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{"ZINC SULFATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Zinc Sulfate Injection is contraindicated in patients with known hypersensitivity to zinc [see Warnings and Precautions ( 5.6 )] . Known hypersensitivity to zinc. ( 4 , 5.6 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS No zinc-related adverse reactions have been reported in clinical studies or post-marketing reports in patients receiving intravenously administered parenteral nutrition solutions containing zinc sulfate within the recommended dosage range. The following were identified in clinical studies or post-marketing reports. Because some of these reactions were 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 with other components of parenteral nutrition solutions: Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions ( 5.1 )] Vein damage and thrombosis [see Warnings and Precautions ( 5.2 )] Aluminum toxicity [see Warnings and Precautions ( 5.3 )] Adverse reactions with the use of zinc-containing products administered by other routes of administration: Copper deficiency [see Warnings and Precautions ( 5.5 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.6 )] No zinc-related adverse reactions in patients receiving intravenously administered parenteral nutrition solutions containing zinc within the recommended dosage range. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ."}', 'drug_interactions': None, 'indications_and_usage': '{"1 INDICATIONS AND USAGE Zinc Sulfate Injection is indicated in adult and pediatric patients as a source of zinc for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Zinc Sulfate Injection is a trace element indicated in adult and pediatric patients as a source of zinc for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. (1)"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Pulmonary Embolism due to Pulmonary Vascular Precipitates: If signs of pulmonary distress occur, stop the infusion and initiate a medical evaluation. ( 5.1 ) Vein Damage and Thrombosis: Solutions with osmolarity of 900 mOsmol/L or more must be infused through a central catheter. ( 2.1 , 5.2 ) Aluminum Toxicity: Increase risk in patients with renal impairment, including preterm infants ( 5.3 , 8.4 ) Monitoring and Laboratory Tests: Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count and coagulation parameters throughout treatment. ( 5.4 , 2.4 ) Copper Deficiency: If signs and symptoms develop, interrupt treatment with Zinc Sulfate Injection and check zinc, copper, and ceruloplasmin levels. ( 5.5 ) Hypersensitivity Reactions: If reactions occur, discontinue Zinc Sulfate Injection and initiate appropriate medical treatment. ( 5.6 ) 5.1 Pulmonary Embolism due to Pulmonary Vascular Precipitates Pulmonary vascular precipitates causing pulmonary vascular emboli and pulmonary distress have been reported in patients receiving parenteral nutrition. The cause of precipitate formation has not been determined in all cases; however, in some fatal cases, pulmonary emboli occurred as a result of calcium phosphate precipitates. Precipitation has occurred following passage through an in-line filter; in vivo precipitate formation may also have occurred. If signs of pulmonary distress occur, stop the parenteral nutrition infusion and initiate a medical evaluation. In addition to inspection of the solution [see Dosage and Administration ( 2.2 , 2.3 )] , the infusion set and catheter should also periodically be checked for precipitates. 5.2 Vein Damage and Thrombosis Zinc Sulfate Injection has a low pH and must be prepared and used as an admixture in parenteral nutrition solutions. It is not for direct intravenous infusion. In addition, consider the osmolarity of the final parenteral nutrition solution in determining peripheral versus central administration. Solutions with an osmolarity of 900 mOsmol/L or greater must be infused through a central catheter [see Dosage and Administration ( 2.1 )] . The infusion of hypertonic nutrient solutions into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. The primary complication of peripheral access is venous thrombophlebitis, which manifests as pain, erythema, tenderness or a palpable cord. Remove the catheter as soon as possible, if thrombophlebitis develops. 5.3 Aluminum Toxicity Zinc Sulfate Injection contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Preterm infants are particularly at risk for aluminum toxicity because the kidneys are immature, and they require large amounts of calcium and phosphate solutions, which also contain aluminum. Patients with impaired kidney function, including preterm infants, who receive greater than 4 mcg/kg/day to 5 mcg/kg/day of parenteral aluminum can accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration. Exposure to aluminum from Zinc Sulfate Injection is not more than 0.6 mcg/kg/day. When prescribing Zinc Sulfate Injection for use in parenteral nutrition containing other small volume parenteral products, the total daily patient exposure to aluminum from the admixture should be considered and maintained at no more than 5 mcg/kg/day [see Use in Specific Populations ( 8.4 )] . 5.4 Monitoring and Laboratory Tests Monitor zinc concentrations, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count and coagulation parameters throughout treatment [see Dosage and Administration ( 2.4 )] . 5.5 Copper Deficiency Several post-marketing cases have reported that high doses of supplemental zinc (approximately 10 times the recommended dosage of 3 mg/day Zinc Sulfate Injection in adults) taken over extended periods of time (i.e., months to years) may result in decreased enteral copper absorption and copper deficiency. The cases reported the following complications of copper deficiency: anemia, leukopenia, thrombocytopenia, myeloneuropathy, and nephrotic-range proteinuria [see Adverse Reactions ( 6 )] . If a patient develops signs and symptoms of copper deficiency during treatment with Zinc Sulfate Injection, interrupt zinc treatment and check zinc, copper, and ceruloplasmin levels. Copper deficiency should be treated with supplemental copper administration and discontinuation of zinc supplementation. 5.6 Hypersensitivity Reactions Hypersensitivity reactions to subcutaneously administered zinc-containing insulin products were identified in postmarketing case reports. Reported reactions included injection site induration, erythema, pruritus, papular rash, generalized urticaria, facial swelling, and dyspnea. Patients did not manifest symptoms after changing to zinc-free insulin or another insulin product with a reduced amount of zinc. In some cases, allergy testing confirmed the allergy to the zinc component of the insulin product. If hypersensitivity reactions occur, discontinue Zinc Sulfate Injection and initiate appropriate medical treatment [see Contraindications ( 4 )] ."}', 'overdosage': '{"10 OVERDOSAGE There are reported cases of overdosage with intravenous zinc in parenteral nutrition: Seven adult patients received an inadvertent overdosage of 50 mg to 75 mg elemental zinc per day in parenteral nutrition solution for 26 days to 60 days; 6 of the 7 patients developed hyperamylasemia (peak amylase values of 557 Klein units to 1850 Klein units; normal: 130 to 310). Amylase was not reported in one patient. Serum zinc concentrations ranged from 310 mcg/dL to 670 mcg/dL. None of the patients developed clinical signs of pancreatitis. Five of the 7 patients died of septic complications. One adult patient died of infectious complications after receiving an inadvertent overdosage of 7.4 grams of zinc sulfate (equivalent to 1.2 grams of elemental zinc per day for 2.5 days) in parenteral nutrition solution over 60 hours. The serum zinc concentration was 4184 mcg/dL. Symptoms of zinc overdosage also included hyperamylasemia, thrombocytopenia, anemia, vomiting and diarrhea. One preterm infant born at 26 weeks gestation died of cardiac failure following a medication error in which the parenteral nutrition solution contained 330 mg/100 mL instead of 330 mcg/100 mL of zinc sulfate (overdosage of 1000-fold). Management There is no known antidote for acute zinc toxicity. Management of zinc overdosage is supportive care based on presenting signs and symptoms."}', 'active_flag': 'Y', 'generic_name': '{"ZINC SULFATE INJECTION,"}', '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 Inform patients, caregivers or home healthcare providers of the following risks of Zinc Sulfate Injection: Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions ( 5.1 )] Vein damage and thrombosis [see Warnings and Precautions ( 5.2 )] Aluminum toxicity [see Warnings and Precautions ( 5.3 )] Copper deficiency [see Warnings and Precautions ( 5.5 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.6 )] Manufactured by: Zydus Lifesciences Ltd. Vadodara - 391510, India. Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 06/23"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Administration of the approved recommended dose of Zinc Sulfate Injection in parenteral nutrition is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with intravenous zinc sulfate. The estimated background risk of major birth defects and miscarriage for the indicated populations 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 Deficiency of trace elements, including zinc, is associated with adverse pregnancy and fetal outcomes. Pregnant women have an increased metabolic demand for trace elements, including zinc. Parenteral nutrition with zinc should be considered if a pregnant woman\'s nutritional requirements cannot be fulfilled by oral or enteral intake."}', 'pediatric_use': '{"8.4 Pediatric Use Zinc Sulfate Injection is approved for use in the pediatric population, including neonates, as a source of zinc for parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Safety and dosing recommendations in pediatric patients are based on published literature describing controlled studies of zinc-containing products in pediatric patients [see Dosage and Administration ( 2.2 )] . Because of immature renal function, preterm infants receiving prolonged parenteral nutrition treatment with Zinc Sulfate Injection may be at higher risk of aluminum toxicity [see Warnings and Precautions ( 5.3 )] ."}', 'geriatric_use': '{"8.5 Geriatric Use Reported clinical experience with intravenous zinc sulfate has not identified a difference in zinc requirements between elderly and younger patients. In general, dose selection should be individualized based on the patient\'s clinical condition, nutritional requirements, and additional nutritional intake provided orally or enterally to the patient."}'}

{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}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"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."}', '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': '{"When using this product do not exceed recommended dose (see overdose warning )"}', '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 ▪ 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. 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 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 When using this product do not exceed recommended dose (see overdose warning ) 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. 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}

{"DIPHENHYDRAMINE 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: • sneezing • itching of the nose or throat • runny nose • itchy, watery eyes"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"DIPHENHYDRAMINE HCL"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': '{"Do not use • with any other product containing diphenhydramine, even one used on skin • to make a child sleepy"}', 'when_using': '{"When using this product • marked drowsiness may occur • excitability may occur, especially in children • sedatives and tranquilizers may increase drowsiness"}', 'warnings': '{"Warnings Do not use • with any other product containing diphenhydramine, even one used on skin • to make a child sleepy Ask a doctor before use if the child has • a breathing problem such as chronic bronchitis • glaucoma • a sodium-restricted diet Ask a doctor or pharmacist before use if the child is taking sedatives or tranquilizers When using this product • marked drowsiness may occur • excitability may occur, especially in children • sedatives and tranquilizers may increase drowsiness 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}

{"LEVOCETIRIZINE DIHYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"USE(S) temporarily relieves these symptoms due to hay fever or other 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': '{"LEVOCETIRIZINE DIHYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"STOP USE AND ASK A DOCTOR IF • you have trouble urinating or emptying your bladder • an allergic reaction to this product occurs. Seek medical help right away."}', 'do_not_use': '{"DO NOT USE • if you have kidney disease • if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing cetirizine"}', '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': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BENZTROPINE MESYLATE"}

{'contraindications': '{"CONTRAINDICATIONS Hypersensitivity to benztropine mesylate tablets or to any component of the tablets. Because of its atropine-like side effects, this drug is contraindicated in pediatric patients under three years of age, and should be used with caution in older pediatric patients."}', 'adverse_reactions': '{"ADVERSE REACTIONS The adverse reactions below, most of which are antichlolinergic in nature, have been reported and within each category are listed in order of decreasing severity. Cardiovascular Tachycardia. Digestive Paralytic ileus, constipation, vomiting, nausea, dry mouth. If dry mouth is so severe that there is difficulty in swallowing or speaking, or loss of appetite and weight, reduce dosage, or discontinue the drug temporarily. Slight reduction in dosage may control nausea and still give sufficient relief of symptoms. Vomiting may be controlled by temporary discontinuation, followed by resumption at a lower dosage. Nervous System Toxic psychosis, including confusion, disorientation, memory impairment, visual hallucinations; exacerbation of preexisting psychotic symptoms; nervousness; depression; listlessness; numbness of fingers. Special Senses Blurred vision, dilated pupils. Urogenital Urinary retention, dysuria. Metabolic/Immune or Skin Occasionally, an allergic reaction, e.g., skin rash, develops. If this cannot be controlled by dosage reduction, the medication should be discontinued. Other Heat stroke, hyperthermia, fever."}', 'drug_interactions': '{"Drug Interactions Antipsychotic drugs such as phenothiazines or haloperidol; tricyclic antidepressants (see WARNINGS )."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Benztropine mesylate tablets, USP are indicated for use as an adjunct in the therapy of all forms of parkinsonism. Useful also in the control of extrapyramidal disorders (except tardive dyskinesia - see PRECAUTIONS ) due to neuroleptic drugs (e.g., phenothiazines)."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Manifestations - May be any of those seen in atropine poisoning or antihistamine overdosage: CNS depression, preceded or followed by stimulation; confusion; nervousness; listlessness; intensification of mental symptoms or toxic psychosis in patients with mental illness being treated with neuroleptic drugs (e.g., phenothiazines); hallucinations (especially visual); dizziness; muscle weakness; ataxia; dry mouth; mydriasis; blurred vision; palpitations; tachycardia; elevated blood pressure; nausea; vomiting; dysuria; numbness of fingers; dysphagia; allergic reactions, e.g., skin rash; headache; hot, dry, flushed skin; delirium; coma; shock; convulsions; respiratory arrest; anhidrosis; hyperthermia; glaucoma; constipation. Treatment - Physostigmine salicylate, 1 to 2 mg, SC or IV, reportedly will reverse symptoms of anticholinergic intoxication. * A second injection may be given after 2 hours if required. Otherwise treatment is symptomatic and supportive. Induce emesis or perform gastric lavage (contraindicated in precomatose convulsive, or psychotic states). Maintain respiration. A short-acting barbiturate may be used for CNS excitement, but with caution to avoid subsequent depression; supportive care for depression (avoid convulsant stimulants such as picrotoxin, pentylenetetrazol, or bemegride); artificial respiration for severe respiratory depression; a local miotic for mydriasis and cycloplegia; ice bags or other cold applications and alcohol sponges for hyperpyrexia, a vasopressor and fluids for circulatory collapse. Darken room for photophobia."}', 'active_flag': 'Y', 'generic_name': '{"BENZTROPINE MESYLATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Safe use in pregnancy has not been established. Benztropine mesylate may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. When benztropine mesylate is given concomitantly with phenothiazines, haloperidol, or other drugs with anticholinergic or antidopaminergic activity, patients should be advised to report gastrointestinal complaints, fever or heat intolerance promptly. Paralytic ileus, hyperthermia and heat stroke, all of which have sometimes been fatal, have occurred in patients taking anticholinergic-type antiparkinsonism drugs, including benztropine mesylate, in combination with phenothiazines and/or tricyclic antidepressants. Since benztropine mesylate contains structural features of atropine, it may produce anhidrosis. For this reason, it should be administered with caution during hot weather, especially when given concomitantly with other atropine-like drugs to the chronically ill, the alcoholic, those who have central nervous system disease, and those who do manual labor in a hot environment. Anhidrosis may occur more readily when some disturbance of sweating already exists. If there is evidence of anhidrosis, the possibility of hyperthermia should be considered. Dosage should be decreased at the discretion of the physician so that the ability to maintain body heat equilibrium by perspiration is not impaired. Severe anhidrosis and fatal hyperthermia have occurred."}', 'precautions': '{"PRECAUTIONS General Since benztropine mesylate has cumulative action, continued supervision is advisable. Patients with a tendency to tachycardia and patients with prostatic hypertrophy should be observed closely during treatment. Dysuria may occur, but rarely becomes a problem. Urinary retention has been reported with benztropine mesylate. The drug may cause complaints of weakness and inability to move particular muscle groups, especially in large doses. For example, if the neck has been rigid and suddenly relaxes, it may feel weak, causing some concern. In this event, dosage adjustment is required. Mental confusion and excitement may occur with large doses, or in susceptible patients. Visual hallucinations have been reported occasionally. Furthermore, in the treatment of extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), in patients with mental disorders, occasionally there may be intensification of mental symptoms. In such cases, antiparkinsonian drugs can precipitate a toxic psychosis. Patients with mental disorders should be kept under careful observation, especially at the beginning of treatment or if dosage is increased. Tardive dyskinesia may appear in some patients on long-term therapy with phenothiazines and related agents, or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them. Benztropine mesylate is not recommended for use in patients with tardive dyskinesia. The physician should be aware of the possible occurrence of glaucoma. Although the drug does not appear to have any adverse effect on simple glaucoma, it probably should not be used in angle-closure glaucoma."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': '{"Pediatric Use Because of the atropine-like side effects, benztropine mesylate should be used with caution in pediatric patients over three years of age (see CONTRAINDICATIONS )."}', '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}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"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."}', '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 has ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': '{"When using this product do not exceed recommended dose (see overdose warning)"}', '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 • 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. 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 has ever had an allergic reaction to this product or any of its ingredients 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 When using this product do not exceed recommended dose (see overdose warning) 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. 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 even if you do not notice any signs or symptoms."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CALCIUM CHLORIDE","DEXTROSE MONOHYDRATE","POTASSIUM CHLORIDE","SODIUM CHLORIDE","SODIUM LACTATE"}

{'contraindications': '{"CONTRAINDICATIONS Solutions containing potassium chloride are contraindicated in diseases where high potassium levels may be encountered. Solutions containing lactate are NOT FOR USE IN THE TREATMENT OF LACTIC ACIDOSIS."}', 'adverse_reactions': '{"ADVERSE REACTIONS Reactions which may occur because of the solutions or technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary. Nausea, vomiting, abdominal pain and diarrhea have been reported with potassium therapy. The signs and symptoms of potassium intoxication include paresthesias of the extremities, flaccid paralysis, listlessness, mental confusion, weakness and heaviness of the legs, hypotension, cardiac arrhythmias, heart block, electrocardiographic abnormalities such as disappearance of P waves, spreading and slurring of the QRS complex with development of a biphasic curve and cardiac arrest. Potassium-containing solutions are intrinsically irritating to tissues. Therefore, extreme care should be taken to avoid perivascular infiltration. Local tissue necrosis and subsequent sloughing may result if extravasation occurs. Chemical phlebitis and venospasm have also been reported. Should perivascular infiltration occur, I.V. administration at that site should be discontinued at once. Local infiltration of the affected area with procaine hydrochloride, 1%, to which hyaluronidase may be added, will often reduce venospasm and dilute the potassium remaining in the tissues locally. Local application of heat may also be helpful. 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."}', 'drug_interactions': '{"Drug Interactions Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. The presence of calcium limits their compatibility with certain drugs that form precipitates of calcium salts, and also prohibits their simultaneous infusion through the same administration set as blood because of the likelihood of coagulation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS ."}', 'indications_and_usage': '{"INDICATIONS AND USAGE This solution is indicated in patients requiring parenteral administration of potassium chloride and the replacement of extracellular losses of fluids and electrolytes with minimal carbohydrate calories."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE In the event of potassium overdosage, discontinue the infusion immediately and institute intensive corrective therapy to reduce serum potassium levels. See WARNINGS and PRECAUTIONS ."}', 'active_flag': 'Y', 'generic_name': '{"POTASSIUM CHLORIDE, SODIUM CHLORIDE, CALCIUM CHLORIDE, SODIUM LACTATE, AND DEXTROSE MONOHYDRATE"}', 'route': '{INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Solutions containing calcium ions should not be administered simultaneously through the same administration set as blood because of the likelihood of coagulation. Solutions which contain potassium ions should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present. To avoid potassium intoxication, do not infuse these solutions rapidly. In patients with severe renal insufficiency or adrenal insufficiency, administration of potassium chloride may cause potassium intoxication. Solutions containing sodium ions should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of solutions containing sodium or potassium ions may result in sodium or potassium retention. Solutions containing lactate ions should be used with great care in patients with metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care where there is an increased level or an impaired utilization of lactate ions, as in severe hepatic insufficiency. The intravenous administration of this solution can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentration of administered parenteral solutions. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of such solutions."}', 'precautions': '{"PRECAUTIONS Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus. Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotropin. Potassium replacement therapy should be guided primarily by serial electrocardiograms. Plasma potassium levels are not necessarily indicative of tissue potassium levels. High plasma concentrations of potassium may cause death through cardiac depression, arrhythmias or arrest. Potassium-containing solutions should be used with caution in the presence of cardiac disease, particularly in digitalized patients or in the presence of renal disease. Solutions containing lactate ions should be used with caution as excess administration may result in metabolic alkalosis. Care should be exercised to insure that the needle (or catheter) is well within the lumen of the vein and that extravasation does not occur. Do not administer unless solution is clear and container is undamaged. Discard unused portion. Pregnancy. Animal reproduction studies have not been conducted with dextrose, potassium chloride or Lactated Ringer\'s Injection. It is also not known whether dextrose, potassium chloride or Lactated Ringer\'s Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose, potassium chloride or Lactated Ringer\'s Injection should be given to a pregnant woman only if clearly needed. Pediatric Use: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy. Animal reproduction studies have not been conducted with dextrose, potassium chloride or Lactated Ringer\'s Injection. It is also not known whether dextrose, potassium chloride or Lactated Ringer\'s Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Dextrose, potassium chloride or Lactated Ringer\'s Injection should be given to a pregnant woman only if clearly needed."}', 'pediatric_use': '{"Pediatric Use: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. Frequent monitoring of serum glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly neonates and low birth weight infants. In very low birth weight infants, excessive or rapid administration of dextrose injection may result in increased serum osmolality and possible intracerebral hemorrhage."}', 'geriatric_use': None}

{"MICONAZOLE NITRATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses • For the treatment of most athlete’s foot (tinea pedis), jock itch (tinea cruris), ringworm (tinea corporis) • Relieves itching, scaling, burning, discomfort and chafing associated with jock itch or itching, burning feet"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"MICONAZOLE NITRATE"}', '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 children under 2 years of age unless directed by a doctor • for diaper rash When using this product • avoid contact with the eyes Stop use and ask a doctor if • irritation occurs • there is no improvement within 2 weeks when used for the treatment of jock itch • there is no improvement within 4 weeks when used for athlete’s foot or ringworm 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}

{"MENTHOL, UNSPECIFIED FORM"}

{'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 • cramps"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{MENTHOL}', '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 product • use only as directed • do not bandage tightly or use with heating pad • avoid contact with eyes and mucous membranes • do not apply to wounds or damaged, broken or irritated skin • a transient burning sensation or redness may occur upon application but generally disappears in several days • if severe burning sensation occurs, discontinue use immediately • do not expose the area treated with product to heat or direct sunlight Stop use and ask a doctor if • Condition worsens or if symptoms persist for more than 7 days or clear up and occur again within a few days Flammable • keep away from fire or flame 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."}', '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': '{"Use helps eliminate bacteria on hands"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZALKONIUM CHLORIDE LIQUID"}', '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 contact, flush with water."}', 'warnings': '{"Warnings For external use only When using this product, avoid contact with eyes. In case of contact, flush with water. Keep out of reach of children, except under adult supervision. 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}

{BENZOCAINE}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses for the temporary relief of occasional minor irritation and pain, associated with canker sores sore mouth and throat minor injury of the mouth and gums minor dental procedures minor irritation of the mouth and gums caused by dentures or orthodontic appliances"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{BENZOCAINE}', 'route': '{DENTAL,ORAL,PERIODONTAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Do Not Use Do not use • if imprinted seal under cap is broken or missing • for teething • in children under 2 years of age"}', 'do_not_use': None, 'when_using': '{"When using this product When using this product avoid contact with eyes"}', 'warnings': '{"Warnings 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 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 if you have a history of allergy to local anesthetics such as procaine, butacaine, benzocaine or other \\"caine\\" anesthetics. 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. If sore mouth symptoms do not improve in 7 days, or irritation, pain, or redness persists or worsens, see your dentist or doctor promptly."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ADAPALENE}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use For the treatment of acne"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ADAPALENE}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask doctor if you become pregnant, or are planning to become pregnant, while using the product you have symptoms of an allergic reaction (such as itching, rash, hives, swelling of the lips, eyelids, and shortness of breath) irritation becomes severe you see no improvement after 3 months of once daily use Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away."}', 'do_not_use': '{"Do not use on damaged skin (cuts, abrasions, eczema, sunburn) if you are allergic to adapalene or any of the ingredients in this product. If pregnant or breast-feeding, ask a doctor before use."}', 'when_using': '{"When using this product limit sun exposure, including light from tanning beds, and use sunscreen when going outdoors do not wax to remove hair in areas where the product has been applied during the early weeks of use, your acne may appear to worsen before it improves (this is normal); continue using as directed, unless you get irritation that becomes severe irritation (redness, itching, dryness, burning) is more likely to occur: in the first few weeks of use if using more than one topical acne medication at a time but irritation usually lessens with continued use of this product it may take up to 3 months of once daily use to see results avoid product contact with eyes, lips, and mouth. If contact occurs, immediately flush the area with water. wash hands after use"}', 'warnings': '{"Warnings For external use only"}', 'precautions': None, 'information_for_patients': '{"Patient Leaflet DIFFERIN GEL ADAPALENE GEL 0.1% ACNE TREATMENT Frequently Asked Questions What is Differin Gel and what is it used for? • Differin Gel is a topical retinoid medication used for the treatment of acne in people 12 years and older. • Use only one time a day. What should I know before using the product? • If pregnant or breast-feeding , ask a doctor before use. • Some other retinoid drugs have been shown to cause birth defects. There is no specific evidence that Differin Gel 0.1% causes birth defects in humans when used topically as directed. • Do not use Differin Gel if you are allergic to adapalene or any of the ingredients in this product. • Keep out of reach of children . If swallowed, get medical help or contact a Poison Control Center right away. How often do I apply the product? • Apply this product only one time a day and try to apply the product at the same time each day. How do I apply the product? • Gently clean the affected areas using a mild (non-irritating) cleanser and pat dry. • Apply Differin Gel as a thin layer to the affected areas of the skin only one time a day . For example, if you get acne on the face, clean, dry and apply the product to the entire face. Differin Gel is not a spot treatment and should not be used to treat a single pimple. • Avoid product contact with eyes, lips and mouth. If contact occurs, immediately flush the area with water . • Do not apply product to damaged skin (cuts, abrasions, eczema, or sunburn). • Wash hands after use. How long will it take for Differin Gel to work? • It may take up to 3 months of daily use for results to appear. • Do not use more than one time a day. Applying more than directed will not provide faster or better results, but may worsen skin irritation. DIFFERIN GEL ADAPALENE GEL 0.1% ACNE TREATMENT Frequently Asked Questions (Continued) What do I do if I need to be in the sun? • When possible, limit sun exposure, including light from tanning beds. • When going outdoors, use a sunscreen as labeled. Your skin may be more sensitive when using Differin Gel. If you use this product during the day, allow it to dry before applying sunscreen. Can I use a moisturizer if my skin is dry? •Yes, use of a moisturizer may help decrease dryness and other signs of irritation. Avoid products containing alpha hydroxyl or glycolic acids which may worsen irritation. When is my skin most likely to become irritated? And what do I do? • Irritation (redness, itching, dryness, burning) is more likely to occur: • In the first weeks of use. • If using abrasive skin cleansers, products with drying effects or more than one topical acne medication at a time. You may want to delay starting Differin Gel until any irritation from using the other product(s) has gone away. • Moisturizers may be used. • Irritation usually lessens after 4 weeks of continued use. What do I do if my skin becomes severely irritated? • If irritation becomes severe (overly bothersome), stop use and ask a doctor before using the product again. Can I remove unwanted facial hair by waxing while using this product? • Do not use wax to remove hair in areas where the product has been applied because it may worsen skin irritation. What ingredients are used in Differin? • Differin Gel contains: The active ingredient is adapalene 0.1%. The other ingredients are: carbomer 940, edetate disodium, methylparaben, poloxamer 182, propylene glycol, purified water, and sodium hydroxide. May contain hydrochloric acid to adjust pH. How should I store this product? • Differin Gel should be stored at room temperature [68° - 77°]. Protect from freezing. • Do not use the product after the expiry date marked on the packaging. Other Questions? Where can I get information? Phone: 1-866-735-4137 P56836-0"}', 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"SALICYLIC ACID"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses For the relief of symptoms associated with seborrheic dermatitis, dandruff, and/or psoriasis, including: itching scaling flaking redness irritation of the skin. Helps prevent recurrence."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"SALICYLIC ACID"}', '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 the eyes. If contact occurs, rinse eyes thoroughly with water. If condition worsens or does not improve after regular use of this product as directed, consult a doctor. If condition covers a large area of the body, consult your doctor before using this product. If this product causes increased irritation, discontinue use and seek medical advice. Keep out of reach of children. If swallowed get medical help or call a poison control center immediately."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CHLORPROMAZINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CHLORPROMAZINE HYDROCHLORIDE"}', 'route': '{INTRAMUSCULAR}', '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}

