antibacterial drugs in the future. Manufactured by : Alkem Laboratories Ltd., INDIA. Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: November, 2021 PT 1199-11"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with cephalosporin use, including cephalexin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Animal reproduction studies with mice and rats using oral doses of cephalexin that are 0.6- and 1.2-times the maximum recommended human dose (MRHD) based on body surface area during organogenesis revealed no evidence of harm to the fetus (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from epidemiologic studies and postmarketing case reports over several decades have not identified a consistent association with cephalosporin use, including cephalexin, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data In animal reproduction studies, pregnant mice and rats administered oral cephalexin doses of 250 or 500 mg/kg/day (approximately 0.6 and 1.2 times the MRHD) based on body surface area, respectively during the period of organogenesis showed no adverse effects on embryofetal development. In a pre-and post-natal developmental toxicity study, pregnant rats that received oral doses of 250 or 500 mg/kg/day of cephalexin from Day 15 of pregnancy to litter Day 21 showed no adverse effects on parturition, litter size, or growth of offspring."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of cephalexin in pediatric patients was established in clinical trials for the dosages described in the dosage and administration section [see Dosage and Administration ( 2.2 )]"}', 'geriatric_use': '{"8.5 Geriatric Use Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. This drug is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection [ see Warnings and Precautions ( 5.4 )]"}'}

{ESZOPICLONE}

{'contraindications': '{"4. Contraindications Eszopiclone tablets are contraindicated in patients who have experienced complex sleep behaviors after taking eszopiclone [see Warnings and Precautions (5.1)]. Eszopiclone tablets are contraindicated in patients with known hypersensitivity to eszopiclone. Hypersensitivity reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.3)]."}', 'adverse_reactions': '{"6. Adverse Reactions Complex Sleep Behaviors [see Boxed Warning and Warnings and Precautions (5.1)] CNS Depressant Effects and Next-Day Impairment [see Warnings and Precautions (5.2)] Need to Evaluate for Comorbid Diagnoses [see Warnings and Precautions (5.3)] Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.4)] Abnormal Thinking and Behavioral Changes [see Warnings and Precautions (5.5)] Withdrawal Effects [see Warnings and Precautions (5.6)] Timing of Drug Administration [see Warnings and Precautions (5.7) Special Populations [see Warnings and Precautions (5.8)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The premarketing development program for eszopiclone included eszopiclone exposures in patients and/or normal subjects from two different groups of studies: approximately 400 normal subjects in clinical pharmacology/pharmacokinetic studies, and approximately 1,550 patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 263 patient-exposure years. The conditions and duration of treatment with eszopiclone varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term and longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while the patient was receiving therapy following baseline evaluation. 6.1 Clinical Trials Experience Adverse Reactions Resulting in Discontinuation of Treatment In placebo-controlled, parallel-group clinical trials in the elderly, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who received 2 mg eszopiclone, and 1.4% of 72 patients who received 1 mg eszopiclone discontinued treatment due to an adverse reaction. In the 6-week parallel-group study in adults, no patients in the 3 mg arm discontinued because of an adverse reaction. In the long-term 6-month study in adult insomnia patients, 7.2% of 195 patients who received placebo and 12.8% of 593 patients who received 3 mg eszopiclone discontinued due to an adverse reaction. No reaction that resulted in discontinuation occurred at a rate of greater than 2%. Adverse Reactions Observed at an Incidence of ≥2% in Controlled Trials Table 1 shows the incidence of adverse reactions from a Phase 3 placebo-controlled study of eszopiclone at doses of 2 or 3 mg in nonelderly adults. Treatment duration in this trial was 44 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 2 mg or 3 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients. Table 1: Incidence (%) of Adverse Reactions in a 6-Week Placebo-Controlled Study in Nonelderly Adults with Eszopiclone1 Adverse Reaction Placebo (n=99) Eszopiclone 2 mg (n=104) Eszopiclone 3 mg (n=105) Body as a Whole Headache 13 21 17 Viral Infection 1 3 3 Digestive System Dry Mouth 3 5 7 Dyspepsia 4 4 5 Nausea 4 5 4 Vomiting 1 3 0 Nervous System Anxiety 0 3 1 Confusion 0 0 3 Depression 0 4 1 Dizziness 4 5 7 Hallucinations 0 1 3 Libido Decreased 0 0 3 Nervousness 3 5 0 Somnolence 3 10 8 Respiratory System Infection 3 5 10 Skin and Appendages Rash 1 3 4 Special Senses Unpleasant Taste 3 17 34 Urogenital System Dysmenorrhea * 0 3 0 Gynecomastia ** 0 3 0 1Reactions for which the eszopiclone incidence was equal to or less than placebo are not listed on the table, but included the following: abnormal dreams, accidental injury, back pain, diarrhea, flu syndrome, myalgia, pain, pharyngitis, and rhinitis. * Gender-specific adverse reaction in females ** Gender-specific adverse reaction in males Adverse reactions from Table 1 that suggest a dose-response relationship in adults include viral infection, dry mouth, dizziness, hallucinations, infection, rash, and unpleasant taste, with this relationship clearest for unpleasant taste. Table 2 shows the incidence of adverse reactions from combined Phase 3 placebo-controlled studies of eszopiclone at doses of 1 or 2 mg in elderly adults (ages 65 to 86). Treatment duration in these trials was 14 days. The table includes only reactions that occurred in 2% or more of patients treated with eszopiclone 1 mg or 2 mg in which the incidence in patients treated with eszopiclone was greater than the incidence in placebo-treated patients. Table 2: Incidence (%) of Adverse Reactions in Elderly Adults (Ages 65 to 86 Years) in 2-Week Placebo-Controlled Trials with Eszopiclone1 Adverse Reactions Placebo (n=208) Eszopiclone 1 mg (n=72) Eszopiclone 2 mg (n=215) Body as a Whole Accidental Injury 1 0 3 Headache 14 15 13 Pain 2 4 5 Digestive System Diarrhea 2 4 2 Dry Mouth 2 3 7 Dyspepsia 2 6 2 Nervous System Abnormal Dreams 0 3 1 Dizziness 2 1 6 Nervousness 1 0 2 Neuralgia 0 3 0 Skin and Appendages Pruritus 1 4 1 Special Senses Unpleasant Taste 0 8 12 Urogenital System Urinary Tract Infection 0 3 0 1Reactions for which the eszopiclone incidence was equal to or less than placebo are not listed on the table, but included the following: abdominal pain, asthenia, nausea, rash, and somnolence. Adverse reactions from Table 2 that suggest a dose-response relationship in elderly adults include pain, dry mouth, and unpleasant taste, with this relationship again clearest for unpleasant taste. These figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice because patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contributions of drug and nondrug factors to the adverse reaction incidence rate in the population studied. Other Reactions Observed During the Premarketing Evaluation of Eszopiclone Following is a list of modified COSTART terms that reflect adverse reactions as defined in the introduction to the Adverse Reactions section and reported by approximately 1,550 subjects treated with eszopiclone at doses in the range of 1 to 3.5 mg/day during Phase 2 and 3 clinical trials throughout the United States and Canada. All reported reactions are included except those already listed in Tables 1 and 2 or elsewhere in labeling, minor reactions common in the general population, and reactions unlikely to be drug-related. Although the reactions reported occurred during treatment with eszopiclone, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those that occurred in fewer than 1/100 patients but in at least 1/1,000 patients; rareadverse reactions are those that occurred in fewer than 1/1,000 patients. Gender-specific reactions are categorized based on their incidence for the appropriate gender. Body as a Whole: Frequent: chest pain; Infrequent: allergic reaction, cellulitis, face edema, fever, halitosis, heat stroke, hernia, malaise, neck rigidity, photosensitivity. Cardiovascular System: Frequent: migraine; Infrequent: hypertension; Rare: thrombophlebitis. Digestive System: Infrequent: anorexia, cholelithiasis, increased appetite, melena, mouth ulceration, thirst, ulcerative stomatitis; Rare: colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, stomach ulcer, stomatitis, tongue edema, rectal hemorrhage. Hemic and Lymphatic System: Infrequent:anemia, lymphadenopathy. Metabolic and Nutritional: Frequent:peripheral edema; Infrequent:hypercholesteremia, weight gain, weight loss; Rare:dehydration, gout, hyperlipemia, hypokalemia. Musculoskeletal System: Infrequent:arthritis, bursitis, joint disorder (mainly swelling, stiffness, and pain), leg cramps, myasthenia, twitching; Rare:arthrosis, myopathy, ptosis. Nervous System: Infrequent:agitation, apathy, ataxia, emotional lability, hostility, hypertonia, hypesthesia, incoordination, insomnia, memory impairment, neurosis, nystagmus, paresthesia, reflexes decreased, thinking abnormal (mainly difficulty concentrating), vertigo; Rare:abnormal gait, euphoria, hyperesthesia, hypokinesia, neuritis, neuropathy, stupor, tremor. Respiratory System: Infrequent:asthma, bronchitis, dyspnea, epistaxis, hiccup, laryngitis. Skin and Appendages: Infrequent:acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rare:erythema multiforme, furunculosis, herpes zoster, hirsutism, maculopapular rash, vesiculobullous rash. Special Senses: Infrequent:conjunctivitis, dry eyes, ear pain, otitis externa, otitis media, tinnitus, vestibular disorder; Rare:hyperacusis, iritis, mydriasis, photophobia. Urogenital System: Infrequent:amenorrhea, breast engorgement, breast enlargement, breast neoplasm, breast pain, cystitis, dysuria, female lactation, hematuria, kidney calculus, kidney pain, mastitis, menorrhagia, metrorrhagia, urinary frequency, urinary incontinence, uterine hemorrhage, vaginal hemorrhage, vaginitis; Rare:oliguria, pyelonephritis, urethritis. 6.2 Postmarketing Experience In addition to the adverse reactions observed during clinical trials, dysosmia, an olfactory dysfunction that is characterized by distortion of the sense of smell, has been reported during postmarketing surveillance with eszopiclone. Because this event is reported spontaneously from a population of unknown size, it is not possible to estimate the frequency of this event."}', 'drug_interactions': '{"7. Drug Interactions 7.1 CNS Active Drugs Ethanol: An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol [see Warnings and Precautions (5.1, 5.2)]. Olanzapine: Coadministration of eszopiclone and olanzapine produced a decrease in DSST scores. The interaction was pharmacodynamic; there was no alteration in the pharmacokinetics of either drug. 7.2 Drugs that Inhibit or Induce CYP3A4 Drugs that Inhibit CYP3A4 (Ketoconazole) CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The exposure of eszopiclone was increased by coadministration of ketoconazole, a potent inhibitor of CYP3A4. Other strong inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly. Dose reduction of eszopiclone is needed for patient co-administered eszopiclone with potent CYP3A4 inhibitors [see Dosage and Administration (2.3)]. Drugs that Induce CYP3A4 (Rifampicin) Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with eszopiclone. Combination use with CYP3A4 inducer may decrease the exposure and effects of eszopiclone."}', 'indications_and_usage': '{"1. Indications and Usage Section 1 INDICATIONS AND USAGE Eszopiclone tablets are indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, eszopiclone tablets are administered at bedtime decreased sleep latency and improved sleep maintenance. The clinical trials performed in support of efficacy were up to 6 months in duration. The final formal assessments of sleep latency and maintenance were performed at 4 weeks in the 6-week study (adults only), at the end of both 2-week studies (elderly only) and at the end of the 6-month study (adults only)."}', 'warnings_and_cautions': '{"5. Warnings and Precautions 5.1 Complex Sleep Behaviors Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the first or any subsequent use of eszopiclone. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in fatal outcomes. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with eszopiclone alone at recommended dosages, with or without the concomitant use of alcohol or other CNS depressants [see Drug Interactions (7.1)]. Discontinue eszopiclone immediately if a patient experiences a complex sleep behavior. 5.2 CNS Depressant Effects and Next-Day Impairment Eszopiclone is a CNS depressant and can impair daytime function in some patients at the higher doses (2 mg or 3 mg), even when used as prescribed. Prescribers should monitor for excess depressant effects, but impairment can occur in the absence of symptoms (or even with subjective improvement), and impairment may not be reliably detected by ordinary clinical exam (i.e., less than formal psychomotor testing). While pharmacodynamic tolerance or adaptation to some adverse depressant effects of eszopiclone may develop, patients using 3 mg eszopiclone should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use. Additive effects occur with concomitant use of other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of eszopiclone and concomitant CNS depressants should be considered [see Dosage and Administration (2.4)]. The use of eszopiclone with other sedative-hypnotics at bedtime or the middle of the night is not recommended. The risk of next-day psychomotor impairment is increased if eszopiclone is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants: or co-administered with other drugs that increase the blood levels of eszopiclone [see Dosage and Administration (2.3) and Clinical Studies (14.3)]. Because eszopiclone can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls. 5.3 Need to Evaluate for Comorbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including eszopiclone. Because some of the important adverse effects of eszopiclone appear to be dose related, it is important to use the lowest possible effective dose, especially in the elderly [see Dosage and Administration (2.1)]. 5.4 Severe Anaphylactic and Anaphylactoid Reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including eszopiclone. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with eszopiclone should not be rechallenged with the drug. 5.5 Abnormal Thinking and Behavioral Changes A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g., aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. 5.6 Withdrawal Effects Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence (9)]. 5.7 Timing of Drug Administration Eszopiclone should be taken immediately before bedtime. Taking a sedative/hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness. 5.8 Special Populations Use in Elderly and/or Debilitated Patients Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. The dose should not exceed 2 mg in elderly or debilitated patients [see Dosage and Administration(2.2)]. Use in Patients with Concomitant Illness Clinical experience with eszopiclone in patients with concomitant illness is limited. Eszopiclone should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses. A study in healthy volunteers did not reveal respiratory-depressant effects at doses 2.5-fold higher (7 mg) than the recommended dose of eszopiclone. Caution is advised, however, if eszopiclone is prescribed to patients with compromised respiratory function. The dose of eszopiclone should not exceed 2 mg in patients with severe hepatic impairment, because systemic exposure is doubled in such subjects. No dose adjustment appears necessary for subjects with mild or moderate hepatic impairment. No dose adjustment appears necessary in subjects with any degree of renal impairment, since less than 10% of eszopiclone is excreted unchanged in the urine. The dose of eszopiclone should be reduced in patients who are administered potent inhibitors of CYP3A4, such as ketoconazole, while taking eszopiclone. Downward dose adjustment is also recommended when eszopiclone is administered with agents having known CNS-depressant effects. Use in Patients with Depression In primarily depressed patients treated with sedative-hypnotics, worsening of depression, including suicidal thoughts and actions (including completed suicides), have been reported in association with the use of sedative/hypnotics. Sedative/hypnotic drugs should be administered with caution to patients exhibiting signs and symptoms of depression. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time."}', 'overdosage': '{"10. Overdosage In clinical trials with eszopiclone, one case of overdose with up to 36 mg of eszopiclone was reported in which the subject fully recovered. Since commercial marketing began, spontaneous cases of eszopiclone overdoses up to 270 mg (90 times the maximum recommended dose of eszopiclone) have been reported, in which patients have recovered. Fatalities related to eszopiclone overdoses were reported only in combination with other CNS drugs or alcohol. 10.1 Signs and Symptoms Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agents. Methemoglobinemia in association with overdoses of racemic zopiclone has been reported. 10.2 Recommended Treatment General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be monitored and treated by appropriate medical intervention. Consider monitoring methemoglobin in the setting of high-dose overdosage.The value of dialysis in the treatment of overdosage has not been determined. As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage."}', 'active_flag': 'Y', 'generic_name': '{ESZOPICLONE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"HYDRALAZINE HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS: Hypersensitivity to hydralazine, coronary artery disease, mitral valvular rheumatic heart disease."}', 'adverse_reactions': '{"ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adverse reactions with hydralazine hydrochloride are usually reversible when dosage is reduced. However, in some cases it may be necessary to discontinue the drug. The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. Common: Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, angina pectoris. Less Frequent: Digestive -constipation, paralytic ileus. Cardiovascular - hypotension, paradoxical pressor response, edema. Respiratory - dyspnea. Neurologic - peripheral neuritis, evidenced by paresthesia, numbness, and tingling; dizziness; tremors; muscle cramps, psychotic reactions characterized by depression, disorientation, or anxiety. Genitourinary - difficulty in urination. Hematologic - blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, purpura; lymphadenopathy; splenomegaly. Hypersensitive Reactions - rash, urticaria, pruritis, fever, chills, arthralgia, eosinophilia, and, rarely, hepatitis. Other - nasal congestion, flushing, lacrimation, conjunctivitis."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE: Severe essential hypertension when the drug cannot be given orally or when there is an urgent need to lower blood pressure."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE: Acute Toxicity No deaths due to acute poisoning have been reported. Highest known dose survived: adults, 10 g orally. Oral LD 50 in rats: 173 and 187 mg/kg. Signs and Symptoms Signs and symptoms of overdosage include hypotension, tachycardia, headache, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock. Treatment There is no specific antidote. Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary, and renal function should be monitored and supported as required. No experience has been reported with extracorporeal or peritoneal dialysis.","Acute Toxicity No deaths due to acute poisoning have been reported. Highest known dose survived: adults, 10 g orally. Oral LD 50 in rats: 173 and 187 mg/kg.","Signs and Symptoms Signs and symptoms of overdosage include hypotension, tachycardia, headache, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock.","Treatment There is no specific antidote. Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary, and renal function should be monitored and supported as required. No experience has been reported with extracorporeal or peritoneal dialysis."}', 'active_flag': 'Y', 'generic_name': '{"HYDRALAZINE HYDROCHLORIDE"}', 'route': '{INTRAMUSCULAR,INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS: In a few patients, hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients, hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later. Long-term treatment with steroids may be necessary (see PRECAUTIONS , Laboratory Tests )."}', 'precautions': '{"PRECAUTIONS: General Myocardial stimulation produced by hydralazine can cause anginal attacks and ECG changes of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease. The “hyperdynamic” circulation caused by hydralazine may accentuate specific cardiovascular inadequacies. For example, hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from hydralazine but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents. In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of hydralazine. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage. Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Publishing evidence suggests an antipyridoxine effect and that pyridoxine should be added to the regimen if symptoms develop. Laboratory Tests Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise or other unexplained signs or symptoms. A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with hydralazine hydrochloride. Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura, have been reported. If such abnormalities develop, therapy should be discontinued. Drug Interactions MAO inhibitors should be used with caution in patients receiving hydralazine. When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injection and hydralazine hydrochloride injection are used concomitantly. Carcinogenesis, Mutagenesis, Impairment of Fertility In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a 2-year carcinogenicity study of rats given hydralazine by gavage at dose levels of 15, 30 and 60 mg/kg/day (approximately 5 to 20 times the recommended human daily dosage), microscopic examination of the liver revealed a small, but statistically significant increase in benign neoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats and a significantly increased incidence was not observed until 18 months of treatment. Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rats and one rabbit hepatocyte in vitro DNA repair studies. Additional in vivo and in vitro studies using lymphoma cells, germinal cells and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine. The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions. Pregnancy Teratogenic Effects Pregnancy Category C Animal studies indicate that hydralazine is teratogenic in mice at 20-30 times the maximum daily human dose of 200-300 mg and possibly in rabbits at 10-15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones. There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hydralazine injection is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established in controlled clinical trials, although there is experience with the use of hydralazine hydrochloride in pediatric patients. The usual recommended parenteral dosage, administered intramuscularly or intravenously, is 1.7-3.5 mg/kg of body weight daily, divided into four to six doses.","General Myocardial stimulation produced by hydralazine can cause anginal attacks and ECG changes of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease. The “hyperdynamic” circulation caused by hydralazine may accentuate specific cardiovascular inadequacies. For example, hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from hydralazine but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents. In hypertensive patients with normal kidneys who are treated with hydralazine, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of hydralazine. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage. Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Publishing evidence suggests an antipyridoxine effect and that pyridoxine should be added to the regimen if symptoms develop.","Laboratory Tests Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise or other unexplained signs or symptoms. A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with hydralazine hydrochloride. Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis, and purpura, have been reported. If such abnormalities develop, therapy should be discontinued.","Drug Interactions MAO inhibitors should be used with caution in patients receiving hydralazine. When other potent parenteral antihypertensive drugs, such as diazoxide, are used in combination with hydralazine, patients should be continuously observed for several hours for any excessive fall in blood pressure. Profound hypotensive episodes may occur when diazoxide injection and hydralazine hydrochloride injection are used concomitantly.","Carcinogenesis, Mutagenesis, Impairment of Fertility In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) of both male and female mice given hydralazine continuously in their drinking water at a dosage of about 250 mg/kg per day (about 80 times the maximum recommended human dose). In a 2-year carcinogenicity study of rats given hydralazine by gavage at dose levels of 15, 30 and 60 mg/kg/day (approximately 5 to 20 times the recommended human daily dosage), microscopic examination of the liver revealed a small, but statistically significant increase in benign neoplastic nodules in male and female rats from the high-dose group and in female rats from the intermediate-dose group. Benign interstitial cell tumors of the testes were also significantly increased in male rats from the high-dose group. The tumors observed are common in aged rats and a significantly increased incidence was not observed until 18 months of treatment. Hydralazine was shown to be mutagenic in bacterial systems (Gene Mutation and DNA Repair) and in one of two rats and one rabbit hepatocyte in vitro DNA repair studies. Additional in vivo and in vitro studies using lymphoma cells, germinal cells and fibroblasts from mice, bone marrow cells from Chinese hamsters and fibroblasts from human cell lines did not demonstrate any mutagenic potential for hydralazine. The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observation has not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusions.","Pregnancy Teratogenic Effects Pregnancy Category C Animal studies indicate that hydralazine is teratogenic in mice at 20-30 times the maximum daily human dose of 200-300 mg and possibly in rabbits at 10-15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones. There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.","Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hydralazine injection is administered to a nursing woman.","Pediatric Use Safety and effectiveness in pediatric patients have not been established in controlled clinical trials, although there is experience with the use of hydralazine hydrochloride in pediatric patients. The usual recommended parenteral dosage, administered intramuscularly or intravenously, is 1.7-3.5 mg/kg of body weight daily, divided into four to six doses."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"USE For hand washing to decrease bacteria on the skin."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ALCOHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warning Flammable, keep away from fire or flame . For external use only. When using this product , Do not use in or near the eyes. In case of contact, rinse eyes thoroughly with water. Stop use and ask a doctor, if irritaion and redness develop; condition persists for ore than 72 hours Other Information： Do not store above 100℉ (38 ℃) May discolor some fabrics or surface ●If swallowed, get medical help or contact a Poison Contrl Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DIPHENHYDRAMINE HYDROCHLORIDE",IBUPROFEN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses ■ for relief of occasional sleeplessness when associated with minor aches and pains ■ helps you fall asleep and stay asleep"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"IBUPROFEN, DIPHENHYDRAMINE HCL"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if ■ you experience any of the following signs of stomach bleeding: ■ feel faint ■ vomit blood ■ have bloody or black stools ■ have stomach pain that does not get better ■ you have symptoms of heart problems or stroke: ■ chest pain ■ trouble breathing ■ weakness in one part or side of body ■ slurred speech ■ leg swelling ■ pain gets worse or lasts more than 10 days ■ sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness ■ redness or swelling is present in the painful area ■ any new symptoms appear"}', 'do_not_use': '{"Do not use ■ if you have ever had an allergic reaction to any other pain reliever/fever reducer ■ unless you have time for a full night’s sleep ■ in children under 12 years of age ■ right before or after heart surgery ■ with any other product containing diphenhydramine, even one used on skin ■ if you have sleeplessness without pain"}', 'when_using': '{"When using this product ■ drowsiness will occur ■ avoid alcoholic drinks ■ do not drive a motor vehicle or operate machinery ■ take with food or milk if stomach upset occurs"}', 'warnings': '{"Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: ■ hives ■ facial swelling ■ asthma (wheezing) ■ shock ■ skin reddening ■ rash ■ blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you ■ are age 60 or older ■ have had stomach ulcers or bleeding problems ■ take a blood thinning (anticoagulant) or steroid drug ■ take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] ■ have 3 or more alcoholic drinks every day while using this product ■ take more or for a longer time than directed Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. Do not use ■ if you have ever had an allergic reaction to any other pain reliever/fever reducer ■ unless you have time for a full night’s sleep ■ in children under 12 years of age ■ right before or after heart surgery ■ with any other product containing diphenhydramine, even one used on skin ■ if you have sleeplessness without pain Ask a doctor before use if ■ stomach bleeding warning applies to you ■ you have problems or serious side effects from taking pain relievers or fever reducers ■ you have a history of stomach problems, such as heartburn ■ you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or had a stroke ■ you are taking a diuretic ■ you have a breathing problem such as emphysema or chronic bronchitis ■ you have glaucoma ■ you have trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are ■ taking sedatives or tranquilizers, or any other sleep-aid ■ under a doctor\'s care for any continuing medical illness ■ taking any other antihistamines ■ taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin ■ taking any other drug When using this product ■ drowsiness will occur ■ avoid alcoholic drinks ■ do not drive a motor vehicle or operate machinery ■ take with food or milk if stomach upset occurs Stop use and ask a doctor if ■ you experience any of the following signs of stomach bleeding: ■ feel faint ■ vomit blood ■ have bloody or black stools ■ have stomach pain that does not get better ■ you have symptoms of heart problems or stroke: ■ chest pain ■ trouble breathing ■ weakness in one part or side of body ■ slurred speech ■ leg swelling ■ pain gets worse or lasts more than 10 days ■ sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness ■ redness or swelling is present in the painful area ■ any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen at 20 weeks or later in pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use(s) Hand sanitizer gives protection from bacteria & germs. Use when soap and water are not available"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ALCOHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings -For external use only. -Flammable, keep away from the flames. DO NOT USE If irritation and skin redness develop. On open skin wounds When using this product Keep out of eyes, ears and mouth, In case of contact with eyes, rinse eyes thoroughly with water. Stop use and ask for a doctor Irritation or rash occurs. These may be signs of a serious condition. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{CHLORTHALIDONE}

{'contraindications': '{"CONTRAINDICATIONS: Anuria. Known hypersensitivity to chlorthalidone or other sulfonamide-derived drugs."}', 'adverse_reactions': '{"ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, please call RiconPharma LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency. Gastrointestinal System Reactions: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis. Central Nervous System Reactions: dizziness, vertigo, paresthesias, headache, xanthopsia. Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia. Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis). Cardiovascular Reactions: orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates, or narcotics. Other Adverse Reactions: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, impotence. Whenever adverse reactions are moderate or severe, chlorthalidone dosage should be reduced or therapy withdrawn"}', 'drug_interactions': '{"Drug Interactions Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Higher dosage of oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during chlorthalidone administration. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Chlorthalidone and related drugs may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use."}', 'indications_and_usage': '{"INDICATIONS AND USAGE: Diuretics such as chlorthalidone are indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. Chlorthalidone is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Chlorthalidone has also been found useful in edema due to various forms of renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. Usage in Pregnancy: The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Chlorthalidone is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS, below). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy that is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but that is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and be appropriate."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE: Symptoms of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD 50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution."}', 'active_flag': 'Y', 'generic_name': '{CHLORTHALIDONE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS: Chlorthalidone should be used with caution in severe renal disease. In patients with renal disease, chlorthalidone or related drugs may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. Chlorthalidone should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics, which are structurally related to chlorthalidone. However, systemic lupus erythematosus has not been reported following chlorthalidone administration."}', 'precautions': '{"PRECAUTIONS: General Hypokalemia may develop with chlorthalidone as with any other diuretic, especially with brisk diuresis when severe cirrhosis is present or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity. Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather, appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient. If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen, a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy. Calcium excretion is decreased by thiazide-like drugs. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in few patients on thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen. Information for Patients Patients should inform their physician if they have: (1) had an allergic reaction to chlorthalidone or other diuretics or have asthma, (2) kidney disease, (3) liver disease, (4) gout, (5) systemic lupus erythematosus, or (6) been taking other drugs such as cortisone, digitalis, lithium carbonate, or drugs for diabetes. Patients should be cautioned to contact their physician if they experience any of the following symptoms of potassium loss: excess thirst, tiredness, drowsiness, restlessness, muscle pains or cramps, nausea, vomiting, or increased heart rate or pulse. Patients should also be cautioned that taking alcohol can increase the chance of dizziness occurring. Laboratory Tests Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving chlorthalidone should be observed for clinical signs of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Drug Interactions Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Higher dosage of oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during chlorthalidone administration. Chlorthalidone and related drugs may increase the responsiveness to tubocurarine. Chlorthalidone and related drugs may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Drug/Laboratory Test Interactions Chlorthalidone and related drugs may decrease serum PBI levels without signs of thyroid disturbance. Carcinogenesis, Mutagenesis, Impairment of Fertility No information available. Pregnancy Teratogenic Effects. Pregnancy Category B Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to chlorthalidone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult. Nursing Mothers Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from chlorthalidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children has not been established."}', 'information_for_patients': '{"Information for Patients Patients should inform their physician if they have: (1) had an allergic reaction to chlorthalidone or other diuretics or have asthma, (2) kidney disease, (3) liver disease, (4) gout, (5) systemic lupus erythematosus, or (6) been taking other drugs such as cortisone, digitalis, lithium carbonate, or drugs for diabetes. Patients should be cautioned to contact their physician if they experience any of the following symptoms of potassium loss: excess thirst, tiredness, drowsiness, restlessness, muscle pains or cramps, nausea, vomiting, or increased heart rate or pulse. Patients should also be cautioned that taking alcohol can increase the chance of dizziness occurring."}', 'pregnancy': '{"Pregnancy Teratogenic Effects. Pregnancy Category B Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to chlorthalidone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness in children has not been established."}', 'geriatric_use': None}

{NITROGEN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{NITROGEN}', 'route': '{"RESPIRATORY (INHALATION)"}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{CHLOROXYLENOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Antibacterial hand cleaner Use in daycare, hospitals, nursing homes, physician offices, dental offices and clinics"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{CHLOROXYLENOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only Avoid contact with eyes If contact occurs, risne thoroghly with water Discontinue use if irritation or redness develops If irritation persists for more than 72 hours, consult a physician KEEP OUT OF REACH OF CHILDREN If swallowed, get medical help or contact a Poison COntrol Center right away"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ISONIAZID}

{'contraindications': '{"CONTRAINDICATIONS Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug- induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology."}', 'adverse_reactions': '{"ADVERSE REACTIONS The most frequent reactions are those affecting the nervous system and the liver. Nervous System Reactions Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics) and is usually preceded by paresthesias of the feet and hands. The incidence is higher in \\"slow inactivators\\". Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis. Hepatic Reactions See boxed warning . Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age. Gastrointestinal Reactions Nausea, vomiting, epigastric distress, and pancreatitis. Hematologic Reactions Agranulocytosis; hemolytic, sideroblastic or aplastic anemia, thrombocytopenia; and eosinophilia. Hypersensitivity Reactions Fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), lymphadenopathy, vasculitis, toxic epidermal necrolysis, and drug reaction with eosinophilia syndrome (DRESS). Metabolic and Endocrine Reactions Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis and gynecomastia. Miscellaneous Reactions Rheumatic syndrome and systemic lupus erythematosus-like syndrome."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Isoniazid Tablets are recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant anti-tuberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with isoniazid or any other medication, is inadequate therapy. Isoniazid Tablets are recommended as preventive therapy for the following groups, regardless of age. (Note: the criterion for a positive reaction to a skin test (in millimeters of induration) for each group is given in parenthesis): Persons with human immunodeficiency virus (HIV) infection (greater than or equal to 5 mm) and persons with risk factors for HIV infection whose HIV infection status is unknown but who are suspected of having HIV infection. Preventive therapy may be considered for HIV infected persons who are tuberculin-negative but belong to groups in which the prevalence of tuberculosis infection is high. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy. Close contacts of persons with newly diagnosed infectious tuberculosis (greater than or equal to 5 mm). In addition, tuberculin-negative (less than 5 mm) children and adolescents who have been close contacts of infectious persons within the past 3 months are candidates for preventive therapy until a repeat tuberculin skin test is done 12 weeks after contact with the infectious source. If the repeat skin test is positive (greater than 5 mm), therapy should be continued. Recent converters, as indicated by a tuberculin skin test (greater than or equal to 10 mm increase within a 2-year period for those less than 35 years old; greater than or equal to 15 mm increase for those greater than or equal to 35 years of age). All infants and children younger than 4 years of age with a greater than 10 mm skin test are included in this category. Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (greater than or equal to 5 mm). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly. Intravenous drug users known to be HIV-seronegative (greater than 10 mm). Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (greater than or equal to 10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorticosteroids; immunosuppressive therapy; some hematologic and reticuloendothelial diseases, such as leukemia or Hodgkin\'s disease; end-stage renal disease; clinical situations associated with substantial rapid weight loss or chronic undernutrition (including: intestinal bypass surgery for obesity, the postgastrectomy state [with or without weight loss], chronic peptic ulcer disease, chronic malabsorption syndromes and carcinomas of the oropharynx and upper gastrointestinal tract that prevent adequate nutritional intake). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly. Additionally, in the absence of any of the above risk factors, persons under the age of 35 with a tuberculin skin test reaction of 10 mm or more are also appropriate candidates for preventive therapy if they are a member of any of the following high-incidence groups: Foreign-born persons from high-prevalence countries who never received BCG vaccine. Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics and Native Americans. Residents of facilities for long-term care (e.g., correctional institutions, nursing homes and mental institutions). Children who are less than 4 years old are candidates for isoniazid preventive therapy if they have greater than 10 mm induration from a PPD Mantoux tuberculin skin test. Finally, persons under the age of 35 who a) have none of the above risk factors (1 to 6); b) belong to none of the high-incidence groups; and c) have a tuberculin skin test reaction of 15 mm or more, are appropriate candidates for preventive therapy. The risk of hepatitis must be weighed against the risk of tuberculosis in positive tuberculin reactors over the age of 35. However, the use of isoniazid is recommended for those with the additional risk factors listed above (1 to 6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Signs and Symptoms Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colors and strange designs) are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycemia are typical laboratory findings. Treatment Untreated or inadequately treated cases of gross isoniazid overdosage, 80 mg/kg to 150 mg/kg, can cause neurotoxicity 6 and terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion. For the Asymptomatic Patient Absorption of drugs from the GI tract may be decreased by giving activated charcoal. Gastric emptying should also be employed in the asymptomatic patient. Safeguard the patient\'s airway when employing these procedures. Patients who acutely ingest greater than 80 mg/kg should be treated with intravenous pyridoxine on a gram per gram basis equal to the isoniazid dose. If an unknown amount of isoniazid is ingested, consider an initial dose of 5 grams of pyridoxine given over 30 to 60 minutes in adults or 80 mg/kg of pyridoxine in children. For the Symptomatic Patient Ensure adequate ventilation, support cardiac output and protect the airway while treating seizures and attempting to limit absorption. If the dose of isoniazid is known, the patient should be treated initially with a slow intravenous bolus of pyridoxine, over 3 to 5 minutes, on a gram per gram basis, equal to the isoniazid dose. If the quantity of isoniazid ingestion is unknown, then consider an initial intravenous bolus of pyridoxine of 5 grams in the adult or 80 mg/kg in the child. If seizures continue, the dosage of pyridoxine may be repeated. It would be rare that more than 10 grams of pyridoxine would need to be given. The maximum safe dose for pyridoxine in isoniazid intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because isoniazid interferes with the metabolism of phenytoin. General Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc.; type and cross-match blood in preparation for possible hemodialysis. Rapid Control of Metabolic Acidosis Patients with this degree of INH intoxication are likely to have hypoventilation. The administration of sodium bicarbonate under these circumstances can cause exacerbation of hypercarbia. Ventilation must be monitored carefully, by measuring blood carbon dioxide levels and supported mechanically, if there is respiratory insufficiency. Dialysis Both peritoneal and hemodialysis have been used in the management of isoniazid overdosage. These procedures are probably not required if control of seizures and acidosis is achieved with pyridoxine, diazepam and bicarbonate. Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration, pneumonitis, etc."}', 'active_flag': 'Y', 'generic_name': '{ISONIAZID}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS See the boxed warning ."}', 'precautions': '{"PRECAUTIONS General All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent hypersensitivity reaction. Use of isoniazid should be carefully monitored in the following: Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis. Patients with active chronic liver disease or severe renal dysfunction. Age greater than 35. Concurrent use of any chronically administered medication. History of previous discontinuation of isoniazid. Existence of peripheral neuropathy or conditions predisposing to neuropathy. Pregnancy. Injection drug use. Women belonging to minority groups, particularly in the postpartum period. HIV seropositive patients. Laboratory Tests Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age greater than 35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy. Drug Interactions Food Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving isoniazid. Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Acetaminophen A report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patient\'s liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats 1,2 . Carbamazepine Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely and appropriate dosage adjustment of the anticonvulsant should be made 3 . Ketoconazole Potential interaction of Ketoconazole and Isoniazid may exist. When Ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88 percent after 5 months of concurrent Isoniazid and Rifampin therapy 4 . Phenytoin Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made 5,6 . Theophylline A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made 7 . Valproate A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co\xad administered and appropriate dosage adjustments of valproate should be made 5 . Carcinogenesis and Mutagenesis Isoniazid has been shown to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation.Pregnancy Teratogenic Effects Pregnancy Category C Isoniazid has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Isoniazid was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Isoniazid should be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus. The benefit of preventive therapy also should be weighed against a possible risk to the fetus. Preventive therapy generally should be started after delivery to prevent putting the fetus at risk of exposure; the low levels of isoniazid in breast milk do not threaten the neonate. Since isoniazid is known to cross the placental barrier, neonates of isoniazid treated mothers should be carefully observed for any evidence of adverse effects. Nonteratogenic Effects Since isoniazid is known to cross the placental barrier, neonates of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects. Nursing Mothers The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they cannot be relied upon for prophylaxis or therapy of nursing infants."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{RUFINAMIDE}