{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}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"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."}', '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 has ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': '{"When using this product do not exceed recommended dose (see overdose warning)"}', '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 • 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. 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 has ever had an allergic reaction to this product or any of its ingredients 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 When using this product do not exceed recommended dose (see overdose warning) 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. 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 even if you do not notice any signs or symptoms."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{OMEPRAZOLE}

{'contraindications': '{"4 CONTRAINDICATIONS Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity reactions including anaphylaxis to the formulation or any substituted benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6 )]. Proton pump inhibitors (PPIs), including omeprazole, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions ( 7 )]. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with omeprazole, refer to the CONTRAINDICATIONS section of their package inserts. Patients with known hypersensitivity to substituted benzimidazoles or any component of the formulation. ( 4 ) Patients receiving rilpivirine-containing products. ( 4 , 7 ) Refer to the Contraindications section of the prescribing information for clarithromycin and amoxicillin, when administered in combination with omeprazole. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Adults: Most common adverse reactions in adults (incidence ≥2%) are Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. ( 6 ) Pediatric patients (1 to 16 years of age): Safety profile similar to that in adults, except that respiratory system events and fever were the most frequently reported reactions in pediatric studies. ( 8.4 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 )] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.6 )] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions ( 5.8 )] Hypomagnesemia [see Warnings and Precautions ( 5.9 )] Fundic Gland Polyps [see Warnings and Precautions ( 5.13 )] 6.1 Clinical Trials Experience with Omeprazole Monotherapy Monotherapy 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 safety data described below reflects exposure to omeprazole delayed-release capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥2%) from omeprazole-treated patients enrolled in these studies included headache (7%), abdominal pain (5%), nausea (4%), diarrhea (4%), vomiting (3%), and flatulence (3%). Additional adverse reactions that were reported with an incidence ≥1% included acid regurgitation (2%), upper respiratory infection (2%), constipation (2%), dizziness (2%), rash (2%), asthenia (1%), back pain (1%), and cough (1%). The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less. The clinical trial safety profile in pediatric patients who received omeprazole delayed-release capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were frequently reported in the 1 month to <1-year age group, the 1 to <2-year age group, and the 2 to 16-year age group (42%, 75%, and 19%, respectively). In addition, otitis media was frequently reported in the 1 month to <1 year age group (22%), fever was frequently reported in the 1 to <2 year age group (33%), and accidental injuries were frequently reported in the 2 to 16 year age group (4%) [see Use in Specific Populations (8.4) ]. 6.2 Clinical Trials Experience with Omeprazole in Combination Therapy for H. pylori Eradication In clinical trials using either dual therapy with omeprazole and clarithromycin, or triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. Dual Therapy (omeprazole/clarithromycin) Adverse reactions observed in controlled clinical trials using combination therapy with omeprazole and clarithromycin (n = 346) that differed from those previously described for omeprazole alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). (For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse Reactions section.) Triple Therapy (omeprazole/clarithromycin/amoxicillin) The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. (For more information on clarithromycin or amoxicillin, refer to the respective prescribing information, Adverse Reactions sections.) 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of omeprazole delayed-release capsules. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Body As a Whole Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise; systemic lupus erythematosus Cardiovascular Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine Gynecomastia Gastrointestinal Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hepatic Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin] Infections and Infestations Clostridium difficile- associated diarrhea Metabolism and Nutritional disorders Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Musculoskeletal Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Nervous System/Psychiatric Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Respiratory Epistaxis, pharyngeal pain Skin Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Special Senses Tinnitus, taste perversion Ocular Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain, erectile dysfunction Hematologic Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with omeprazole 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 Co-Administered with Omeprazole and Interaction 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 omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3 )] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology ( 12.3 )] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Intervention: Rilpivirine-containing products : Concomitant use with omeprazole is contraindicated [see Contraindications ( 4 )] . Atazanavir : Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals : See prescribing information for specific antiretroviral drugs. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. Methotrexate Clinical Impact: Concomitant use of omeprazole 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 ( 5.12 )] . Intervention: A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3 )] . There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. Intervention: Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.7 )] . Citalopram Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3 )] . Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. Cilostazol Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3 )] . Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Phenytoin Clinical Impact: Potential for increased exposure of phenytoin. Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed. Digoxin Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole 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 omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3 )] . See the prescribing information for other drugs dependent on gastric pH for absorption. Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. Intervention: See Contraindications , Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. Tacrolimus Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (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 ( 5.11 ), Clinical Pharmacology ( 12.2 )] . Intervention: Temporarily stop omeprazole 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 omeprazole treatment at least 14 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. Other Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3 )] . Intervention: St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.10 )] . Ritonavir-containing products: see prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3 )] . Intervention: Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. See full prescribing information for a list of clinically important drug interactions. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Omeprazole is a proton pump inhibitor (PPI) indicated for the: Treatment of active duodenal ulcer in adults ( 1.1 ) Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence in adults ( 1.2 ) Treatment of active benign gastric ulcer in adults ( 1.3 ) Treatment of symptomatic gastroesophageal reflux disease (GERD) in patients 1 year of age and older ( 1.4 ) Treatment of erosive esophagitis (EE) due to acid-mediated GERD in patients 1 month of age and older ( 1.5 ) Maintenance of healing of EE due to acid-mediated GERD in patients 1 year of age and older ( 1.6 ) Pathologic hypersecretory conditions in adults ( 1.7 ) 1.1 Treatment of Active Duodenal Ulcer Omeprazole delayed-release capsules are indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. 1.2 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. Triple Therapy Omeprazole delayed-release capsules in combination with clarithromycin and amoxicillin, are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year history) to eradicate H. pylori in adults. Dual Therapy Omeprazole delayed-release capsules in combination with clarithromycin are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori in adults. Among patients who fail therapy, omeprazole delayed-release capsules with clarithromycin are more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see Clinical Pharmacology ( 12.4 ) and the clarithromycin prescribing information, Microbiology section ] . 1.3 Treatment of Active Benign Gastric Ulcer Omeprazole delayed-release capsules are indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults. 1.4 Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) Omeprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms associated with GERD for up to 4 weeks in patients 1 year of age and older. 1.5 Treatment of Erosive Esophagitis (EE) Due to Acid-Mediated GERD Pediatric Patients 1 Year of Age to Adults Omeprazole delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) of EE due to acid-mediated GERD that has been diagnosed by endoscopy in patients 1 year of age and older. The efficacy of omeprazole delayed-release capsules used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8-week courses of omeprazole may be considered. Pediatric Patients 1 Month to Less than 1 Year of Age Omeprazole is indicated for the short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age. 1.6 Maintenance of Healing of EE Due to Acid-Mediated GERD Omeprazole delayed-release capsules are indicated for the maintenance healing of EE due to acid-mediated GERD in patients 1 year of age and older. Controlled studies do not extend beyond 12 months. 1.7 Pathological Hypersecretory Conditions Omeprazole delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response 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 omeprazole and refer to specialist for evaluation. ( 5.6 ) Interaction with Clopidogrel : Avoid concomitant use of omeprazole. ( 5.7 , 7 ) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.8 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.9 ) Interaction with St. John’s Wort or Rifampin : Avoid concomitant use of omeprazole. ( 5.10 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop omeprazole at least 14 days before assessing CgA levels. ( 5.11 , 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 omeprazole. ( 5.12 , 7 ) Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.13 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with omeprazole 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 decrease 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 omeprazole delayed-release capsules and evaluate patients with suspected acute TIN [see Contraindications ( 4 )]. 5.3 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like omeprazole 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. Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with omeprazole, refer to Warnings and Precautions sections of the corresponding prescribing information. 5.4 Bone Fracture Several published observational studies suggest that proton pump inhibitor (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 condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration ( 2.1 ), Adverse Reactions (6.3) ]. 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 omeprazole 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, including omeprazole. 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 non-drug 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 omeprazole, 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 Interaction with Clopidogrel Avoid concomitant use of omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole, consider alternative anti-platelet therapy [ see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 ) ]. 5.8 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) 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 omeprazole. 5.9 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 omeprazole 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. 5.10 Interaction with St. John\'s Wort or Rifampin Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease omeprazole concentrations [see Drug Interactions ( 7 )] . Avoid concomitant use of omeprazole with St. John’s Wort or rifampin. 5.11 Interactions with Diagnostic 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 omeprazole 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 )] . 5.12 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 )] . 5.13 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."}', 'overdosage': '{"10 OVERDOSAGE Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience [see Adverse Reactions (6) ] . Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, 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 overdosage."}', 'active_flag': 'Y', 'generic_name': '{OMEPRAZOLE}', '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 )] . Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.6 )] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions ( 5.8 )] . Hypomagnesemia [see Warnings and Precautions ( 5.9 )] . Drug Interactions Advise patients to report to their healthcare provider if they start treatment with clopidogrel, St. John’s Wort or rifampin; or, if they take high-dose methotrexate [see Warnings and Precautions ( 5.7 , 5.10 , 5.12 )] . Administration Take omeprazole before meals. Antacids may be used concomitantly with omeprazole. 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. Omeprazole Delayed-Release Capsules Swallow omeprazole delayed-release capsules whole; do not chew. For patients unable to swallow an intact capsule, omeprazole delayed-release capsules can be opened and administered in applesauce, as described in the Medication Guide. Dispense with Medication Guide available at www1.apotex.com/products/us APOTEX INC. OMEPRAZOLE DELAYED-RELEASE CAPSULES, USP 10 mg, 20 mg and 40 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 USA 33326 Revision: 30"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person). Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg esomeprazole or 40 mg omeprazole (based on body surface area for a 60 kg person). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data] . The estimated background risks of major birth defects and miscarriage for the indicated population are 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 Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 -receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H 2 -blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H 2 -blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non\xad-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Omeprazole Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times an oral human doses of 40 mg on a body surface area basis), administered prior to mating through the lactation period. Esomeprazole The data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of omeprazole have been established in pediatric patients 1 to 16 years for the treatment of symptomatic GERD, treatment of EE due to acid-mediated GERD, and maintenance of healing of EE due to acid- mediated GERD. Use of omeprazole in this age group is supported by adequate and well-controlled studies in adults and uncontrolled safety, efficacy and pharmacokinetic studies performed in pediatric and adolescent patients [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.8 )] . The safety and effectiveness of omeprazole have been established in pediatric patients 1 month to less than 1 year of age for the treatment of EE due to acid-mediated GERD and is supported by adequate and well-controlled studies in adults and safety, pharmacokinetic, and pharmacodynamic studies performed in pediatric patients [see Clinical Pharmacology ( 12.3 )] . In the pediatric population, adverse reactions of the respiratory system were frequently reported in the entire (1 month to 16 year) age group. Otitis media was frequently reported in the 1 month to <1 year age group, fever was frequently reported in the 1 to < 2 year age group, and accidental injuries were frequently reported in the 2 to 16 year age group [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of omeprazole have not been established in: patients less than 1 year of age for: Treatment of symptomatic GERD Maintenance of healing of EE due to acid-mediated GERD pediatric patients for: Treatment of active duodenal ulcer H. pylori eradication to reduce the risk of duodenal ulcer recurrence Treatment of active benign gastric ulcer Pathological hypersecretory conditions patients less than 1 month of age for any indication. Juvenile Animal Data Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazole based on body surface area in a juvenile rat toxicity study. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole."}', 'geriatric_use': '{"8.5 Geriatric Use Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly [ see Clinical Pharmacology (12.3) ]."}'}

{"DOXYCYCLINE HYCLATE"}

{'contraindications': '{"CONTRAINDICATIONS This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines."}', 'adverse_reactions': '{"ADVERSE REACTIONS Due to oral doxycycline\'s virtually complete absorption, side effects of the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development. (See WARNINGS .) Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION .) Skin: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, skin hyperpigmentation, maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS .) Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS .) Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), and Jarisch-Herxheimer reaction has been reported in the setting of spirochete infections treated with doxycycline. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Other: Bulging fontanels in infants and intracranial hypertension in adults. (See WARNINGS .) When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur."}', 'drug_interactions': '{"Drug Interactions Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective."}', 'indications_and_usage': '{"INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible 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. Treatment: Doxycycline is indicated for the treatment of the following infections: • Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. • Respiratory tract infections caused by Mycoplasma pneumoniae . • Lymphogranuloma venereum caused by Chlamydia trachomatis . • Psittacosis (ornithosis) caused by Chlamydophila psittaci . • Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated, as judged by immunofluorescence. • Inclusion conjunctivitis caused by Chlamydia trachomatis . • Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis . • Nongonococcal urethritis caused by Ureaplasma urealyticum . • Relapsing fever due to Borrelia recurrentis . Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms: • Chancroid caused by Haemophilus ducreyi . • Plague due to Yersinia pestis . • Tularemia due to Francisella tularensis . • Cholera caused by Vibrio cholerae . • Campylobacter fetus infections caused by Campylobacter fetus . • Brucellosis due to Brucella species (in conjunction with streptomycin). • Bartonellosis due to Bartonella bacilliformis . • Granuloma inguinale caused by Klebsiella granulomatis . Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative bacteria, when bacteriologic testing indicates appropriate susceptibility to the drug: • Escherichia coli. • Enterobacter aerogenes . • Shigella species. • Acinetobacter species. • Respiratory tract infections caused by Haemophilus influenzae . • Respiratory tract and urinary tract infections caused by Klebsiella species. Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: • Upper respiratory infections caused by Streptococcus pneumoniae . • Anthrax due to Bacillus anthracis , including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis . When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: • Uncomplicated gonorrhea caused by Neisseria gonorrhoeae . • Syphilis caused by Treponema pallidum . • Yaws caused by Treponema pallidum subspecies pertenue . • Listeriosis due to Listeria monocytogenes . • Vincent\'s infection caused by Fusobacterium fusiforme . • Actinomycosis caused by Actinomyces israelii . • Infections caused by Clostridium species. In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. Prophylaxis: Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (<4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. (See DOSAGE AND ADMINISTRATION section and Information for Patients subsection of the PRECAUTIONS section.)"}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage."}', 'active_flag': 'Y', 'generic_name': '{"DOXYCYCLINE HYCLATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline hyclate, 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 the use of antibacterial drugs. 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 use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. (See ADVERSE REACTIONS .) If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted. Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline hyclate. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline hyclate should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema."}', 'precautions': '{"PRECAUTIONS General As with other antibacterial drugs, use of doxycycline hyclate may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, doxycycline hyclate should be discontinued and appropriate therapy instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy, when indicated. Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum \'s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. Prescribing doxycycline hyclate in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information For Patients Patients taking doxycycline for malaria prophylaxis should be advised: • that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. • to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). • that doxycycline prophylaxis: • should begin 1-2 days before travel to the malarious area, • should be continued daily while in the malarious area and after leaving the malarious area, • should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, • should not exceed 4 months. All patients taking doxycycline should be advised: • to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS .) • to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .) • that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See DRUG INTERACTIONS .) • that the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See DRUG INTERACTIONS .) • that the use of doxycycline might increase the incidence of vaginal candidiasis. Patients should be counseled that antibacterial drugs, including doxycycline hyclate should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline hyclate is prescribed to treat a bacterial infection, patients should be told 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 doxycycline hyclate or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible. Laboratory Tests In venereal disease, when co-existent syphilis is suspected, dark field examinations should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies, should be performed. Drug Interactions Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective. Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterial drugs (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied. Pregnancy: Teratogenic Effects. There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women, such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and fifty-six (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 Nonteratogenic Effects: (See WARNINGS .) Labor and Delivery The effect of tetracyclines on labor and delivery is unknown. Nursing Mothers Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown. 4 Because of the potential for serious adverse reactions in nursing infants from doxycycline, 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. (See WARNINGS .) Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. (See WARNINGS and DOSAGE AND ADMINISTRATION .)"}', 'information_for_patients': '{"Information For Patients Patients taking doxycycline for malaria prophylaxis should be advised: • that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. • to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). • that doxycycline prophylaxis: • should begin 1-2 days before travel to the malarious area, • should be continued daily while in the malarious area and after leaving the malarious area, • should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, • should not exceed 4 months. All patients taking doxycycline should be advised: • to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS .) • to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .) • that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See DRUG INTERACTIONS .) • that the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See DRUG INTERACTIONS .) • that the use of doxycycline might increase the incidence of vaginal candidiasis. Patients should be counseled that antibacterial drugs, including doxycycline hyclate should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline hyclate is prescribed to treat a bacterial infection, patients should be told 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 doxycycline hyclate or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible."}', 'pregnancy': '{"Pregnancy: Teratogenic Effects. There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women, such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and fifty-six (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 Nonteratogenic Effects: (See WARNINGS .)"}', 'pediatric_use': '{"Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. (See WARNINGS and DOSAGE AND ADMINISTRATION .)"}', 'geriatric_use': None}

{"BACITRACIN ZINC","NEOMYCIN SULFATE","POLYMYXIN B SULFATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses first aid to help prevent infection in minor: cuts scrapes burns"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BACITRACIN ZINC, NEOMYCIN SULFATE, AND POLYMYXIN B SULFATE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if you need to use longer than 1 week condition persists or gets worse rash or other allergic reaction develops"}', 'do_not_use': '{"Do not use if you are allergic to any of the ingredients in the eyes over large areas of the body"}', 'when_using': None, 'warnings': '{"Warnings For external use only. Do not use if you are allergic to any of the ingredients in the eyes over large areas of the body Ask a doctor before use if you have deep or puncture wounds animal bites serious burns Stop use and ask a doctor if you need to use longer than 1 week condition persists or gets worse rash or other allergic reaction develops 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}