{'contraindications': '{"4 CONTRAINDICATIONS Rufinamide tablets are contraindicated in patients with Familial Short QT syndrome [see Warnings and Precautions (5.3) ] . \xadRufinamide tablets are contraindicated in patients with Familial Short QT syndrome ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Behavior and Ideation [see Warnings and Precautions (5.1) ] Central Nervous System Reactions [see Warnings and Precautions (5.2) ] QT Shortening [see Warnings and Precautions (5.3) ] Multi-Organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4) ] Leukopenia [see Warnings and Precautions (5.7) ] Most common adverse reactions (≥ 10% and greater than placebo) were headache, dizziness, fatigue, somnolence, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adult and Pediatric Patients ages 3 to 17 years of age In the pooled, double-blind, adjunctive therapy studies in adult and pediatric patients ages 3 to 17 years of age, the most common (≥10%) adverse reactions in rufinamide-treated patients, in all doses studied (200 to 3200 mg per day) with a higher frequency than in patients on placebo were: headache, dizziness, fatigue, somnolence, and nausea. Table 2 lists adverse reactions that occurred in at least 3% of pediatric patients (ages 3 to less than 17 years) with epilepsy treated with rufinamide in controlled adjunctive studies and were numerically more common in patients treated with rufinamide than in patients on placebo. At the target dose of 45 mg/kg per day for adjunctive therapy in pediatric patients (ages 3 to less than 17 years), the most common (≥3%) adverse reactions with an incidence greater than in placebo for rufinamide were somnolence, vomiting, and headache. Table 2: Adverse Reactions in Pediatric Patients (Ages 3 to less than 17 years) in Pooled Double-Blind Adjunctive Trials Adverse Reaction Rufinamide (N=187) % Placebo (N=182) % Somnolence 17 9 Vomiting 17 7 Headache 16 8 Fatigue 9 8 Dizziness 8 6 Nausea 7 3 Influenza 5 4 Nasopharyngitis 5 3 Decreased Appetite 5 2 Rash 4 2 Ataxia 4 1 Diplopia 4 1 Bronchitis 3 2 Sinusitis 3 2 Psychomotor Hyperactivity 3 1 Upper Abdominal Pain 3 2 Aggression 3 2 Ear Infection 3 1 Disturbance in Attention 3 1 Pruritis 3 0 Table 3 lists adverse reactions that occurred in at least 3% of adult patients with epilepsy treated with rufinamide (up to 3200 mg per day) in adjunctive controlled studies and were numerically more common in patients treated with rufinamide than in patients on placebo. In these studies, either rufinamide or placebo was added to the current AED therapy. At all doses studied of up to 3200 mg per day given as adjunctive therapy in adults, the most common (≥ 3%) adverse reactions, and with the greatest increase in incidence compared to placebo, for rufinamide were dizziness, fatigue, nausea, diplopia, vision blurred, and ataxia. Table 3: Adverse Reactions in Adults in Pooled Double-Blind Adjunctive Trials Adverse Reaction Rufinamide (N=823) % Placebo (N=376) % Headache 27 26 Dizziness 19 12 Fatigue 16 10 Nausea 12 9 Somnolence 11 9 Diplopia 9 3 Tremor 6 5 Nystagmus 6 5 Blurred Vision 6 2 Vomiting 5 4 Ataxia 4 0 Upper Abdominal Pain 3 2 Anxiety 3 2 Constipation 3 2 Dyspepsia 3 2 Back Pain 3 1 Gait Disturbance 3 1 Vertigo 3 1 Discontinuation in Controlled Clinical Studies In controlled, double-blind, adjunctive clinical studies, 9% of pediatric and adult patients receiving rufinamide as adjunctive therapy and 4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of rufinamide (>1%) used as adjunctive therapy were generally similar in adults and pediatric patients. In pediatric patients (ages 4 to less than 17 years) double-blind adjunctive clinical studies, 8% of patients receiving rufinamide as adjunctive therapy (at the recommended dose of 45 mg/kg per day) and 2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of rufinamide (>1%) used as adjunctive therapy are presented in Table 4. Table 4: Most Common Adverse Reactions Leading to Discontinuation in Pediatric Patients (Ages 4 to less than 17 years) in Pooled Double-Blind Adjunctive Trials Adverse Reaction Rufinamide (N=187) % Placebo (N=182) % Convulsion 2 1 Rash 2 1 Fatigue 2 0 Vomiting 1 0 In adult double-blind, adjunctive clinical studies, 10% of patients receiving rufinamide as adjunctive therapy (at doses up to 3200 mg per day) and 6% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of rufinamide (>1%) used as adjunctive therapy are presented in Table 5. Table 5: Most Common Adverse Reactions Leading to Discontinuation in Adult Patients in Pooled Double-Blind Adjunctive Trials Adverse Reaction Rufinamide (N=823) % Placebo (N=376) % Dizziness 3 1 Fatigue 2 1 Headache 2 1 Nausea 1 0 Ataxia 1 0 Pediatric Patients ages 1 to less than 4 years In a multicenter, parallel group, open-label study comparing rufinamide (45 mg/kg per day) adjunctive treatment (n=25) to the adjunctive treatment with an AED of the investigator’s choice (n=11) in pediatric patients (1 year to less than 4 years of age) with inadequately controlled Lennox-Gastaut Syndrome, the adverse reaction profile was generally similar to that observed in adults and pediatric patients 4 years of age and older treated with rufinamide. Adverse reactions that occurred in at least 2 (8 %) rufinamide-treated patients and with a higher frequency than in the AED comparator group were: vomiting (24%), somnolence (16%), bronchitis (12%), constipation (12%), cough (12%), decreased appetite (12%), rash (12%), otitis media (8%), pneumonia (8%), decreased weight (8%), gastroenteritis (8%), nasal congestion (8%), and pneumonia aspiration (8%). Other Adverse Reactions Observed During Clinical Trials Rufinamide has been administered to 1978 individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse reactions occurring during these studies were recorded by the investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of patients having adverse reactions, these events were grouped into standardized categories using the MedDRA dictionary. Adverse events occurring at least three times and considered possibly related to treatment are included in the System Organ Class listings below. Terms not included in the listings are those already included in the tables above, those too general to be informative, those related to procedures, and terms describing events common in the population. Some events occurring fewer than 3 times are also included based on their medical significance. Because the reports include events observed in open-label, uncontrolled observations, the role of rufinamide in their causation cannot be reliably determined. Events are classified by body system and listed in order of decreasing frequency as follows: frequent adverse events— those occurring in at least 1/100 patients; infrequent adverse events— those occurring in 1/100 to 1/1000 patients; rare— those occurring in fewer than 1/1000 patients. Blood and Lymphatic System Disorders: Frequent : anemia. Infrequent : lymphadenopathy, leukopenia, neutropenia, iron deficiency anemia, thrombocytopenia. Cardiac Disorders: Infrequent: bundle branch block right, atrioventricular block first degree. Metabolic and Nutritional Disorders: Frequent: decreased appetite, increased appetite. Renal and Urinary Disorders: Frequent: pollakiuria. Infrequent: urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, incontinence. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of rufinamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: Stevens-Johnson syndrome and other serious skin rashes with mucosal involvement."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) ( 7.2 ) Hormonal contraceptives may be less effective with rufinamide; use additional non-hormonal forms of contraception ( 7.3 ) 7.1 Effects of Rufinamide on other AEDs Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide C avss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population. Table 6 summarizes the drug-drug interactions of rufinamide with other AEDs. Table 6: Summary of drug-drug interactions of rufinamide with other antiepileptic drugs AED Co-administered Influence of Rufinamide on AED concentration a) Influence of AED on Rufinamide concentration Carbamazepine Decrease by 7 to 13% b) Decrease by 19 to 26% Dependent on dose of carbamazepine Lamotrigine Decrease by 7 to 13% b) No Effect Phenobarbital Increase by 8 to 13% b) Decrease by 25 to 46% c), d) Independent of dose or concentration of phenobarbital Phenytoin Increase by 7 to 21% b) Decrease by 25 to 46% c), d) Independent of dose or concentration of phenytoin Topiramate No Effect No Effect Valproate No Effect Increase by <16 to 70% c) Dependent on concentration of valproate Primidone Not Investigated Decrease by 25 to 46% c), d) Independent of dose or concentration of primidone Benzodiazepines e) Not Investigated No Effect a) Predictions are based on rufinamide concentrations at the maximum recommended dose of rufinamide. b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of rufinamide, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in pediatric patients at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on rufinamide clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on rufinamide clearance. Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (C avss 15 mcg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction. 7.2 Effects of Other AEDs on Rufinamide Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital, appear to increase the clearance of rufinamide (see Table 6). Given that the majority of clearance of rufinamide is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred, were likely to be more marked in the pediatric population. Valproate Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults) [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ] . 7.3 Effects of Rufinamide on Hormonal Contraceptives Female patients of childbearing age should be warned that the concurrent use of rufinamide with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using rufinamide [see Use in Specific Populations (8.3) , Clinical Pharmacology (12.3) and Patient Counseling Information (17) ] ."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Rufinamide tablets are indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in pediatric patients 1 year of age and older and in adults. Rufinamide tablets are indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in pediatric patients 1 year of age and older, and in adults ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Monitor patients for new or worsening depression, suicidal thoughts/behavior, and unusual changes in mood or behavior ( 5.1 ) Central nervous system reactions can occur ( 5.2 ) Use caution when administering rufinamide with other drugs that shorten the QT interval ( 5.3 ) Discontinue rufinamide if multi-organ hypersensitivity reaction occurs ( 5.4 ) Withdraw rufinamide gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus ( 5.5 ) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including rufinamide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1: Absolute and Relative Risk of Suicidal Behavior and Ideation Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing rufinamide or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.2 Central Nervous System Reactions Use of rufinamide has been associated with central nervous system-related adverse reactions in the controlled clinical trial of patients 4 years or older with Lennox-Gastaut Syndrome. The most significant of these can be classified into two general categories: 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia. Somnolence was reported in 24% of rufinamide-treated patients compared to 13% of patients on placebo, and led to study discontinuation in 3% of rufinamide-treated patients compared to 0% of patients on placebo. Fatigue was reported in 10% of rufinamide-treated patients compared to 8% of patients on placebo patients. It led to study discontinuation in 1% of rufinamide-treated patients and 0% of patients on placebo patients. Dizziness was reported in 2.7% of rufinamide-treated patients compared to 0% of patients on placebo, and did not lead to study discontinuation. Ataxia and gait disturbance were reported in 5.4% and 1.4% of rufinamide-treated patients, respectively, compared to no patient on placebo. None of these reactions led to study discontinuation. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on rufinamide to gauge whether it adversely affects their ability to drive or operate machinery. 5.3 QT Shortening Formal cardiac ECG studies demonstrated shortening of the QT interval (mean = 20 msec, for doses > 2400 mg twice daily) with rufinamide. In a placebo-controlled study of the QT interval, a higher percentage of rufinamide-treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at T max compared to placebo (5 to 10%). Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg per day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias. The degree of QT shortening induced by rufinamide is without any known clinical risk. Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation. Patients with Familial Short QT syndrome should not be treated with rufinamide. Caution should be used when administering rufinamide with other drugs that shorten the QT interval [see Contraindications (4) ] . 5.4 Multi-organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has been reported in patients taking antiepileptic drugs, including rufinamide. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Because this disorder is variable in its expression, other organ systems not noted here may be involved. All cases of DRESS identified in clinical trials with rufinamide occurred in pediatric patients less than 12 years of age, occurred within 4 weeks of treatment initiation, and resolved or improved with rufinamide discontinuation. DRESS has also been reported in adult and pediatric patients taking rufinamide in the postmarketing setting. If DRESS is suspected, the patient should be evaluated immediately, rufinamide should be discontinued, and alternative treatment should be started. 5.5 Withdrawal of AEDs As with all antiepileptic drugs, rufinamide should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, rufinamide discontinuation was achieved by reducing the dose by approximately 25% every 2 days. 5.6 Status Epilepticus Estimates of the incidence of treatment emergent status epilepticus among patients treated with rufinamide are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut Syndrome trial, 3 of 74 (4.1%) rufinamide-treated patients had episodes that could be described as status epilepticus in the rufinamide-treated patients compared with none of the 64 patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) rufinamide-treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients. 5.7 Leukopenia Rufinamide has been shown to reduce white cell count. Leukopenia (white cell count < 3X10 9 L) was more commonly observed in rufinamide-treated patients 43 of 1171 (3.7%) than placebo-treated patients, 7 of 579 (1.2%) in all controlled trials."}', 'overdosage': '{"10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Certified Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. One overdose of 7200 mg per day rufinamide was reported in an adult during the clinical trials. The overdose was associated with no major signs or symptoms, no medical intervention was required, and the patient continued in the study at the target dose. Treatment or Management of Overdose: There is no specific antidote for overdose with rufinamide. If clinically indicated, elimination of unabsorbed drug should be attempted by induction of emesis or gastric lavage. Usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Hemodialysis: Standard hemodialysis procedures may result in limited clearance of rufinamide. Although there is no experience to date in treating overdose with hemodialysis, the procedure may be considered when indicated by the patient’s clinical state."}', 'active_flag': 'Y', 'generic_name': '{RUFINAMIDE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Information Advise patients to take rufinamide tablets with food [see Dosage and Administration (2.2) ] . Advise patients who are prescribed the oral suspension to shake the bottle vigorously before every administration and to use the adaptor and oral dosing syringe [see Dosage and Administration (2.2) ] . Suicidal Thinking and Behavior Inform patients, their caregivers, and families that antiepileptic drugs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.1) ] . Central Nervous System Reactions Inform patients about the potential for somnolence or dizziness and advise them not to drive or operate machinery until they have gained sufficient experience on rufinamide tablets to gauge whether it adversely affects their mental and/or motor performance [see Warnings and Precautions (5.2) ] . Multi-Organ Hypersensitivity Reactions Advise patients to notify their physician if they experience a rash associated with fever [see Warnings and Precautions (5.4) ] . Drug Interactions Inform female patients of childbearing age that the concurrent use of rufinamide tablets with hormonal contraceptives may render this method of contraception less effective. Recommend patients use additional non-hormonal forms of contraception when using rufinamide tablets [see Drug Interactions (7.3) and Use in Specific Populations (8.3) ] . Inform patients that alcohol in combination with rufinamide tablets may cause additive central nervous system effects. Pregnancy Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1) ] . Breast-feeding Advise patients to notify their physician if they are breast-feeding or intend to breast-feed [see Use in Specific Populations (8.2) ] . The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Issued: December 2022"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as rufinamide, during pregnancy. Encourage women who are taking rufinamide during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary There are no adequate data on the developmental risks associated with use of rufinamide in pregnant women. In animal reproduction studies, oral administration of rufinamide resulted in developmental toxicity in pregnant rats and rabbits at clinically relevant doses [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal data Oral administration of rufinamide (0, 20, 100, or 300 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal weight and increased incidence of fetal skeletal abnormalities at 100 and 300 mg/kg/day, which were associated with maternal toxicity. The maternal plasma exposure (AUC) at the no-adverse effect dose (20 mg/kg/day) for developmental toxicity was less than that in humans at the maximum recommended human dose (MRHD) of 3200 mg/day. Oral administration of rufinamide (0, 30, 200, or 1000 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in embryofetal death, decreased fetal body weight, and increased incidence of fetal visceral and skeletal abnormalities at doses of 200 and 1000 mg/kg/day. The high dose (1000 mg/kg/day) was associated with abortion. Plasma exposure (AUC) at the no-adverse effect dose (30 mg/kg/day) was less than that in humans at the MRHD. When rufinamide was orally administered (0, 5, 30, or 150 mg/kg/day) to pregnant rats throughout pregnancy and lactation, decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and postnatal development was not established. At the lowest dose tested (5 mg/kg/day), plasma exposure (AUC) was less than that in humans at the MRHD."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness have been established in pediatric patients 1 to 17 years of age. The effectiveness of rufinamide in pediatric patients 4 years of age and older was based upon an adequate and well-controlled trial of rufinamide that included both adults and pediatric patients, 4 years of age and older, with Lennox Gastaut Syndrome. The effectiveness in patients 1 to less than 4 years was based upon a bridging pharmacokinetic and safety study [see Dosage and Administration (2.1) , Adverse Reactions (6.1) , and Clinical Studies (14) ]. The pharmacokinetics of rufinamide in the pediatric patients, ages 1 to less than 4 years of age is similar to children older than 4 years of age and adults [see Clinical Pharmacology (12.3) ] . Safety and effectiveness in pediatric patients below the age of 1 year has not been established. Oral administration of rufinamide (0, 15, 50, or 150 mg/kg) to young rats for 10 weeks starting on postnatal day 7 resulted in decreased brain weights at the mid and high doses and neurobehavioral impairment (learning and memory deficit, altered startle response, decreased locomotor activity) and decreased growth (decreased body weight) at the highest dose tested. The no-effect dose for adverse effects on postnatal development in rats (15 mg/kg) was associated with a plasma exposure (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 3200 mg/day."}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of rufinamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Pharmacokinetics of rufinamide in the elderly are similar to that in the young subjects [see Clinical Pharmacology (12.3) ] ."}'}

{"INSULIN LISPRO"}

{'contraindications': '{"4 CONTRAINDICATIONS HUMALOG is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . in patients who are hypersensitive to insulin lispro or to any of the excipients in HUMALOG [see Warnings and Precautions ( 5.5 )] . Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to insulin lispro or any of the excipients in HUMALOG. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )]. Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )]. Hypokalemia [see Warnings and Precautions ( 5.6 )] . Adverse reactions associated with HUMALOG include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% of patients treated with insulin lispro or regular human insulin. The frequencies of adverse reactions during HUMALOG clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Adverse Reactions That Occurred in ≥5% in Patients with Type 1 Diabetes Mellitus HUMALOG (%) (n=81) Regular human insulin (%) (n=86) Flu syndrome 34.6 32.6 Pharyngitis 33.3 33.7 Rhinitis 24.7 29.1 Headache 29.6 22.1 Pain 19.8 16.3 Cough increased 17.3 17.4 Infection 13.6 20.9 Nausea 6.2 15.1 Accidental injury 8.6 11.6 Surgical procedure 6.2 14.0 Fever 6.2 11.6 Abdominal pain 7.4 8.1 Asthenia 7.4 8.1 Bronchitis 7.4 7.0 Diarrhea 8.6 5.8 Dysmenorrhea 6.2 7.0 Myalgia 7.4 5.8 Urinary tract infection 6.2 4.7 Table 2: Adverse Reactions That Occurred in ≥5% in Patients with Type 2 Diabetes Mellitus HUMALOG (%) (n=714) Regular human insulin (%) (n=709) Headache 11.6 9.3 Pain 10.8 10.0 Infection 10.1 7.6 Pharyngitis 6.6 8.2 Rhinitis 8.1 6.6 Flu syndrome 6.2 8.2 Surgical procedure 7.4 6.8 Insulin initiation and intensification of glucose control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMALOG. Lipodystrophy Long-term use of insulin, including HUMALOG, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration ( 2.2 )] . Weight gain Weight gain can occur with insulins, including HUMALOG, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulins, including HUMALOG, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) — HUMALOG U-100 In a 12-week, randomized, crossover study in adult patients with type 1 diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for HUMALOG U-100 and regular human insulin treated patients ( see Table 3 ). Table 3: Catheter Occlusions and Infusion Site Reactions HUMALOG U-100 (n=38) Regular human insulin (n=39) Catheter occlusions/month 0.09 0.10 Infusion site reactions 2.6% (1/38) 2.6% (1/39) In a randomized, 16-week, open-label, parallel design study of pediatric patients with type 1 diabetes, adverse reactions related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site reactions were infusion site erythema and infusion site reaction. Allergic Reactions Local Allergy — As with any insulin, patients taking HUMALOG may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of HUMALOG. Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including HUMALOG. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944). Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in HUMALOG [see Contraindications ( 4 )] . Antibody Production In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and HUMALOG (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study. These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of HUMALOG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors in which other insulins have been accidentally substituted for HUMALOG have been identified during post-approval use. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site."}', 'drug_interactions': '{"7 DRUG INTERACTIONS The table below includes clinically significant drug interactions with HUMALOG. Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of HUMALOG Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMALOG Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine and reserpine. Intervention: Increased frequency of glucose monitoring may be required when HUMALOG is co-administered with these drugs. Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics ( 7 ). Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones ( 7 ). Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine ( 7 ). Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine ( 7 )."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE HUMALOG is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. HUMALOG is a rapid acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Never share a HUMALOG prefilled pen, cartridge, reusable pen compatible with Lilly 3 mL cartridges, or syringe between patients, even if the needle is changed. ( 5.1 ) Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to a patient\'s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.2 ) Hypoglycemia: May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. ( 5.3 , 7 , 8.6 , 8.7 ) Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. Do not transfer HUMALOG U-200 from the HUMALOG KwikPen to a syringe as overdosage and severe hypoglycemia can result. ( 5.4 ) Hypersensitivity Reactions: May be life-threatening. Discontinue HUMALOG, monitor and treat if indicated. ( 5.5 ) Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 5.6 ) Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.7 ) Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer HUMALOG U-100 by subcutaneous injection if pump malfunction occurs. ( 5.8 ) 5.1 Never Share a HUMALOG Prefilled Pen, Cartridge, Reusable Pen Compatible with Lilly 3 mL Cartridges 1 , or Syringe Between Patients HUMALOG prefilled pens, cartridges, and reusable pens compatible with Lilly 3 mL cartridges must never be shared between patients, even if the needle is changed. Patients using HUMALOG vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6 )] . Make any changes to a patient\'s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulins, including HUMALOG. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly, and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of HUMALOG may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology ( 12.2 )] . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions ( 7 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported. To avoid medication errors between HUMALOG and other insulins, instruct patients to always check the insulin label before each injection. Do not transfer HUMALOG U-200 from the HUMALOG KwikPen to a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )] . 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including HUMALOG. If hypersensitivity reactions occur, discontinue HUMALOG; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions ( 6.1 )] . HUMALOG is contraindicated in patients who have had hypersensitivity reactions to insulin lispro or any of the excipients in HUMALOG [see Contraindications ( 4 )] . 5.6 Hypokalemia All insulins, including HUMALOG, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMALOG, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. 5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with HUMALOG may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see How Supplied/Storage and Handling ( 16.2 ) and Patient Counseling Information ( 17 )] ."}', 'overdosage': '{"10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately."}', 'active_flag': 'Y', 'generic_name': '{"INSULIN LISPRO"}', 'route': '{INTRAVENOUS,SUBCUTANEOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Never Share a HUMALOG Prefilled Pen, Cartridge, Reusable Pen Compatible with Lilly 3 mL Cartridges, or Syringe Between Patients Advise patients that they must never share a HUMALOG prefilled pen, cartridge, or reusable pen compatible with Lilly 3 mL cartridges with another person, even if the needle is changed. Advise patients using HUMALOG vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )] . Hyperglycemia or Hypoglycemia Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMALOG therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions ( 5.3 )] . Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )] . Hypoglycemia due to Medication Errors Instruct patients to always check the insulin container label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions ( 5.4 )] . Inform patients that HUMALOG U-200 contains 2 times as much insulin per mL as HUMALOG U-100. The HUMALOG U-200 KwikPen dose window shows the number of units of HUMALOG U-200 to be injected so no dose conversion is required [see Dosage and Administration ( 2.1 )]. Instruct patients to NOT transfer HUMALOG U-200 from the HUMALOG U-200 KwikPen to a syringe. The markings on the syringe will not measure the dose correctly and this can result in overdosage and severe hypoglycemia. [see Warnings and Precautions ( 5.4 )]. Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with HUMALOG. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] . Administration Instruction for HUMALOG U-200 Instruct patients to NOT mix HUMALOG U-200 with any other insulin. Instructions For Patients Using Continuous Subcutaneous Insulin Pumps Do not use HUMALOG U-200 in a subcutaneous insulin pump. Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories. Instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings. Refer to the continuous subcutaneous infusion pump user manual to see if HUMALOG can be used with the pump. See recommended reservoir and infusion sets in the insulin pump user manual. Instruct patients to replace insulin in the reservoir at least every 7 days, or according to the pump user manual, whichever is shorter; infusion sets and infusion set insertion sites should be changed in accordance with the manufacturers\' user manual. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative. Instruct patients to discard insulin exposed to temperatures higher than 98.6°F (37°C). The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing or sport case is exposed to sunlight or radiant heat. Instruct patients to inform healthcare provider and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened. Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see Warnings and Precautions ( 5 ) and How Supplied/Storage and Handling ( 16.2 )] . Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 1 3 mL cartridge is for use in compatible insulin delivery devices, including HumaPen ® Luxura ® HD Humalog ® , Humalog KwikPen ® , Humalog Tempo Penä, Humalog ® Junior KwikPen ® , HumaPen ® , HumaPen ® Luxura ® and HumaPen ® Luxura ® HD are trademarks of Eli Lilly and Company. www.humalog.com Copyright © 1996, 2023, Eli Lilly and Company. All rights reserved. LOG-0011-USPI-20230802"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations) . Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups. Animal Data In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter. In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of HUMALOG to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of HUMALOG for this indication is supported by evidence from adequate and well-controlled studies in 831 pediatric patients with type 1 diabetes mellitus aged 3 years and older and from studies in adults with diabetes mellitus [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )]."}', 'geriatric_use': '{"8.5 Geriatric Use Of the total number of patients (n=2,834) in eight clinical studies of HUMALOG, twelve percent (n=338) were 65 years of age or over. The majority of these patients had type 2 diabetes. HbA 1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of HUMALOG action have not been performed."}'}