{BORTEZOMIB}

{'contraindications': '{"4 CONTRAINDICATIONS Bortezomib is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions (6.1) ] . Bortezomib is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 ) Contraindicated for intrathecal administration. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: Peripheral Neuropathy [see Warnings and Precautions (5.1) ] Hypotension [see Warnings and Precautions (5.2) ] Cardiac Toxicity [see Warnings and Precautions (5.3) ] Pulmonary Toxicity [see Warnings and Precautions (5.4) ] Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.5) ] Gastrointestinal Toxicity [see Warnings and Precautions (5.6) ] Thrombocytopenia/Neutropenia [see Warnings and Precautions (5.7) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.8) ] Hepatic Toxicity [see Warnings and Precautions (5.9) ] Thrombotic Microangiopathy [see Warnings and Precautions (5.10) ] Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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. Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma Table 9 describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m 2 ) administered intravenously in combination with melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) in a prospective randomized study. The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone. Table 9: Most Commonly Reported Adverse Reactions (≥10% in the Bortezomib, Melphalan and Prednisone Arm) with Grades 3 and ≥4 Intensity in the Previously Untreated Multiple Myeloma Study * Represents High Level Term Peripheral Neuropathies NEC Bortezomib, Melphalan and Prednisone Melphalan and Prednisone (n=340) (n=337) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 ≥4 n (%) 3 ≥4 Blood and Lymphatic System Disorders Thrombocytopenia 164 (48) 60 (18) 57 (17) 140 (42) 48 (14) 39 (12) Neutropenia 160 (47) 101 (30) 33 (10) 143 (42) 77 (23) 42 (12) Anemia 109 (32) 41 (12) 4 (1) 156 (46) 61 (18) 18 (5) Leukopenia 108 (32) 64 (19) 8 (2) 93 (28) 53 (16) 11 (3) Lymphopenia 78 (23) 46 (14) 17 (5) 51 (15) 26 (8) 7 (2) Gastrointestinal Disorders Nausea 134 (39) 10 (3) 0 70 (21) 1 (<1) 0 Diarrhea 119 (35) 19 (6) 2 (1) 20 (6) 1 (<1) 0 Vomiting 87 (26) 13 (4) 0 41 (12) 2 (1) 0 Constipation 77 (23) 2 (1) 0 14 (4) 0 0 Abdominal pain upper 34 (10) 1 (<1) 0 20 (6) 0 0 Nervous System Disorders Peripheral neuropathy* 156 (46) 42 (12) 2 (1) 4 (1) 0 0 Neuralgia 117 (34) 27 (8) 2 (1) 1 (<1) 0 0 Paresthesia 42 (12) 6 (2) 0 4 (1) 0 0 General Disorders and Administration Site Conditions Fatigue 85 (25) 19 (6) 2 (1) 48 (14) 4 (1) 0 Asthenia 54 (16) 18 (5) 0 23 (7) 3 (1) 0 Pyrexia 53 (16) 4 (1) 0 19 (6) 1 (<1) 1 (<1) Infections and Infestations Herpes Zoster 39 (11) 11 (3) 0 9 (3) 4 (1) 0 Metabolism and Nutrition Disorders Anorexia 64 (19) 6 (2) 0 19 (6) 0 0 Skin and Subcutaneous Tissue Disorders Rash 38 (11) 2 (1) 0 7 (2) 0 0 Psychiatric Disorders Insomnia 35 (10) 1 (<1) 0 21 (6) 0 0 Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone The safety data described below and in Table 10 reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m 2 twice weekly for two out of three weeks (21 day cycle). After eight, 21 day cycles patients continued therapy for three, 35 day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients <65 and ≥65 years of age. Most patients were Caucasian [see Clinical Studies (14.1) ] . Among the 331 bortezomib-treated patients, the most commonly reported (>20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (>20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each). A total of 145 patients, including 84 (25%) of 331 patients in the bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 bortezomib-treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each). Four deaths were considered to be bortezomib-related in this relapsed multiple myeloma study: one case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: two cases of sepsis, one case of bacterial meningitis, and one case of sudden death at home. Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥10% in the bortezomib arm are included. Table 10: Most Commonly Reported Adverse Reactions (≥10% in Bortezomib Arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone (N=663) * Represents High Level Term Peripheral Neuropathies NEC Bortezomib N=331 Dexamethasone N=332 Adverse Reactions All Grade 3 Grade 4 All Grade 3 Grade 4 Any Adverse Reactions 324 (98) 193 (58) 28 (8) 297 (89) 110 (33) 29 (9) Nausea 172 (52) 8 (2) 0 31 (9) 0 0 Diarrhea NOS 171 (52) 22 (7) 0 36 (11) 2 (<1) 0 Fatigue 130 (39) 15 (5) 0 82 (25) 8 (2) 0 Peripheral neuropathies* 115 (35) 23 (7) 2 (<1) 14 (4) 0 1 (<1) Thrombocytopenia 109 (33) 80 (24) 12 (4) 11 (3) 5 (2) 1 (<1) Constipation 99 (30) 6 (2) 0 27 (8) 1 (<1) 0 Vomiting NOS 96 (29) 8 (2) 0 10 (3) 1 (<1) 0 Anorexia 68 (21) 8 (2) 0 8 (2) 1 (<1) 0 Pyrexia 66 (20) 2 (<1) 0 21 (6) 3 (<1) 1 (<1) Paresthesia 64 (19) 5 (2) 0 24 (7) 0 0 Anemia NOS 63 (19) 20 (6) 1 (<1) 21 (6) 8 (2) 0 Headache NOS 62 (19) 3 (<1) 0 23 (7) 1 (<1) 0 Neutropenia 58 (18) 37 (11) 8 (2) 1 (<1) 1 (<1) 0 Rash NOS 43 (13) 3 (<1) 0 7 (2) 0 0 Appetite decreased NOS 36 (11) 0 0 12 (4) 0 0 Dyspnea NOS 35 (11) 11 (3) 1 (<1) 37 (11) 7 (2) 1 (<1) Abdominal pain NOS 35 (11) 5 (2) 0 7 (2) 0 0 Weakness 34 (10) 10 (3) 0 28 (8) 8 (2) 0 Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study [see Clinical Studies (14.1) ] . Safety Experience from the Phase 3 Open-Label Study of Bortezomib Subcutaneous vs Intravenous in Relapsed Multiple Myeloma The safety and efficacy of bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m 2 . This was a randomized, comparative study of bortezomib subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 11 reflect exposure to either bortezomib subcutaneous (N=147) or bortezomib intravenous (N=74) [see Clinical Studies (14.1) ] . Table 11: Most Commonly Reported Adverse Reactions (≥10%), with Grade 3 and ≥4 Intensity in the Relapsed Multiple Myeloma Study (N=221) of Bortezomib Subcutaneous vs Intravenous Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least one dose of study medication * Represents High Level Term Peripheral Neuropathies NEC Subcutaneous Intravenous (N=147) (N=74) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 ≥4 n (%) 3 ≥4 Blood and Lymphatic System Disorders Anemia 28 (19) 8 (5) 0 17 (23) 3 (4) 0 Leukopenia 26 (18) 8 (5) 0 15 (20) 4 (5) 1 (1) Neutropenia 34 (23) 15 (10) 4 (3) 20 (27) 10 (14) 3 (4) Thrombocytopenia 44 (30) 7 (5) 5 (3) 25 (34) 7 (9) 5 (7) Gastrointestinal Disorders Diarrhea 28 (19) 1 (1) 0 21 (28) 3 (4) 0 Nausea 24 (16) 0 0 10 (14) 0 0 Vomiting 13 (9) 3 (2) 0 8 (11) 0 0 General Disorders and Administration Site Conditions Asthenia 10 (7) 1 (1) 0 12 (16) 4 (5) 0 Fatigue 11 (7) 3 (2) 0 11 (15) 3 (4) 0 Pyrexia 18 (12) 0 0 6 (8) 0 0 Nervous System Disorders Neuralgia 34 (23) 5 (3) 0 17 (23) 7 (9) 0 Peripheral neuropathies* 55 (37) 8 (5) 1 (1) 37 (50) 10 (14) 1 (1) In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥3 adverse reactions. Differences of ≥5% were reported in neuralgia (3% subcutaneous vs 9% intravenous), peripheral neuropathies (6% subcutaneous vs 15% intravenous), neutropenia (13% subcutaneous vs 18% intravenous), and thrombocytopenia (8% subcutaneous vs 16% intravenous). A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only two (1%) patients were reported as having severe reactions, one case of pruritus and one case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of six days. Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group). Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib Subcutaneous vs Intravenous The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each). In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group . Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%). Two patients (1%) in the subcutaneous treatment group and one (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency. Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma Table 12 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received bortezomib (1.3 mg/m 2 ) administered intravenously in combination with rituximab (375 mg/m 2 ), cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and prednisone (100 mg/m 2 ) (VcR-CAP) in a prospective randomized study. Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% vs R-CHOP 5%). Table 12: Most Commonly Reported Adverse Reactions (≥5%) with Grades 3 and ≥4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = Bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. * Represents High Level Term Peripheral Neuropathies NEC VcR-CAP (n=240) R-CHOP (n=242) Body System Adverse Reactions All n (%) Toxicity Grade 3 n (%) Toxicity Grade ≥4 n (%) All n (%) Toxicity Grade 3 n (%) Toxicity Grade ≥4 n (%) Blood and Lymphatic System Disorders Neutropenia 209 (87) 32 (13) 168 (70) 172 (71) 31 (13) 125 (52) Leukopenia 116 (48) 34 (14) 69 (29) 87 (36) 39 (16) 27 (11) Anemia 106 (44) 27 (11) 4 (2) 71 (29) 23 (10) 4 (2) Thrombocytopenia 172 (72) 59 (25) 76 (32) 42 (17) 9 (4) 3 (1) Febrile neutropenia 41 (17) 24 (10) 12 (5) 33 (14) 17 (7) 15 (6) Lymphopenia 68 (28) 25 (10) 36 (15) 28 (12) 15 (6) 2 (1) Nervous System Disorders Peripheral neuropathy* 71 (30) 17 (7) 1 (<1) 65 (27) 10 (4) 0 Hypoesthesia 14 (6) 3 (1) 0 13 (5) 0 0 Paresthesia 14 (6) 2 (1) 0 11 (5) 0 0 Neuralgia 25 (10) 9 (4) 0 1 (<1) 0 0 General Disorders and Administration Site Conditions Fatigue 43 (18) 11 (5) 1 (<1) 38 (16) 5 (2) 0 Pyrexia 48 (20) 7 (3) 0 23 (10) 5 (2) 0 Asthenia 29 (12) 4 (2) 1 (<1) 18 (7) 1 (<1) 0 Edema peripheral 16 (7) 1 (<1) 0 13 (5) 0 0 Gastrointestinal Disorders Nausea 54 (23) 1 (<1) 0 28 (12) 0 0 Constipation 42 (18) 1 (<1) 0 22 (9) 2 (1) 0 Stomatitis 20 (8) 2 (1) 0 19 (8) 0 1 (<1) Diarrhea 59 (25) 11 (5) 0 11 (5) 3 (1) 1 (<1) Vomiting 24 (10) 1 (<1) 0 8 (3) 0 0 Abdominal distension 13 (5) 0 0 4 (2) 0 0 Infections and Infestations Pneumonia 20 (8) 8 (3) 5 (2) 11 (5) 5 (2) 3 (1) Skin and Subcutaneous Tissue Disorders Alopecia 31 (13) 1 (<1) 1 (<1) 33 (14) 4 (2) 0 Metabolism and Nutrition Disorders Hyperglycemia 10 (4) 1 (<1) 0 17 (7) 10 (4) 0 Decreased appetite 36 (15) 2 (1) 0 15 (6) 1 (<1) 0 Vascular Disorders Hypertension 15 (6) 1 (<1) 0 3 (1) 0 0 Psychiatric Disorders Insomnia 16 (7) 1 (<1) 0 8 (3) 0 0 The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment. The incidences of Grade ≥3 bleeding events were similar between the two arms (four patients in the VcR-CAP arm and three patients in the R-CHOP arm). All of the Grade ≥3 bleeding events resolved without sequelae in the VcR-CAP arm. Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; three patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (<1%; two patients). Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma) Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m 2 /dose twice weekly for two weeks followed by a ten day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 open-label study of bortezomib subcutaneous vs intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (>20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). In the Phase 2 relapsed multiple myeloma clinical trials of bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of bortezomib was not associated with tissue damage. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each). Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each). In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis. Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety The most common adverse reactions are shown in Table 13. All adverse reactions occurring at ≥10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient\'s underlying disease. Please see the discussion of specific adverse reactions that follows. Table 13: Most Commonly Reported (≥10% Overall) Adverse Reactions in Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studies Using the 1.3 mg/m 2 Dose (N=1163) * Represents High Level Term Peripheral Neuropathies NEC All Patients (N=1163) Multiple Myeloma (N=1008) Mantle Cell Lymphoma (N=155) Adverse Reactions All ≥Grade 3 All ≥Grade 3 All ≥Grade 3 Nausea 567 (49) 36 (3) 511 (51) 32 (3) 56 (36) 4 (3) Diarrhea NOS 530 (46) 83 (7) 470 (47) 72 (7) 60 (39) 11 (7) Fatigue 477 (41) 86 (7) 396 (39) 71 (7) 81 (52) 15 (10) Peripheral neuropathies* 443 (38) 129 (11) 359 (36) 110 (11) 84 (54) 19 (12) Thrombocytopenia 369 (32) 295 (25) 344 (34) 283 (28) 25 (16) 12 (8) Vomiting NOS 321 (28) 44 (4) 286 (28) 40 (4) 35 (23) 4 (3) Constipation 296 (25) 17 (1) 244 (24) 14 (1) 52 (34) 3 (2) Pyrexia 249 (21) 16 (1) 233 (23) 15 (1) 16 (10) 1 (<1) Anorexia 227 (20) 19 (2) 205 (20) 16 (2) 22 (14) 3 (2) Anemia NOS 209 (18) 65 (6) 190 (19) 63 (6) 19 (12) 2 (1) Headache NOS 175 (15) 8 (<1) 160 (16) 8 (<1) 15 (10) 0 Neutropenia 172 (15) 121 (10) 164 (16) 117 (12) 8 (5) 4 (3) Rash NOS 156 (13) 8 (<1) 120 (12) 4 (<1) 36 (23) 4 (3) Paresthesia 147 (13) 9 (<1) 136 (13) 8 (<1) 11 (7) 1 (<1) Dizziness (excl vertigo) 129 (11) 13 (1) 101 (10) 9 (<1) 28 (18) 4 (3) Weakness 124 (11) 31 (3) 106 (11) 28 (3) 18 (12) 3 (2) Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 Relapsed Mantle Cell Lymphoma Studies Gastrointestinal Toxicity A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥Grade 4 adverse reactions were ≤1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%). Thrombocytopenia Across the studies, bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (Days 1 to 11) and a return toward baseline during the ten day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients [see Warnings and Precautions (5.7) ] . Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%). Peripheral Neuropathy Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and ≥Grade 4 for <1% of patients. Eight percent (8%) of patients discontinued bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%). In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 bortezomib-treated patients who experienced ≥Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset. In the Phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one grade or more from the last dose of bortezomib. Hypotension The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥Grade 4 in <1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, <1% of patients experienced hypotension associated with a syncopal reaction. Neutropenia Neutrophil counts decreased during the bortezomib dosing period (Days 1 to 11) and returned toward baseline during the ten day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in <1% of patients and <1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%). Asthenic Conditions (Fatigue, Malaise, Weakness, Asthenia) Asthenic conditions were reported in 54% of patients. Fatigue was reported as Grade 3 in 7% and ≥Grade 4 in <1% of patients. Asthenia was reported as Grade 3 in 2% and ≥Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma. Pyrexia Pyrexia (>38°C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥Grade 4 in <1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to bortezomib discontinuation in <1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥Grade 3 pyrexia was 1% in patients with multiple myeloma and <1% in patients with mantle cell lymphoma. Herpes Virus Infection Consider using antiviral prophylaxis in subjects being treated with bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between 6 to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in 1 to 3% in subjects treated with bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%). Retreatment in Relapsed Multiple Myeloma A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in Tables 10, 11, and 13; no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of ≥Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of ≥Grade 3 peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each). Adverse reactions leading to discontinuation occurred in 13% of patients. The reasons for discontinuation included peripheral neuropathy (5%) and diarrhea (3%). Two deaths considered to be bortezomib-related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis. Additional Adverse Reactions from Clinical Studies The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors. Blood and Lymphatic System Disorders: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia Cardiac Disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes , ventricular tachycardia Ear and Labyrinth Disorders: Hearing impaired, vertigo Eye Disorders: Diplopia and blurred vision, conjunctival infection, irritation Gastrointestinal Disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux General Disorders and Administration Site Conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis Hepatobiliary Disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure Immune System Disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema Infections and Infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter-related infection Injury, Poisoning and Procedural Complications: Catheter-related complication, skeletal fracture, subdural hematoma Investigations: Weight decreased Metabolism and Nutrition Disorders: Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremity Nervous System Disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack Psychiatric Disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation Renal and Urinary Disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension Skin and Subcutaneous Tissue Disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus Vascular Disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension 6.2 Postmarketing Experience The following adverse reactions have been identified from the worldwide postmarketing experience with bortezomib. 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: Cardiac Disorders: Cardiac tamponade Ear and Labyrinth Disorders: Deafness bilateral Eye Disorders: Optic neuropathy, blindness, chalazion/blepharitis Gastrointestinal Disorders: Ischemic colitis Infections and Infestations: Progressive multifocal leukoencephalopathy (PML), ophthalmic herpes, herpes meningoencephalitis Nervous System Disorders: Posterior reversible encephalopathy syndrome (PRES, formerly RPLS), Guillain-Barre syndrome, demyelinating polyneuropathy Respiratory, Thoracic and Mediastinal Disorders: Acute diffuse infiltrative pulmonary disease Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute febrile neutrophilic dermatosis (Sweet\'s syndrome)"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. ( 7.1 ) Strong CYP3A4 Inducers: Avoid concomitant use. (7.3) 7.1 Effects of Other Drugs on Bortezomib Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3) ] which may decrease bortezomib efficacy. Avoid coadministration with strong CYP3A4 inducers. Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib [see Clinical Pharmacology (12.3) ] which may increase the risk of bortezomib toxicities. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors. 7.2 Drugs Without Clinically Significant Interactions with Bortezomib No clinically significant drug interactions have been observed when bortezomib was coadministered with dexamethasone, omeprazole, or melphalan in combination with prednisone [see Clinical Pharmacology (12.3) ] ."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Bortezomib for Injection is a proteasome inhibitor indicated for: treatment of adult patients with multiple myeloma ( 1.1 ) treatment of adult patients with mantle cell lymphoma ( 1.2 ) 1.1 Multiple Myeloma Bortezomib for Injection is indicated for the treatment of adult patients with multiple myeloma. 1.2 Mantle Cell Lymphoma Bortezomib for Injection is indicated for the treatment of adult patients with mantle cell lymphoma."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with preexisting severe neuropathy should be treated with Bortezomib only after careful risk-benefit assessment. ( 2.7 , 5.1 ) Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ( 5.2 ) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ( 5.3 ) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting Bortezomib therapy. ( 5.4 ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib if suspected. ( 5.5 ) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ( 5.6 ) Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. ( 5.7 ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. ( 5.8 ) Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt Bortezomib therapy to assess reversibility. ( 5.9 ) Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Bortezomib if suspected. ( 5.10 ) Embryo-Fetal Toxicity: Bortezomib can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 ) 5.1 Peripheral Neuropathy Bortezomib treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with preexisting symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with bortezomib. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing bortezomib subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group [see Adverse Reactions ( 6.1 )] . Starting bortezomib subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during bortezomib therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2.7) ] . In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the Phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. 5.2 Hypotension The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8% [see Adverse Reactions ( 6.1 )] . These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. 5.3 Cardiac Toxicity Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction [see Adverse Reactions ( 6.1 )] . Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of bortezomib vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the bortezomib group. In the dexamethasone group the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. 5.4 Pulmonary Toxicity Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving bortezomib. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m 2 per day) by continuous infusion with daunorubicin and bortezomib for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with bortezomib administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting bortezomib until a prompt and comprehensive diagnostic evaluation is conducted. 5.5 Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue bortezomib. The safety of reinitiating bortezomib therapy in patients previously experiencing PRES is not known. 5.6 Gastrointestinal Toxicity Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions (6.1) ] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt bortezomib for severe symptoms. 5.7 Thrombocytopenia/Neutropenia Bortezomib is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied. Monitor complete blood counts (CBC) frequently during treatment with bortezomib. Measure platelet counts prior to each dose of bortezomib. Adjust dose/schedule for thrombocytopenia [see Dosage and Administration ( 2.6 )] . Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with bortezomib. Support with transfusions and supportive care, according to published guidelines. In the single agent, relapsed multiple myeloma study of bortezomib vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 8. The incidence of bleeding (≥Grade 3) was 2% on the bortezomib arm and was <1% in the dexamethasone arm. Table 8: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone * A baseline platelet count of 50,000/µL was required for study eligibility ‡ Data were missing at baseline for one patient Pretreatment Platelet Count * Number of Patients (N=331) ‡ Number (%) of Patients with Platelet Count <10,000/µL Number (%) of Patients with Platelet Count 10,000 to 25,000/µL ≥75,000/µL 309 8 (3%) 36 (12%) ≥50,000/µL to <75,000/µL 14 2 (14%) 11 (79%) ≥10,000/µL to <50,000/µL 7 1 (14%) 5 (71%) In the combination study of bortezomib with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥Grade 4) was 32% vs 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 12. The incidence of bleeding events (≥Grade 3) was 1.7% in the VcR-CAP arm (four patients) and was 1.2% in the R-CHOP arm (three patients). Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm. The incidence of neutropenia (≥Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm. 5.8 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. 5.9 Hepatic Toxicity Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt bortezomib therapy to assess reversibility. There is limited re-challenge information in these patients. 5.10 Thrombotic Microangiopathy Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received bortezomib. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop bortezomib and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting bortezomib. The safety of reinitiating bortezomib therapy in patients previously experiencing TTP/HUS is not known. 5.11 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, bortezomib can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area caused postimplantation loss and a decreased number of live fetuses [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with bortezomib and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with bortezomib and for four months following treatment. If bortezomib is used during pregnancy or if the patient becomes pregnant during bortezomib treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1 , 8.3 ), Nonclinical Toxicology (13.1) ]."}', 'overdosage': '{"10 OVERDOSAGE There is no known specific antidote for bortezomib overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient\'s vital signs should be monitored and appropriate supportive care given. Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m 2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m 2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at one hour postadministration, with progression to death in 12 to 14 hours following drug administration."}', 'active_flag': 'Y', 'generic_name': '{BORTEZOMIB}', '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 Discuss the following with patients prior to treatment with bortezomib: Peripheral Neuropathy Advise patients to report the development or worsening of sensory and motor peripheral neuropathy to their healthcare provider [see Warnings and Precautions (5.1) ]. Hypotension Advise patients to drink adequate fluids to avoid dehydration and to report symptoms of hypotension to their healthcare provider [see Warnings and Precautions (5.2) ]. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps. Cardiac Toxicity Advise patients to report signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3) ] . Pulmonary Toxicity Advise patients to report symptoms of ARDS, pulmonary hypertension, pneumonitis, and pneumonia immediately to their healthcare provider [see Warnings and Precautions (5.4) ] . Posterior Reversible Encephalopathy Syndrome (PRES) Advise patients to seek immediate medical attention for signs or symptoms of PRES [see Warnings and Precautions (5.5) ]. Gastrointestinal Toxicity Advise patients to report symptoms of gastrointestinal toxicity to their healthcare provider and to drink adequate fluids to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps [see Warnings and Precautions (5.6) ]. Thrombocytopenia/Neutropenia Advise patients to report signs or symptoms of bleeding or infection immediately to their healthcare provider [see Warnings and Precautions (5.7) ] . Tumor Lysis Syndrome Advise patients of the risk of tumor lysis syndrome and to drink adequate fluids to avoid dehydration [see Warnings and Precautions (5.8) ]. Hepatic Toxicity Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.9) ]. Thrombotic Microangiopathy Advise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see Warnings and Precautions (5.10) ]. Ability to Drive or Operate Machinery or Impairment of Mental Ability Bortezomib may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions (5.2 , 5.5 )] . Embryo-Fetal Toxicity Advise females of the potential risk to the fetus and to use effective contraception during treatment with bortezomib and for seven months following the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with bortezomib and for four months following the last dose. Instruct patients to report pregnancy to their physicians immediately if they or their female partner becomes pregnant during treatment or within seven months following last dose [see Warnings and Precautions (5.11) ] . Lactation Advise women not to breastfeed while receiving bortezomib and for two months after last dose [see Use in Specific Populations (8.2) ] . Concomitant Medications Advise patients to speak with their physicians about any other medication they are currently taking. Diabetic Patients Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level. Dermal Advise patients to contact their physicians if they experience rash, severe injection site reactions [see Dosage and Administration (2.9) ] , or skin pain. Discuss with patients the option for antiviral prophylaxis for herpes virus infection [see Adverse Reactions ( 6.1 )] . Other Instruct patients to contact their physicians if they develop an increase in blood pressure, bleeding, fever, constipation, or decreased appetite."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, bortezomib can cause fetal harm when administered to a pregnant woman. There are no studies with the use of bortezomib in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data) . Advise pregnant women of the potential risk to the fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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 to 4% and 15 to 20%, respectively. Data Animal Data Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m 2 in the rat and 0.05 mg/kg; 0.6 mg/m 2 in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area). Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/m 2 ) experienced significant postimplantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. The activity and safety of bortezomib in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, non-randomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in three blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; Block 2 included cyclophosphamide, etoposide and methotrexate; Block 3 included high-dose cytosine arabinoside and asparaginase. bortezomib was administered at a dose of 1.3 mg/m 2 as a bolus intravenous injection on Days 1, 4, 8, and 11 of Block 1 and Days 1, 4, and 8 of Block 2. There were 140 patients with ALL or LL enrolled and evaluated for safety. The median age was ten years (range: 1 to 26), 57% were male, 70% were white, 14% were black, 4% were Asian, 2% were American Indian/Alaska Native, 1% were Pacific Islander. The activity was evaluated in a pre-specified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL ≤21 years and relapsed <36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without bortezomib. There was no evidence that the addition of bortezomib had any impact on the CR rate. No new safety concerns were observed when bortezomib was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without bortezomib. The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults."}', 'geriatric_use': '{"8.5 Geriatric Use Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥65 were longer on bortezomib compared to dexamethasone [5.5 mo vs 4.3 mo, and 8.0 mo vs 4.9 mo, respectively]. On the bortezomib arm, 40% (n=46) of evaluable patients aged ≥65 experienced response (CR + PR) vs 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for bortezomib patients ≤50, 51 to 64 and ≥65 years old, respectively [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving bortezomib; but greater sensitivity of some older individuals cannot be ruled out."}'}

{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 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. 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 Light-headedness Dizziness Akathisia Gastrointestinal disorders Dry mouth Increased salivation 41% 21% 2% 2% 15% 4% 22% 19% 1% 1% 13% 2% Cardiovascular disorders Hypotension Skin and subcutaneous tissue disorders Dermatitis/allergy 5% 4% 2% 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 Occuring 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 Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization 77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2% 43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1% Gastrointestinal disorders Constipation Increased salivation Skin and subcutaneous tissue disorders Rash 26% 6% 11% 15% 4% 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 Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness 29.5% 19.3% 17.3% 17.0% 6.9% 6.6% 5.9% 5.8% Psychiatric disorders Anxiety Fatigue and Tiredness Irritability Cognitive disorder Memory impairment Depression Confusional state 19.2% 18.4% 10.5% 10.3% 5.5% 5.1% 5.0% Gastrointestinal disorders Nausea/Vomiting Diarrhea Decreased salivation 16.5% 13.6% 10.6% Metabolism and nutrition disorders Weight loss Decreased appetite 13.3% 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 gammaaminobutyric 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 is 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, 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 may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam 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 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 due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam [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 during pregnancy [see Use in Specific Populations ( 8.1 )]. Lactation Advise patients that breastfeeding is not recommended during treatment with alprazolam [see Use in Specific Populations ( 8.2 )] . This product’s labeling may have been updated. For the most recent prescribing information, please visit www.sandoz.com."}', '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 )] ."}'}

{MENTHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Directions Adults and children 12 years of age and older: Apply to affected area"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{MENTHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if condition worsens, or if symptoms persist for more than 7 days or clear up and occur again within a few days."}', 'do_not_use': '{"Do not use on wounds or damaged skin if allergic to plants of the asteraceae/compositae/daisy family."}', 'when_using': '{"When using this product avoid contact with the eyes do not bandage tightly"}', 'warnings': '{"Warnings For external use only. Flammable: Keep away from fire or flame."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{IBUPROFEN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE temporarily relieves minor aches and pains due to: headache toothache backache menstrual cramps the common cold muscular aches minor pain of arthritis temporarily reduces fever"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{IBUPROFEN}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"OTC - STOP USE Stop use and ask a doctor if you experience any of the follwing 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 in the painful area any new symptoms appear"}', 'do_not_use': '{"OTC - 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': '{"OTC - WHEN USING When using this product take with food or milk if upset stomach occurs the risk of heart attack or stroke may increase if you use more than directed or for longer than directed"}', '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 a nonsteroidal anti-inflammatory drug (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"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{PREGABALIN}

{'contraindications': '{"4 CONTRAINDICATIONS Pregabalin is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see Warnings and Precautions (5.2) ] . Known hypersensitivity to pregabalin or any of its components. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Angioedema [see Warnings and Precautions (5.1) ] Hypersensitivity [see Warnings and Precautions (5.2) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.3) ] Respiratory Depression [see Warnings and Precautions (5.4) ] Dizziness and Somnolence [see Warnings and Precautions (5.5) ] Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.6) ] Peripheral Edema [see Warnings and Precautions (5.7) ] Weight Gain [see Warnings and Precautions (5.8) ] Tumorigenic Potential [see Warnings and Precautions (5.9) ] Ophthalmological Effects [see Warnings and Precautions (5.10) ] Creatine Kinase Elevations [see Warnings and Precautions (5.11) ] Decreased Platelet Count [see Warnings and Precautions (5.12) ] PR Interval Prolongation [see Warnings and Precautions (5.13) ] Most common adverse reactions (greater than or equal to 5% and twice placebo) in adults are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention). ( 6.1 ) Most common adverse reactions (greater than or equal to 5% and twice placebo) in pediatric patients for the treatment of partial-onset seizures are increased weight and increased appetite. ( 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. In all controlled and uncontrolled trials across various patient populations during the premarketing development of pregabalin, more than 10,000 patients have received pregabalin. Approximately 5,000 patients were treated for 6 months or more, over 3,100 patients were treated for 1 year or longer, and over 1,400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all adult populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the pregabalin group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Controlled Clinical Studies in Adults In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and \\"thinking abnormal\\" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with pregabalin than by subjects treated with placebo (greater than or equal to 5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”. Table 4. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Body system Preferred term 75 mg/day [N=77] % 150 mg/day [N=212] % 300 mg/day [N=321] % 600 mg/day [N=369] % All PGB PGB: pregabalin Placebo [N=979] % [N=459] % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 Thinking abnormal Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. 1 0 1 3 2 0 Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses Blurry vision Investigator term; summary level term is amblyopia 3 1 3 6 4 2 Abnormal vision 1 0 1 1 1 0 Controlled Studies in Postherpetic Neuralgia Adverse Reactions Leading to Discontinuation In clinical trials in adults with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the pregabalin group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each). Most Common Adverse Reactions Table 5 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. In addition, an event is included, even if the incidence in the all pregabalin group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”. Overall, 12.4% of all pregabalin-treated patients and 9.0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event. Table 5. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia Body system Preferred term 75 mg/d [N=84] % 150 mg/d [N=302] % 300 mg/d [N=312] % 600 mg/d [N=154] % All PGB PGB: pregabalin [N=852] % Placebo [N=398] % Body as a whole Infection 14 8 6 3 7 4 Headache 5 9 5 8 7 5 Pain 5 4 5 5 5 4 Accidental injury 4 3 3 5 3 2 Flu syndrome 1 2 2 1 2 1 Face edema 0 2 1 3 2 1 Digestive system Dry mouth 7 7 6 15 8 3 Constipation 4 5 5 5 5 2 Flatulence 2 1 2 3 2 1 Vomiting 1 1 3 3 2 1 Metabolic and nutritional disorders Peripheral edema 0 8 16 16 12 4 Weight gain 1 2 5 7 4 0 Edema 0 1 2 6 2 1 Musculoskeletal system Myasthenia 1 1 1 1 1 0 Nervous system Dizziness 11 18 31 37 26 9 Somnolence 8 12 18 25 16 5 Ataxia 1 2 5 9 5 1 Abnormal gait 0 2 4 8 4 1 Confusion 1 2 3 7 3 0 Thinking abnormal Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. 0 2 1 6 2 2 Incoordination 2 2 1 3 2 0 Amnesia 0 1 1 4 2 0 Speech disorder 0 0 1 3 1 0 Respiratory system Bronchitis 0 1 1 3 1 1 Special senses Blurry vision Investigator term; summary level term is amblyopia 1 5 5 9 5 3 Diplopia 0 2 2 4 2 0 Abnormal vision 0 1 2 5 2 0 Eye Disorder 0 1 1 2 1 0 Urogenital System Urinary Incontinence 0 1 1 2 1 0 Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Adverse Reactions Leading to Discontinuation Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 1% of patients in the placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation of at least 1% of patients in the pregabalin group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients). Most Common Adverse Reactions Table 6 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received pregabalin and 294 patients received placebo for up to 12 weeks. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”. Table 6. Dose-related Adverse Reaction Incidence in Controlled Trials of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients 150 mg/d 300 mg/d 600 mg/d All PGB PGB: pregabalin Placebo Body System Preferred Term [N = 185] [N = 90] [N = 395] [N = 670] Excludes patients who received the 50 mg dose in Study E1. [N = 294] % % % % % Body as a Whole Accidental Injury 7 11 10 9 5 Pain 3 2 5 4 3 Digestive System Increased Appetite 2 3 6 5 1 Dry Mouth 1 2 6 4 1 Constipation 1 1 7 4 2 Metabolic and Nutritional Disorders Weight Gain 5 7 16 12 1 Peripheral Edema 3 3 6 5 2 Nervous System Dizziness 18 31 38 32 11 Somnolence 11 18 28 22 11 Ataxia 6 10 20 15 4 Tremor 3 7 11 8 4 Thinking Abnormal Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. 4 8 9 8 2 Amnesia 3 2 6 5 2 Speech Disorder 1 2 7 5 1 Incoordination 1 3 6 4 1 Abnormal Gait 1 3 5 4 0 Twitching 0 4 5 4 1 Confusion 1 2 5 4 2 Myoclonus 1 0 4 2 0 Special Senses Blurred Vision Investigator term; summary level term is amblyopia. 5 8 12 10 4 Diplopia 5 7 12 9 4 Abnormal Vision 3 1 5 4 1 Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients 4 to Less Than 17 Years of Age Adverse Reactions Leading to Discontinuation Approximately 2.5% of patients receiving pregabalin and no patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions leading to discontinuation were somnolence (3 patients), worsening of epilepsy (1 patient), and hallucination (1 patient). Most Common Adverse Reactions Table 7 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin -treated patients. Dose-relatedness was defined as an incidence of the adverse event in the 10 mg/kg/day group that was at least 2% greater than the rate in both the placebo and 2.5 mg/kg/day groups. In this study, 201 patients received pregabalin and 94 patients received placebo for up to 12 weeks. A majority of pregabalin-treated patients in the clinical study had adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate”. Table 7. Dose-related Adverse Reaction Incidence in a Controlled Trial in Adjunctive Therapy for Partial-Onset Seizures in Patients 4 to Less Than 17 Years of Age Body System Preferred Term 2.5 mg/kg/day 2.5 mg/kg/day: Maximum dose 150 mg/day. Includes patients less than 30 kg for whom dose was adjusted to 3.5 mg/kg/day. [N=104] % 10 mg/kg/day 10 mg/kg/day: Maximum dose 600 mg/day. Includes patients less than 30 kg for whom dose was adjusted to 14 mg/kg/day. [N=97] % All PGB [N=201] % Placebo [N=94] % Abbreviations: N=number of patients; PGB = pregabalin. Gastrointestinal disorders Salivary hypersecretion 1 4 2 0 Investigations Weight increased 4 13 8 4 Metabolism and nutrition disorders Increased appetite 7 10 8 4 Nervous system disorders Somnolence 17 26 21 14 Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients 1 Month to Less Than 4 Years of Age Most Common Adverse Reactions Table 8 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as an incidence of the adverse event in the 14 mg/kg/day group that was at least 2% greater than the rate in both the placebo and 7 mg/kg/day groups. In this study, 105 patients received pregabalin and 70 patients received placebo for up to 14 days. Table 8. Dose-related Adverse Reaction Incidence in a Controlled Trial in Adjunctive Therapy for Partial-Onset Seizures in Patients 1 Month to Less Than 4 Years of Age Body System Preferred Term 7 mg/kg/day [N=71] % 14 mg/kg/day [N=34] % All PGB [N=105] % Placebo [N=70] % Abbreviations: N=number of patients; PGB=pregabalin. Nervous system disorders Somnolence includes related terms including lethargy, sluggishness, and hypersomnia. 13 21 15 9 Infections and infestations Pneumonia 1 9 4 0 Viral infection 3 6 4 3 Controlled Studies with Fibromyalgia Adverse Reactions Leading to Discontinuation In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150 mg/day to 600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, less than 1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 9 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients with fibromyalgia in the ‘all pregabalin’ treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate\\". Table 9. Adverse Reaction Incidence in Controlled Trials in Fibromyalgia System Organ Class Preferred term 150 mg/d [N=132] % 300 mg/d [N=502] % 450 mg/d [N=505] % 600 mg/d [N=378] % All PGB PGB: pregabalin Placebo [N=1,517] % [N=505] % Ear and Labyrinth Disorders Vertigo 2 2 2 1 2 0 Eye Disorders Vision blurred 8 7 7 12 8 1 Gastrointestinal Disorders Dry mouth 7 6 9 9 8 2 Constipation 4 4 7 10 7 2 Vomiting 2 3 3 2 3 2 Flatulence 1 1 2 2 2 1 Abdominal distension 2 2 2 2 2 1 General Disorders and Administrative Site Conditions Fatigue 5 7 6 8 7 4 Edema peripheral 5 5 6 9 6 2 Chest pain 2 1 1 2 2 1 Feeling abnormal 1 3 2 2 2 0 Edema 1 2 1 2 2 1 Feeling drunk 1 2 1 2 2 0 Infections and Infestations Sinusitis 4 5 7 5 5 4 Investigations Weight increased 8 10 10 14 11 2 Metabolism and Nutrition Disorders Increased appetite 4 3 5 7 5 1 Fluid retention 2 3 3 2 2 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 3 3 6 4 2 Muscle spasms 2 4 4 4 4 2 Back pain 2 3 4 3 3 3 Nervous System Disorders Dizziness 23 31 43 45 38 9 Somnolence 13 18 22 22 20 4 Headache 11 12 14 10 12 12 Disturbance in attention 4 4 6 6 5 1 Balance disorder 2 3 6 9 5 0 Memory impairment 1 3 4 4 3 0 Coordination abnormal 2 1 2 2 2 1 Hypoesthesia 2 2 3 2 2 1 Lethargy 2 2 1 2 2 0 Tremor 0 1 3 2 2 0 Psychiatric Disorders Euphoric Mood 2 5 6 7 6 1 Confusional state 0 2 3 4 3 0 Anxiety 2 2 2 2 2 1 Disorientation 1 0 2 1 2 0 Depression 2 2 2 2 2 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 2 1 3 3 2 2 Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury Adverse Reactions Leading to Discontinuation In clinical trials of adults with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients. Most Common Adverse Reactions Table 10 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients for which the incidence was greater than in the placebo treatment group with neuropathic pain associated with spinal cord injury in the controlled trials. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate\\". Table 10. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Spinal Cord Injury System Organ Class Preferred term PGB PGB: Pregabalin (N=182) Placebo (N=174) % % Ear and labyrinth disorders Vertigo 2.7 1.1 Eye disorders Vision blurred 6.6 1.1 Gastrointestinal disorders Dry mouth 11.0 2.9 Constipation 8.2 5.7 Nausea 4.9 4.0 Vomiting 2.7 1.1 General disorders and administration site conditions Fatigue 11.0 4.0 Edema peripheral 10.4 5.2 Edema 8.2 1.1 Pain 3.3 1.1 Infections and infestations Nasopharyngitis 8.2 4.6 Investigations Weight increased 3.3 1.1 Blood creatine phosphokinase increased 2.7 0 Musculoskeletal and connective tissue disorders Muscular weakness 4.9 1.7 Pain in extremity 3.3 2.3 Neck pain 2.7 1.1 Back pain 2.2 1.7 Joint swelling 2.2 0 Nervous system disorders Somnolence 35.7 11.5 Dizziness 20.9 6.9 Disturbance in attention 3.8 0 Memory impairment 3.3 1.1 Paresthesia 2.2 0.6 Psychiatric disorders Insomnia 3.8 2.9 Euphoric mood 2.2 0.6 Renal and urinary disorders Urinary incontinence 2.7 1.1 Skin and subcutaneous tissue disorders Decubitus ulcer 2.7 1.1 Vascular disorders Hypertension 2.2 1.1 Hypotension 2.2 0 Other Adverse Reactions Observed During the Clinical Studies of Pregabalin Following is a list of treatment-emergent adverse reactions reported by patients treated with pregabalin during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are described in the Warnings and Precautions section (5) . Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased, Aspartate aminotransferase increased Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pregabalin. 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 – Headache Gastrointestinal Disorders – Nausea, Diarrhea Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement Skin and subcutaneous tissue disorders – Bullous pemphigoid There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking pregabalin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment. In addition, there are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between pregabalin and commonly used antiepileptic drugs [see Clinical Pharmacology (12) ] . Pharmacodynamics Multiple oral doses of pregabalin were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when pregabalin was co-administered with these drugs. No clinically important effects on respiration were seen."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Pregabalin capsules are indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy • Management of postherpetic neuralgia • Adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older • Management of fibromyalgia • Management of neuropathic pain associated with spinal cord injury Pregabalin capsules are indicated for: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) ( 1 ) Postherpetic neuralgia (PHN) ( 1 ) Adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older ( 1 ) Fibromyalgia ( 1 ) Neuropathic pain associated with spinal cord injury ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Angioedema (e.g., swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in these cases. ( 5.1 ) Hypersensitivity reactions (e.g., hives, dyspnea, and wheezing) can occur. Discontinue pregabalin immediately in these patients. ( 5.2 ) Antiepileptic drugs, including pregabalin, increase the risk of suicidal thoughts or behavior. ( 5.3 ) Respiratory depression: May occur with pregabalin, when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. ( 5.4 ) Pregabalin may cause dizziness and somnolence and impair patients’ ability to drive or operate machinery. ( 5.5 ) Increased seizure frequency or other adverse reactions may occur if pregabalin is rapidly discontinued. Withdraw pregabalin gradually over a minimum of 1 week. ( 5.6 ) Pregabalin may cause peripheral edema. Exercise caution when co-administering pregabalin and thiazolidinedione antidiabetic agents. ( 5.7 ) 5.1 Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with pregabalin. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in patients with these symptoms. Exercise caution when prescribing Pregabalin capsules to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. 5.2 Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin capsules immediately in patients with these symptoms. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication 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 one 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 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 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 pregabalin 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, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.4 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe pregabalin with another CNS depressant, particularly an opioid, or to prescribe pregabalin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating pregabalin at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including pregabalin). There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment. 5.5 Dizziness and Somnolence Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17) ] . In the pregabalin controlled trials in adult patients, dizziness was experienced by 30% of pregabalin-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In pregabalin-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients [see Drug Interactions (7) ] . In the pregabalin controlled trials in pediatric patients 4 to less than 17 years of age and 1 month to less than 4 years of age for the treatment of partial-onset seizures, somnolence was reported in 21% and 15% of pregabalin-treated patients compared to 14% and 9% of placebo-treated patients, respectively, and occurred more frequently at higher doses. For patients 1 month to less than 4 years of age, somnolence includes related terms lethargy, sluggishness, and hypersomnia. 5.6 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation As with all antiepileptic drugs (AEDs), withdraw pregabalin gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. If pregabalin is discontinued, taper the drug gradually over a minimum of 1 week rather than discontinue the drug abruptly. 5.7 Peripheral Edema Pregabalin treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials in adult patients, the incidence of peripheral edema was 6% in the pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of pregabalin patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering pregabalin and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using pregabalin in these patients. 5.8 Weight Gain Pregabalin treatment may cause weight gain. In pregabalin controlled clinical trials in adult patients of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of pregabalin-treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.3%) withdrew from controlled trials due to weight gain. Pregabalin associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions (5.7) ] . Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown. Among diabetic patients, pregabalin-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received pregabalin for at least 2 years, the average weight gain was 5.2 kg. While the effects of pregabalin-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA 1C ). 5.9 Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology (13.1) ] . The clinical significance of this finding is unknown. Clinical experience during pregabalin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6,396 patient-years of exposure in patients greater than 12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with pregabalin, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. 5.10 Ophthalmological Effects In controlled studies in adult patients, a higher proportion of patients treated with pregabalin reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued pregabalin treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3,600 patients. In these patients, visual acuity was reduced in 7% of patients treated with pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions [see Patient Counseling Information (17) ] . 5.11 Creatine Kinase Elevations Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials in adult patients across multiple patient populations, 1.5% of patients on pregabalin and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. 5.12 Decreased Platelet Count Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-treated subjects experienced a mean maximal decrease in platelet count of 20 × 10 3 /μL, compared to 11 × 10 3 /μL in placebo patients. In the overall database of controlled trials in adult patients, 2% of placebo patients and 3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 10 3 /μL. A single pregabalin-treated subject developed severe thrombocytopenia with a platelet count less than 20 × 10 3 / μL. In randomized controlled trials, Pregabalin was not associated with an increase in bleeding-related adverse reactions. 5.13 PR Interval Prolongation Pregabalin treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data in adult patients, the mean PR interval increase was 3 msec to 6 msec at pregabalin doses greater than or equal to 300 mg/day. This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories."}', 'overdosage': '{"10 OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans In the postmarketing experience, the most commonly reported adverse events observed with pregabalin when taken in overdose include reduced consciousness, depression/anxiety, confusional state, agitation, and restlessness. Seizures and heart block have also been reported. Deaths have been reported in the setting of lone pregabalin overdose and in combination with other CNS depressants. Treatment or Management of Overdose There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions 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. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with pregabalin. Pregabalin can be removed by hemodialysis. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours)."}', 'active_flag': 'Y', 'generic_name': '{PREGABALIN}', '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 ). Angioedema Advise patients that pregabalin may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue pregabalin and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.1) ] . Hypersensitivity Advise patients that pregabalin has been associated with hypersensitivity reactions such as wheezing, dyspnea, rash, hives, and blisters. Instruct patients to discontinue pregabalin and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.2) ] . Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including pregabalin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.3) ] . Respiratory Depression Inform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant central nervous system (CNS) depressants (such as opioid analgesics) or in those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see Warnings and Precautions (5.4) ] . Dizziness and Somnolence Counsel patients that pregabalin may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms. Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on pregabalin to gauge whether or not it affects their mental, visual, and/or motor performance adversely [see Warnings and Precautions (5.5) ] . CNS Depressants Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as respiratory depression, somnolence, and dizziness [see Warnings and Precautions (5.4 , 5.5) and Drug Interactions (7) ]. Advise patients to avoid consuming alcohol while taking pregabalin, as pregabalin may potentiate the impairment of motor skills and sedating effects of alcohol. Adverse Reactions with Abrupt or Rapid Discontinuation Advise patients to take pregabalin as prescribed. Abrupt or rapid discontinuation may result in increased seizure frequency in patients with seizure disorders, and insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea [see Warnings and Precautions (5.6) ] . Missed Dose Counsel patients if they miss a dose, they should take it as soon as they remember. If it is almost time for the next dose, they should skip the missed dose and take the next dose at their regularly scheduled time. Instruct patients not to take two doses at the same time. Weight Gain and Edema Counsel patients that pregabalin may cause edema and weight gain. Advise patients that concomitant treatment with pregabalin and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. For patients with preexisting cardiac conditions, this may increase the risk of heart failure [see Warnings and Precautions (5.7 , 5.8) ] . Ophthalmological Effects Counsel patients that pregabalin may cause visual disturbances. Inform patients that if changes in vision occur, they should notify their physician [see Warnings and Precautions (5.10) ] . Creatine Kinase Elevations Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever [see Warnings and Precautions (5.11) ] . Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise nursing mothers that breastfeeding is not recommended during treatment with pregabalin [ see Use in Specific Populations (8.2) ] . Male Fertility Inform men being treated with pregabalin who plan to father a child of the potential risk of male-mediated teratogenicity. In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity. The clinical significance of this finding is uncertain [see Nonclinical Toxicology (13.1) and Use in specific populations (8.3) ] . Dermatopathy Instruct diabetic patients to pay particular attention to skin integrity while being treated with pregabalin and to inform their healthcare provider about any sores or skin problems. Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with pregabalin was observed in clinical trials [see Nonclinical Toxicology (13.2) ] . Manufactured by: ScieGen Pharmaceuticals, Inc. Hauppauge, NY 11788 Rev. 2/2023"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information regarding the effects of in utero exposure to pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Risk Summary There are no adequate and well-controlled studies with pregabalin in pregnant women. However, in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day [see Data ] . In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to a fetus. Data Animal Data When pregnant rats were given pregabalin (500 mg/kg, 1,250 mg/kg, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1,250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given pregabalin (250 mg/kg, 500 mg/kg, or 1,250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with pregabalin (50 mg/kg, 100 mg/kg, 250 mg/kg, 1,250 mg/kg, or 2,500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1,250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1,250 mg/kg. The no-effect dose for pre-and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0–24) of 123 μg∙hr/mL) at the MRD."}', 'pediatric_use': '{"8.4 Pediatric Use Neuropathic Pain Associated with Diabetic Peripheral Neuropathy, Postherpetic Neuralgia, and Neuropathic Pain Associated with Spinal Cord Injury Safety and effectiveness in pediatric patients have not been established. Fibromyalgia Safety and effectiveness in pediatric patients have not been established. A 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at pregabalin total daily doses of 75 mg to 450 mg per day. The primary efficacy endpoint of change from baseline to Week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance. The most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue. The overall safety profile in adolescents was similar to that observed in adults with fibromyalgia. Adjunctive Therapy for Partial-Onset Seizures Safety and effectiveness in pediatric patients below the age of 1 month have not been established. 4 to Less Than 17 Years of Age with Partial-Onset Seizures The safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 4 to less than 17 years of age have been established in a 12-week, double-blind, placebo-controlled study (n=295) [see Clinical Studies (14.3) ] . Patients treated with pregabalin 10 mg/kg/day had, on average, a 21.0% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0185). Patients treated with pregabalin 2.5 mg/kg/day had, on average, a 10.5% greater reduction in partial-onset seizures than patients treated with placebo, but the difference was not statistically significant (p=0.2577). Responder rates (50% or greater reduction in partial-onset seizure frequency) were a key secondary efficacy parameter and showed numerical improvement with pregabalin compared with placebo: the responder rates were 40.6%, 29.1%, and 22.6%, for pregabalin 10 mg/kg/day, pregabalin 2.5 mg/kg/day, and placebo, respectively. The most common adverse reactions (≥5%) with pregabalin in this study were somnolence, weight increased, and increased appetite [see Adverse Reactions (6.1) ] . The use of pregabalin 2.5 mg/kg/day in pediatric patients is further supported by evidence from adequate and well-controlled studies in adults with partial-onset seizures and pharmacokinetic data from adult and pediatric patients [see Clinical Pharmacology (12.3) ] . 1 Month to Less than 4 Years of Age with Partial-Onset Seizures The safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 1 month to less than 4 years of age have been established in a 14-day double-blind, placebo-controlled study (N=175) [see Clinical Studies (14.3) ] . The youngest subject evaluated was 3 months of age; use in patients 1 month to less than 3 months of age is supported by additional pharmacokinetic analyses. Patients treated with pregabalin 14 mg/kg/day had, on average, 43.9% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0223). In addition, pediatric patients treated with pregabalin 14 mg/kg/day showed numerical improvement in responder rates (≥50% reduction in partial-onset seizure frequency) compared with placebo (53.6% versus 41.5%). Patients treated with pregabalin 7 mg/kg/day did not show improvement relative to placebo for either endpoint. The most common dose-related adverse reactions (>5%) with pregabalin in this study were somnolence, pneumonia, and viral infection [see Adverse Reactions (6.1) ] . Juvenile Animal Data In studies in which pregabalin (50 mg/kg to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg. The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established."}', 'geriatric_use': '{"8.5 Geriatric Use In controlled clinical studies of pregabalin in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of pregabalin in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. In controlled clinical studies of pregabalin in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of pregabalin in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. Pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to pregabalin may be greater in patients with impaired renal function. Because pregabalin is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.7) ] ."}'}

{"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 HCL"}', '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 (1-800-222-1222) right away."}', '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 Adverse reactions with hydralazine 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, pruritus, fever, chills, arthralgia, eosinophilia, and rarely, hepatitis. Other nasal congestion, flushing, lacrimation, conjunctivitis."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Essential hypertension, alone or as an adjunct."}', '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. The gastric contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. These manipulations may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock. 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': '{ORAL}', '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. Published evidence suggests an antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop. Information for Patients Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed. 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. 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/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 are used concomitantly. Drug/Food Interactions Administration of hydralazine with food results in higher plasma levels. 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 to 30 times the maximum daily human dose of 200 to 300 mg and possibly in rabbits at 10 to 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 Hydralazine has been shown to be excreted in breast milk. 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 in pediatric patients. The usual recommended oral starting dosage is 0.75 mg/kg of body weight daily in four divided doses. Dosage may be increased gradually over the next 3 to 4 weeks to a maximum of 7.5 mg/kg or 200 mg daily."}', 'information_for_patients': '{"Information for Patients Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed."}', 'pregnancy': '{"Pregnancy Teratogenic Effects Pregnancy Category C Animal studies indicate that hydralazine is teratogenic in mice at 20 to 30 times the maximum daily human dose of 200 to 300 mg and possibly in rabbits at 10 to 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."}', 'pediatric_use': '{"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 in pediatric patients. The usual recommended oral starting dosage is 0.75 mg/kg of body weight daily in four divided doses. Dosage may be increased gradually over the next 3 to 4 weeks to a maximum of 7.5 mg/kg or 200 mg daily."}', 'geriatric_use': None}