{"SALICYLIC ACID"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Helps prevent recurrence of flaking and itching associated with dandruff."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"APPLE CIDER VINEGAR ANTI-DANDRUFF CONDITIONER"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only When using this produc t avoid contact with eyes. If contact occurs, rinse eyes thoroughtly with water. Stop use and ask a doctor if condition worsens or does not improve after regular use of this product as directed."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{AMOXICILLIN}

{'contraindications': '{"4 CONTRAINDICATIONS Amoxicillinfor oral suspension is contraindicated in patients who have experienced a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin for oral suspension or to other β-lactam antibiotics (e.g., penicillins and cephalosporins). History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin for oral suspension or to other beta-lactams (e.g., penicillins or cephalosporins). (4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Anaphylactic reactions [see Warnings and Precautions (5.1) ] • CDAD [see Warnings and Precautions (5.2) ] The most common adverse reactions (> 1%) observed in clinical trials of amoxicillin for oral suspension were diarrhea, rash, vomiting, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (> 1%) observed in clinical trials of amoxicillin for oral suspension were diarrhea, rash, vomiting, and nausea. Triple Therapy: The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%). Dual Therapy: The most frequently reported adverse events for patients who received double therapy amoxicillin/lansoprazole were diarrhea (8%) and headache (7%). For more information on adverse reactions with clarithromycin or lansoprazole, refer to the Adverse Reactions section of their package inserts. 6.2 Postmarketing or Other Experience In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of penicillins. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin. • Infections and Infestations: Mucocutaneous candidiasis. • Gastrointestinal: Black hairy tongue, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.2) ] . • Hypersensitivity Reactions: Anaphylaxis [see Warnings and Precautions (5.1) ] . Serum sickness–like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and urticaria have been reported. • Liver: A moderate rise in AST and/or ALT has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported. • Renal: Crystalluria has been reported [see Overdosage (10) ] . • Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. • Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported. • Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases."}', 'drug_interactions': '{"7 DRUG INTERACTIONS • Probenicid decreases renal tubular secretion of amoxicillin which may result in increased blood levels of amoxicillin. (7.1) • Concomitant use of amoxicillin and oral anticoagulants may increase the prolongation of prothrombin time. (7.2) • Coadministration with allopurinol increases the risk of rash. (7.3) • Amoxicillin may reduce the efficacy of oral contraceptives. (7.4) 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin. 7.2 Oral Anticoagulants Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. 7.3 Allopurinol The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. 7.5 Other Antibacterials Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro ; however, the clinical significance of this interaction is not well documented. 7.6 Drug/Laboratory Interactions High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST ® , Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX ® ) be used. Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin for oral suspension, USP and other antibacterial drugs, amoxicillin for oral suspension, USP should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Amoxicillin for oral suspension, USP is indicated in the treatment of infections due to susceptible (ONLY β-lactamase–negative) isolates of the designated bacteria in the conditions listed below: Amoxicillin for oral suspension, USP is a penicillin-class antibacterial indicated for treatment of infections due to susceptible strains of designated microorganisms. • Infections of the ear, nose, throat, genitourinary tract, skin and skin structure, and lower respiratory tract. ( 1.1 - 1.5 ) • In combination for treatment of H. pylori infection and duodenal ulcer disease. ( 1.6 , 1.7 ) 1.1 Infections of the Ear, Nose, and Throat due to Streptococcus species (α- and β-hemolytic isolates only), Streptococcus pneumoniae , Staphylococcus spp., or Haemophilus influenzae . 1.2 Infections of the Genitourinary Tract due to Escherichia coli, Proteus mirabilis , or Enterococcus faecalis . 1.3 Infections of the Skin and Skin Structure due to Streptococcus spp. (α- and β-hemolytic isolates only), Staphylococcus spp., or E. coli . 1.4 Infections of the Lower Respiratory Tract due to Streptococcus spp. (α- and β-hemolytic isolates only), S. pneumoniae, Staphylococcus spp., or H. influenzae . 1.5 Gonorrhea, Acute Uncomplicated (ano-genital and urethral infections) due to Neisseria gonorrhoeae . Because of high rates of amoxicillin resistance, amoxicillin for oral suspension, USP is not recommended for empiric treatment of gonorrhea. Amoxicillin for oral suspension, USP use should be limited to situations where N. gonorrhoeae isolates are known to be susceptible to amoxicillin. 1.6 Triple Therapy for Helicobacter pylori with Clarithromycin and Lansoprazole Amoxicillin for oral suspension, USP, in combination with clarithromycin plus lansoprazole as triple therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) to eradicate H. pylori . Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. 1.7 Dual Therapy for H. pylori with Lansoprazole Amoxicillin for oral suspension, USP, in combination with lansoprazole delayed-release capsules as dual therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected. (See the clarithromycin package insert, MICROBIOLOGY.) Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Anaphylactic Reactions: Serious and occasionally fatal anaphylactic reactions have been reported in patients on penicillin therapy. Serious anaphylactic reactions require immediate emergency treatment with supportive measures. (5.1) • Clostridium difficile Associated Diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs. (5.2) 5.1 Anaphylactic Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with amoxicillin, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. 5.2 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.3 Potential for Microbial Overgrowth or Bacterial Resistance The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, amoxicillin should be discontinued and appropriate therapy instituted. Prescribing amoxicillin either in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria. 5.4 Uses in Patients With Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus amoxicillin should not be administered to patients with mononucleosis. 5.5 Phenylketonurics The oral suspension of amoxicillin do not contain phenylalanine and can be used by phenylketonurics."}', 'overdosage': '{"10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms. Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin 1 . Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin may be removed from circulation by hemodialysis."}', 'active_flag': 'Y', 'generic_name': '{AMOXICILLIN}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients ."}', 'pregnancy': '{"8.1 Pregnancy Teratogenic Effects : Pregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 2000 mg/kg (3 and 6 times the 3 g human dose, based on body surface area). There was no evidence of harm to the fetus due to amoxicillin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, amoxicillin should be used during pregnancy only if clearly needed."}', 'pediatric_use': '{"8.4 Pediatric Use Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin should be modified in pediatric patients 12 weeks or younger (≤ 3 months). [See Dosage and Administration (2.2) .]"}', 'geriatric_use': '{"8.5 Geriatric Use An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. These analyses have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function."}'}

{NAPROXEN}

{'contraindications': '{"4 CONTRAINDICATIONS Naproxen tablets are contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [ see Warnings and Precautions (5.7 , 5.9) ] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions (5.7 , 5.8) ] In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1) ] Known hypersensitivity to naproxen or any components of the drug product (4) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) In the setting of CABG surgery (4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions (5.1) ] GI Bleeding, Ulceration, and Perforation [ see Warnings and Precautions (5.2) ] Hepatotoxicity [ see Warnings and Precautions (5.3) ] Hypertension [ see Warnings and Precautions (5.4) ] Heart Failure and Edema [ see Warnings and Precautions (5.5) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions (5.6) ] Anaphylactic Reactions [ see Warnings and Precautions (5.7) ] Serious Skin Reactions [ see Warnings and Precautions (5.9) ] Hematologic Toxicity [ see Warnings and Precautions (5.12) ] Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen. In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were: Gastrointestinal (GI) Experiences, including: heartburn * , abdominal pain * , nausea * , constipation * , diarrhea, dyspepsia, stomatitis C entral Nervous System: headache * , dizziness * , drowsiness * , lightheadedness, vertigo Dermatologic: pruritus (itching) * , skin eruptions * , ecchymoses * , sweating, purpura Special Senses: tinnitus * , visual disturbances, hearing disturbances C ardiovascular: edema * , palpitations General: dyspnea * , thirst * Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis, vomiting Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever) Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease). Hepatobiliary: abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female): infertility In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria"}', 'drug_interactions': '{"7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with naproxen Drugs That Interfere with Hemostasis Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.12) ]. Aspirin Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen ( see 12.2 Pharmacodynamics ). There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.12) ]. Naproxen Tablets are not substitutes for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin Intervention: During concomitant use of naproxen and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with naproxen is not recommended. Probenecid Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Intervention: Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking Naproxen Tablets with drugs that interfere with hemostasis. Concomitant use of Naproxen Tablets and analgesic doses of aspirin is not generally recommended. (7) ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with Naproxen Tablets may diminish the antihypertensive effect of these drugs. Monitor blood pressure. (7) ACE Inhibitors and ARBs : Concomitant use with Naproxen Tablets in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7) Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7) Digoxin : Concomitant use with Naproxen Tablets can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7)"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Naproxen Tablets are indicated for: the relief of the signs and symptoms of: rheumatoid arthritis osteoarthritis ankylosing spondylitis polyarticular juvenile idiopathic arthritis tendonitis bursitis acute gout the management of: pain primary dysmenorrhea Naproxen tablets are non-steroidal anti-inflammatory drugs indicated for: the relief of the signs and symptoms of: rheumatoid arthritis osteoarthritis ankylosing spondylitis polyarticular juvenile idiopathic arthritis tendonitis bursitis acute gout the management of: pain primary dysmenorrhea"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4 , 7) Heart Failure and Edema: Avoid use of naproxen tablets in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of naproxen tablets in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: Naproxen tablets are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue naproxen tablets at first appearance of skin rash or other signs of hypersensitivity. (5.9) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ). Fetal Toxicity : Limit use of NSAIDs, including Naproxen Tablets, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 5.11 , 8.1 ) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12 , 7) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions (5.2) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of naproxen in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If naproxen tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue naproxen until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions (7) ]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and \\"flu-like\\" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue naproxen immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including naproxen can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions (7) ]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions (7) ]. Avoid the use of naproxen in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If naproxen is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of naproxen in patients with advanced renal disease. The renal effects of naproxen may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating naproxen. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of naproxen [ see Drug Interactions (7) ]. Avoid the use of naproxen in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If naproxen is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [ see Contraindications (4) and Warnings and Precautions (5.8) ]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, naproxen is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4) ]. When naproxen is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of naproxen at the first appearance of skin rash or any other sign of hypersensitivity. Naproxen Tablets are contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications (4) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Naproxen tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue naproxen tablets and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including Naproxen tablets, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including Naroxen tablets increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including Naproxen tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit naproxen use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if naproxen treatment extends beyond 48 hours. Discontinue naproxen if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations (8.1) ]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with naproxen has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including naproxen may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions (7) ]. 5.13 Masking of Inflammation and Fever The pharmacological activity of naproxen in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Long-Term Use and Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions (5.2 , 5.3 , 5.6) ]. Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically. Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs."}', 'overdosage': '{"10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 ) ]. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222)."}', 'active_flag': 'Y', 'generic_name': '{NAPROXEN}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with naproxen tablets and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions (5.1) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Warnings and Precautions (5.2) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop naproxen tablets and seek immediate medical therapy [ see Warnings and Precautions (5.3) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions (5.5) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications (4) and Warnings and Precautions (5.7) ]. Serious Skin Reactions, including DRESS Advise patients to stop taking Naproxen tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions (5.9 , 5.10) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including Naproxen tablets, may be associated with a reversible delay in ovulation [ see Use in Specific Populations (8.3) ] Fetal Toxicity Inform pregnant women to avoid use of Naproxen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Naproxen tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see Warnings and Precautions (5.11) and Use in Specific Populations (8.1) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of Naproxen tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with Naproxen tablets until they talk to their healthcare provider [ see Drug Interactions (7) ]. Manufactured by: ScieGen Pharmaceuticals Inc Hauppauge, NY 11788 USA Rev. 5/2021"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Use of NSAIDs, including naproxen can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of naproxen use between about 20 and 30 weeks of gestation, and avoid naproxen use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations , Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including naproxen at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively [ see Data ]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including naproxen can cause premature closure of the fetal ductus arteriosus (see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If naproxen treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue naproxen, and follow up according to clinical practice (see Data ). Labor or Delivery There are no studies on the effects of naproxen during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies [ see Dosage and Administration (2) ]. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 mg/kg to 5 mg/kg as naproxen suspension, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age."}', 'geriatric_use': '{"8.5 Geriatric Use The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.6 , 5.14) ]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [ see Warnings and Precautions (5.2) ]. Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [ see Clinical Pharmacology (12.3) ]. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [ see Warnings and Precautions (5.6) ]."}'}

{"HYDROGEN PEROXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses first aid to help prevent the risk of infection in minor cuts, scrapes and burns aids in removal of phlegm, mucous, or other secretions associated with occasional sore mouth"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"HYDROGEN PEROXIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if the condition persists or gets worse sore mouth symptoms do not improve in 7 days irritation, pain, or redness persists or worsens swelling, rash, or fever develops"}', 'do_not_use': '{"Do not use in the eyes or apply over large areas of the body longer than 1 week"}', 'when_using': None, 'warnings': '{"Warnings For external use only Do not use in the eyes or apply over large areas of the body longer than 1 week Ask a doctor before use if you have deep puncture wounds, animal bites or serious burns. Stop use and ask a doctor if the condition persists or gets worse sore mouth symptoms do not improve in 7 days irritation, pain, or redness persists or worsens swelling, rash, or fever develops Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away (1-800-222-1222)."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ASPIRIN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses for the temporary relief of minor aches and pains or as recommended by your doctor. Because of its delayed action, this product will not provide fast relief of headaches or other symptoms needing immediate relief."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ASPIRIN}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • an allergic reaction occurs. Seek medical help right away. • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain that does not get better • pain gets worse or lasts more than 10 days • fever gets worse or lasts more than 3 days • redness or swelling is present • new symptoms occur • ringing in the ears or a loss of hearing occurs"}', 'do_not_use': '{"Do not use • if you are allergic to aspirin or any other pain reliever/fever reducer • if you have ever had an allergic reaction to this or product or any of its ingredients"}', 'when_using': None, 'warnings': '{"Warnings Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye’s syndrome, a rare but serious illness. Aspirin may cause a severe allergic reaction which may include: • hives • facial swelling • asthma (wheezing) • shock Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you • are age 60 or older • have had stomach ulcers or bleeding problems • take a blood thinning (anticoagulant) or steroid drug • take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) • have 3 or more alcoholic drinks every day while using this product • take more or for a longer time than directed Reye’s syndrome: Allergy alert: Do not use • if you are allergic to aspirin or any other pain reliever/fever reducer • if you have ever had an allergic reaction to this or product or any of its ingredients Ask a doctor before use if • stomach bleeding warning applies to you • you have a history of stomach problems, such as heartburn • you have high blood pressure, heart disease, liver cirrhosis, or kidney disease • you are taking a diuretic • you have asthma Ask a doctor or pharmacist before use if you are taking a prescription drug for • gout • diabetes • arthritis Stop use and ask a doctor if • an allergic reaction occurs. Seek medical help right away. • you experience any of the following signs of stomach bleeding: • feel faint • vomit blood • have bloody or black stools • have stomach pain that does not get better • pain gets worse or lasts more than 10 days • fever gets worse or lasts more than 3 days • redness or swelling is present • new symptoms occur • ringing in the ears or a loss of hearing occurs If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BENZALKONIUM CHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses - For hand sanitizing to decrease the bacteria on skin. - Recommended for repeated use."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZALKONIUM CHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours."}', 'do_not_use': None, 'when_using': '{"When using this product avoid contact with eyes. In case of eye contact, flush eyes with water"}', 'warnings': '{"Warnings For external use only. When using this product avoid contact with eyes. In case of eye contact, flush eyes with water Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours. KEEP OUT OF REACH OF CHILDREN. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"MAGNESIUM HYDROXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves occasional constipation (irregularity) usually produces bowel movement in 1/2 to 6 hours"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"MAGNESIUM HYDROXIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Ask a doctor before use if you have • kidney disease • a magnesium-restricted diet • stomach pain, nausea, or vomiting • a sudden change in bowel habits that lasts over 14 days Ask a doctor or pharmacist before use if you are taking a prescription drug. This product may interact with certain prescription drugs. Stop use and ask a doctor if • you have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition. • you need to use a laxative for more than 1 week If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222)."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ACETAMINOPHEN,"DIPHENHYDRAMINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporary relief of occasional headaches and minor aches and pains with accompanying sleeplessness"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ACETAMINOPHEN AND DIPHENHYDRAMINE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of serious underlying medical illness. pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present new symptoms occur These could be signs of a serious condition."}', 'do_not_use': '{"Do not use with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. with any other product containing diphenhydramine, even one used on skin in children under 12 years of age if you have ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': '{"When using this product drowsiness will occur avoid alcoholic drinks do not drive a motor vehicle or operate machinery"}', 'warnings': '{"Warnings Liver warning This product contains acetaminophen. Severe liver damage may occur if you take more than 4,000 mg of acetaminophen in 24 hours with other drugs containing acetaminophen 3 or more alcoholic drinks every day while using this product Do not use with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. with any other product containing diphenhydramine, even one used on skin in children under 12 years of age if you have ever had an allergic reaction to this product or any of its ingredients Ask a doctor before use if you have liver disease a breathing problem such as emphysema or chronic bronchitis trouble urinating due to an enlarged prostate gland glaucoma Ask a doctor or pharmacist before use if you are taking the blood thinning drug warfarin taking sedatives or tranquilizers When using this product drowsiness will occur avoid alcoholic drinks do not drive a motor vehicle or operate machinery Stop use and ask a doctor if sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of serious underlying medical illness. pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present new symptoms occur These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. Overdose warning In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222). Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ALUMINUM HYDROXIDE",DIMETHICONE,"MAGNESIUM HYDROXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves heartburn sour stomach acid indigestion the symptoms referred to as gas"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ALUMINUM HYDROXIDE, MAGNESIUM HYDROXIDE, DIMETHICONE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Do not take more than 16 teaspoonfuls in 24 hours or use the maximum dosage for more than 2 weeks. Ask a doctor before use if you have • kidney disease • a magnesium-restricted diet Ask a doctor or pharmacist before use if you are presently taking a prescription drug. Antacids may interact with certain prescription drugs. Stop use and ask a doctor if symptoms last more than 2 weeks If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{CELECOXIB}