{LEVETIRACETAM}

{'contraindications': '{"4 CONTRAINDICATIONS ELEPSIA XR is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4) ]. Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of labeling: Behavioral Abnormalities and Psychotic Symptoms [see Warnings and Precautions (5.1) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] Somnolence and Fatigue [see Warnings and Precautions (5.3) ] Anaphylaxis and Angioedema [see Warnings and Precautions (5.4) ] Serious Dermatological Reactions [see Warnings and Precautions (5.5) ] Coordination Difficulties [see Warnings and Precautions (5.6) ] Hematologic Abnormalities [see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence ≥5% more than placebo) include: somnolence and irritability ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 833-SUN-INFO (833-786-4636) 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. Levetiracetam Extended-Release Tablets In the controlled clinical study in patients with partial-onset seizures, the most common adverse reactions in patients receiving levetiracetam extended-release tablets in combination with other AEDs, for events with rates greater than placebo, were irritability and somnolence. Table 3 lists adverse reactions that occurred in at least 5% of epilepsy patients receiving levetiracetam extended-release tablets in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either levetiracetam extended-release tablets or placebo was added to concurrent AED therapy. Table 3: Adverse Reactions in the Placebo-Controlled, Add-On Study in Patients Experiencing Partial- Onset Seizures Adverse Reactions Levetiracetam Extended-Release Tablets (N=77) % Placebo (N=79) % Influenza 8 4 Somnolence 8 3 Irritability 7 0 Nasopharyngitis 7 5 Dizziness 5 3 Nausea 5 3 Discontinuation or Dose Reduction in the Levetiracetam Extended-Release Tablets Controlled Clinical Study In the controlled clinical study, 5% of patients receiving levetiracetam extended-release tablets and 3% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions that resulted in discontinuation and that occurred more frequently in levetiracetam extended-release tablet-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash, and respiratory failure. Each of these adverse reactions led to discontinuation in a levetiracetam extended-release tablet-treated patient and no placebo-treated patients. Immediate-Release Levetiracetam Tablets Table 4 lists the adverse reactions in the controlled studies of immediate-release levetiracetam tablets in adult patients experiencing partial-onset seizures. Although the pattern of adverse reactions in the levetiracetam extended-release tablets study seems somewhat different from that seen in partial-onset seizure controlled studies for immediate-release levetiracetam tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for levetiracetam extended-release tablets are expected to be similar to those seen with immediate-release levetiracetam tablets. Adults In controlled clinical studies of immediate-release levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial-onset seizures, the most common adverse reactions, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Table 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving immediate-release levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED therapy. Table 4: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Adults Experiencing Partial-Onset Seizures Adverse Reaction Immediate-Release Levetiracetam Tablets (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 Pediatric Patients 4 Years to <16 Years In a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with partial-onset seizures, the adverse reactions most frequently reported with the use of immediate-release levetiracetam tablets in combination with other AEDs, and with greater frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate -release levetiracetam tablets and were more common than in pediatric patients on placebo. In these studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial-Onset Seizures Adverse Reaction Immediate-Release Levetiracetam Tablets (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Abdominal Pain Upper 9 8 Cough 9 5 Nasal Congestion 9 2 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 5 Lethargy 6 2 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Mood Altered 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In controlled pediatric clinical studies in patients 4 to 16 years of age, 7% of patients treated with immediate-release levetiracetam tablets and 9% of patients on placebo discontinued as a result of an adverse event. In addition, the following adverse reactions were seen in other controlled studies of immediate-release levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and blurred vision. Comparison of Gender, Age and Race There are insufficient data for levetiracetam extended-release tablets to support a statement regarding the distribution of adverse reactions by gender, age, and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of immediate-release levetiracetam 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 listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss and worsening of seizures. Alopecia has been reported with immediate-release levetiracetam tablet use; recovery was observed in majority of cases where immediate-release levetiracetam tablets were discontinued."}', 'drug_interactions': None, 'indications_and_usage': '{"1 INDICATIONS AND USAGE ELEPSIA XR is indicated as adjunctive therapy for the treatment of partial-onset seizures in patients 12 years of age and older. ELEPSIA XR is indicated as adjunctive therapy for the treatment of partial-onset seizures in patients 12 years of age and older ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed; monitor patients for psychiatric signs and symptoms ( 5.1 ) Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior ( 5.2 ) Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained sufficient experience on ELEPSIA XR ( 5.3 ) Serious Dermatological Reactions: Discontinue ELEPSIA XR at the first sign of rash unless clearly not drug related ( 5.5 ) Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. Advise patients to not drive or operate machinery until they have gained experience on ELEPSIA XR ( 5.6 ) Withdrawal Seizures: ELEPSIA XR must be gradually withdrawn ( 5.7 ) 5.1 Behavioral Abnormalities and Psychotic Symptoms ELEPSIA XR may cause behavioral abnormalities and psychotic symptoms. Patients treated with ELEPSIA XR should be monitored for psychiatric signs and symptoms. Behavioral Abnormalities Levetiracetam Extended-Release Tablets A total of 7% of levetiracetam extended-release tablets-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression), compared to 0% of placebo-treated patients. Irritability was reported in 7% of levetiracetam extended-release tablet-treated patients. Aggression was reported in 1% of levetiracetam extended-release tablet-treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam controlled trials will likely to occur in patients receiving ELEPSIA XR. Immediate-Release Levetiracetam Tablets A total of 13% of adult patients and 38% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam tablets experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder), compared to 6% and 19% of adult and pediatric patients on placebo. A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). An exploratory analysis suggested a worsening in aggressive behavior in patients treated with immediate-release levetiracetam tablets in that study [see Use in Specific Populations (8.4) ] . A total of 1.7% of adult patients treated with immediate-release levetiracetam tablets discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult patients treated with immediate-release levetiracetam tablets, compared to 0.5% of placebo-treated patients. Overall, 11% of pediatric patients treated with immediate-release levetiracetam tablets experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo-treated pediatric patients. One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam tablets experienced psychotic symptoms, compared to 0.2% and 2%, respectively, in adult and pediatric placebo-treated patients. In the controlled study that assessed the neurocognitive and behavioral effects of immediate-release levetiracetam tablets in pediatric patients 4 to 16 years of age, 1.6% levetiracetam -treated patients experienced paranoia, compared to no placebo-treated patients. There were 3.1% patients treated with immediate-release levetiracetam tablets who experienced confusional state, compared to no placebo-treated patients [see Use in Specific Populations (8.4) ] . Psychotic Symptoms Immediate-Release Levetiracetam Tablets One percent of immediate-release levetiracetam tablets-treated adult patients experienced psychotic symptoms, compared to 0.2% of placebo-treated patients. Two (0.3%) immediate-release levetiracetam tablets-treated adult patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug and placebo-treated patients in the incidence of pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including ELEPSIA XR, 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 one 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 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis 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 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 ELEPSIA XR 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, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.3 Somnolence and Fatigue ELEPSIA XR may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on ELEPSIA XR to gauge whether it adversely affects their ability to drive or operate machinery. Somnolence Levetiracetam Extended-Release Tablets In the levetiracetam extended-release tablets double-blind, controlled trial in patients experiencing partial-onset seizures, 8% of levetiracetam extended-release tablets-treated patients experienced somnolence, compared to 3% of placebo-treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled trials will likely occur in patients receiving ELEPSIA XR. Immediate-Release Levetiracetam Tablets In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of immediate-release levetiracetam tablets-treated patients reported somnolence, compared to 8% of placebo treated patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day (1.33 times the maximum recommended dosage) reported somnolence. The somnolence was considered serious in 0.3% of the immediate-release levetiracetam tablets-treated patients, compared to 0% in the placebo group. About 3% of immediate-release levetiracetam tablets-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of immediate-release levetiracetam tablets-treated patients and in 0.9% of placebo-treated patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. Asthenia Immediate-Release Levetiracetam Tablets In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of immediate-release levetiracetam tablets-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of immediate-release levetiracetam tablets-treated patients, as compared to 0.5% of placebo treated patients. In 0.5% of immediate-release levetiracetam tablets-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. 5.4 Anaphylaxis and Angioedema ELEPSIA XR can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting in patients treated with levetiracetam have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, ELEPSIA XR should be discontinued and the patient should seek immediate medical attention. ELEPSIA XR should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4) ] . 5.5 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. ELEPSIA XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. 5.6 Coordination Difficulties Coordination difficulties were not observed in the extended-release levetiracetam controlled trials, however, the number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. However, adverse reactions observed in the immediate-release levetiracetam controlled trials may also occur in patients receiving ELEPSIA XR. Immediate-Release Levetiracetam Tablets A total of 3.4% of adult immediate-release levetiracetam tablets-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination), compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled trials discontinued immediate-release levetiracetam tablets treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of immediate-release levetiracetam tablets-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the immediate-release levetiracetam tablets-treated patients was hospitalized due to worsening of preexisting ataxia. These events occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on ELEPSIA XR to gauge whether it could adversely affect their ability to drive or operate machinery. 5.7 Withdrawal Seizures As with most antiepileptic drugs, ELEPSIA XR should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (2.3) ] . But if withdrawal is needed because of an adverse event, rapid discontinuation can be considered. 5.8 Hematologic Abnormalities ELEPSIA XR can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials of immediate-release levetiracetam and included decreases in white blood cells (WBC), neutrophil, and red blood cell (RBC) counts; decreases in hemoglobin and hematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have also been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders. Immediate-Release Levetiracetam Tablets In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial-onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10 6 /mm 3 ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release levetiracetam tablets-treated patients. A total of 3.2% of immediate-release levetiracetam tablets-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 10 9 /L) decreased WBC, and 2.4% of immediate-release levetiracetam tablets-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 10 9 /L) decreased neutrophil count. Of the immediate-release levetiracetam tablets-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. In pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release levetiracetam tablets, as compared to placebo. The mean decreases from baseline in the immediate-release levetiracetam tablets group were -0.4 × 10 9 /L and -0.3 × 10 9 /L, respectively, whereas there were small increases in the placebo group. A significant increase in mean relative lymphocyte counts was observed in 1.7% of patients treated with immediate-release levetiracetam tablets compared to a decrease of 4% in patients on placebo. In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release levetiracetam tablets, compared to no patients on placebo. However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts. In the controlled pediatric cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the immediate-release levetiracetam tablets-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7X10 9 /L). 5.9 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy."}', 'overdosage': '{"10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The signs and symptoms for ELEPSIA XR overdose are expected to be similar to those seen with immediate-release levetiracetam tablets. The highest known dose of oral immediate-release levetiracetam tablets received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with immediate-release levetiracetam tablet overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with ELEPSIA XR. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with ELEPSIA XR. 10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient\'s clinical state or in patients with significant renal impairment."}', 'active_flag': 'Y', 'generic_name': '{LEVETIRACETAM}', '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 ). Psychiatric Reactions and Changes in Behavior Advise patients that ELEPSIA XR may cause changes in behavior (e.g. irritability and aggression). In addition, patients should be advised that they may experience changes in behavior that have been seen with other formulations of levetiracetam, which include agitation, anger, anxiety, apathy, depression, hostility, psychotic symptoms [see Warnings and Precautions (5.1) ] . Suicidal Behavior and Ideation Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including ELEPSIA XR, may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider [see Warnings and Precautions (5.2) ] . Effects on Driving or Operating Machinery Inform patients that ELEPSIA XR may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on ELEPSIA XR to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions (5.3) ] . Anaphylaxis and Angioedema Advise patients to discontinue ELEPSIA XR and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.4) ] . Dermatological Adverse Reactions Advise patients that serious dermatological adverse reactions have occurred in patients treated with levetiracetam and instruct them to call their physician immediately if a rash develops [see Warnings and Precautions (5.5) ] . Dosing and Administration Patients should be instructed to only take ELEPSIA XR once daily and to swallow the tablets whole. The tablet should not be chewed, broken, or crushed [see Dosage and Administration (2.1) ] . Inform patients that they should not be concerned if they occasionally notice something that looks like inert fragments of coating and/or swollen pieces of the original tablet in their stool. Each coated bilayer tablet consists of a distinctly visible blue layer and a white to off white layer. Do not consume the tablet if one layer is absent and report this to your pharmacist [see Dosage Forms and Strengths (3) ] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during ELEPSIA XR therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1) ] . Rx Only Manufactured for Sun Pharma Global FZE by Sun Pharmaceutical Industries, Ltd. Halol-Baroda Highway Halol 389350, Gujarat, India Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Copyright 2020, Sun Pharma Global FZE All rights reserved 12 2020 uspi-ELEPSIA-XR-tab-00002"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including ELEPSIA XR, during pregnancy. Encourage women who are taking ELEPSIA XR 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 Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades [see Human Data ] . In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see Animal 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Levetiracetam levels may decrease during pregnancy [see Warnings and Precautions (5.9) ] . Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester. Dose adjustments may be necessary to maintain clinical response. Data Human Data While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. Animal Data When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m 2 ) basis. Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m 2 basis. Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m 2 basis. Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis)."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness of ELEPSIA XR in pediatric patients 12 years of age and older has been established based on pharmacokinetic data in adults and adolescents using levetiracetam extended-release tablets and efficacy and safety data in controlled pediatric studies using immediate-release levetiracetam tablets [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]. Safety and effectiveness in pediatric patients below the age of 12 years have not been established. A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam tablets as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (levetiracetam N=64; placebo N=34). The target dose of immediate-release levetiracetam tablets was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which assesses various aspects of a child\'s memory and attention. Although no substantive differences were observed between the placebo-and levetiracetam-treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority between the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6-18 indicated a worsening in aggressive behavior, one of the eight syndrome scores, in patients treated with levetiracetam [see Warnings and Precautions (5.1) ] . Juvenile Animal Toxicity Data Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1,800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not indicate a potential for age-specific toxicity."}', 'geriatric_use': '{"8.5 Geriatric Use There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam extended-release tablets in these patients. It is expected that the safety of ELEPSIA XR in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release levetiracetam tablets. There were 347 subjects in clinical studies of immediate-release levetiracetam that were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of immediate-release levetiracetam tablets in these patients. Levetiracetam 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. 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) ] ."}'}

{GABAPENTIN}

{'contraindications': '{"CONTRAINDICATIONS Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients."}', 'adverse_reactions': '{"ADVERSE REACTIONS Postherpetic Neuralgia The most commonly observed adverse events associated with the use of gabapentin in adults, not seen at an equivalent frequency among placebo-treated patients, were dizziness, somnolence, and peripheral edema. In the 2 controlled studies in postherpetic neuralgia, 16% of the 336 patients who received gabapentin and 9% of the 227 patients who received placebo discontinued treatment because of an adverse event. The adverse events that most frequently led to withdrawal in gabapentin-treated patients were dizziness, somnolence, and nausea. Incidence in Controlled Clinical Trials Table 3 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients with postherpetic neuralgia participating in placebo-controlled trials and that were numerically more frequent in the gabapentin group than in the placebo group. Adverse events were usually mild to moderate in intensity. Table 3. Treatment-Emergent Adverse Event Incidence in Controlled Trials in Postherpetic Neuralgia (Events in at least 1% of Gabapentin-Treated Patients and Numerically More Frequent Than in the Placebo Group) Body System/ Gabapentin Placebo Preferred Term N=336 N=227 % % a Reported as blurred vision Body as a Whole Asthenia 5.7 4.8 Infection 5.1 3.5 Headache 3.3 3.1 Accidental injury 3.3 1.3 Abdominal pain 2.7 2.6 Digestive System Diarrhea 5.7 3.1 Dry mouth 4.8 1.3 Constipation 3.9 1.8 Nausea 3.9 3.1 Vomiting 3.3 1.8 Flatulence 2.1 1.8 Metabolic and Nutritional Disorders Peripheral edema 8.3 2.2 Weight gain 1.8 0.0 Hyperglycemia 1.2 0.4 Nervous System Dizziness 28.0 7.5 Somnolence 21.4 5.3 Ataxia 3.3 0.0 Thinking abnormal 2.7 0.0 Abnormal gait 1.5 0.0 Incoordination 1.5 0.0 Amnesia 1.2 0.9 Hypesthesia 1.2 0.9 Respiratory System Pharyngitis 1.2 0.4 Skin and Appendages Rash 1.2 0.9 Special Senses Amblyopia a 2.7 0.9 Conjunctivitis 1.2 0.0 Diplopia 1.2 0.0 Otitis media 1.2 0.0 Other events in more than 1% of patients but equally or more frequent in the placebo group included pain, tremor, neuralgia, back pain, dyspepsia, dyspnea, and flu syndrome. There were no clinically important differences between men and women in the types and incidence of adverse events. Because there were few patients whose race was reported as other than white, there are insufficient data to support a statement regarding the distribution of adverse events by race. Epilepsy The most commonly observed adverse events associated with the use of gabapentin in combination with other antiepileptic drugs in patients >12 years of age, not seen at an equivalent frequency among placebo-treated patients, were somnolence, dizziness, ataxia, fatigue, and nystagmus. The most commonly observed adverse events reported with the use of gabapentin in combination with other antiepileptic drugs in pediatric patients 3 to 12 years of age, not seen at an equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, somnolence, and hostility (see WARNINGS , Neuropsychiatric Adverse Events-Adverse Events-Pediatric Patients 3 to 12 years of age ). Approximately 7% of the 2074 patients >12 years of age and approximately 7% of the 449 pediatric patients 3 to 12 years of age who received gabapentin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal in patients >12 years of age were somnolence (1.2%), ataxia (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%). The adverse events most commonly associated with withdrawal in pediatric patients were emotional lability (1.6%), hostility (1.3%), and hyperkinesia (1.1%). Incidence in Controlled Clinical Trials Table 4 lists treatment-emergent signs and symptoms that occurred in at least 1% of gabapentin-treated patients >12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. In these studies, either gabapentin or placebo was added to the patient’s current antiepileptic drug therapy. Adverse events were usually mild to moderate in intensity. The prescriber should be aware that these figures, obtained when gabapentin was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. Table 4. Treatment-Emergent Adverse Event Incidence in Controlled Add-On Trials in Patients >12 Years of Age (Events in at Least 1% of Gabapentin Patients and Numerically More Frequent Than in the Placebo Group) Body System/ Gabapentin a Placebo a Adverse Event N = 543 N = 378 % % a Plus background antiepileptic drug therapy b Amblyopia was often described as blurred vision. Body As A Whole Fatigue 11.0 5.0 Weight Increase 2.9 1.6 Back Pain 1.8 0.5 Peripheral Edema 1.7 0.5 Cardiovascular Vasodilatation 1.1 0.3 Digestive System Dyspepsia 2.2 0.5 Mouth or Throat Dry 1.7 0.5 Constipation 1.5 0.8 Dental Abnormalities 1.5 0.3 Increased Appetite 1.1 0.8 Hematologic and Lymphatic Systems Leukopenia 1.1 0.5 Musculoskeletal System Myalgia 2.0 1.9 Fracture 1.1 0.8 Nervous System Somnolence 19.3 8.7 Dizziness 17.1 6.9 Ataxia 12.5 5.6 Nystagmus 8.3 4.0 Tremor 6.8 3.2 Nervousness 2.4 1.9 Dysarthria 2.4 0.5 Amnesia 2.2 0.0 Depression 1.8 1.1 Thinking Abnormal 1.7 1.3 Twitching 1.3 0.5 Coordination Abnormal 1.1 0.3 Respiratory System Rhinitis 4.1 3.7 Pharyngitis 2.8 1.6 Coughing 1.8 1.3 Skin and Appendages Abrasion 1.3 0.0 Pruritus 1.3 0.5 Urogenital System Impotence 1.5 1.1 Special Senses Diplopia 5.9 1.9 Amblyopia b 4.2 1.1 Laboratory Deviations WBC Decreased 1.1 0.5 Other events in more than 1% of patients >12 years of age but equally or more frequent in the placebo group included: headache, viral infection, fever, nausea and/or vomiting, abdominal pain, diarrhea, convulsions, confusion, insomnia, emotional lability, rash, acne. Among the treatment-emergent adverse events occurring at an incidence of at least 10% in gabapentin-treated patients, somnolence and ataxia appeared to exhibit a positive dose-response relationship. The overall incidence of adverse events and the types of adverse events seen were similar among men and women treated with gabapentin. The incidence of adverse events increased slightly with increasing age in patients treated with either gabapentin or placebo. Because only 3% of patients (28/921) in placebo-controlled studies were identified as nonwhite (black or other), there are insufficient data to support a statement regarding the distribution of adverse events by race. Table 5 lists treatment-emergent signs and symptoms that occurred in at least 2% of gabapentin-treated patients age 3 to 12 years of age with epilepsy participating in placebo-controlled trials and were numerically more common in the gabapentin group. Adverse events were usually mild to moderate in intensity. Table 5. Treatment-Emergent Adverse Event Incidence in Pediatric Patients Age 3 to 12 Years in a Controlled Add-On Trial (Events in at Least 2% of Gabapentin Patients and Numerically More Frequent Than in the Placebo Group) Body System/ Gabapentin a Placebo a Adverse Event N = 119 N = 128 % % a Plus background antiepileptic drug therapy Body As A Whole Viral Infection 10.9 3.1 Fever 10.1 3.1 Weight Increase 3.4 0.8 Fatigue 3.4 1.6 Digestive System Nausea and/or Vomiting 8.4 7.0 Nervous System Somnolence 8.4 4.7 Hostility 7.6 2.3 Emotional Lability 4.2 1.6 Dizziness 2.5 1.6 Hyperkinesia 2.5 0.8 Respiratory System Bronchitis 3.4 0.8 Respiratory Infection 2.5 0.8 Other events in more than 2% of pediatric patients 3 to 12 years of age but equally or more frequent in the placebo group included: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media. Other Adverse Events Observed During All Clinical Trials Clinical Trials in Adults And Adolescents ( Except Clinical Trials In Neuropathic Pain ) Gabapentin has been administered to 4717 patients >12 years of age during all adjunctive therapy clinical trials (except clinical trials in patients with neuropathic pain), only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 4717 patients >12 years of age exposed to gabapentin who experienced an event of the type cited on at least one occasion while receiving gabapentin. All reported events are included except those already listed in Table 4, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body As A Whole: Frequent : asthenia, malaise, face edema; Infrequent : allergy, generalized edema, weight decrease, chill; Rare : strange feelings, lassitude, alcohol intolerance, hangover effect. Cardiovascular System: Frequent : hypertension; Infrequent : hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare : atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis. Digestive System: Frequent : anorexia, flatulence, gingivitis; Infrequent : glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare : dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm. Endocrine System: Rare : hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance. Hematologic and Lymphatic Systems: Frequent : purpura most often described as bruises resulting from physical trauma; Infrequent : anemia, thrombocytopenia, lymphadenopathy; Rare : WBC count increased, lymphocytosis, non-Hodgkin’s lymphoma, bleeding time increased. Musculoskeletal System: Frequent : arthralgia; Infrequent : tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare : costochondritis, osteoporosis, bursitis, contracture. Nervous System: Frequent : vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent : CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, psychosis; Rare : choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction. Respiratory System: Frequent : pneumonia; Infrequent : epistaxis, dyspnea, apnea; Rare : mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema. Dermatological: Infrequent : alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare : herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling. Urogenital System: Infrequent : hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare : kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain. Special Senses: Frequent : abnormal vision; Infrequent : cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare : eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell. Clinical Trials in Pediatric Patients With Epilepsy Adverse events occurring during epilepsy clinical trials in 449 pediatric patients 3 to 12 years of age treated with gabapentin that were not reported in adjunctive trials in adults are: Body as a Whole: dehydration, infectious mononucleosis Digestive System: hepatitis Hematologic and Lymphatic Systems : coagulation defect Nervous System: aura disappeared, occipital neuralgia Psychobiologic Function: sleepwalking Respiratory System: pseudocroup, hoarseness Clinical Trials in Adults with Neuropathic Pain of Various Etiologies Safety information was obtained in 1173 patients during double-blind and open-label clinical trials including neuropathic pain conditions for which efficacy has not been demonstrated. Adverse events reported by investigators were grouped into standardized categories using modified COSTART IV terminology. Listed below are all reported events except those already listed in Table 3 and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a Whole: Infrequent : chest pain, cellulitis, malaise, neck pain, face edema, allergic reaction, abscess, chills, chills and fever, mucous membrane disorder; Rare : body odor, cyst, fever, hernia, abnormal BUN value, lump in neck, pelvic pain, sepsis, viral infection. Cardiovascular System: Infrequent : hypertension, syncope, palpitation, migraine, hypotension, peripheral vascular disorder, cardiovascular disorder, cerebrovascular accident, congestive heart failure, myocardial infarction, vasodilatation; Rare : angina pectoris, heart failure, increased capillary fragility, phlebitis, thrombophlebitis, varicose vein. Digestive System: Infrequent : gastroenteritis, increased appetite, gastrointestinal disorder, oral moniliasis, gastritis, tongue disorder, thirst, tooth disorder, abnormal stools, anorexia, liver function tests abnormal, periodontal abscess; Rare : cholecystitis, cholelithiasis, duodenal ulcer, fecal incontinence, gamma glutamyl transpeptidase increased, gingivitis, intestinal obstruction, intestinal ulcer, melena, mouth ulceration, rectal disorder, rectal hemorrhage, stomatitis. Endocrine System: Infrequent : diabetes mellitus. Hematologic and Lymphatic Systems: Infrequent : ecchymosis, anemia; Rare : lymphadenopathy, lymphoma-like reaction, prothrombin decreased. Metabolic and Nutritional: Infrequent : edema, gout, hypoglycemia, weight loss; Rare : alkaline phosphatase increased, diabetic ketoacidosis, lactic dehydrogenase increased. Musculoskeletal: Infrequent : arthritis, arthralgia, myalgia, arthrosis, leg cramps, myasthenia; Rare : shin bone pain, joint disorder, tendon disorder. Nervous System: Frequent: confusion, depression; Infrequent : vertigo, nervousness, paresthesia, insomnia, neuropathy, libido decreased, anxiety, depersonalization, reflexes decreased, speech disorder, abnormal dreams, dysarthria, emotional lability, nystagmus, stupor, circumoral paresthesia, euphoria, hyperesthesia, hypokinesia; Rare : agitation, hypertonia, libido increased, movement disorder, myoclonus, vestibular disorder. Respiratory System: Infrequent : cough increased, bronchitis, rhinitis, sinusitis, pneumonia, asthma, lung disorder, epistaxis; Rare : hemoptysis, voice alteration. Skin and Appendages: Infrequent : pruritus, skin ulcer, dry skin, herpes zoster, skin disorder, fungal dermatitis, furunculosis, herpes simplex, psoriasis, sweating, urticaria, vesiculobullous rash; Rare : acne, hair disorder, maculopapular rash, nail disorder, skin carcinoma, skin discoloration, skin hypertrophy. Special Senses: Infrequent : abnormal vision, ear pain, eye disorder, taste perversion, deafness; Rare : conjunctival hyperemia, diabetic retinopathy, eye pain, fundi with microhemorrhage, retinal vein thrombosis, taste loss. Urogenital System: Infrequent : urinary tract infection, dysuria, impotence, urinary incontinence, vaginal moniliasis, breast pain, menstrual disorder, polyuria, urinary retention; Rare : cystitis, ejaculation abnormal, swollen penis, gynecomastia, nocturia, pyelonephritis, swollen scrotum, urinary frequency, urinary urgency, urine abnormality. Postmarketing and Other Experience In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, rhabdomyolysis, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Postherpetic Neuralgia Gabapentin is indicated for the management of postherpetic neuralgia in adults. Epilepsy Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy. Gabapentin is also indicated as adjunctive therapy in the treatment of partial seizures in pediatric patients age 3 to 12 years."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea, were observed. All patients recovered with supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment."}', 'active_flag': 'Y', 'generic_name': '{GABAPENTIN}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, 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 one 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 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by indication for antiepileptic drugs in the pooled analysis Indication Relative Risk: Incidence of Risk Difference: Drug Patients Events in Drug Additional Drug Placebo Patients with Events Patients/ Patients with Events with Events Per Per 1000 Incidence in Per 1000 1000 Patients Patients Placebo Patients 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 gabapentin 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, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs 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. Neuropsychiatric Adverse Events-Pediatric Patients 3 to 12 years of age Gabapentin use in pediatric patients with epilepsy 3 to 12 years of age is associated with the occurrence of central nervous system related adverse events. The most significant of these can be classified into the following categories: 1) emotional lability (primarily behavioral problems), 2) hostility, including aggressive behaviors, 3) thought disorder, including concentration problems and change in school performance, and 4) hyperkinesia (primarily restlessness and hyperactivity). Among the gabapentin-treated patients, most of the events were mild to moderate in intensity. In controlled trials in pediatric patients 3 to 12 years of age, the incidence of these adverse events was: emotional lability 6% (gabapentin-treated patients) vs. 1.3% (placebo-treated patients); hostility 5.2% vs. 1.3%; hyperkinesia 4.7% vs. 2.9%; and thought disorder 1.7% vs. 0%. One of these events, a report of hostility, was considered serious. Discontinuation of gabapentin treatment occurred in 1.3% of patients reporting emotional lability and hyperkinesia and 0.9% of gabapentin-treated patients reporting hostility and thought disorder. One placebo-treated patient (0.4%) withdrew due to emotional lability. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency. In the placebo-controlled studies in patients >12 years of age, the incidence of status epilepticus in patients receiving gabapentin was 0.6% (3 of 543) vs. 0.5% in patients receiving placebo (2 of 378). Among the 2074 patients >12 years of age treated with gabapentin across all studies (controlled and uncontrolled) 31 (1.5%) had status epilepticus. Of these, 14 patients had no prior history of status epilepticus either before treatment or while on other medications. Because adequate historical data are not available, it is impossible to say whether or not treatment with gabapentin is associated with a higher or lower rate of status epilepticus than would be expected to occur in a similar population not treated with gabapentin. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. (See PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility .) The clinical significance of this finding is unknown. Clinical experience during gabapentin’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies in adjunctive therapy in epilepsy comprising 2085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin’s lymphoma, 1 endometrial carcinoma in situ ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence seen in this cohort is or is not affected by treatment. Sudden and Unexplained Death in Patients With Epilepsy During the course of premarketing development of gabapentin, 8 sudden and unexplained deaths were recorded among a cohort of 2203 patients treated (2103 patient-years of exposure). Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0038 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving gabapentin (ranging from 0.0005 for the general population of epileptics to 0.003 for a clinical trial population similar to that in the gabapentin program, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or raise further concern depends on comparability of the populations reported upon to the gabapentin cohort and the accuracy of the estimates provided. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, 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. Because this disorder is variable in its expression, 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, the patient should be evaluated immediately. Gabapentin tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established."}', 'precautions': '{"PRECAUTIONS Information for Patients Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking gabapentin. Instruct patients to take gabapentin only as prescribed. Patients, their caregivers, and families should be counseled that AEDs, including gabapentin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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. Patients should be advised that gabapentin may cause dizziness, somnolence, and other symptoms and signs of CNS depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely. Patients who require concomitant treatment with morphine may experience increases in gabapentin concentrations. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately (see Drug Interactions ). Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy ). Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (such as fever or lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. Laboratory Tests Clinical trials data do not indicate that routine monitoring of clinical laboratory parameters is necessary for the safe use of gabapentin. The value of monitoring gabapentin blood concentrations has not been established. Gabapentin may be used in combination with other antiepileptic drugs without concern for alteration of the blood concentrations of gabapentin or of other antiepileptic drugs. Drug Interactions In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL; 1 mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL (approximately 15 times the C max at 3600 mg/day). Gabapentin is not appreciably metabolized nor does it interfere with the metabolism of commonly coadministered antiepileptic drugs. The drug interaction data described in this section were obtained from studies involving healthy adults and adult patients with epilepsy. Phenytoin: In a single (400 mg) and multiple dose (400 mg TID) study of gabapentin in epileptic patients (N=8) maintained on phenytoin monotherapy for at least 2 months, gabapentin had no effect on the steady-state trough plasma concentrations of phenytoin and phenytoin had no effect on gabapentin pharmacokinetics. Carbamazepine: Steady-state trough plasma carbamazepine and carbamazepine 10, 11 epoxide concentrations were not affected by concomitant gabapentin (400 mg TID; N=12) administration. Likewise, gabapentin pharmacokinetics were unaltered by carbamazepine administration. Valproic Acid: The mean steady-state trough serum valproic acid concentrations prior to and during concomitant gabapentin administration (400 mg TID; N=17) were not different and neither were gabapentin pharmacokinetic parameters affected by valproic acid. Phenobarbital: Estimates of steady-state pharmacokinetic parameters for phenobarbital or gabapentin (300 mg TID; N=12) are identical whether the drugs are administered alone or together. Naproxen: Coadministration (N=18) of naproxen sodium capsules (250 mg) with gabapentin (125 mg) appears to increase the amount of gabapentin absorbed by 12% to 15%. Gabapentin had no effect on naproxen pharmacokinetic parameters. These doses are lower than the therapeutic doses for both drugs. The magnitude of interaction within the recommended dose ranges of either drug is not known. Hydrocodone: Coadministration of gabapentin (125 to 500 mg; N=48) decreases hydrocodone (10 mg; N=50) C max and AUC values in a dose-dependent manner relative to administration of hydrocodone alone; C max and AUC values are 3% to 4% lower, respectively, after administration of 125 mg gabapentin and 21% to 22% lower, respectively, after administration of 500 mg gabapentin. The mechanism for this interaction is unknown. Hydrocodone increases gabapentin AUC values by 14%. The magnitude of interaction at other doses is not known. Morphine: A literature article reported that when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule (N=12), mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine (see PRECAUTIONS ). Morphine pharmacokinetic parameter values were not affected by administration of gabapentin 2 hours after morphine. The magnitude of interaction at other doses is not known. Cimetidine: In the presence of cimetidine at 300 mg QID (N=12), the mean apparent oral clearance of gabapentin fell by 14% and creatinine clearance fell by 10%. Thus cimetidine appeared to alter the renal excretion of both gabapentin and creatinine, an endogenous marker of renal function. This small decrease in excretion of gabapentin by cimetidine is not expected to be of clinical importance. The effect of gabapentin on cimetidine was not evaluated. Oral Contraceptive: Based on AUC and half-life, multiple-dose pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of tablets containing 2.5 mg of norethindrone acetate and 50 mcg of ethinyl estradiol were similar with and without coadministration of gabapentin (400 mg TID; N=13). The C max of norethindrone was 13% higher when it was coadministered with gabapentin; this interaction is not expected to be of clinical importance. Antacid Maalox ® (Aluminum Hydroxide and Magnesium Hydroxide Suspension): Maalox ® (Aluminum Hydroxide and Magnesium Hydroxide Suspension) reduced the bioavailability of gabapentin (N=16) by about 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after Maalox ® (Aluminum Hydroxide and Magnesium Hydroxide Suspension). It is recommended that gabapentin be taken at least 2 hours following Maalox ® (Aluminum Hydroxide and Magnesium Hydroxide Suspension) administration. Effect of Probenecid: Probenecid is a blocker of renal tubular secretion. Gabapentin pharmacokinetic parameters without and with probenecid were comparable. This indicates that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid. DRUG & OR LABORATORY TEST INTERACTIONS Because false positive readings were reported with the Ames N-Multistix SG ® dipstick test for urinary protein when gabapentin was added to other antiepileptic drugs, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein. Carcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenomas and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg were 10 times higher than plasma concentrations in humans receiving 3600 mg per day, and in rats receiving 1000 mg/kg/day, peak plasma concentrations were 6.5 times higher than in humans receiving 3600 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize, and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. Gabapentin did not demonstrate mutagenic or genotoxic potential in three in vitro and four in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin. No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 5 times the maximum recommended human dose on a mg/m 2 basis). Pregnancy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during the period of organogenesis, or approximately 1 to 4 times the maximum dose of 3600 mg/day given to epileptic patients on a mg/m 2 basis. The no-effect level was 500 mg/kg/day or approximately ½ of the human dose on a mg/m 2 basis. When rats were dosed prior to and during mating, and throughout gestation, pups from all dose groups (500, 1000, and 2000 mg/kg/day) were affected. These doses are equivalent to less than approximately 1 to 5 times the maximum human dose on a mg/m 2 basis. There was an increased incidence of hydroureter and/or hydronephrosis in rats in a study of fertility and general reproductive performance at 2000 mg/kg/day with no effect at 1000 mg/kg/day, in a teratology study at 1500 mg/kg/day with no effect at 300 mg/kg/day, and in a perinatal and postnatal study at all doses studied (500, 1000, and 2000 mg/kg/day). The doses at which the effects occurred are approximately 1 to 5 times the maximum human dose of 3600 mg/day on a mg/m 2 basis; the no-effect doses were approximately 3 times (Fertility and General Reproductive Performance study) and approximately equal to (Teratogenicity study) the maximum human dose on a mg/m 2 basis. Other than hydroureter and hydronephrosis, the etiologies of which are unclear, the incidence of malformations was not increased compared to controls in offspring of mice, rats, or rabbits given doses up to 50 times (mice), 30 times (rats), and 25 times (rabbits) the human daily dose on a mg/kg basis, or 4 times (mice), 5 times (rats), or 8 times (rabbits) the human daily dose on a mg/m 2 basis. In a teratology study in rabbits, an increased incidence of post implantation fetal loss occurred in dams exposed to 60, 300, and 1500 mg/kg/day, or less than approximately ¼ to 8 times the maximum human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to gabapentin, physicians are advised to recommend that pregnant patients taking gabapentin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Use in Nursing Mothers Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, gabapentin should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use Safety and effectiveness of gabapentin in the management of postherpetic neuralgia in pediatric patients have not been established. Effectiveness as adjunctive therapy in the treatment of partial seizures in pediatric patients below the age of 3 years has not been established (see CLINICAL PHARMACOLOGY, Clinical Studies ). Geriatric Use The total number of patients treated with gabapentin in controlled clinical trials in patients with postherpetic neuralgia was 336, of which 102 (30%) were 65 to 74 years of age, and 168 (50%) were 75 years of age and older. There was a larger treatment effect in patients 75 years of age and older compared with younger patients who received the same dosage. Since gabapentin is almost exclusively eliminated by renal excretion, the larger treatment effect observed in patients > 75 years may be a consequence of increased gabapentin exposure for a given dose that results from an age-related decrease in renal function. However, other factors cannot be excluded. The types and incidence of adverse events were similar across age groups except for peripheral edema and ataxia, which tended to increase in incidence with age. Clinical studies of gabapentin in epilepsy did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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. 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 dose should be adjusted based on creatinine clearance values in these patients (see CLINICAL PHARMACOLOGY , ADVERSE REACTIONS , and DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{GLYCOPYRROLATE}