{'contraindications': '{"4. CONTRAINDICATIONS Celecoxib is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product [ see Warnings and Precautions (5.7 , 5.9) ]. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients [ see Warnings and Precautions (5.7 , 5.8) ]. In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1) ]. In patients who have demonstrated allergic-type reactions to sulfonamides Known hypersensitivity to celecoxib, or any components of the drug product or sulfonamides ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 )"}', 'adverse_reactions': '{"6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions (5.1) ] GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions (5.2) ] Hepatotoxicity [ see Warnings and Precautions (5.3) ] Hypertension [ see Warnings and Precautions (5.4) ] Heart Failure and Edema [ see Warnings and Precautions (5.5) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions (5.6) ] Anaphylactic Reactions [ see Warnings and Precautions (5.7) ] Serious Skin Reactions [ see Warnings and Precautions (5.9) ] Hematologic Toxicity [ see Warnings and Precautions (5.11) ] Most common adverse reactions in arthritis trials (>2% and >placebo) are: abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC Professional Information Services at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Of the celecoxib-treated patients in the pre-marketing controlled clinical trials, approximately 4,250 were patients with OA, approximately 2,100 were patients with RA, and approximately 1,050 were patients with post-surgical pain. More than 8,500 patients received a total daily dose of celecoxib of 200 mg (100 mg twice daily or 200 mg once daily) or more, including more than 400 treated at 800 mg (400 mg twice daily). Approximately 3,900 patients received celecoxib at these doses for 6 months or more; approximately 2,300 of these have received it for 1 year or more and 124 of these have received it for 2 years or more. Pre-marketing Controlled Arthritis Trials Table 1 lists all adverse events, regardless of causality, occurring in ≥2% of patients receiving celecoxib from 12 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. Since these 12 trials were of different durations, and patients in the trials may not have been exposed for the same duration of time, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Events Occurring in ≥2% of Celecoxib Patients from Pre-marketing Controlled Arthritis Trials CBX N=4146 Placebo N=1864 NAP N=1366 DCF N=387 IBU N=345 CBX = Celecoxib 100 – 200 mg twice daily or 200 mg once daily; NAP = Naproxen 500 mg twice daily; DCF = Diclofenac 75 mg twice daily; IBU = Ibuprofen 800 mg three times daily. Gastrointestinal Abdominal Pain 4.1% 2.8% 7.7% 9.0% 9.0% Diarrhea 5.6% 3.8% 5.3% 9.3% 5.8% Dyspepsia 8.8% 6.2% 12.2% 10.9% 12.8% Flatulence 2.2% 1.0% 3.6% 4.1% 3.5% Nausea 3.5% 4.2% 6.0% 3.4% 6.7% Body as a whole Back Pain 2.8% 3.6% 2.2% 2.6% 0.9% Peripheral Edema 2.1% 1.1% 2.1% 1.0% 3.5% Injury-Accidental 2.9% 2.3% 3.0% 2.6% 3.2% Central, Peripheral Nervous system Dizziness 2.0% 1.7% 2.6% 1.3% 2.3% Headache 15.8% 20.2% 14.5% 15.5% 15.4% Psychiatric Insomnia 2.3% 2.3% 2.9% 1.3% 1.4% Respiratory Pharyngitis 2.3% 1.1% 1.7% 1.6% 2.6% Rhinitis 2.0% 1.3% 2.4% 2.3% 0.6% Sinusitis 5.0% 4.3% 4.0% 5.4% 5.8% Upper Respiratory Infection 8.1% 6.7% 9.9% 9.8% 9.9% Skin Rash 2.2% 2.1% 2.1% 1.3% 1.2% In placebo- or active-controlled clinical trials, the discontinuation rate due to adverse events was 7.1% for patients receiving celecoxib and 6.1% for patients receiving placebo. Among the most common reasons for discontinuation due to adverse events in the celecoxib treatment groups were dyspepsia and abdominal pain (cited as reasons for discontinuation in 0.8% and 0.7% of celecoxib patients, respectively). Among patients receiving placebo, 0.6% discontinued due to dyspepsia and 0.6% withdrew due to abdominal pain. The following adverse reactions occurred in 0.1 – 1.9% of patients treated with celecoxib (100 – 200 mg twice daily or 200 mg once daily): Gastrointestinal : Constipation, diverticulitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, dry mouth, stomatitis, tenesmus, vomiting Cardiovascular : Aggravated hypertension, angina pectoris, coronary artery disorder, myocardial infarction General : Hypersensitivity, allergic reaction, chest pain, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, influenza-like symptoms, pain, peripheral pain Central, peripheral Nervous system : Leg cramps, hypertonia, hypoesthesia, migraine, paresthesia, vertigo Hearing and vestibular : Deafness, tinnitus Heart rate and rhythm : Palpitation, tachycardia Liver and biliary : Hepatic enzyme increased (including SGOT increased, SGPT increased) Metabolic and nutritional : BUN increased, CPK increased, hypercholesterolemia, hyperglycemia, hypokalemia, NPN increased, creatinine increased, alkaline phosphatase increased, weight increased Musculoskeletal : Arthralgia, arthrosis, myalgia, synovitis, tendinitis Platelets (bleeding or clotting) : Ecchymosis, epistaxis, thrombocythemia, Psychiatric : Anorexia, anxiety, appetite increased, depression, nervousness, somnolence Hemic : Anemia Respiratory : Bronchitis, bronchospasm, bronchospasm aggravated, cough, dyspnea, laryngitis, pneumonia Skin and appendages : Alopecia, dermatitis, photosensitivity reaction, pruritus, rash erythematous, rash maculopapular, skin disorder, skin dry, sweating increased, urticaria Application site disorders : Cellulitis, dermatitis contact Urinary : Albuminuria, cystitis, dysuria, hematuria, micturition frequency, renal calculus The following serious adverse events (causality not evaluated) occurred in <0.1% of patients: Cardiovascular : Syncope, congestive heart failure, ventricular fibrillation, pulmonary embolism, cerebrovascular accident, peripheral gangrene, thrombophlebitis Gastrointestinal : Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, pancreatitis, ileus General: Sepsis, sudden death Liver and biliary : Cholelithiasis Hemic and lymphatic : Thrombocytopenia Nervous : Ataxia, suicide [see Drug Interactions (7.1)] Renal : Acute renal failure The Celecoxib Long-Term Arthritis Safety Study [ see Clinical Studies (14.7) ] Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on celecoxib 400 mg twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower incidence of events with celecoxib was maintained with or without aspirin use [ see Clinical Pharmacology (12.2) ]. Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for celecoxib, diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%, respectively). Juvenile Rheumatoid Arthritis Study In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, and 83 patients were treated with naproxen 7.5 mg/kg twice daily. The most commonly occurring (≥5%) adverse events in celecoxib treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, diarrhea and vomiting. The most commonly occurring (≥5%) adverse experiences for naproxen-treated patients were headache, nausea, vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA among treatment groups. In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg twice daily. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events of clinical importance emerged. Table 2: Adverse Events Occurring in ≥5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with events) All Doses Twice Daily System Organ Class Preferred Term Celecoxib 3 mg/kg N=77 Celecoxib 6 mg/kg N=82 Naproxen 7.5 mg/kg N=83 Any Event 64 70 72 Eye Disorders 5 5 5 Gastrointestinal 26 24 36 Abdominal pain NOS 4 7 7 Abdominal pain upper 8 6 10 Vomiting NOS 3 6 11 Diarrhea NOS 5 4 8 Nausea 7 4 11 General 13 11 18 Pyrexia 8 9 11 Infections 25 20 27 Nasopharyngitis 5 6 5 Injury and Poisoning 4 6 5 Investigations Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS increased, Urine analysis abnormal NOS 3 11 7 Musculoskeletal 8 10 17 Arthralgia 3 7 4 Nervous System 17 11 21 Headache NOS 13 10 16 Dizziness (excl vertigo) 1 1 7 Respiratory 8 15 15 Cough 7 7 8 Skin & Subcutaneous 10 7 18 Other Pre-Approval Studies Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with celecoxib in placebo- and active-controlled AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported in the OA/RA studies. Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with celecoxib in analgesia and dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of celecoxib were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. The APC and PreSAP Trials Adverse reactions from long-term, placebo-controlled polyp prevention studies : Exposure to celecoxib in the APC and PreSAP trials was 400 to 800 mg daily for up to 3 years [ see Special Studies Adenomatous Polyp Prevention Studies (14.7) ]. Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to 12 weeks; see Adverse events from celecoxib pre-marketing controlled arthritis trials , above). The adverse reactions for which these differences in patients treated with celecoxib were greater as compared to the arthritis pre-marketing trials were as follows: Celecoxib (400 to 800 mg daily) N = 2285 Placebo N=1303 Diarrhea 10.5% 7.0% Gastroesophageal reflux disease 4.7% 3.1% Nausea 6.8% 5.3% Vomiting 3.2% 2.1% Dyspnea 2.8% 1.6% Hypertension 12.5% 9.8% Nephrolithiasis 2.1% 0.8% The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking celecoxib, at an incidence greater than placebo in the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater frequency in the long-term, placebo-controlled polyp prevention studies: Nervous system disorders : Cerebral infarction Eye disorders: Vitreous floaters, conjunctival hemorrhage Ear and labyrinth: Labyrinthitis Cardiac disorders: Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy Vascular disorders: Deep vein thrombosis Reproductive system and breast disorders: Ovarian cyst Investigations: Blood potassium increased, blood sodium increased, blood testosterone decreased Injury, poisoning and procedural complications: Epicondylitis, tendon rupture 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of celecoxib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Cardiovascular: Vasculitis, deep venous thrombosis General: Anaphylactoid reaction, angioedema Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure Hemic and lymphatic : Agranulocytosis, aplastic anemia, pancytopenia, leucopenia Metabolic: Hypoglycemia, hyponatremia Nervous: Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage Renal: Interstitial nephritis"}', 'drug_interactions': '{"7. DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with celecoxib. Table 3: Clinically Significant Drug Interactions with Celecoxib Drugs That Interfere with Hemostasis Clinical Impact: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200–400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100–325 mg). Intervention: Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ] . When these drugs are administered concomitantly, , patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ]. Digoxin Clinical Impact: The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. Intervention: During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of celecoxib and cyclosporine may increase cyclosporine\'s nephrotoxicity. Intervention: During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ] . Intervention: The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or inducers Clinical Impact: Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. Intervention Evaluate each patient\'s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12.3) ]. CYP2D6 substrates Clinical Impact: In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. Intervention Evaluate each patient\'s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ see Clinical Pharmacology (12.3) ]. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. Intervention Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [ see Warnings and Precautions (5.2) ]. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking with drugs that interfere with hemostasis. Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with celecoxib may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs : Concomitant use with celecoxib in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7 ) Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 ) Digoxin : Concomitant use with celecoxib can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )"}', 'indications_and_usage': '{"1. INDICATIONS AND USAGE Celecoxib is indicated Celecoxib is a nonsteroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) ( 1.1 ) Rheumatoid Arthritis (RA) ( 1.2 ) Juvenile Rheumatoid Arthritis (JRA) in patients 2 years and older ( 1.3 ) Ankylosing Spondylitis (AS) ( 1.4 ) Acute Pain (AP) ( 1.5 ) Primary Dysmenorrhea (PD) ( 1.6 ) 1.1 Osteoarthritis (OA) For the management of the signs and symptoms of OA [ see Clinical Studies (14.1) ] 1.2 Rheumatoid Arthritis (RA) For the management of the signs and symptoms of RA [ see Clinical Studies (14.2) ] 1.3 Juvenile Rheumatoid Arthritis (JRA) For the management of the signs and symptoms of JRA in patients 2 years and older [ see Clinical Studies (14.3) ] 1.4 Ankylosing Spondylitis (AS) For the management of the signs and symptoms of AS [ see Clinical Studies (14.4) ] 1.5 Acute Pain For the management of acute pain in adults [ see Clinical Studies (14.5) ] 1.6 Primary Dysmenorrhea For the management of primary dysmenorrhea [ see Clinical Studies (14.5) ]"}', 'warnings_and_cautions': '{"5. WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of celecoxib in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of celecoxib in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : celecoxib is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue celecoxib at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Premature Closure of Fetal Ductus Arteriosus : Avoid use in pregnant women starting at 30 weeks of gestation ( 5.10 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.11 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo. The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [ see Clinical Studies (14.7) ]. A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen(PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen. Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists\' Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke [ see Clinical Studies (14.6) ]. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions (5.2) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of celecoxib in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If celecoxib is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including celecoxib cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with celecoxib. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3–6 months, and in about 2%–4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [ see Clinical Studies (14.7) ]. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue celecoxib until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions (7) ]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including celecoxib. In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and \\"flu-like\\" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue celecoxib immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including celecoxib, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions (7) ]. See Clinical Studies (14.6 , 14.7) for additional blood pressure data for Celecoxib. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists\' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of celecoxib may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions (7) ]. In the CLASS study [ see Clinical Studies (14.7) ], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively. Avoid the use of celecoxib in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If celecoxib is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors or the ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced renal disease. The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating celecoxib. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of celecoxib [ see Drug Interactions (7) ] . Avoid the use of celecoxib in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If celecoxib is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic- hypoaldosteronism state. 5.7 Anaphylactic Reactions Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma. Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [ see Contraindications (4) and Warnings and Precautions (5.8) ]. Seek emergency help if any anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celecoxib is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4) ]. When celecoxib is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of celecoxib at the first appearance of skin rash or any other sign of hypersensitivity. Celecoxib is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications (4) ]. 5.10 Premature Closure of Fetal Ductus Arteriosus Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including celecoxib, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Use in Specific Populations (8.1) ]. 5.11 Hematological Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with celecoxib has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo. Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. NSAIDs, including celecoxib, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions (7) ]. 5.12 Masking of Inflammation and Fever The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions (5.2 , 5.3 , 5.6) ]. In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo. This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this abnormality has not been established. 5.14 Disseminated Intravascular Coagulation (DIC) Because of the risk of disseminated intravascular coagulation with use of celecoxib in pediatric patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, and inform patients and their caregivers to report symptoms as soon as possible."}', 'overdosage': '{"10. OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.6) ]. No overdoses of celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222)."}', 'active_flag': 'Y', 'generic_name': '{CELECOXIB}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with celecoxib and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately. [ see Warnings and Precautions (5.1) ]. Gastrointestinal Bleeding, Ulceration and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding[ see Warnings and Precautions (5.2) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea jaundice, right upper quadrant tenderness, and \\"flu-like\\" symptoms). If these occur, instruct patients to stop celecoxib and seek immediate medical therapy [ see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions (5.5) ] Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications (4) and Warnings and Precautions (5.7) ]. Serious Skin Reactions Advise patients to stop celecoxib immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.[ see Warnings and Precautions (5.9) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including celecoxib, may be associated with a reversible delay in ovulation [ see Use in Specific Populations (8.3) ]. Fetal Toxicity Inform pregnant women to avoid use of celecoxib and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closing of the fetal ductus arteriosus [ see Warnings and Precautions (5.10) and Use in Specific Populations (8.1) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Alert patients that NSAIDs may be present in \\"over the counter\\" medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with celecoxib until they talk to their healthcare provider [ see Drug Interactions (7) ]."}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward. Risk Summary Use of NSAIDs, including celecoxib, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including celecoxib, in pregnant women starting at 30 weeks of gestation. There are no adequate and well-controlled studies of celecoxib in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD [see Data ]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. Clinical Considerations Labor or Delivery There are no studies on the effects of celecoxib during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data The available data do not establish the presence or absence of developmental toxicity related to the use of celecoxib. Animal data Celecoxib at oral doses ≥150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC 0–24 ), caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6 times human exposure based on the AUC 0–24 at 200 mg twice daily for RA) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses at oral doses ≥50 mg/kg/day (approximately 6 times human exposure based on the AUC 0–24 at 200 mg twice daily for RA). Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure as measured by the AUC 0–24 at 200 mg twice daily). The effects of celecoxib on labor and delivery in pregnant women are unknown."}', 'pediatric_use': '{"8.4 Pediatric Use Celecoxib is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to celecoxib has not been evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to celecoxib or other COX-2 selective and non-selective NSAIDs [ (see Boxed Warning , Warnings and Precautions (5.12) , and Clinical Studies (14.3) ]. The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). When NSAIDs including celecoxib are used in patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, due to the risk of disseminated intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [ see Dosage and Administration (2.4) , Warnings and Precautions (5.12) , Adverse Reactions (6.3), Animal Toxicology (13.2) , Clinical Studies (14.3) ] . Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [ see Poor Metabolizers of CYP2C9 substrates (8.8) ]."}', 'geriatric_use': '{"8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.6 , 5.13) ] Of the total number of patients who received celecoxib in pre-approval clinical trials, more than 3,300 were 65–74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients [ see Warnings and Precautions (5.4 , 5.6) ]."}'}

{"BISMUTH SUBSALICYLATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves • travelers\' diarrhea • diarrhea • upset stomach due to overindulgence in food and drink, including: • heartburn • indigestion • nausea • gas • belching • fullness"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BISMUTH SUBSALICYLATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms get worse ringing in the ears or loss of hearing occurs diarrhea lasts more than 2 days"}', 'do_not_use': '{"Do not use if you have an ulcer a bleeding problem bloody or black stool"}', 'when_using': None, 'warnings': '{"Warnings Reye\'s syndrome Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye\'s syndrome, a rare but serious illness. Allergy alert Contains salicylate. Do not take if you are allergic to salicylates (including aspirin) taking other salicylate products Do not use if you have an ulcer a bleeding problem bloody or black stool Ask a doctor before use if you have fever mucus in the stool Ask a doctor or pharmacist before use if you are taking any drug for anticoagulation (thinning the blood) diabetes gout arthritis When using this produc t a temporary, but harmless, darkening of the stool and/or tongue may occur Stop use and ask a doctor if symptoms get worse ringing in the ears or loss of hearing occurs diarrhea lasts more than 2 days If pregnant or breast feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ESCITALOPRAM OXALATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Do not use MAOIs intended to treat psychiatric disorders with escitalopram or within 14 days of stopping treatment with escitalopram. Do not use escitalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start escitalopram in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ) Concomitant use of pimozide ( 4 ) Known hypersensitivity to escitalopram or citalopram or any of the inactive ingredients ( 4 ) Escitalopram tablets are contraindicated in patients: • taking MAOIs with escitalopram tablets or within 14 days of stopping treatment with escitalopram tablets because of an increased risk of serotonin syndrome. The use of escitalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.2 )] . Starting escitalopram tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.2 )] . • taking pimozide [see Drug Interactions ( 7 )] . • with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram tablets."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most commonly observed adverse reactions (incidence ≥ 5% and at least twice the incidence of placebo patients) are: insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue and somnolence, decreased libido, and anorgasmia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions ( 5.1 )] • Serotonin syndrome [see Warnings and Precautions ( 5.2 )] • Discontinuation syndrome [see Warnings and Precautions ( 5.3 )] • Seizures [see Warnings and Precautions ( 5.4 )] • Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )] • Hyponatremia [see Warnings and Precautions ( 5.6 )] • Increased Risk of Bleeding [see Warnings and Precautions ( 5.7 )] • Interference with Cognitive and Motor Performance [see Warnings and Precautions ( 5.8 )] • Angle-closure glaucoma [see Warnings and Precautions ( 5.9 )] • Use in Patients with Concomitant Illness [see Warnings and Precautions ( 5.10 )] • Sexual Dysfunction [see Warnings and Precautions ( 5.11 )] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Trial Data Sources Adults Adverse reactions information for escitalopram was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The adverse reaction information for escitalopram in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials. Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Pediatric Patients Adverse reaction information for pediatric patients was collected in double-blind placebo-controlled studies in 576 pediatric patients 6 to 17 years of age, (286 escitalopram, 290 placebo) with major depressive disorder. The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD or less than 7 years of age with GAD. Adverse Reactions Associated with Discontinuation of Treatment Major Depressive Disorder Adults Among the 715 depressed patients who received escitalopram in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse reactions in patients receiving 10 mg/day escitalopram was not significantly different from the rate of discontinuation for adverse reactions in patients receiving placebo. The rate of discontinuation for adverse reactions in patients assigned to a fixed dose of 20 mg/day escitalopram was 10%, which was significantly different from the rate of discontinuation for adverse reactions in patients receiving 10 mg/day escitalopram (4%) and placebo (3%). Adverse reactions that were associated with the discontinuation of at least 1% of patients treated with escitalopram tablets, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients). Pediatric Patients Adverse reactions in pediatric patients 6 to 17 years of age were associated with discontinuation of 3.5% of 286 patients receiving escitalopram and 1% of 290 patients receiving placebo. The most common adverse reaction (incidence at least 1% for escitalopram and greater than placebo) associated with discontinuation was insomnia (1% escitalopram, 0% placebo). The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD. Generalized Anxiety Disorder Adults Among the 429 GAD patients who received escitalopram 10 to 20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse reactions that were associated with the discontinuation of at least 1% of patients treated with escitalopram, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%). Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials Major Depressive Disorder Adults The most commonly observed adverse reactions in escitalopram patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence. Table 2 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred among 715 depressed patients who received escitalopram at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Reactions included are those occurring in 2% or more of patients treated with escitalopram and for which the incidence in patients treated with escitalopram was greater than the incidence in placebo-treated patients. 1 Primarily ejaculatory delay. 2 Denominator used was for males only (N=225 escitalopram; N=188 placebo). 3 Denominator used was for females only (N=490 escitalopram; N=404 placebo). TABLE 2 Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Major Depressive Disorder (Adults) Adverse Reaction Escitalopram Placebo (N=715) % (N=592) % Autonomic Nervous System Disorders Dry Mouth 6% 5% Sweating Increased 5% 2% Central & Peripheral Nervous System Disorders Dizziness 5% 3% Gastrointestinal Disorders Nausea 15% 7% Diarrhea 8% 5% Constipation 3% 1% Indigestion 3% 1% Abdominal Pain 2% 1% General Influenza-like Symptoms 5% 4% Fatigue 5% 2% Psychiatric Disorders Insomnia 9% 4% Somnolence 6% 2% Appetite Decreased 3% 1% Libido Decreased 3% 1% Respiratory System Disorders Rhinitis 5% 4% Sinusitis 3% 2% Urogenital Ejaculation Disorder 1,2 9% <1% Impotence 2 3% <1% Anorgasmia 3 2% <1% Pediatric Patients The overall profile of adverse reactions in pediatric patients 6 to 17 years in major depressive disorder was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for escitalopram and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion. The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD. Generalized Anxiety Disorder Adults The most commonly observed adverse reactions in escitalopram patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia. Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse reactions that occurred among 429 GAD patients who received escitalopram 10 to 20 mg/day in placebo-controlled trials. Reactions included are those occurring in 2% or more of patients treated with escitalopram and for which the incidence in patients treated with escitalopram was greater than the incidence in placebo-treated patients. 1 Primarily ejaculatory delay. 2 Denominator used was for males only (N=182 escitalopram; N=195 placebo). 3 Denominator used was for females only (N=247 escitalopram; N=232 placebo). TABLE 3 Adverse Reactions Observed with a Frequency of ≥ 2% and > placebo for Generalized Anxiety Disorder (Adults) Adverse Reactions Escitalopram Placebo (N=429) % (N=427) % Autonomic Nervous System Disorders Dry Mouth 9% 5% Sweating Increased 4% 1% Central & Peripheral Nervous System Disorders Headache 24% 17% Paresthesia 2% 1% Gastrointestinal Disorders Nausea 18% 8% Diarrhea 8% 6% Constipation 5% 4% Indigestion 3% 2% Vomiting 3% 1% Abdominal Pain 2% 1% Flatulence 2% 1% Toothache 2% 0% General Fatigue 8% 2% Influenza-like Symptoms 5% 4% Musculoskeletal System Disorder Neck/Shoulder Pain 3% 1% Psychiatric Disorders Somnolence 13% 7% Insomnia 12% 6% Libido Decreased 7% 2% Dreaming Abnormal 3% 2% Appetite Decreased 3% 1% Lethargy 3% 1% Respiratory System Disorders Yawning 2% 1% Urogenital Ejaculation Disorder 1,2 14% 2% Anorgasmia 3 6% <1% Menstrual Disorder 2% 1% Dose Dependency of Adverse Reactions The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥5% in either the 10 mg or 20 mg escitalopram groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse reactions in 10 mg escitalopram-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day escitalopram group with an incidence that was approximately twice that of the 10 mg/day escitalopram group and approximately twice that of the placebo group. TABLE 4 Incidence of Common Adverse Reactions in Patients with Major Depressive Disorder Adverse Reaction Placebo 10 mg/day 20 mg/day (N=311) Escitalopram Escitalopram (N=310) (N=125) Insomnia 4% 7% 14% Diarrhea 5% 6% 14% Dry Mouth 3% 4% 9% Somnolence 1% 4% 9% Dizziness 2% 4% 7% Sweating Increased <1% 3% 8% Constipation 1% 3% 6% Fatigue 2% 2% 6% Indigestion 1% 2% 6% Male and Female Sexual Dysfunction with SSRIs Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. TABLE 5 Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials Adverse Event Escitalopram Placebo In Males Only (N=407) (N=383) Ejaculation Disorder (primarily ejaculatory delay) 12% 1% Libido Decreased 6% 2% Impotence 2% <1% In Females Only (N=737) (N=636) Libido Decreased 3% 1% Anorgasmia 3% <1% There are no adequately designed studies examining sexual dysfunction with escitalopram treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Vital Sign Changes Escitalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with escitalopram treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving escitalopram indicated that escitalopram treatment is not associated with orthostatic changes. Weight Changes Patients treated with escitalopram in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight. Laboratory Changes Escitalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with escitalopram treatment. ECG Changes Electrocardiograms from escitalopram (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the escitalopram group had a QTcF interval >500 msec or a prolongation >60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the escitalopram and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram group and 0.2% in the placebo group. QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the Cmax for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean Cmax of 1.7-fold higher than the mean Cmax for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg. Other Reactions Observed During the Premarketing Evaluation of Escitalopram Tablets Following is a list of treatment-emergent adverse reactions, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1,428 patients treated with escitalopram tablets for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those reactions already listed in Tables 2 & 3, those reactions for which a drug cause was remote and at a rate less than 1% or lower than placebo, those reactions which were so general as to be uninformative, and those reactions reported only once which did not have a substantial probability of being acutely life threatening. Reactions are categorized by body system. Reactions of major clinical importance are described in the Warnings and Precautions section (5). Cardiovascular : hypertension, palpitation. Central and Peripheral Nervous System Disorders : light-headed feeling, migraine. Gastrointestinal Disorders : abdominal cramp, heartburn, gastroenteritis. General : allergy, chest pain, fever, hot flushes, pain in limb. Metabolic and Nutritional Disorders : increased weight. Musculoskeletal System Disorders : arthralgia, myalgia jaw stiffness. Psychiatric Disorders : appetite increased, concentration impaired, irritability. Reproductive Disorders/Female : menstrual cramps, menstrual disorder. Respiratory System Disorders : bronchitis, coughing, nasal congestion, sinus congestion, sinus headache. Skin and Appendages Disorders : rash. Special Senses : vision blurred, tinnitus. Urinary System Disorders : urinary frequency, urinary tract infection. Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO ® (escitalopram) tablets. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Post-Marketing Experience Adverse Reactions Reported Subsequent to the Marketing of Escitalopram The following adverse reactions have been identified during post-approval use of escitalopram. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia. Cardiac Disorders : atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia. Ear and labyrinth disorders : vertigo Endocrine Disorders : diabetes mellitus, hyperprolactinemia, SIADH. Eye Disorders : angle closure glaucoma, diplopia, mydriasis, visual disturbance. Gastrointestinal Disorder : dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage. General Disorders and Administration Site Conditions : abnormal gait, asthenia, edema, fall, feeling abnormal, malaise. Hepatobiliary Disorders : fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis. Immune System Disorders : allergic reaction, anaphylaxis. Investigations : bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased. Metabolism and Nutrition Disorders : hyperglycemia, hypoglycemia, hypokalemia, hyponatremia. Musculoskeletal and Connective Tissue Disorders : muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis. Nervous System Disorders : akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor. Pregnancy, Puerperium and Perinatal Conditions : spontaneous abortion. Psychiatric Disorders : acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency. Renal and Urinary Disorders : acute renal failure, dysuria, urinary retention. Reproductive System and Breast Disorders : menorrhagia, priapism. Respiratory, Thoracic and Mediastinal Disorders : anosmia, dyspnea, epistaxis, pulmonary embolism, hyposmia, pulmonary hypertension of the newborn. Skin and Subcutaneous Tissue Disorders : alopecia, angioedema, dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS), ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria. Vascular Disorders : deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis."}', 'drug_interactions': '{"7 DRUG INTERACTIONS • Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended ( 7 ) • Use caution when concomitant use with drugs that affect Hemostasis (NSAIDs, Aspirin, Warfarin) ( 7 ) Table 6 presents clinically important drug interactions with escitalopram. TABLE 6 Clinically Important Drug Interactions with Escitalopram Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs, including Escitalopram, and MAOIs increases the risk of serotonin syndrome. Intervention: Escitalopram is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.7 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] . Pimozide Clinical Impact: Concomitant use of racemic citalopram with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of racemic citalopram alone [see Clinical Pharmacology ( 12.3 )] . Intervention: Escitalopram is contraindicated in patients taking pimozide [see Contraindications ( 4 )] . Other Serotonergic Drugs Clinical Impact: Concomitant use of Escitalopram and other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John\'s Wort) increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during Escitalopram initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Escitalopram and/or concomitant serotonergic drugs [see Warning and Precautions ( 5.2 )] . Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) Clinical Impact: Concomitant use of Escitalopram and an antiplatelet or anticoagulant may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of Escitalopram and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warning and Precautions ( 5.7 )] . Sumatriptan Clinical Impact: There have been postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. Intervention: If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised [see Warning and Precautions ( 5.2 )] . Carbamazepine Clinical Impact: Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Intervention: Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered. Drugs Metabolized by CYP2D6 Clinical Impact: Coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. Intervention: The clinical significance of this finding is unknown. Exercise caution during coadministration of escitalopram and drugs metabolized by CYP2D6."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Escitalopram is a selective serotonin reuptake inhibitor (SSRI) indicated for the: • treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years of age and older ( 1 ) • treatment of generalized anxiety disorder (GAD) in adults ( 1 ) Escitalopram tablets are indicated for the treatment of: • major depressive disorder (MDD) in adults and pediatric patients 12 years of age and older. • generalized anxiety disorder (GAD) in adults. Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO ® (escitalopram) tablets. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents but also when taken alone. If it occurs, discontinue Escitalopram and serotonergic agents and initiate supportive treatment ( 4 , 5.2 ) • Discontinuation syndrome: When discontinuing Escitalopram, reduce dosage gradually whenever possible, and monitor for discontinuation symptoms ( 5.3 ) • Seizures: Use with caution in patients with a history of seizure ( 5.4 ) • Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 5.5 ) • Hyponatremia: Can occur in association with syndrome of inappropriate antidiuretic hormone secretion ( 5.6 ) • Increased Risk of Bleeding: Concomitant use of nonsteroidal anti-inflammatory drugs, aspirin, other antiplatelet drugs, warfarin and other drugs that affect coagulation may increase risk ( 5.7 ) • Interference with Cognitive and Motor Performance: Use caution when operating machinery ( 5.8 ) • Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.9 ) • Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses ( 5.10 ) • Sexual Dysfunction: Escitalopram may cause symptoms of sexual dysfunction ( 5.11 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing escitalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including escitalopram tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] . Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination) seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of escitalopram with MAOIs is contraindicated. In addition, do not initiate Escitalopram in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Escitalopram, discontinue Escitalopram before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration ( 2.7 )] . Monitor all patients taking escitalopram tablets for the emergence of serotonin syndrome. Discontinue treatment with escitalopram tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of escitalopram with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Discontinuation Syndrome During marketing of escitalopram tablets and other SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Monitor for these symptoms when discontinuing treatment with escitalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration ( 2.6 )] . 5.4 Seizures Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product\'s premarketing testing. In clinical trials of escitalopram, cases of convulsion have been reported in association with escitalopram treatment. Like other drugs effective in the treatment of major depressive disorder, escitalopram tablets should be introduced with care in patients with a history of seizure disorder. 5.5 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with escitalopram or another antidepressant may precipitate a mixed/manic episode. In placebo-controlled trials of escitalopram in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with escitalopram and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with escitalopram treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. Prior to initiating treatment with escitalopram, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.4 )] . 5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including escitalopram. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations ( 8.5 )] . Consider discontinuation of escitalopram in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.7 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including escitalopram, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )] . Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of escitalopram and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Drug Interactions ( 7 )] . 5.8 Interference with Cognitive and Motor Performance In a study in normal volunteers, escitalopram 10 mg daily did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram tablets therapy does not affect their ability to engage in such activities. 5.9 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including escitalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.10 Use in Patients with Concomitant Illness Clinical experience with escitalopram in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using escitalopram tablets in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Escitalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product\'s premarketing testing. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of escitalopram tablets in hepatically impaired patients is 10 mg daily [see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.6)] . Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with escitalopram tablets, however, it should be used with caution in such patients [see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.7)] . 5.11 Sexual Dysfunction Use of SSRIs, including escitalopram, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of escitalopram and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment."}', 'overdosage': '{"10 OVERDOSAGE The following have been reported with escitalopram tablet overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Prolonged cardiac monitoring is recommended in escitalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a escitalopram overdose. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations."}', 'active_flag': 'Y', 'generic_name': '{"ESCITALOPRAM OXALATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients, their families and caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to their healthcare provider [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of escitalopram with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . Discontinuation Syndrome Advise patients not to abruptly discontinue escitalopram tablets and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when escitalopram tablets are discontinued [see Warnings and Precautions ( 5.3 )] . Activation of Mania or Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions ( 5.5 )]. Increased Risk of Bleeding Inform patients about the concomitant use of escitalopram with NSAIDs, aspirin, warfarin, other antiplatelet drugs, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their healthcare providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions ( 5.7 )] . Angle Closure Glaucoma Advise patients that taking escitalopram tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions ( 5.9 )] . Sexual Dysfunction Advise patients that use of escitalopram may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.11 )] . Concomitant Medications Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Interference with Psychomotor Performance Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram tablets therapy does not affect their ability to engage in such activities. Alcohol Patients should be told that, although escitalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of escitalopram and alcohol in depressed patients is not advised. Pregnancy Advise pregnant women to notify their healthcare providers if they become pregnant or intend to become pregnant during treatment with escitalopram tablets. Advise patients that escitalopram use later in pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension (PPHN) of the newborn [see Use in Specific Populations ( 8.1 )]. Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to escitalopram during pregnancy [see Use in Specific Populations ( 8.1 )]. Lactation Advise breastfeeding women using escitalopram to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )]. Trademarks are the property of their respective owners. Manufactured by: TORRENT PHARMACEUTICALS LTD., INDIA. 8096558 Revised: May 2024 Or VKT Pharma Private Limited, Srikakulam-532409, India. 8096587 Revised: May 2024 800246 Manufactured for: TORRENT PHARMA INC., Basking Ridge, NJ 07920."}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 ) and Clinical Considerations] . Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage. There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation (see Clinical Considerations) with exposure to selective serotonin reuptake inhibitors (SSRIs), including escitalopram, during pregnancy. There are risks associated with untreated depression in pregnancy (see Clinical Considerations). In animal reproduction studies, both escitalopram and racemic citalopram have been shown to have adverse effects on embryo/fetal and postnatal development, including fetal structural abnormalities, when administered at doses greater than human therapeutic doses (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal risk and/or embryo/fetal risk Women who discontinue antidepressants are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depression, who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of escitalopram tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 )]. Fetal/Neonatal adverse reactions Neonates exposed to SSRIs or SNRIs, including escitalopram, late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.2 )] . Data Human Data Exposure to SSRIs, particularly later in pregnancy, may increase the risk for PPHN. PPHN occurs in 1 to 2 per 1,000 live births in the general populations and is associated with substantial neonatal morbidity and mortality. Animal Data In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses [approximately ≥ 55 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m 2 basis]. Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 27 times the MRHD of 20 mg on a mg/m 2 basis. No malformations were observed at any of the doses tested (as high as 73 times the MRHD on a mg/m 2 basis). When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 23 times the MRHD of 20 mg on a mg/m 2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD of 20 mg on a mg/m 2 basis. In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a mg/m 2 basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day is approximately 9 times the MRHD on a mg/m 2 basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m 2 basis. Thus, developmental effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD of 60 mg on a mg/m 2 basis. The no-effect dose was 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m 2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m 2 basis. A no-effect dose was not determined in that study."}', 'pediatric_use': '{"8.4 Pediatric Use Major Depressive Disorder The safety and effectiveness of escitalopram for the treatment of major depressive disorder have been established in pediatric patients 12 years of age and older. Use of escitalopram for this indication is supported by evidence from adequate and well-controlled studies in adults with additional evidence from an 8-week, flexible-dose, placebo-controlled study that compared escitalopram tablets 10 mg to 20 mg once daily to placebo in pediatric patients 12 to 17 years of age with major depressive disorder [see Clinical Studies ( 14.1 )] . The safety of escitalopram was similar to adult patients with MDD [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of escitalopram for the treatment of major depressive disorder have not been established in pediatric patients younger than 12 years of age. In a 24-week, open-label safety study in 118 pediatric patients aged 7 to 11 years who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for escitalopram. Generalized Anxiety Disorder The safety and effectiveness of escitalopram for the treatment of generalized anxiety disorder have not been established in pediatric patients younger than 7 years of age. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions ( 5.1 )] . Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as escitalopram. Juvenile Animal Toxicity Data In a juvenile animal study, male and female rats were administered escitalopram at 5, 40, or 80 mg/kg/day by oral gavage from postnatal day (PND) 21 to PND 69. A delay in sexual maturation was observed in both males and females at ≥ 40 mg/kg/day with a No Observed Adverse Effect Level (NOAEL) of 5 mg/kg/day. This NOAEL was associated with plasma AUC levels less than those measured at the maximum recommended dose (MRHD) in pediatrics (20 mg). However, there was no effect on reproductive function. Increased motor activity (both ambulatory and fine movements) was observed in females prior to daily dosing at ≥ 40 mg/kg/day (3.5 times the MRHD based on AUC levels). A reversible disruption of learning and memory function was observed in males at 80 mg/kg/day with a NOAEL of 40 mg/kg/day, which was associated with an AUC level 3.5 times those measured at the MRHD in pediatrics. There was no effect on learning and memory function in treated female rats. Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO ® (escitalopram) tablets. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information."}', 'geriatric_use': '{"8.5 Geriatric Use Approximately 69 patients (6%) of the 1,144 patients receiving escitalopram in controlled trials of escitalopram in major depressive disorder and GAD were 60 years of age or older [see Clinical Studies ( 14.1 , 14.2 )] . The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram cannot be ruled out. In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in subjects 65 years and older as compared to young subjects and C max was unchanged [see Clinical Pharmacology ( 12.3 )] . The recommended dosage of escitalopram tablets for elderly patients is 10 mg daily [see Dosage and Administration ( 2.5 )] . SSRIs, including escitalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.6 )] . Of 4,422 patients in clinical studies of racemic citalopram, 1,357 were 60 and over, 1,034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the geriatric and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out."}'}