{'contraindications': '{"CONTRAINDICATIONS Known hypersensitivity to glycopyrrolate or any of its inactive ingredients. In addition, in the management of peptic ulcer patients, because of the longer duration of therapy, glycopyrrolate injection may be contraindicated in patients with the following concurrent conditions: glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis."}', 'adverse_reactions': '{"ADVERSE REACTIONS Anticholinergics, including glycopyrrolate injection, can produce certain effects, most of which are extensions of their pharmacologic actions. Adverse reactions may include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; increased ocular tension; tachycardia; palpitation; decreased sweating; loss of taste; headache; nervousness; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; impotence; suppression of lactation; constipation; bloated feeling; severe allergic reactions including anaphylactic/anaphylactoid reactions; hypersensitivity; urticaria, pruritus, dry skin, and other dermal manifestations; some degree of mental confusion and/or excitement, especially in elderly persons. In addition, the following adverse events have been reported from post-marketing experience with glycopyrrolate: malignant hyperthermia; cardiac arrhythmias (including bradycardia, ventricular tachycardia, ventricular fibrillation); cardiac arrest; hypertension; hypotension; seizures; and respiratory arrest. Post-marketing reports have included cases of heart block and QTc interval prolongation associated with the combined use of glycopyrrolate and an anticholinesterase. Injection site reactions including pruritus, edema, erythema, and pain have also been reported. Glycopyrrolate is chemically a quaternary ammonium compound; hence, its passage across lipid membranes, such as the blood-brain barrier is limited in contrast to atropine sulfate and scopolamine hydrobromide. For this reason the occurrence of CNS-related side effects is lower, in comparison to their incidence following administration of anticholinergics which are chemically tertiary amines that can cross this barrier readily. To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-233-2001, or FDA at 1-800‑FDA‑1088 or www.fda.gov/medwatch ."}', 'drug_interactions': '{"Drug Interactions The concurrent use of glycopyrrolate injection with other anticholinergics or medications with anticholinergic activity, such as phenothiazines, antiparkinson drugs, or tricyclic antidepressants, may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects. Concomitant administration of glycopyrrolate injection and potassium chloride in a wax matrix may increase the severity of potassium chloride-induced gastrointestinal lesions as a result of a slower gastrointestinal transit time."}', 'indications_and_usage': '{"INDICATIONS AND USAGE In Anesthesia Glycopyrrolate Injection, USP is indicated for use as a preoperative antimuscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions; to reduce the volume and free acidity of gastric secretions; and to block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation. When indicated, Glycopyrrolate Injection, USP may be used intraoperatively to counteract surgically or drug-induced or vagal reflexes associated arrhythmias. Glycopyrrolate protects against the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing muscle relaxants. In Peptic Ulcer For use in adults as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE To combat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methylsulfate (which does not cross the blood-brain barrier) may be given intravenously in increments of 0.25 mg in adults. This dosage may be repeated every five to ten minutes until anticholinergic overactivity is reversed or up to a maximum of 2.5 mg. Proportionately smaller doses should be used in pediatric patients. Indication for repetitive doses of neostigmine should be based on close monitoring of the decrease in heart rate and the return of bowel sounds. If CNS symptoms (e.g., excitement, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the blood–brain barrier) may be used. Physostigmine 0.5 to 2 mg should be slowly administered intravenously and repeated as necessary up to a total of 5 mg in adults. Proportionately smaller doses should be used in pediatric patients. To combat hypotension, administer IV fluids and/or pressor agents along with supportive care. Fever should be treated symptomatically. Following overdosage, a curare-like action may occur, i.e., neuromuscular blockade leading to muscular weakness and possible paralysis. In the event of a curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns."}', 'active_flag': 'Y', 'generic_name': '{GLYCOPYRROLATE}', 'route': '{INTRAMUSCULAR,INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS This drug should be used with great caution, if at all, in patients with glaucoma. 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 containing this preservative must take into account the total amount of benzyl alcohol administered. 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 PRECAUTIONS, Pediatric Use ). Glycopyrrolate injection may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug. In addition, in the presence of fever, high environmental temperature and/or during physical exercise, heat prostration can occur with use of anticholinergic agents including glycopyrrolate (due to decreased sweating), particularly in children and the elderly. Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with glycopyrrolate injection would be inappropriate and possibly harmful."}', 'precautions': '{"PRECAUTIONS General Investigate any tachycardia before giving glycopyrrolate injection since an increase in the heart rate may occur. Use with caution in patients with: coronary artery disease; congestive heart failure; cardiac arrhythmias; hypertension; hyperthyroidism. Use with caution in patients with renal disease since the renal elimination of glycopyrrolate may be severely impaired in patients with renal failure. Dosage adjustments may be necessary (see Pharmacokinetics, Renal Impairment ). Use glycopyrrolate with caution in the elderly and in all patients with autonomic neuropathy, hepatic disease, ulcerative colitis, prostic hypertrophy, or hiatal hernia, since anticholinergic drugs may aggravate these conditions. The use of anticholinergetic drugs in the treatment of gastric ulcer may produce a delay in gastric emptying due to antral statis. Information for the Patient Because glycopyrrolate injection may produce drowsiness or blurred vision, the patient should be cautioned not to engage in activities requiring mental alertness and/or visual acuity such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug (see WARNINGS ). The patient also should be cautioned about the use of this drug during exercise or hot weather since overheating may result in heat stroke. The patient may experience a possible sensitivity of the eyes to light. Drug Interactions The concurrent use of glycopyrrolate injection with other anticholinergics or medications with anticholinergic activity, such as phenothiazines, antiparkinson drugs, or tricyclic antidepressants, may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects. Concomitant administration of glycopyrrolate injection and potassium chloride in a wax matrix may increase the severity of potassium chloride-induced gastrointestinal lesions as a result of a slower gastrointestinal transit time. Carcinogenesis and Mutagenesis and Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to evaluate the mutagenic potential of glycopyrrolate have not been conducted. In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rates of conception in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate. Pregnancy Teratogenic Effects - Pregnancy Category B. Reproduction studies with glycopyrrolate were performed in rats at a dietary dose of approximately 65 mg/kg/day (exposure was approximately 320 times the maximum recommended daily human dose of 2 mg on a mg/m 2 basis) and rabbits at intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 5 times the maximum recommended daily human dose on a mg/m 2 basis). These studies produced no teratogenic effects to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Single-dose studies in humans found that very small amounts of glycopyrrolate passed the placental barrier. Nonteratogenic Effects Published literature suggest the following regarding the use of glycopyrrolate during pregnancy. Unlike atropine, glycopyrrolate in normal doses (0.004 mg/kg) does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and aterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts. In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rates of pup survival in a dose-related manner. 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 glycopyrrolate injection is administered to a nursing woman. As with other anticholinergics, glycopyrrolate may cause suppression of lactation (see ADVERSE REACTIONS ). Pediatric Use Due to its benzyl alcohol content, glycopyrrolate injection should not be used in neonates, i.e., patients less than 1 month of age. Safety and effectiveness in pediatric patients have not been established for the management of peptic ulcer. Dysrhythmias associated with the use of glycopyrrolate intravenously as a premedicant or during anesthesia have been observed in pediatric patients. Infants, patients with Down’s syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects. A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients taking large doses of anticholinergics including glycopyrrolate injection. Infants and young children are especially susceptible to the toxic effects of anticholinergics. Benzyl alcohol, a component of this drug 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 >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hemotologic 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-birthweight 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. Geriatric Use Clinical Studies of glycopyrrolate injection 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 therapy."}', 'information_for_patients': '{"Information for the Patient Because glycopyrrolate injection may produce drowsiness or blurred vision, the patient should be cautioned not to engage in activities requiring mental alertness and/or visual acuity such as operating a motor vehicle or other machinery, or performing hazardous work while taking this drug (see WARNINGS ). The patient also should be cautioned about the use of this drug during exercise or hot weather since overheating may result in heat stroke. The patient may experience a possible sensitivity of the eyes to light."}', 'pregnancy': '{"Pregnancy Teratogenic Effects - Pregnancy Category B. Reproduction studies with glycopyrrolate were performed in rats at a dietary dose of approximately 65 mg/kg/day (exposure was approximately 320 times the maximum recommended daily human dose of 2 mg on a mg/m 2 basis) and rabbits at intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 5 times the maximum recommended daily human dose on a mg/m 2 basis). These studies produced no teratogenic effects to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Single-dose studies in humans found that very small amounts of glycopyrrolate passed the placental barrier. Nonteratogenic Effects Published literature suggest the following regarding the use of glycopyrrolate during pregnancy. Unlike atropine, glycopyrrolate in normal doses (0.004 mg/kg) does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and aterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts. In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rates of pup survival in a dose-related manner."}', 'pediatric_use': '{"Pediatric Use Due to its benzyl alcohol content, glycopyrrolate injection should not be used in neonates, i.e., patients less than 1 month of age. Safety and effectiveness in pediatric patients have not been established for the management of peptic ulcer. Dysrhythmias associated with the use of glycopyrrolate intravenously as a premedicant or during anesthesia have been observed in pediatric patients. Infants, patients with Down’s syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects. A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients taking large doses of anticholinergics including glycopyrrolate injection. Infants and young children are especially susceptible to the toxic effects of anticholinergics. Benzyl alcohol, a component of this drug 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 >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hemotologic 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-birthweight 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."}', 'geriatric_use': '{"Geriatric Use Clinical Studies of glycopyrrolate injection 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 therapy."}'}

{MENTHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Temporarily relieves minor aches and pains of muscles and joints associated with simple backache arthritis strains bruises sprains"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{MENTHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if: Condition worsens, or if symptoms persist for more than 7 day or clear up and occur again withing a few days"}', 'do_not_use': None, 'when_using': '{"Do not use with other topical pain relievers Do not use with heating pads or other heating devices Avoid contact with eyes Do not bandage tightly Do not apply to wounds or damage skin"}', 'warnings': '{"For external use only"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALLYLTHIOUREA}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Old and hard scars*"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ALLYLTHIOUREA}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist for more than 3 days or worsen"}', 'do_not_use': None, 'when_using': None, 'warnings': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"FEXOFENADINE HYDROCHLORIDE","PSEUDOEPHEDRINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use(s) 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 temporarily relives nasal congestion due to the common cold, hay fever or other upper respiratory allergies reduces swelling of nasal passages temporarily relieves sinus congestion and pressure temporarily restores freer breathing through the nose"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"FEXOFENADINE HCL AND PSEUDOEPHEDRINE HCI"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask doctor if an allergic reaction to this product occurs. Seek medical help right away. symptoms do not improve within 7 days or are accompanied by a fever you get nervous, dizzy, or sleepless"}', 'do_not_use': '{"Do not use if you have ever had an allergic reaction to this product or any of its ingredients if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. if you have difficulty swallowing"}', 'when_using': '{"When using this product do not take more than directed do not take at the same time as aluminum or magnesium antacids do not take with fruit juices (see Directions) the tablet coating may be seen in the stool (this is normal). Continue to take as directed (see Directions)."}', 'warnings': '{"Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. if you have difficulty swallowing Ask a doctor before use if you have heart disease thyroid disease glaucoma high blood pressure diabetes trouble urinating due to an enlarged prostate gland kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed do not take at the same time as aluminum or magnesium antacids do not take with fruit juices (see Directions) the tablet coating may be seen in the stool (this is normal). Continue to take as directed (see Directions). Stop use and ask doctor if an allergic reaction to this product occurs. Seek medical help right away. symptoms do not improve within 7 days or are accompanied by a fever you get nervous, dizzy, or sleepless 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}