{FENOFIBRATE}

{'contraindications': '{"4 CONTRAINDICATIONS Fenofibrate tablets are contraindicated in: patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology (12.3) ] . patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.2) ] . patients with preexisting gallbladder disease [see Warnings and Precautions (5.5) ] . nursing mothers [see Use in Specific Populations (8.2) ] . patients with known hypersensitivity to fenofibrate or fenofibric acid [see Warnings and Precautions (5.9) ] . Severe renal dysfunction, including dialysis patients ( 4 , 8.6 , 12.3 ). Active liver disease ( 4 , 5.3 ). Gallbladder disease ( 4 , 5.5 ). Known hypersensitivity to fenofibrate ( 4 ). Nursing mothers ( 4 , 8.2 )."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Mortality and coronary heart disease morbidity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.7) ] Hypersensitivity reactions [see Warnings and Precautions (5.9) ] Venothromboembolic disease [see Warnings and Precautions (5.10) ] Adverse reactions > 2% and at least 1% greater than placebo; Abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1 below. Adverse events led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Reaction Fenofibrate Dosage equivalent to 160 mg fenofibrate tablet (N = 439) Placebo (N = 365) BODY AS A WHOLE Abdominal Pain 4.6% 4.4% Back Pain 3.4% 2.5% Headache 3.2% 2.7% DIGESTIVE Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Function Tests 7.5% Significantly different from Placebo 1.4% Increased ALT 3.0% 1.6% Increased CPK 3.0% 1.4% Increased AST 3.4% 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% Urticaria was seen in 1.1% vs. 0%, and rash in 1.4% vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials. Increases in Liver Enzymes In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 107 mg to 160 mg fenofibrate daily versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 107 mg to 160 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 54 mg or less fenofibrate daily or placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, severely depressed HDL-cholesterol levels, and interstitial lung disease. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Coumarin anticoagulants: ( 7.1 ). Immunosuppressants: ( 7.2 ). Bile acid resins: ( 7.3 ). 7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate tablets. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized [see Warnings and Precautions (5.6) ] . 7.2 Immunosuppressants Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate tablets, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibrate tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored. 7.3 Bile Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibrate tablets at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. 7.4 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Fenofibrate tablets are a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as an adjunct to diet: To reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia ( 1.1 ). For treatment of adult patients with severe hypertriglyceridemia ( 1.2 ). Limitations of Use: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus ( 5.1 ). 1.1 Primary Hypercholesterolemia or Mixed Dyslipidemia Fenofibrate tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. 1.2 Severe Hypertriglyceridemia Fenofibrate tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied. 1.3 Important Limitations of Use Fenofibrate at a dose equivalent to 160 mg of fenofibrate tablet was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1) ] ."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrate. Monitor patient\'s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist ( 5.2 ). Myopathy and rhabdomyolysis: have been reported in patients taking fenofibrate. Risks are increased during co-administration with a statin (with a significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism ( 5.3 ). Serum Creatinine: Fenofibrate tablets can reversibly increase serum creatinine levels (5.4). Monitor renal function periodically in patients with renal impairment ( 8.6 ). Cholelithiasis: Fenofibrate tablets increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated ( 5.5 ). Coumarin Anticoagulants: Use caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications ( 5.6 ). Hypersensitivity Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue fenofibrate and treat patients appropriately if reactions occur ( 5.9 ). 5.1 Mortality and Coronary Heart Disease Morbidity The effect of fenofibrate tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5 year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. Because of chemical, pharmacological, and clinical similarities between fenofibrate tablets, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate tablets. In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3% vs. 1.8%). In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age − adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p = < 0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p = 0.19, 95% confidence interval for relative risk G:P = 0.91 to 1.64). Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (RR=1.29). A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94 to 5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p = 0.07). 5.2 Hepatotoxicity Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibrate. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibrate treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis. In clinical trials, fenofibrate at doses equivalent to 107 mg to 160 mg fenofibrate daily has been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see ADVERSE REACTIONS (6.1) ] . Fenofibrate is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see CONTRAINDICATIONS (4) ] . Monitor patient\'s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibrate. Discontinue fenofibrate if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart fenofibrate in these patients if there is no alternative explanation for the liver injury. 5.3 Myopathy and Rhabdomyolysis Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal insufficiency, or hypothyroidism. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed. Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3) ] . Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see Drug Interactions (7.4) ]. 5.4 Serum Creatinine Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking fenofibrate tablets. Renal monitoring should also be considered for patients taking fenofibrate tablets at risk for renal insufficiency such as the elderly and patients with diabetes. 5.5 Cholelithiasis Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate tablets therapy should be discontinued if gallstones are found. 5.6 Coumarin Anticoagulants Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate tablets because of the potentiation of coumarin-type anticoagulant effects in prolonging the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1) ] . 5.7 Pancreatitis Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. 5.8 Hematologic Changes Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of fenofibrate tablets administration. 5.9 Hypersensitivity Reactions Acute Hypersensitivity Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate. Delayed Hypersensitivity Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected. 5.10 Venothromboembolic Disease In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate-than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022). In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01). 5.11 Paradoxical Decreases in HDL Cholesterol Levels There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated."}', 'overdosage': '{"10 OVERDOSAGE There is no specific treatment for overdose with fenofibrate tablets. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered."}', 'active_flag': 'Y', 'generic_name': '{FENOFIBRATE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Patients should be advised: of the potential benefits and risks of fenofibrate tablets. not to use fenofibrate tablets if there is a known hypersensitivity to fenofibrate or fenofibric acid. of medications that should not be taken in combination with fenofibrate tablets. that if they are taking coumarin anticoagulants, fenofibrate tablets may increase their anti-coagulant effect, and increased monitoring may be necessary. to continue to follow an appropriate lipid-modifying diet while taking fenofibrate tablets. to take fenofibrate tablets once daily with a meal at the prescribed dose, swallowing each tablet whole. to return to their physician\'s office for routine monitoring. to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking fenofibrate tablets. to inform their physician of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. not to breastfeed during treatment with fenofibrate tablets and for 5 days after the final dose. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 160 mg daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data ). Fenofibrate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 160 mg fenofibrate tablets daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain. In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients."}', 'geriatric_use': '{"8.5 Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking fenofibrate tablets."}'}

{"MICONAZOLE NITRATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Cures most athlete\'s foot (tinea pedis), jock itch (tinea cruris) and ringworm (tinea corporis) relieves itching, cracking, burning and scaling"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"MICONAZOLE NITRATE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if irritation occurs if there is no improvement within 4 weeks (for athlete\'s foot and ringworm) or 2 weeks (for jock itch)"}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor. When using this product avoid contact with the eyes Stop use and ask a doctor if irritation occurs if there is no improvement within 4 weeks (for athlete\'s foot and ringworm) or 2 weeks (for jock itch) Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{INTERLEUKIN-11}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Take 15 minutes before meals."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{INTERLEUKIN-11}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"WARNINGS Stop use and ask doctor if symptoms worsen or persist more than 5 days"}', 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Keep this and all medicines out of reach of children"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"PROPRANOLOL HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride."}', 'adverse_reactions': '{"ADVERSE REACTIONS The following adverse events were observed and have been reported in patients using propranolol. Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type. Central Nervous System: Light-headedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy, and vivid dreams appear dose-related. Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. Respiratory: Bronchospasm. Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Autoimmune: Systemic lupus erythematosus (SLE). Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol. Genitourinary: Male impotence; Peyronie\'s disease."}', 'drug_interactions': '{"Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol\'s metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS ). Substrates or Inhibitors of CYP2D6 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole. Substrates or Inhibitors of CYP1A2 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. Substrates or Inhibitors of CYP2C19 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole. Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations. Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% by co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two‑three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. Calcium Channel Blockers The mean C max and AUC of propranolol are increased, respectively, by 50% and 30% by co‑administration of nisoldipine and by 80% and 47%, by co‑administration of nicardipine. The mean C max and AUC of nifedipine are increased by 64% and 79%, respectively, by co‑administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol. Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C max by 37%) or rizatriptan (the AUC and C max were increased by 67% and 75%, respectively). Theophylline Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. Neuroleptic Drugs Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level. Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C max by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol\'s pharmacokinetics. Lipid Lowering Drugs Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin. Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time. Alcohol Concomitant use of alcohol may increase plasma levels of propranolol.","Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol\'s metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS ).","Substrates or Inhibitors of CYP2D6 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.","Substrates or Inhibitors of CYP1A2 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.","Substrates or Inhibitors of CYP2C19 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.","Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.","Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% by co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two‑three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. Calcium Channel Blockers The mean C max and AUC of propranolol are increased, respectively, by 50% and 30% by co‑administration of nisoldipine and by 80% and 47%, by co‑administration of nicardipine. The mean C max and AUC of nifedipine are increased by 64% and 79%, respectively, by co‑administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.","Antiarrhythmics The AUC of propafenone is increased by more than 200% by co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two‑three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.","Calcium Channel Blockers The mean C max and AUC of propranolol are increased, respectively, by 50% and 30% by co‑administration of nisoldipine and by 80% and 47%, by co‑administration of nicardipine. The mean C max and AUC of nifedipine are increased by 64% and 79%, respectively, by co‑administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.","Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C max by 37%) or rizatriptan (the AUC and C max were increased by 67% and 75%, respectively). Theophylline Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. Neuroleptic Drugs Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level. Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C max by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol\'s pharmacokinetics. Lipid Lowering Drugs Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin. Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time. Alcohol Concomitant use of alcohol may increase plasma levels of propranolol.","Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C max by 37%) or rizatriptan (the AUC and C max were increased by 67% and 75%, respectively).","Theophylline Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.","Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.","Neuroleptic Drugs Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.","Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C max by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol\'s pharmacokinetics.","Lipid Lowering Drugs Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.","Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.","Alcohol Concomitant use of alcohol may increase plasma levels of propranolol.","Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM ). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.","Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.","Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers.","Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.","Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure.","ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine.","Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin.","Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.","Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ).","Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.","Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.","Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate.","Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol.","Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.","Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored.","Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.","Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol.","Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Hypertension Propranolol hydrochloride tablets, USP are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride tablets, USP are not indicated in the management of hypertensive emergencies. Angina Pectoris Due to Coronary Atherosclerosis Propranolol hydrochloride tablets, USP are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Atrial Fibrillation Propranolol hydrochloride tablets, USP are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Myocardial Infarction Propranolol hydrochloride tablets, USP are indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Migraine Propranolol hydrochloride tablets, USP are indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use. Essential Tremor Propranolol hydrochloride tablets, USP are indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol hydrochloride tablets, USP cause a reduction in the tremor amplitude, but not in the tremor frequency. Propranolol hydrochloride tablets, USP are not indicated for the treatment of tremor associated with Parkinsonism. Hypertrophic Subaortic Stenosis Propranolol hydrochloride tablets, USP improve NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis. Pheochromocytoma Propranolol hydrochloride tablets, USP are indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors.","Hypertension Propranolol hydrochloride tablets, USP are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride tablets, USP are not indicated in the management of hypertensive emergencies.","Angina Pectoris Due to Coronary Atherosclerosis Propranolol hydrochloride tablets, USP are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris.","Atrial Fibrillation Propranolol hydrochloride tablets, USP are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response.","Myocardial Infarction Propranolol hydrochloride tablets, USP are indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable.","Migraine Propranolol hydrochloride tablets, USP are indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use.","Essential Tremor Propranolol hydrochloride tablets, USP are indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol hydrochloride tablets, USP cause a reduction in the tremor amplitude, but not in the tremor frequency. Propranolol hydrochloride tablets, USP are not indicated for the treatment of tremor associated with Parkinsonism.","Hypertrophic Subaortic Stenosis Propranolol hydrochloride tablets, USP improve NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.","Pheochromocytoma Propranolol hydrochloride tablets, USP are indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration. Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. Glucagon should be administered as 50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing. The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm."}', 'active_flag': 'Y', 'generic_name': '{"PROPRANOLOL HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician\'s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications. Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS ). Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS ). Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure. Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T 4 and reverse T 3 and decreasing T 3 . Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol. Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure.","Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician\'s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications.","Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS ). Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS ).","Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure.","In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure.","Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.","Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.","Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency.","Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T 4 and reverse T 3 and decreasing T 3 .","Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this result was reported after an initial dose of 5 mg propranolol.","Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed. In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure."}', 'precautions': '{"PRECAUTIONS General Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol is not indicated for the treatment of hypertensive emergencies. Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure. While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen. Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM ). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers. Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure. ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol should be administered cautiously to patients withdrawing from clonidine. Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers. Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin. Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ). Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia. Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents. Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate. Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol. Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol. Warfarin Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored. Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol. Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol. Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol. Carcinogenesis, Mutagenesis, Impairment of Fertility In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol hydrochloride in bacteria ( S. typhimurium strain TA 1538). Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing woman. Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients. Geriatric Use Clinical studies of propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted. There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established. Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients."}', 'geriatric_use': '{"Geriatric In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the clearance of S(-)-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life of both the R(+)- and S(-)-propranolol were prolonged in the elderly compared with the young (11 hours vs. 5 hours). Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side-chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP-ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG-conjugation).","Geriatric Use Clinical studies of propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."}'}

{"DYCLONINE HYDROCHLORIDE",GLYCERIN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses for temporary relief of: occasional minor irritation, pain, sore mouth, and sore throat pain associated with canker sores minor discomfort and protection of irritated areas in sore mouth and sore throat"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"DYCLONINE HYDROCHLORIDE AND GLYCERIN"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor or dentist if sore mouth symptoms do not improve in 7 days"}', 'do_not_use': None, 'when_using': '{"When using this product try to avoid swallowing spray."}', 'warnings': '{"Warnings Sore throat warning If sore throat is severe, persists for more than 2 days, is accompanied or followed by fever, headache, rash, swelling, nausea or vomiting, consult a doctor promptly. Stop use and ask a doctor or dentist if sore mouth symptoms do not improve in 7 days If pregnant or breast-feeding, ask a health professional before use. Keep out of the reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Do not exceed recommended dosage. When using this product try to avoid swallowing spray."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{BENZOCAINE,"WHITE PETROLATUM"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses For temporary relief of pain and itching associated with symptoms of fever blisters and cold sores Helps prevent and protect dry, chapped lips"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZOCAINE, WHITE PETROLATUM"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if cold sore symptoms do not improve in 7 days irritation, pain, or redness persists or worsens swelling, rash, or fever develops"}', 'do_not_use': '{"Do not use on • deep or puncture wounds • animal bites • serious burns"}', 'when_using': '{"When using this product keep out of eyes. Rinse with water to remove. Do not exceed recommended dosage."}', 'warnings': '{"Warnings For external use only. Allergy Alert: Do not use this product if you have a history of allergy to local anesthetics such as procaine, butacaine, benzocaine, or other \\"caine\\" anesthetics Stop use and ask a doctor if cold sore symptoms do not improve in 7 days irritation, pain, or redness persists or worsens swelling, rash, or fever develops Do not use on • deep or puncture wounds • animal bites • serious burns When using this product keep out of eyes. Rinse with water to remove. Do not exceed recommended dosage. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CAMPHOR (NATURAL)"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses For temporary relief of pain"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{CAMPHOR}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop using and Ask a Doctor if irritation or rash occurs."}', 'do_not_use': '{"Do Not use In large quantities, particularly over raw surfaces or blistered areas.• If condition worsens or if symptoms persist for more than 7 days or clear up and ocur again within a few days, discontinue use of this product and consult a doctor."}', 'when_using': '{"When Using This Product Avoid contact with the eyes"}', 'warnings': '{"Warnings For external use only. Contains bee venom."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CALCIUM CARBONATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Relieves Heartburn Sour stomach Acid indigestion Upset stomach due to these symptoms"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CALCIUM CARBONATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': '{"Do not use the maximum dosage for more than 2 weeks, except under the advice and supervision of a physician."}', 'when_using': '{"When using this product constipation may occur."}', 'warnings': '{"Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BENZALKONIUM CHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses - For hand sanitizing to decrease the bacteria on skin. - Recommended for repeated use."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZALKONIUM CHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours."}', 'do_not_use': None, 'when_using': '{"When using this product avoid contact with eyes. In case of eye contact, flush eyes with water"}', 'warnings': '{"Warnings For external use only. When using this product avoid contact with eyes. In case of eye contact, flush eyes with water Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours. KEEP OUT OF REACH OF CHILDREN. If swallowed, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ISOPROPYL ALCOHOL"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"First aid to help prevent the risk of infection in minor cuts, scrapes or burns."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ISOPROPYL ALCOHOL"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask doctor if condition persists or get worse"}', 'do_not_use': None, 'when_using': '{"Do not use in or near the eyes Do not apply over large areas Do not use longer than 1 week unless directed by doctor"}', 'warnings': '{"For external use only"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CARBON DIOXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CARBON DIOXIDE"}', 'route': '{"RESPIRATORY (INHALATION)"}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALPRAZOLAM}

{'contraindications': '{"4 CONTRAINDICATIONS Alprazolam is contraindicated in patients: with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions ( 6.2 )] . taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.1 )] Known hypersensitivity to alprazolam or other benzodiazepines. ( 4 ) Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. ( 4 , 5.5 , 7.1 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions ( 5.1 )] Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.2 )] Dependence and Withdrawal Reactions [see Warnings and Precautions ( 5.3 )] Effects on Driving and Operating Machinery [see Warnings and Precautions ( 5.4 )] Patients with Depression [see Warnings and Precautions ( 5.6 )] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions ( 5.8 )] Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions ( 5.9 )] The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence ≥5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in: 4-week placebo-controlled clinical studies with alprazolam dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1) Short-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2). Table 1: Adverse Reactions Occurring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety Alprazolam n=565 Placebo n=505 Nervous system disorders Drowsiness 41% 22% Light-headedness 21% 19% Dizziness 2% 1% Akathisia 2% 1% Gastrointestinal disorders Dry mouth 15% 13% Increased salivation 4% 2% Cardiovascular disorders Hypotension 5% 2% Skin and subcutaneous tissue disorders Dermatitis/allergy 4% 3% In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention. Table 2: Adverse Reactions Occurring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder Alprazolam n=1388 Placebo n=1231 Drowsiness 77% 43% Fatigue and Tiredness 49% 42% Impaired Coordination 40% 18% Irritability 33% 30% Memory Impairment 33% 22% Cognitive Disorder 29% 21% Decreased Libido 14% 8% Dysarthria 23% 6% Confusional state 10% 8% Increased libido 8% 4% Change in libido (not specified) 7% 6% Disinhibition 3% 2% Talkativeness 2% 1% Derealization 2% 1% Gastrointestinal disorders Constipation Increased salivation 26% 6% 15% 4% Skin and subcutaneous tissue disorders Rash 11% 8% Other Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence 33% 28% 27% 23% 12% 11% 7% 2% 23% 24% 18% 17% 9% 9% 4% 1% In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice. Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo-treated group are shown in Table 3. Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam-treated Patients and > Placebo-treated Patients Alprazolam-treated Patients n=641 Nervous system disorders Insomnia 29.5% Light-headedness 19.3% Abnormal involuntary movement 17.3% Headache 17.0% Muscular twitching 6.9% Impaired coordination 6.6% Muscle tone disorders 5.9% Weakness 5.8% Psychiatric disorders Anxiety 19.2% Fatigue and Tiredness 18.4% Irritability 10.5% Cognitive disorder 10.3% Memory impairment 5.5% Depression 5.1% Confusional state 5.0% Gastrointestinal disorders Nausea/Vomiting 16.5% Diarrhea 13.6% Decreased salivation 10.6% Metabolism and nutrition disorders Weight loss 13.3% Decreased appetite 12.8% Dermatological disorders Sweating 14.4% Cardiovascular disorders Tachycardia 12.2% Special Senses Blurred vision 10.0% n=number of patients. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3)] . Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of alprazolam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Endocrine disorders: Hyperprolactinemia General disorders and administration site conditions: Edema peripheral Hepatobiliary disorders: Hepatitis, hepatic failure Investigations: Liver enzyme elevations Psychiatric disorders: Hypomania, mania Reproductive system and breast disorders: Gynecomastia, galactorrhea Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Use with Opioids: Increase the risk of respiratory depression. ( 7.1 ) Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 ) Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 ) Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.5 , 7.1 ) Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Alprazolam Table 4 includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology ( 12.3 )] . Table 4: Clinically Significant Drug Interactions with Alprazolam Opioids Clinical implication The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid(GABA A ) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Prevention or management Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions ( 5.1 )]. Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. CNS Depressants Clinical implication The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. Prevention or management Limit dosage and duration of alprazolam during concomitant use with CNS depressants [see Warnings and Precautions ( 5.3 )]. Examples Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology ( 12.3 )] . Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications ( 4 ), Warnings and Precautions ( 5.5 )] . Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology ( 12.3 )]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions ( 5.5 )] . Examples Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A Inducers Clinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology ( 12.3 )] . Prevention or management Caution is recommended during coadministration with alprazolam. Examples Carbamazepine, phenytoin Ritonavir Clinical implication Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. Prevention or management Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration ( 2.6 )] . Concomitant use of alprazolam with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4), Warnings and Precautions ( 5.5 )]. Digoxin Clinical implication Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age). Prevention or management In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary. 7.2 Drug/Laboratory Test Interactions Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Alprazolam tablets are indicated for the: acute treatment of generalized anxiety disorder (GAD) in adults. treatment of panic disorder (PD), with or without agoraphobia in adults. Alprazolam tablets are a benzodiazepine indicated for the: Acute treatment of generalized anxiety disorder in adults. ( 1 ) Treatment of panic disorder with or without agoraphobia in adults. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Effects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 ) Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. ( 5.6 ) Neonatal Sedation and Withdrawal Syndrome: Alprazolam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.8 , 8.1 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe alprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions ( 7.1 )] . 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including alprazolam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence ( 9.2 )] . Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration ( 2.3 )] . Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence ( 9.3 )] . Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence ( 9.3 )] . Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)] . Even after relatively short-term use at doses of ≤ 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day. In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal. Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval. 5.4 Effects on Driving and Operating Machinery Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with alprazolam [see Drug Interactions ( 7.1 )] . 5.5 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Strong CYP3A Inhibitors Alprazolam is contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications ( 4 )] . Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. Dosage adjustment is necessary when alprazolam and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam [see Dosage and Administration ( 2.6 ), Drug Interactions ( 7.1 )] . Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction ( 7.1 ), Clinical Pharmacology ( 12.3 )] . Use caution and consider dose reduction of alprazolam, as appropriate, during co-administration with these drugs. 5.6 Patients with Depression Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression. 5.7 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression [see Adverse Reactions (6.2)] . 5.8 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations ( 8.1 )] . Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.9 Risk in Patients with Impaired Respiratory Function There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam."}', 'overdosage': '{"10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions ( 5.2 )] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help Line (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations."}', 'active_flag': 'Y', 'generic_name': '{ALPRAZOLAM}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam tablets are used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )] . Abuse, Misuse, and Addiction Inform patients that the use of alprazolam tablets, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions ( 5.2 ), Drug Abuse and Dependence ( 9.2 )] . Withdrawal Reactions Inform patients that the continued use of alprazolam tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam tablets may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of alprazolam tablets may require a slow taper [see Warnings and Precautions ( 5.3 ), Drug Abuse and Dependence ( 9.3 )] . Effects on Driving and Operating Machinery Advise patients not to drive a motor vehicle or operate heavy machinery while taking alprazolam tablets due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam tablets [see Warnings and Precautions ( 5.3 )] . Patients with Depression Advise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patient’s healthcare provider immediately [see Warnings and Precautions ( 5.6 )] . Concomitant Medications Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions ( 7 )] . Pregnancy Advise pregnant females that use of alprazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.1 )] . Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam tablets during pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise patients that breastfeeding is not recommended during treatment with alprazolam tablets [see Use in Specific Populations ( 8.2 )] . Dispense with Medication Guide available at: www.tevausa.com/medguides Manufactured In India By: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. C 1/2023"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions ( 5.8 ) and Clinical Considerations)] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions ( 5.8 )]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients."}', 'geriatric_use': '{"8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )] ."}'}

{LIDOCAINE,MENTHOL}

{'contraindications': '{"CONTRAINDICATIONS: Lidothol is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product."}', 'adverse_reactions': '{"ADVERSE REACTIONS: The most common adverse reactions occur at the application site, including dermatitis, itching or scaling. These tend to be dose-\xad‐limiting and diminish with time. Serious adverse experiences following the administration of Lidothol are similar in nature to those observed in other amide anesthetic-\xad‐containing agents. These adverse experiences are, in general, dose-\xad‐related and may result from high plasma levels caused by excessive dosage, rapid absorption, or may result from hypersensitivity, idiosyncrasy, or a diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. During or immediately after treatment with Lidothol, the skin at the site of application may develop redness, blisters, bruising, burning sensation, depigmentation, dermatitis, or mild irritation. Allergic Reactions Allergic and anaphylactoid reactions associated with Lidocaine, although rare, can occur. They are characterized by angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria. If they occur, consult your doctor."}', 'drug_interactions': '{"DRUG INTERACTIONS Patients that are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following oxidizing agents Class Nitrates/Nitrites Local Anesthetics Antineoplastic agents Antibiotics Antimalarials Anticonvulsants Other drugs Examples nitroglycerin, nitroprusside, nitric oxide, nitrous oxide benzocaine, lidocaine, bupivacaine, mepivacaine, tetracaine, prilocaine, procaine, articaine, ropivacaine cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea dapsone, sulfonamides, nitrofurantoin, para-aminosalicyclic acid chloroquine, primaquine phenytoin, sodium valproate, phenobarbital acetaminophen, metoclopramide, sulfa drugs (i.e., sulfasalazine), quinine"}', 'indications_and_usage': '{"INDICATIONS AND USAGE: Lidothol is a formulation used to assist patients in the treatment of mild to moderate acute or chronic aches or pain. Muscle or joint pain can be due to muscle or ligament strains, simple backache, tendonitis, osteoarthritis, rheumatoid arthritis, peripheral neuropathies such as diabetic neuropathy or post herpetic neuralgia, and other complex regional pains. It can also be used to help with certain types of headaches, but use with caution when applying in order to avoid eye contact. Other uses may be considered if deemed clinically relevant."}', 'warnings_and_cautions': '{"WARNINGS AND PRECAUTIONS Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Lidothol and any other oxidizing agents. Depending on the severity of the symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen."}', 'overdosage': '{"OVERDOSAGE: There have been no reports of over-\xad‐dosage with Lidothol. Signs of overdosage would include vomiting, drowsiness, coma, respiratory depression, and seizures. In the case of overdosage, discontinue the product immediately, treat the patient symptomatically, and institute supportive measures."}', 'active_flag': 'Y', 'generic_name': '{"LIDOCAINE, MENTHOL"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS: Excessive dosage or short interval between doses can result in high plasma levels and serious adverse effects. Patients should be instructed to strictly adhere to the recommended dosage and administration guidelines set forth in this literature and on your prescription label. The management of serious adverse reactions may require the use of resuscitative equipment, oxygen or other resuscitative drugs. Accidental Exposure in Children Even a used Lidothol patch contains a large amount of Lidocaine. The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used Lidothol patch, although the risk with this formulation has not been evaluated. It is important for patients to store and dispose of Lidothol beyond the reach of children, pets and others. (See HANDLING AND DISPOSAL) Excessive Dosing Excessive dosing by applying Lidothol to larger areas for longer than the recommended wearing time could result in increased absorption of Lidocaine and high blood concentrations, leading to serious adverse effects. Lidocaine toxicity could be expected at Lidocaine blood concentrations above 5 µg/mL. The blood concentration of Lidocaine is determined by the rate of systemic absorption and elimination. Longer duration of application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of Lidocaine. With recommended dosing of Lidothol, the average blood concentration is about 0.13 µg/mL, but concentration higher than 0.25 µg/mL have been observed in some patients."}', 'precautions': '{"PRECAUTIONS: Because of the possibility of sedation, patients should be cautioned regarding the use of heavy machinery or automobiles, also any activities made hazardous by decreased alertness. Hepatic Disease Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of Lidocaine, because of their inability to metabolize Lidocaine normally. Allergic Reactions Patients allergic to para-\xad‐aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to Lidocaine. However, Lidothol should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. Non-\xadintact Skin Application to broken or inflamed skin, although not tested, may result in higher blood concentrations of Lidocaine from increased absorption. Lidothol is only recommended for use on intact skin. Eye Exposure The contact of Lidothol with eyes, although not studied, should be avoided based on the findings of severe eye irritations with the use of similar products in animals. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns. External Heat Sources Placement of external heat sources, such as heating pads or electric blankets, over patches is not recommended as this has not been evaluated and may increase plasma Lidocaine levels. Drug Interactions: Antiarrhythmic Drugs Lidothol should be used with caution in patients receiving Class 1 antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. Local Anesthetics When Lidothol is used concurrently with other products containing local anesthetic agents the amount absorbed from all formulations must be considered. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A minor metabolite, 2,6-\xad‐xylidine, has been found to be carcinogenic in rats. The blood concentration of this metabolite is negligible following application of Lidothol Mutagenesis Lidocaine is not mutagenic in Salmonella/mammalian microsome test nor clastogenic in chromosome aberration assay with human lymphocytes and mouse micronucleus test. Impairment of Fertility The effect of Lidothol on fertility has not been studied. PREGNANCY: The safety of Lidothol has not been established during pregnancy. There are no well-\xad‐controlled studies in pregnant women. Lidothol should not be used during pregnancy unless absolutely needed. Discuss with physician prior to using Lidothol during pregnancy. NURSING MOTHERS: The effect of Lidothol on the nursing infant has not been evaluated. Lidothol has not been studied in nursing mothers. Caution should be exercised when Lidothol is administered to a nursing mother. PEDIATRIC/GERIATRIC USE: Safety and effectiveness in pediatric and geriatric patients have not been established."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses To decrease bacteria on skin that could cause disease Recommended for repeated use"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ETHYL ALCOHOL"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if irritation or redness develops. If condition persists for more than 72 hours consult a doctor."}', 'do_not_use': None, 'when_using': '{"When using this product do not use in or near eyes."}', 'warnings': '{"Warnings FLAMMABLE, keep away from fire or flame For external use only"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ANHYDROUS CITRIC ACID",ASPIRIN,"SODIUM BICARBONATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses for the relief of: heartburn, acid indigestion, and sour stomach when accompanied with headache or body aches and pains upset stomach with headache from overindulgence in food or drink headache, body aches, and pain alone"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ANHYDROUS CITRIC ACID, ASPIRIN, AND SODIUM BICARBONATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs of stomach bleeding feel faint vomit blood have bloody or black stools have stomach pain that does not get better symptoms get worse or last more than 10 days redness or swelling is present ringing in the ears or a loss of hearing occurs new symptoms occur"}', 'do_not_use': '{"Do not use if you are allergic to aspirin or any other pain reliever/fever reducer"}', 'when_using': '{"When using this product do not exceed recommended dosage"}', 'warnings': '{"Warnings Reye\'s syndrome Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye\'s syndrome, a rare but serious illness. Allergy alert Aspirin may cause a severe allergic reaction which may include: hives facial swelling asthma (wheezing) shock Stomach bleeding warning This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Do not use if you are allergic to aspirin or any other pain reliever/fever reducer Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, or kidney disease you are taking a diuretic you have asthma you have a sodium-restricted diet Ask a doctor or pharmacist before use if you are presently taking a prescription drug. Antacids may interact with certain prescription drugs. taking a prescription drug for diabetes, gout, or arthritis When using this product do not exceed recommended dosage Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs of stomach bleeding feel faint vomit blood have bloody or black stools have stomach pain that does not get better symptoms get worse or last more than 10 days redness or swelling is present ringing in the ears or a loss of hearing occurs new symptoms occur If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ZINC OXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses dries the oozing and weeping o poison ivy, poison oak, and poison sumac."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CALAMINE 8% AND ZINC OXIDE 8%"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': '{"When using this product Discontinue use if condition worsens or does not improve within 7 days and consult a doctor."}', 'warnings': '{"Warnings For external use only. Use only as directed. Avoid contact with eyes and mucous membranes. Ask a doctor before using on chilren 6 months of age."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ISOPROPYL ALCOHOL"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses to decrease germs in minor cuts and scrapes helps relieve minor muscular aches due to exertion"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ISOPROPYL ALCOHOL"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if condition persists or gets worse"}', 'do_not_use': '{"When using this product do not get into eyes or mucous membranes use only in a well-ventilated area"}', 'when_using': None, 'warnings': '{"Warnings For external use only flammable, keep away from fire and flame will produce serious gastric disturbances if taken internally"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ZINC OXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"dries the oozing and weeping o poison ivy, poison oak, and poison sumac."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CALAMINE 8% AND ZINC OXIDE 8% LOTION"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"For external use only. Use only as directed. Avoid contact with eyes and mucous membranes. Ask a doctor before using on chilren 2 years of age."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DOCUSATE SODIUM"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses ■ relieves occasional constipation (irregularity) ■ generally produces bowel movement in 12 to 72 hours"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"DOCUSATE SODIUM"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': '{"Stop use and ask a doctor if ■ you have rectal bleeding or fail to have a bowel movement after use of a laxative. These could be signs of a serious condition. ■ you need to use a stool softener laxative for more than 1 week"}', 'when_using': None, 'warnings': '{"Warnings Do not use ■ if you are presently taking mineral oil, unless told to do so by a doctor"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ACYCLOVIR}

{'contraindications': '{"4 CONTRAINDICATIONS Acyclovir Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir, or any component of the formulation. Acyclovir Cream is contraindicated in patients with known hypersensitivity to acyclovir, valacyclovir or any component of the formulation. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The most common adverse reactions reported were local skin reactions at the application site. ( 6.1 ) Angioedema, anaphylaxis, contact dermatitis and eczema have been reported. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in clinical practice. In five double-blind, placebo-controlled trials, 1124 patients were treated with Acyclovir Cream and 1161 with placebo (vehicle) cream. Local application site reactions were reported by 5% of patients receiving Acyclovir Cream and 4% of patients receiving placebo. The most common adverse reactions at the site of topical application were dry lips, desquamation, dryness of skin, cracked lips, burning skin, pruritus, flakiness of skin, and stinging on skin; each adverse reaction occurred in less than 1% of patients receiving Acyclovir Cream and placebo. Three patients on Acyclovir Cream and one patient on placebo discontinued treatment due to an adverse event. An additional study, enrolling 22 healthy adults, was conducted to evaluate the dermal tolerance of Acyclovir Cream compared with vehicle using single occluded and semi-occluded patch testing methodology. Both Acyclovir Cream and placebo showed a high and cumulative irritation potential. Another study, enrolling 251 healthy adults, was conducted to evaluate the contact sensitization potential of Acyclovir Cream using repeat insult patch testing methodology. Of 202 evaluable subjects, possible cutaneous sensitization reactions were observed in the same 4 (2%) subjects with both Acyclovir Cream and placebo, and these reactions to both Acyclovir Cream and placebo were confirmed in 3 subjects upon rechallenge. The sensitizing ingredient(s) has not been identified. The safety profile in patients 12 to 17 years of age was similar to that observed in adults. 6.2 Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during postapproval use of acyclovir cream. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to acyclovir cream. General: Angioedema, anaphylaxis. Skin: Contact dermatitis, eczema."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with Acyclovir Cream. Due to minimal systemic absorption of Acyclovir Cream, systemic drug interactions are unlikely. Clinical experience has identified no interactions resulting from topical or systemic administration of other drugs concomitantly with Acyclovir Cream. Due to minimal systemic absorption of Acyclovir Cream, systemic drug interactions are unlikely. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Acyclovir Cream is a herpes simplex virus (HSV) deoxynucleoside analogue DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents 12 years of age and older. Acyclovir Cream is a herpes simplex virus (HSV) deoxynucleoside analogue DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults and adolescents 12 years of age and older. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Only for topical use of recurrent HSV lesions on the external aspect of lips and the face. Acyclovir Cream should not be applied on mucous membranes including in the eye or inside the mouth or nose. ( 5.1 ) There is a potential for irritation and contact sensitization. ( 5.2 ) 5.1 General Acyclovir Cream should only be applied on the affected external aspects of the lips and face in patients with herpes labialis. Because no data are available, application to human mucous membranes is not recommended. Acyclovir Cream is intended for cutaneous use only and should not be used in the eye or inside the mouth or nose. 5.2 Contact Sensitization Acyclovir Cream has a potential for irritation and contact sensitization [see Adverse Reactions (6.1) ] . The effect of Acyclovir Cream has not been established in immunocompromised patients."}', 'overdosage': '{"10 OVERDOSAGE Overdosage by topical application of Acyclovir Cream is unlikely because of minimal systemic exposure [see Clinical Pharmacology (12.3) ] . There is no information available for overdose."}', 'active_flag': 'Y', 'generic_name': '{ACYCLOVIR}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). General Patients should be informed that Acyclovir Cream is a prescription topical cream for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips. Acyclovir Cream is not a cure for cold sores. Patients should be instructed that Acyclovir Cream is intended for cutaneous use only for herpes labialis of the lips and around the mouth. Patients should be advised that Acyclovir Cream should not be used in the eye, inside the mouth or nose, or on the genitals. Patients should be instructed to avoid applying other topical products to the affected area while using Acyclovir Cream. Do not use if you are allergic to Acyclovir Cream or any of the ingredients in Acyclovir Cream. Before you use Acyclovir Cream, tell your doctor if you are pregnant, planning to become pregnant, or are breast-feeding. Instructions for Use Treatment should be initiated at the earliest sign or symptom of recurrence. Instruct patients to wash hands prior to application and ensure the face and/or lips are clean and dry. Advise patients to apply Acyclovir Cream topically 5 times per day for 4 days. Instruct patients to topically apply a quantity of Acyclovir Cream sufficient to cover the affected area, including the outer margin. Advise patients to avoid unnecessary rubbing of the affected area to avoid aggravating or transferring the infection. Instruct patients to wash their hands with soap and water after using Acyclovir Cream. Keep out of reach of children. Possible Side Effects Common skin-related side effects that occurred when Acyclovir Cream was applied include application site reactions. Acyclovir Cream has the potential for irritation and contact sensitization. Manufactured in Canada by: Bausch Health Companies Inc. Laval, Quebec H7L 4A8, Canada Manufactured for: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Revised February 2021 9673501"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Acyclovir is minimally absorbed systemically following topical route of administration, and maternal use is not expected to result in fetal exposure to the Acyclovir Cream [see Clinical Pharmacology (12.3) ] . Experience with topical acyclovir use in pregnant women over several decades, based on published literature including observational studies, has not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies with systemic exposure of acyclovir have been conducted. Refer to acyclovir prescribing information for additional details. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively."}', 'pediatric_use': '{"8.4 Pediatric Use An open-label, uncontrolled trial with Acyclovir Cream was conducted in 113 patients aged 12 to 17 years with recurrent herpes labialis. In this trial, therapy was applied using the same dosing regimen as in adults and subjects were followed for adverse events. The safety profile was similar to that observed in adults. Safety and effectiveness in pediatric patients less than 12 years of age have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of acyclovir cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Systemic absorption of acyclovir after topical administration is minimal [see Clinical Pharmacology (12.3) ] ."}'}

{OXYGEN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{OXYGEN}', 'route': '{"RESPIRATORY (INHALATION)"}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use Decreases bacteria on hands."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ALCOHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': '{"When using this product keep out of eyes. Stop use and ask a doctor if irritation or redness develops."}', 'warnings': '{"Warnings Flammable: Keep away from flame or high heat.","For external use only."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"PRAMOXINE HYDROCHLORIDE","ZINC OXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Dries the oozing and weeping, and temporarily relieves pain and itching of poison ivy, oak, and sumac or other skin irritations."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ZINC ACETATE AND PRAMOXINE HYDROCHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only. Use only as directed. When using this product. Avoid contact with eyes and moucous membranes. Ask a doctor before using on children 2 years of age."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}