{"VENLAFAXINE HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with Venlafaxine Hydrochloride Extended-Release Tablets or within 7 days of stopping treatment with Venlafaxine Hydrochloride Extended-Release Tablets. Do not use Venlafaxine Hydrochloride Extended-Release Tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Venlafaxine Hydrochloride Extended-Release Tablets in a patient who is being treated with linezolid or intravenous methylene blue. ( 4.1 ) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Venlafaxine Hydrochloride Extended-Release Tablets or within 7 days of stopping treatment with Venlafaxine Hydrochloride Extended-Release Tablets is contraindicated because of an increased risk of serotonin syndrome. The use of Venlafaxine Hydrochloride Extended-Release Tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [ see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.2 ) ]. Starting Venlafaxine Hydrochloride Extended-Release 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 ( 2.7 ) and Warnings and Precautions ( 5.2 ) ]."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Major Depressive Disorder - Adverse events in short-term studies that occurred in at least 5% of the patients receiving venlafaxine extended-release capsules and at a rate at least twice that of the placebo group were abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. ( 6 ) Social Anxiety Disorder - Adverse events in short-term studies that occurred in at least 5% of the patients receiving venlafaxine extended-release capsules and at a rate at least twice that of the placebo group were asthenia, gastrointestinal complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and abnormal vision. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Data Sources The information included in subsection \\"Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Venlafaxine Hydrochloride Extended-Release Capsules\\" is based on data from a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trials and one European trial), and on data up to 12 weeks from a pool of two controlled clinical trials in Social Anxiety Disorder. Information on additional adverse reactions associated with venlafaxine hydrochloride extended-release capsules in the entire development program for the formulation and with venlafaxine hydrochloride immediate-release tablets is included in the subsection \\"Other Adverse Reactions Observed During the Premarketing Evaluation of Venlafaxine Hydrochloride Immediate-Release Tablets and Venlafaxine Hydrochloride Extended-Release Capsules\\" [ see also Warnings and Precautions ( 5 ) ]. 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 Findings Observed in Short-Term, Placebo-Controlled Studies with Venlafaxine Hydrochloride Extended-Release Capsules Adverse Reactions Associated with Discontinuation of Treatment Major Depressive Disorder: Approximately 11% of the 357 patients who received venlafaxine hydrochloride extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse reaction, compared with 6% of the 285 placebo-treated patients in those studies. Adverse reactions that led to treatment discontinuation in a least 2% of drug-treated patients were nausea, dizziness, and somnolence. Social Anxiety Disorder: Approximately 17% of the 277 patients who received venlafaxine hydrochloride extended-release capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse reaction, compared with 5% of the 274 placebo-treated patients in those studies. Adverse reactions that led to treatment discontinuation in a least 2% of drug-treated patients were nausea, insomnia, impotence, headache, dizziness, and somnolence. Adverse Reactions Occurring at an Incidence of 5% or More Major Depressive Disorder: Note in particular the following adverse reactions that occurred in at least 5% of the patients receiving venlafaxine hydrochloride extended-release capsules and at a rate at least twice that of the placebo group for all placebo-controlled trials for the major depressive disorder indication (see Table 6): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S. placebo-controlled trials, the following additional reactions occurred in at least 5% of patients treated with venlafaxine hydrochloride extended-release capsules (n = 192) and at a rate at least twice that of the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia, nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), and yawning. Social Anxiety Disorder: Note in particular the following adverse reactions that occurred in at least 5% of the patients receiving venlafaxine hydrochloride extended-release capsules and at a rate at least twice that of the placebo group for the 2 placebo-controlled trials for the Social Anxiety Disorder indication (see Table 7): Asthenia, gastrointestinal complaints (anorexia, constipation, dry mouth, nausea), CNS complaints (dizziness, insomnia, libido decreased, nervousness, somnolence), abnormalities of sexual function (abnormal ejaculation, impotence, libido decreased, orgasmic dysfunction), yawn, sweating, and abnormal vision. Adverse Reactions Occurring at an Incidence of 2% or More Among Patients Treated with Venlafaxine Hydrochloride Extended-Release Capsules Tables 6 and 7 enumerate the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 to 225 mg/day) and of Social Anxiety Disorder (up to 12 weeks; dose range of 75 to 225 mg/day), respectively, in 2% or more of patients treated with venlafaxine hydrochloride extended-release capsules where the incidence in patients treated with venlafaxine hydrochloride extended-release capsules was greater than the incidence for the respective placebo-treated patients. The table shows the percentage of patients in each group who had at least one episode of a reaction at some time during their treatment. Reported adverse reactions were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice where patient characteristics and other factors differ from those which 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 contribution of drug and nondrug factors to the adverse reaction incidence rate in the population studied. Table 6: Treatment-Emergent Adverse Reaction Incidence in Short-Term Placebo-Controlled Clinical Trials with Venlafaxine Hydrochloride Extended-Release Capsules in Patients with Major Depressive Disorder 1,2 Body System Preferred Term Venlafaxine Hydrochloride Extended-Release Capsules (n = 357) Placebo (n = 285) Body as a Whole Asthenia 8% 7% Cardiovascular System Vasodilatation 3 Hypertension 4% 4% 2% 1% Digestive System Nausea Constipation Anorexia Vomiting Flatulence 31% 8% 8% 4% 4% 12% 5% 4% 2% 3% Metabolic/Nutritional Weight Loss 3% 0% Nervous System Dizziness Somnolence Insomnia Dry Mouth Nervousness Abnormal Dreams 4 Tremor Depression Paresthesia Libido Decreased Agitation 20% 17% 17% 12% 10% 7% 5% 3% 3% 3% 3% 9% 8% 11% 6% 5% 2% 2% <1% 1% <1% 1% Respiratory System Pharyngitis Yawn 7% 3% 6% 0% Skin Sweating 14% 3% Special Senses Abnormal Vision 5 4% <1% Urogenital System Abnormal Ejaculation (male) 6,7 Impotence 7 Anorgasmia (female) 8,9 16% 4% 3% <1% <1% <1% 1 Incidence, rounded to the nearest %, for reactions reported by at least 2% of patients treated with venlafaxine hydrochloride extended-release capsules, except for reactions which had an incidence equal to or less than placebo. 2 <1% indicates an incidence greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 5 Mostly “blurred vision” and “difficulty focusing eyes.” 6 Mostly “delayed ejaculation.” 7 Incidence is based on the number of male patients. 8 Mostly “delayed orgasm” or “anorgasmia.” 9 Incidence is based on the number of female patients. Table 7: Treatment-Emergent Adverse Reaction Incidence in Short-Term Placebo-Controlled Clinical Trials with Venlafaxine Hydrochloride Extended-Release Capsules in Social Anxiety Disorder Patients 1,2 Body System % Reporting Reaction Preferred Term Venlafaxine Hydrochloride Extended-Release Capsules (n=277) Placebo (n=274) Body as a Whole Headache 34% 33% Asthenia 17% 8% Flu Syndrome 6% 5% Accidental Injury 5% 3% Abdominal Pain 4% 3% Cardiovascular System Hypertension 5% 4% Vasodilatation 3 3% 1% Palpitation Digestive System 3% 1% Nausea 29% 9% Anorexia 4 20% 1% Constipation 8% 4% Diarrhea 6% 5% Vomiting 3% 2% Eructation 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Nervous System Insomnia 23% 7% Dry Mouth 17% 4% Dizziness 16% 8% Somnolence 16% 8% Nervousness 11% 3% Libido Decreased 9% <1% Anxiety 5% 3% Agitation 4% 1% Tremor 4% <1% Abnormal Dreams 5 4% <1% Paresthesia 3% <1% Twitching 2% 0% Respiratory System Yawn 5% <1% Sinusitis 2% 1% Skin Sweating 13% 2% Special Senses Abnormal Vision 6 6% 3% Urogenital System Abnormal Ejaculation 7,8 16% 1% Impotence 8 10% 1% Orgasmic Dysfunction 9,10 8% 0% 1 Adverse reactions for which the venlafaxine hydrochloride extended-release capsules reporting rate was less than or equal to the placebo rate are not included. 2 <1% means greater than zero but less than 1%. 3 Mostly “hot flashes.” 4 Mostly “decreased appetite” and “loss of appetite.” 5 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.” 6 Mostly “blurred vision.” 7 Includes “delayed ejaculation” and “anorgasmia.” 8 Percentage based on the number of males (venlafaxine hydrochloride extended-release capsules = 158, placebo = 153). 9 Includes “abnormal orgasm” and “anorgasmia.” 10 Percentage based on the number of females (venlafaxine hydrochloride extended-release capsules = 119, placebo = 121). Vital Sign Changes Treatment with venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Treatment with venlafaxine hydrochloride extended-release capsules for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 4 beats per minute, compared with an increase of 1 beat per minute for placebo. [ See Warnings and Precautions ( 5.4 ) for effects on blood pressure]. In a flexible-dose study in MDD, with doses of venlafaxine hydrochloride immediate-release tablets in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo [ see Warnings and Precautions ( 5.16 ) for effects on heart rate]. Laboratory Changes Serum Cholesterol Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in other premarketing placebo-controlled trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL compared with a mean final decrease of 2.9 mg/dL for placebo. Patients treated with venlafaxine hydrochloride immediate-release tablets for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients [ see Warnings and Precautions ( 5.14 ) ]. Serum Triglycerides Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in pooled premarketing trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 8.2 mg/dL, compared with a mean final increase of 0.4 mg/dL for placebo. ECG Changes In a flexible-dose MDD study with doses of venlafaxine hydrochloride immediate-release tablets in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo [ see Warnings and Precautions ( 5.16 ) ]. Other Adverse Reactions Observed During the Premarketing Evaluation of Venlafaxine Hydrochloride Immediate-Release Tablets and Venlafaxine Hydrochloride Extended-Release Capsules. During its premarketing assessment, multiple doses of venlafaxine hydrochloride extended-release capsules were administered to 705 patients in Phase 3 major depressive disorder studies and venlafaxine hydrochloride immediate-release tablets were administered to 96 patients. During its premarketing assessment, multiple doses of venlafaxine hydrochloride extended-release capsules were also administered to 3514 patients in other Phase 3 studies. In addition, in premarketing assessment of venlafaxine hydrochloride immediate-release tablets, multiple doses were administered to 2,897 patients in Phase 2 to Phase 3 studies for major depressive disorder. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine hydrochloride immediate-release tablets only) and outpatient studies, fixed-dose, and titration studies. Adverse reactions associated with this exposure were 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 untoward events into a smaller number of standardized reaction categories. In the tabulations that follow, reported adverse reactions were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7,212 patients exposed to multiple doses of either formulation of venlafaxine who experienced a reaction of the type cited on at least one occasion while receiving venlafaxine. All reported reactions are included except those already listed in Tables 6 and 7 and those reactions for which a drug cause was remote. If the COSTART term for a reaction was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the reactions reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Reactions are further categorized by body system and listed in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; I nfrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; Rare reactions are those occurring in fewer than 1/1,000 patients. Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, cellulitis, granuloma. Cardiovascular system - Frequent: migraine, tachycardia; Infrequent: angina pectoris, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), postural hypotension, syncope; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia, thrombophlebitis. Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue edema, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, salivary gland enlargement, increased salivation, soft stools, tongue discoloration. Endocrine system - Rare: galactorrhoea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia. Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipidemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia. Musculoskeletal system - Infrequent: arthritis, arthrosis, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, stupor, suicidal ideation; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis. Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia; Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea. Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin, eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased. Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent: conjunctivitis, diplopia, dry eyes, otitis media, parosmia, photophobia, taste loss; Rare: blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, hyperacusis, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual field defect. Urogenital system - Frequent: albuminuria, urination impaired; Infrequent: amenorrhea,* cystitis, dysuria, hematuria, kidney calculus, kidney pain, leukorrhea,* menorrhagia,* metrorrhagia,* nocturia, breast pain, polyuria, pyuria, prostatic disorder (prostatitis, enlarged prostate, and prostate irritability),* urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage,* vaginitis*; Rare: abortion,* anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* bladder pain, prolonged erection,* gynecomastia (male),* hypomenorrhea,* mastitis, menopause,* pyelonephritis, oliguria, salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.* *Based on the number of men and women as appropriate. 6.2 Post-Marketing Experience Voluntary reports of other adverse reactions temporally associated with the use of venlafaxine have been received since market introduction. Because these reactions are reported 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 reports include the following reactions: agranulocytosis, anaphylaxis, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, Takotsubo cardiomyopathy, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic reactions (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neuroleptic malignant syndrome-like reactions (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly)."}', 'drug_interactions': '{"7 DRUG INTERACTIONS MAOIs: concomitant use contraindicated. ( 4 ) Avoid MAOIs 14 days before starting venlafaxine and 7 days after stopping venlafaxine. ( 5.2 ) Cimetidine: Caution in patients with pre-existing hypertension, in elderly patients and patients with hepatic dysfunction. ( 7.2 ) Haloperidol: Increase in haloperidol AUC and C max . ( 7.4 ) Ketoconazole: Increase in venlafaxine and O-desmethylvenlafaxine AUC and C max . Caution when using venlafaxine with substances that inhibit both CYP2D6 and CYP3A4. ( 7.7 ) Metoprolol: Possibly reduced blood pressure lowering effect despite increased metoprolol plasma levels. Caution should be exercised with co-administration of venlafaxine and metoprolol. ( 7.8 ) CNS-active drugs: Caution when using venlafaxine with such drugs. ( 7.10 ) Serotonergic drugs (e.g., triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St. John\'s Wort): Potential for serotonin syndrome. Careful patient observation advised. ( 7.10 ) Tryptophan supplements: Concomitant use not recommended. ( 7.10 ) 7.1 Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O‑desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine. 7.2 Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C max ) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients. 7.3 Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. 7.4 Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged. The mechanism explaining this finding is unknown. 7.5 Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below). 7.6 Drugs Highly Bound to Plasma Proteins Venlafaxine is not highly bound to plasma proteins; therefore, administration of Venlafaxine Hydrochloride Extended-Release Tablets to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. 7.7 Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers [ see Clinical Pharmacology ( 12.3 ) ]. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n=14) and 25 mg in poor metabolizers (PM; n=6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desmethylvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine C max increased by 26% in EM subjects and 48% in PM subjects. C max values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PM subjects: -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PM subjects: - 38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EM subjects and 53% in PM subjects (range in PM subjects: 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. 7.8 Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6 In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max , and C min increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Metoprolol - Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α‑hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Venlafaxine Hydrochloride Extended-Release Tablets have regular monitoring of blood pressure [ see Warnings and Precautions ( 5.3 ) ]. Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4 Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2 Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9 Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19 Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above). 7.9 Monoamine Oxidase Inhibitors (MAOIs) [ See Dosage and Administration ( 2.6 and 2.7 ), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.2 ) ]. 7.10 Serotonergic Drugs [ See Dosage and Administration ( 2.6 and 2.7 ), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.2 ) ]. 7.11 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. These studies 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 and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Venlafaxine Hydrochloride Extended-Release Tablets are initiated or discontinued [ see Warnings and Precautions ( 5.13 ) ]. 7.12 Electroconvulsive Therapy There are no clinical data establishing the benefit of electroconvulsive therapy combined with Venlafaxine Hydrochloride Extended-Release Tablets treatment. 7.13 Postmarketing Spontaneous Drug Interaction Reports There have been reports of elevated clozapine levels that were temporally associated with adverse reactions, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy. 7.14 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Venlafaxine Hydrochloride Extended-Release Tablets are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: Major Depressive Disorder (MDD) ( 1.1 ) Social Anxiety Disorder (SAD) ( 1.2 ) 1.1 Major Depressive Disorder Venlafaxine Hydrochloride Extended-Release Tablets are indicated for the treatment of major depressive disorder (MDD). Efficacy of venlafaxine in MDD was shown in both short-term trials and a longer-term trial in MDD [ see Clinical Studies ( 14.1 ) ]. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. 1.2 Social Anxiety Disorder Venlafaxine Hydrochloride Extended-Release Tablets are indicated for the treatment of Social Anxiety Disorder (SAD), also known as Social Phobia, as defined in DSM-IV. Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person\'s normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. Efficacy of venlafaxine extended release in the treatment of SAD was established in short-term SAD trials [ see Clinical Studies ( 14.2 ) ]."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including Venlafaxine Hydrochloride Extended-Release Tablets, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John\'s Wort). If such symptoms occur, discontinue Venlafaxine Hydrochloride Extended-Release Tablets and initiate supportive treatment. If concomitant use of Venlafaxine Hydrochloride Extended-Release Tablets with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. ( 5.2 ) Suicidality: Monitor for clinical worsening and suicide risk. ( 5.1 ) Sustained hypertension may occur. Blood pressure monitoring recommended. ( 5.3 ) Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.4 ) Abrupt discontinuation or dose reduction: Discontinuation symptoms may occur (generally self-limiting; serious symptoms possible). Dose reduction recommended to be gradual. ( 5.5 ) Activation of Mania/Hypomania has occurred. ( 5.10 ) Symptomatic hyponatremia may occur. ( 5.11 ) Seizures have been reported. Use with caution in patients with seizure history. ( 5.12 ) Abnormal bleeding (most commonly ecchymosis) has been reported. ( 5.13 ) Serum cholesterol: Clinically relevant cholesterol increases may occur. Cholesterol measurements should be considered during long-term therapy. ( 5.14 ) Interstitial lung disease and eosinophilic pneumonia have been reported. ( 5.15 ) 5.1 Clinical Worsening and Suicide Risk 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 4,400 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 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 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 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 trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug 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 abrupt discontinuation can be associated with certain symptoms [ see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.5 ) ]. 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 Venlafaxine Hydrochloride Extended-Release Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 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 Venlafaxine Hydrochloride Extended-Release Tablets are not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Venlafaxine Hydrochloride Extended-Release Tablets, alone but particularly 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 (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). 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). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Venlafaxine Hydrochloride Extended-Release Tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Venlafaxine Hydrochloride Extended-Release Tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking Venlafaxine Hydrochloride Extended-Release Tablets. Venlafaxine Hydrochloride Extended-Release Tablets should be discontinued before initiating treatment with the MAOI [ see Contraindications ( 4.1 ) and Dosage and Administration ( 2.6 and 2.7 ) ]. If concomitant use of Venlafaxine Hydrochloride Extended-Release Tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John\'s Wort is clinically warranted, patients should be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with Venlafaxine Hydrochloride Extended-Release Tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Sustained Hypertension Venlafaxine hydrochloride extended-release capsule treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits) (see Table 2). An analysis for patients in venlafaxine hydrochloride immediate-release tablet studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for immediate-release venlafaxine hydrochloride (see Table 3). An insufficient number of patients received mean doses of venlafaxine hydrochloride extended release capsules over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. Table 2: Number (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride Extended-Release Capsule Premarketing Studies by Indication Major Depressive Disorder (75-375 mg/day) Other Clinical Trials (75-225 mg/day) 19/705 (3) 5/771 (0.6) Table 3: Incidence (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride Immediate-Release Tablet Studies Venlafaxine mg/day Incidence <100 3% >100 to ≤200 5% >200 to ≤300 7% >300 13% In premarketing major depressive disorder studies, 0.7% (5/705) of the venlafaxine hydrochloride extended-release capsule-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In other clinical studies, 0.6% (5/771) of the venlafaxine hydrochloride extended-release capsule-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1 to 24 mm Hg, SDBP). Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Venlafaxine Hydrochloride Extended-Release Tablets have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered. Elevations in Systolic and Diastolic Blood Pressure In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean change in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in venlafaxine hydrochloride extended-release capsule-treated patients. Table 4: Final On-Therapy Mean Changes from Baseline in Supine Systolic and Diastolic Blood Pressure (mm Hg) Results by Indication, Study Duration, and Dose in Placebo-Controlled Trials Venlafaxine Hydrochloride Extended-Release Capsules mg/day Placebo ≤75 >75 SSBP 1 SDBP 2 SSBP SDBP SSBP SDBP Major Depressive Disorder 8-12 weeks -0.28 0.37 2.93 3.56 -1.08 -0.10 Other Clinical Trials 12 weeks -0.29 -1.26 1.18 1.34 -1.96 -1.22 1 Supine Systolic Blood Pressure 2 Supine Diastolic Blood Pressure Across all clinical trials, 1.4% of patients in the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups. 5.4 Angle Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Venlafaxine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.5 Discontinuation of Treatment with Venlafaxine Hydrochloride Extended-Release Tablets Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials and retrospective surveys of trials in major depressive disorder and social anxiety disorder. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), 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, hypomania, tinnitus, and seizures. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with Venlafaxine Hydrochloride Extended-Release Tablets. 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 ( 2.4 ) ]. 5.6 Insomnia and Nervousness Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine hydrochloride extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder and other clinical studies, as shown in Table 5. Table 5: Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder and Other Trials Major Depressive Disorder Other Trials Venlafaxine Hydrochloride Extended-Release Capsules Placebo Venlafaxine Hydrochloride Extended-Release Capsules Placebo Symptom n = 357 n = 285 n = 819 n = 695 Insomnia 17% 11% 24% 8% Nervousness 10% 5% 10% 5% Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with venlafaxine hydrochloride extended-release capsules in major depressive disorder studies. In other clinical trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with venlafaxine hydrochloride extended-release capsules up to 12 weeks. 5.7 Changes in Weight Adult Patients: A loss of 5% or more of body weight occurred in 7% of patients treated with venlafaxine hydrochloride extended-release capsules and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with venlafaxine hydrochloride extended-release capsules was 0.1% in major depressive disorder studies. In other placebo-controlled trials, 4% of the patients treated with venlafaxine hydrochloride extended-release capsules and 1% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 6 months of treatment. None of the patients receiving venlafaxine hydrochloride extended-release capsules in other studies discontinued for weight loss. The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Venlafaxine Hydrochloride Extended-Release Tablets and weight loss agents is not recommended. Venlafaxine Hydrochloride Extended-Release Tablets are not indicated for weight loss alone or in combination with other products. Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving venlafaxine hydrochloride extended-release capsules. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and another disorder, patients treated with venlafaxine hydrochloride extended-release capsules lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with venlafaxine hydrochloride extended-release capsules than with placebo experienced a weight loss of at least 3.5% in the studies (18% of patients treated with venlafaxine hydrochloride extended-release capsules vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient study for another disorder, venlafaxine hydrochloride extended-release capsule-treated patients lost an average of 0.75 kg (n=137), while placebo-treated patients gained an average of 0.76 kg (n=148). More patients treated with venlafaxine hydrochloride extended-release capsules than with placebo experienced a weight loss of at least 3.5% in the study (47% of patients treated with venlafaxine hydrochloride extended-release capsules vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia [ see Warnings and Precautions ( 5.9 ) ]. The risks associated with longer-term use of venlafaxine hydrochloride extended-release capsules were assessed in an open-label MDD study of children and adolescents who received venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old). 5.8 Changes in Height Pediatric Patients: During an eight-week, placebo-controlled non-MDD study, venlafaxine hydrochloride extended-release capsule-treated patients (ages 6-17) grew an average of 0.3 cm (n=122), while placebo-treated patients grew an average of 1.0 cm (n=132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, venlafaxine hydrochloride extended-release capsule-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). During a 16-week, placebo-controlled non-MDD study, both the venlafaxine hydrochloride extended-release capsule-treated patients (n=109) and the placebo-treated (n=112) patients each grew an average of 1.0 cm. In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old). 5.9 Changes in Appetite Adult Patients: Treatment-emergent anorexia was more commonly reported for patients treated with venlafaxine hydrochloride extended-release capsules (8%) than for placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with venlafaxine hydrochloride extended-release capsules was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for patients treated with venlafaxine hydrochloride extended-release capsules (20%) than for placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled Social Anxiety Disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving venlafaxine hydrochloride extended-release capsules for up to 12 weeks in Social Anxiety Disorder studies. Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving venlafaxine hydrochloride extended-release capsules. In placebo-controlled trials in MDD and another disorder, 10% of patients aged 6-17 treated with venlafaxine hydrochloride extended release capsules for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving venlafaxine hydrochloride extended-release capsules discontinued for anorexia or weight loss. In a placebo-controlled non-MDD trial, 22% and 3% of patients aged 8-17 treated for up to 16 weeks with venlafaxine hydrochloride extended-release capsules and placebo, respectively, reported treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving venlafaxine hydrochloride extended-release capsules and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine hydrochloride extended-release capsules or placebo. 5.10 Activation of Mania/Hypomania During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of patients treated with venlafaxine hydrochloride extended-release capsules and 0.0% placebo patients. In premarketing Social Anxiety Disorder studies, no patients treated with venlafaxine hydrochloride extended-release capsules and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with venlafaxine hydrochloride immediate-release tablets, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0.0% of placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Venlafaxine Hydrochloride Extended-Release Tablets should be used cautiously in patients with a history of mania. 5.11 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Venlafaxine Hydrochloride Extended-Release Tablets. 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. 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 ) ]. Discontinuation of Venlafaxine Hydrochloride Extended-Release Tablets 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. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.12 Seizures During premarketing experience, no seizures occurred among 705 patients treated with venlafaxine hydrochloride extended-release capsules in the major depressive disorder studies or among 277 patients treated with venlafaxine hydrochloride extended-release capsules in Social Anxiety Disorder studies. In all premarketing major depressive disorder trials with venlafaxine hydrochloride immediate-release tablets, seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Venlafaxine Hydrochloride Extended-Release Tablets, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. 5.13 Abnormal Bleeding SSRIs and SNRIs, including Venlafaxine Hydrochloride Extended-Release Tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory 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 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Venlafaxine Hydrochloride Extended-Release Tablets and NSAIDs, aspirin, or other drugs that affect coagulation. 5.14 Serum Cholesterol Elevation Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials [ see Adverse Reactions ( 6.1 ) ]. Measurement of serum cholesterol levels should be considered during long-term treatment. 5.15 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse reactions should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered. 5.16 Use in Patients With Heart Disease Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Venlafaxine Hydrochloride Extended-Release Tablets to patients with diseases or conditions that could affect hemodynamic responses. Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine\'s premarketing testing. The electrocardiograms were analyzed for 275 patients who received venlafaxine hydrochloride extended-release capsules and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder as well as for 195 patients who received venlafaxine hydrochloride extended-release capsules and 228 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for patients treated with venlafaxine hydrochloride extended-release capsules in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine hydrochloride extended-release capsules and decrease of 1.9 msec for placebo). The mean change from baseline in QTc for patients treated with venlafaxine hydrochloride extended-release capsules in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for venlafaxine hydrochloride extended-release capsules and decrease of 2.0 msec for placebo). In these same trials, the mean change from baseline in heart rate for patients treated with venlafaxine hydrochloride extended-release capsules in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine hydrochloride extended-release capsules and 1 beat per minute for placebo). The mean change from baseline in heart rate for patients treated with venlafaxine hydrochloride extended-release capsules in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for venlafaxine hydrochloride extended-release capsules and no change for placebo). In a flexible-dose study, with doses of venlafaxine hydrochloride immediate-release tablets in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, patients treated with venlafaxine hydrochloride immediate-release tablets had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction). Evaluation of the electrocardiograms for 769 patients who received venlafaxine hydrochloride immediate-release tablets in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. 5.17 Laboratory Tests There are no specific laboratory tests recommended."}', 'overdosage': '{"10 OVERDOSAGE 10.1 Human Experience Among the patients included in the premarketing evaluation of venlafaxine hydrochloride extended-release capsules, there were 2 reports of acute overdosage with venlafaxine hydrochloride extended-release capsules in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of venlafaxine hydrochloride extended-release capsules and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of venlafaxine hydrochloride extended-release capsules. This patient reported paresthesia of all four limbs but recovered without sequelae. There were no reports of acute overdose with venlafaxine hydrochloride extended-release capsules in Social Anxiety Disorder trials. Among the patients included in the premarketing evaluation with venlafaxine hydrochloride immediate-release tablets, there were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL, respectively, and the peak plasma levels of O‑desmethylvenlafaxine were 3.37 and 1.30 μg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported reactions in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is not clear. Prescriptions for Venlafaxine Hydrochloride Extended-Release Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 10.2 Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. 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. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians\' Desk Reference ® (PDR)."}', 'active_flag': 'Y', 'generic_name': '{"VENLAFAXINE 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 See FDA-approved Medication Guide (17.9) Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Venlafaxine Hydrochloride Extended-Release Tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Venlafaxine Hydrochloride Extended-Release Tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Venlafaxine Hydrochloride Extended-Release Tablets. 17.1 Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient\'s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient\'s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. 17.2 Interference with Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities. 17.3 Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Venlafaxine Hydrochloride Extended-Release Tablets and triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements or other serotonergic agents [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.10 ) ]. Patients should be cautioned about the concomitant use of Venlafaxine Hydrochloride Extended-Release Tablets 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 ( 5.13 ) and Drug Interactions ( 7.11 ) ]. 17.4 Alcohol Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine. 17.5 Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon. 17.6 Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. 17.7 Nursing Patients should be advised to notify their physician if they are breast-feeding an infant. 17.8 Angle Closure Glaucoma Patients should be advised that taking Venlafaxine 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 ( 5.4 ) ]. 17.9 FDA-Approved Medication Guide Manufactured by: Dexcel Pharma Technologies Ltd. 10 Hakidma St. Yokneam 2069200, Israel Distributed by: Lannett Company, Inc. Philadelphia, PA 19136 All Product/Brand names are the trademarks of their respective owners. L7051A"}', 'pregnancy': '{"8.1 Pregnancy Teratogenic Effects Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m 2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m 2 basis. There are 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. Non-Teratogenic Effects Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors) 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 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) ]. When treating a pregnant woman with Venlafaxine Hydrochloride Extended-Release Tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment [ see Dosage and Administration ( 2 ) ]."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [ see BOXED WARNING and Warnings and Precautions ( 5.1 ) ]. Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in another disorder in 793 pediatric patients have been conducted with venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Venlafaxine Hydrochloride Extended-Release Tablets in a child or adolescent must balance the potential risks with the clinical need. Although no studies have been designed to primarily assess impact of venlafaxine hydrochloride extended-release capsules on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Venlafaxine Hydrochloride Extended-Release Tablets may adversely affect weight and height [ see Warnings and Precautions (5.7, 5.8, and 5.9) ]. Should the decision be made to treat a pediatric patient with Venlafaxine Hydrochloride Extended-Release Tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Venlafaxine Hydrochloride Extended-Release Tablets treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients [ see Warnings and Precautions ( 5.3 and 5.14 ) ]."}', 'geriatric_use': '{"8.5 Geriatric Use Approximately 4% (14/357) and 2% (6/277) of patients treated with venlafaxine hydrochloride extended-release capsules in placebo-controlled premarketing major depressive disorder and Social Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 patients treated with venlafaxine hydrochloride immediate-release tablets in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules, 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 ( 5.11 ) ]. The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [ see Clinical Pharmacology ( 12.3 ) ]. No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction [ see Dosage and Administration ( 2.3 ) ]."}'}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Healthcare Personnel Handwash to decrease transient bacteria on the skin before contact with patients under medical care or treatment."}', '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 develop. If irritation persists for more than 3 days, consult a physician."}', 'do_not_use': None, 'when_using': '{"When using this product avoid contact with eyes. If splashed in eyes, rinse promptly and thoroughly with water do not puncture or incinerate; contents under pressure."}', 'warnings': '{"Warnings For external use only. Flammable. Keep away from fire or flame. When using this product avoid contact with eyes. If splashed in eyes, rinse promptly and thoroughly with water do not puncture or incinerate; contents under pressure. Stop use and ask a doctor if irritation and redness develop. If irritation persists for more than 3 days, consult a physician. Keep out of reach children. In case of accidental ingestion, seek professional assistance or contact a Poison Control Center immediately."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{SENNOSIDES}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves occasional constipation (irregularity) generally produces bowel movement in 6 to 12 hours"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{SENNOSIDES}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if rectal bleeding or failure to have a bowel movement occur after use of a laxative. These may be signs of a serious condition."}', 'do_not_use': '{"Do not use laxative products when abdominal pain, nausea, or vomiting are present unless directed by a doctor."}', 'when_using': '{"When using this product do not use for a period longer than 1 week"}', 'warnings': '{"Warnings Do not use laxative products when abdominal pain, nausea, or vomiting are present unless directed by a doctor. Ask a doctor before use if you have noticed a sudden change in bowel habits that persists over a period of 2 weeks Ask a doctor or pharmacist before use if you are taking a prescription drug. Laxatives may affect how other drugs work. Take this product 2 or more hours before or after other drugs. When using this product do not use for a period longer than 1 week Stop use and ask a doctor if rectal bleeding or failure to have a bowel movement occur after use of a laxative. These may be signs of a serious condition. 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 Posion Control Center right away."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{TESTOSTERONE}

{'contraindications': '{"4 CONTRAINDICATIONS Testosterone topical solution is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate [see Warnings and Precaution ( 5.1 )] . Testosterone topical solution is contraindicated in women who are, or who may become pregnant, or who are breastfeeding. Testosterone topical solution may cause fetal harm when administered to a pregnant woman. Testosterone topical solution may cause serious adverse reactions in nursing infants. If a pregnant woman is exposed to testosterone topical solution, she should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 , 8.3 )] . Men with carcinoma of the breast or known or suspected carcinoma of the prostate ( 4 , 5.1 ) Pregnant or breastfeeding women. Testosterone may cause fetal harm ( 4 , 8.1 , 8.3 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse reactions (incidence >4%) are skin application site reactions, increased hematocrit, headache, diarrhea, vomiting, and increased serum PSA ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 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. Clinical Trials in Hypogonadal Men Table 2 shows the treatment emergent adverse reactions that were reported by either >4% of 155 patients in a 120 day, Phase 3 study or by >4% of 71 patients who continued to use testosterone topical solution for up to 180 days. These data reflect the experience primarily with a testosterone dose of 60 mg, which was taken by all patients at the start of the study, and was the maintenance dose for 97 patients. However, the doses used varied from 30 mg to 120 mg. Table 2:Adverse Reactions Seen with the Use of Testosterone Topical Solution in either the 120 Day Clinical Trial or in the Extension to 180 Days (>4%) Event 120 Days (155 Patients) 180 Days (71 Patients) Application Site Irritation 11 (7%) 6 (8%) Application Site Erythema 8 (5%) 5 (7%) Headache 8 (5%) 4 (6%) Hematocrit Increased 6 (4%) 5 (7%) Diarrhea 4 (3%) 3 (4%) Vomiting 4 (3%) 3 (4%) PSA Increased 2 (1%) 3 (4%) Other less common adverse reactions reported by at least 2 patients in the 120 day trial included: application site edema, application site warmth, increased hemoglobin, hypertension, erythema (general), increased blood glucose, acne, nasopharyngitis, anger and anxiety. Other less common adverse reactions reported in fewer than 1% of patients in the 120 day trial included: asthenia, affect lability, folliculitis, increased lacrimation, breast tenderness, increased blood pressure, increased blood testosterone, neoplasm prostate and elevated red blood cell count. During the 120 day trial one patient discontinued treatment because of affect lability/anger which was considered possibly related to testosterone topical solution administration. During the 120 day clinical trial there was an increase in mean PSA values of 0.13 ± 0.68 ng/mL from baseline. At the end of the 180 day extension clinical trial, there was an overall increase in mean PSA values of 0.1 ± 0.54 ng/mL. Following the 120 day study, seventy-one (71) patients entered a two-month extension study with testosterone topical solution. Two patients (3%) had adverse reactions that led to discontinuation of treatment during the period from Day 120 to Day 180. These reactions were: one patient with application site irritation (considered possibly related to testosterone topical solution application) and one patient with dry skin and erythema, but not at the application site (considered not related to testosterone topical solution administration) and application site erythema (considered possibly related to testosterone topical solution administration). No serious adverse reactions to testosterone topical solution were reported during either the 120 day trial, or the extension to 180 days. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of testosterone topical solution. 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 Disorders: myocardial infarction, stroke [see Warnings and Precautions ( 5.5 )] . Vascular Disorders: Venous thromboembolism [see Warnings and Precautions ( 5.4 )] ."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Androgens may decrease blood glucose and insulin requirement in diabetic patients (7.1). Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of International Normalized Ratio (INR) and prothrombin time is recommended ( 7.2 ). Use of testosterone with Adrenocorticotropic Hormone (ACTH) or corticosteroids may result in increased fluid retention. Use with caution, particularly in patients with cardiac, renal, or hepatic disease ( 7.3 ) 7.1 Insulin Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirement. 7.2 Oral anticoagulants Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen therapy. 7.3 Corticosteroids The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be monitored cautiously, particularly in patients with cardiac, renal or hepatic disease."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Testosterone topical solution is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone. Primary hypogonadism (congenital or acquired): testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter\'s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above the normal range. Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range. Limitations of use: Safety and efficacy of testosterone topical solution in men with \\"age-related hypogonadism\\" (also referred to as \\"late-onset hypogonadism\\") have not been established. Safety and efficacy of testosterone topical solution in males <18 years old have not been established [see Use in Specific Populations ( 8.4 )]. Testosterone topical solution is indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired) ( 1 ) Hypogonadotropic hypogonadism (congenital or acquired) ( 1 ) Limitations of use: Safety and efficacy of testosterone topical solution in men with \\"age-related hypogonadism\\" have not been established. ( 1 ) Safety and efficacy of testosterone topical solution in males <18 years old have not been established. ( 8.4 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH ( 5.1 ) Avoid unintentional exposure of women or children to testosterone topical solution. Secondary exposure to testosterone can produce signs of virilization. Testosterone topical solution should be discontinued until the cause of the virilization is identified ( 2.2 , 5.2 ) Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients using testosterone products. Evaluate patients with signs or symptoms consistent with DVT or PE. ( 5.4 ) Some postmarketing studies have shown an increased risk of myocardial infarction and stroke associated with use of testosterone replacement therapy. ( 5.5 ) Exogenous administration of testosterone may lead to azoospermia ( 5.8 ) Edema with or without congestive heart failure, may be a complication in patients with preexisting cardiac, renal, or hepatic disease ( 5.10 ). Sleep apnea may occur in those with risk factors ( 5.12 ) Monitor serum testosterone, prostate specific antigen (PSA), liver function, lipid concentrations , hematocrit and hemoglobin periodically ( 5.1 , 5.3 , 5.9 , 5.13 ) Testosterone topical solution is flammable until dry ( 5.16 ) 5.1 Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer Monitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH. Patients treated with Androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer prior to initiating treatment. It would be appropriate to reevaluate patients 3 to 6 months after initiation of treatment, and then in accordance with prostate cancer screening practices [see Contraindications ( 4 )] . 5.2 Potential for Secondary Exposure to Testosterone Cases of secondary exposure to testosterone in children and women have been reported with topical testosterone products applied to the abdomen or upper arms, including cases of secondary exposure resulting in virilization of children. Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. In most cases, these signs and symptoms regressed with removal of the exposure to testosterone. In a few cases, however, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronological age. The risk of transfer was increased in some of these cases by not adhering to precautions for the appropriate use of the topical testosterone product. Children and women should avoid contact with unwashed or unclothed application sites in men using testosterone topical solution [see Dosage and Administration ( 2.2 ), Use in Specific Populations (8.1) and Clinical Pharmacology ( 12.3 )] . Inappropriate changes in genital size or development of pubic hair or libido in children, or changes in body hair distribution, significant increase in acne, or other signs of virilization in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone should also be brought to the attention of a physician. Testosterone therapy should be promptly discontinued at least until the cause of virilization has been identified [see Dosage and Administration ( 2.2 )] . 5.3 Polycythemia Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of testosterone. Check hematocrit prior to initiating testosterone treatment. It would be appropriate to re-evaluate the hematocrit 3 to 6 months after starting testosterone treatment, and then annually. If hematocrit becomes elevated, stop therapy until hematocrit decreases to an acceptable level. An increase in red blood cell mass may increase the risk of thromboembolic events. 5.4 Venous Thromboembolism There have been postmarketing reports of venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients using testosterone products, such as testosterone topical solution. Evaluate patients who report symptoms of pain, edema, warmth and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a venous thromboembolic event is suspected, discontinue treatment with testosterone topical solution and initiate appropriate workup and management [see Adverse Reactions ( 6.2 )] . 5.5 Cardiovascular Risk Long term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events (MACE), such as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with the use of testosterone compared to non-use. Some studies, but not all, have reported an increased risk of MACE in association with use of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use testosterone topical solution. 5.6 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions [see Drug Abuse and Dependence ( 9 )] . If testosterone abuse is suspected, check serum testosterone concentrations to ensure they are within therapeutic range. However, testosterone levels may be in the normal or subnormal range in men abusing synthetic testosterone derivatives. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events. 5.7 Use in Women Due to lack of controlled studies in women and potential virilizing effects, testosterone topical solution is not indicated for use in women [see Contraindications (4) and Use in Specific Populations ( 8.1 , 8.3 )] . 5.8 Potential for Adverse Effects on Spermatogenesis At large doses of exogenous androgens, including testosterone, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count. 5.9 Hepatic Adverse Effects Prolonged use of high doses of orally active 17-alpha-alkyl androgens (methyltestosterone) has been associated with serious hepatic adverse effects (peliosis hepatitis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis hepatitis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate has produced multiple hepatic adenomas. Testosterone topical solution is not known to cause these adverse effects. 5.10 Edema Androgens, including testosterone, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease [see Adverse Reactions ( 6 )] . 5.11 Gynecomastia Gynecomastia may develop and may persist in patients being treated with androgens, including testosterone, for hypogonadism. 5.12 Sleep Apnea The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity and chronic lung disease. 5.13 Lipids Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy. 5.14 Hypercalcemia Androgens, including testosterone, should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients. 5.15 Decreased Thyroxine-binding Globulin Androgens, including testosterone, may decrease concentrations of thyroxin-binding globulins, resulting in decreased total T4 serum concentration and increased resin uptake of T3 and T4. Free thyroid hormone concentration remain unchanged, however there is no clinical evidence of thyroid dysfunction. 5.16 Flammability Alcohol based products, including testosterone topical solution, are flammable; therefore, patients should be advised to avoid smoking, fire or flame until the testosterone topical solution dose applied has dried."}', 'overdosage': '{"10 OVERDOSAGE No cases of overdose with testosterone topical solution have been reported in clinical trials. There is one report of acute overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of testosterone topical solution together with appropriate symptomatic and supportive care."}', 'active_flag': 'Y', 'generic_name': '{TESTOSTERONE}', '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 See FDA-Approved Medication Guide. Patients should be informed of the following information: 17.1 Use Men with Known in or Suspected Prostate or Breast Cancer Men with known or suspected prostate or breast cancer should not use testosterone topical solution [see Contraindications ( 4 ) and Warnings and Precaution ( 5.1 )] . 17.2 Potential for Secondary Exposure to Testosterone and Steps to Prevent Secondary Exposure Cases of secondary exposure to testosterone in children and women have been reported with topical testosterone products applied to the abdomen, shoulders or upper arms, including cases of secondary exposure resulting in virilization of children, with signs and symptoms including enlargement of the penis or clitoris, premature development of pubic hair, increased erections, aggressive behavior and advanced bone age. Inappropriate changes in genital size or premature development of pubic hair or libido in children, or changes in hair distribution, increase in acne, or other signs of testosterone effects in adult women should be brought to the attention of a physician and the possibility of secondary exposure to testosterone topical solution also should be brought to the attention of a physician. Testosterone topical solution should be promptly discontinued at least until the cause of virilization is identified. Strict adherence to the following precautions is advised in order to minimize the potential for secondary exposure to testosterone from testosterone topical solution treated skin: Testosterone topical solution should only be applied to the axilla, not to any other part of the body. Children and women should avoid contact with the unwashed skin of the axilla or unclothed application sites of men where testosterone topical solution has been applied. Patients should wash their hands immediately with soap and water after application of testosterone topical solution. Patients should cover the axilla application site(s) with clothing (e.g., a shirt) after waiting 3 minutes for the solution to dry. Prior to any situation in which direct skin-to-skin contact of the axilla is anticipated, patients should wash the axilla to which testosterone topical solution has been applied thoroughly with soap and water to remove any testosterone residue. In the event that unwashed or unclothed skin to which testosterone topical solution has been applied comes in direct contact with the skin of another person, the general area of contact on the other person should be washed with soap and water as soon as possible. [See Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )]. 17.3 Potential Adverse Reactions with Androgens Patients should be informed that treatment with Androgens may lead to adverse reactions which include: Changes in urinary habits such as increased urination at night, trouble starting your urine stream, passing urine many times during the day, having an urge that you have to go to the bathroom right away, having urine accident, being unable to pass urine and having a weak urine flow. Breathing disturbances, including those associated with sleep, or excessive daytime sleepiness. Too frequent or persistent erections of the penis. Nausea, vomiting, changes in skin color, or ankle swelling. 17.4 Patients Should be Advised of these Application Instructions ● Ensure that the patient understands how to administer the correct dose. ● The pump should be primed by depressing it 3 times prior to its first use. No priming is needed with subsequent uses of that pump. ● Testosterone topical solution should NOT be applied to the scrotum, penis, abdomen, shoulders or upper arms. ● With testosterone doses greater than 60 mg, which require two applications of testosterone topical solution to the same axilla, the product should be allowed to dry after the first application before the second is applied. ● Testosterone topical solution should be applied once daily at approximately the same time each day. Testosterone topical solution should be applied to clean, dry skin. ● Patients may use an antiperspirant or deodorant spray before applying testosterone topical solution. If patients use a stick or roll-on antiperspirant or deodorant, then it should be applied alteast 2 minutes prior to application of testosterone topical solution to avoid contamination of the stick or roll-on product. ● Avoid swimming or washing the application site until two hours following application of testosterone topical solution [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )] . ● Avoid splashing in the eyes. In case of contact with eyes, flush thoroughly with water. If irritation persists, seek medical advice. ● Do not drink testosterone topical solution. Manufactured by: Cipla Limited, Verna Goa, India. Manufactured for : Cipla USA, Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059 Revised: 2/2020"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Category X [see Contraindications (4)] — Testosterone topical solution is contraindicated during pregnancy or in women who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and efficacy of testosterone topical solution has not been established in males <18 years of age. Improper use may result in acceleration of bone age and premature closure of epiphyses."}', 'geriatric_use': '{"8.5 Geriatric Use There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing testosterone topical solution to determine whether efficacy in those over 65 years of age differs from younger patients. Of the 155 patients enrolled in the pivotal clinical study utilizing testosterone topical solution, 21 were over 65 years of age. Additionally, there were insufficient long-term safety data in these patients utilizing testosterone topical solution to assess a potential incremental risk of cardiovascular disease and prostate cancer."}'}

{"ESCHERICHIA COLI"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Rx Only*"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ESCHERICHIA COLI"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist for more than 3 days or worsen"}', 'do_not_use': None, 'when_using': None, 'warnings': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{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}', 'route': '{TRANSDERMAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if skin redness caused by the patch does not go away after four days, or if your skin swells, or you get a rash irregular heartbeat or palpitations occur you get symptoms of nicotine overdose, such as nausea, vomiting, dizziness, weakness and rapid heartbeat you have symptoms of an allergic reaction (such as difficulty breathing or rash)"}', 'do_not_use': None, 'when_using': '{"When using this product if you have vivid dreams or other sleep disturbances remove this patch at bedtime"}', '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 heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. high blood pressure not controlled with medication. Nicotine can increase your blood pressure. an allergy to adhesive tape or have skin problems, because you are more likely to get rashes. 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 a prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. When using this product if you have vivid dreams or other sleep disturbances remove this patch at bedtime Stop use and ask a doctor if skin redness caused by the patch does not go away after four days, or if your skin swells, or you get a rash irregular heartbeat or palpitations occur you get symptoms of nicotine overdose, such as nausea, vomiting, dizziness, 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. Used patches have enough nicotine to poison children and pets. If swallowed, get medical help or contact a Poison Control Center right away. Save pouch to use for patch disposal. Dispose of the used patches by folding sticky ends together and putting in pouch."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BUPROPION HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Seizure disorder. ( 4 , 5.3 ) Current or prior diagnosis of bulimia or anorexia nervosa ( 4 , 5.3 ) Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs. ( 4 , 5.3 ) Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with bupropion hydrochloride extended-release tablets (XL) or within 14 days of stopping treatment with bupropion hydrochloride extended-release tablets (XL). Do not use bupropion hydrochloride extended-release tablets (XL) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start bupropion hydrochloride extended-release tablets (XL) in a patient who is being treated with linezolid or intravenous methylene blue. ( 4 , 7.6 ) Known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (XL) ( 4 , 5.8 ) Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with seizure disorder. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with seizure disorder. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with bupropion hydrochloride extended-release tablets (XL) [see WARNINGS AND PRECAUTIONS ( 5.3 )]. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see WARNINGS AND PRECAUTIONS ( 5.3 ) and DRUG INTERACTIONS ( 7.3 )]. The use of MAOIs (intended to treat psychiatric disorders) concomitantly with bupropion hydrochloride extended-release tablets (XL) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (XL) are contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are used concomitantly with MAOIs. The use of bupropion hydrochloride extended-release tablets (XL) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride extended-release tablets (XL) in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see DOSAGE AND ADMINISTRATION ( 2.9 ), WARNINGS AND PRECAUTIONS ( 5.4 ) and DRUG INTERACTIONS ( 7.6 )]. Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (XL). Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see WARNINGS AND PRECAUTIONS ( 5.8 )]."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse reactions are (incidence ≥5%; ≥2× placebo rate): dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash. ( 6.1 ) 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 . The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal thoughts and behaviors in children, adolescents, and young adults [see WARNINGS AND PRECAUTIONS ( 5.1 )] • Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see WARNINGS AND PRECAUTIONS ( 5.2 )] • Seizure [see WARNINGS AND PRECAUTIONS ( 5.3 )] • Hypertension [see WARNINGS AND PRECAUTIONS ( 5.4 )] • Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS ( 5.5 )] • Psychosis and other neuropsychiatric events [see WARNINGS AND PRECAUTIONS ( 5.6 )] • Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS ( 5.7 )] • Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS ( 5.8 )] 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. Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained- release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below. 300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. Bupropion hydrochloride extended-release tablets (XL) have been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride. Major Depressive Disorder Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-release in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2. Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-ControlledTrials in MDD A dverse Reaction Term Placebo ( n=385) Bup r opion HCl Su stained-Release 300 mg/day ( n=376) Bup r opion HCl Su stained-Release 400 mg/day ( n=114) Rash 0.0% 2.4% 0.9% Nausea 0.3% 0.8% 1.8% Agitation 0.3% 0.3% 1.8% Migraine 0.3% 0.0% 1.8% In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances. Adverse Reactions Occurring at an Incidence of >1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group. Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD * Incidence based on the number of female patients. † Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients. Body System/ Adverse Reaction Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day (n=376) Bupropion HCl Sustained-Release 400 mg/day (n=114) Body (General) Headache 23% 26% 25% Infection 6% 8% 9% Abdominal pain 2% 3% 9% Asthenia 2% 2% 4% Chest pain 1% 3% 4% Pain 2% 2% 3% Fever ‑ 1% 2% Cardiovascular Palpitation 2% 2% 6% Flushing - 1% 4% Migraine 1% 1% 4% Hot flashes 1% 1% 3% Digestive Dry mouth 7% 17% 24% Nausea 8% 13% 18% Constipation 7% 10% 5% Diarrhea 6% 5% 7% Anorexia 2% 5% 3% Vomiting 2% 4% 2% Dysphagia 0% 0% 2% Musculoskeletal Myalgia 3% 2% 6% Arthralgia 1% 1% 4% Arthritis 0% 0% 2% Twitch ‑ 1% 2% Nervous System Insomnia 6% 11% 16% Dizziness 5% 7% 11% Agitation 2% 3% 9% Anxiety 3% 5% 6% Tremor 1% 6% 3% Nervousness 3% 5% 3% Somnolence 2% 2% 3% Irritability 2% 3% 2% Memory decreased 1% - 3% Paresthesia 1% 1% 2% Central nervous system stimulation 1% 2% 1% Respiratory Pharyngitis 2% 3% 11% Sinusitis 2% 3% 1% Increased cough 1% 1% 2% Skin Sweating 2% 6% 5% Rash 1% 5% 4% Pruritus 2% 2% 4% Urticaria 0% 2% 1% Special Senses Tinnitus 2% 6% 6% Taste perversion - 2% 4% Blurred vision or diplopia 2% 3% 2% Urogenital Urinary frequency 2% 2% 5% Urinary urgency 0% _ 2% Vaginal hemorrhage * _ 0% 2% Urinary tract infection _† 1% 0% The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%). Seasonal Affective Disorder In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion hydrochloride extended-release tablets (XL) and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. <1%) and headache (1% vs. <1%). Table 4 summarizes the adverse reactions that occurred in patients treated with bupropion hydrochloride extended-release tablets (XL) for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group. Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD S ystem Organ Class/ Preferred Term P lacebo ( n =511) Bup r opion HCl E xtended-Release ( n =537) Gastrointestinal Disorder Dry mouth 15% 26% Nausea 8% 13% Constipation 2% 9% Flatulence 3% 6% Abdominal pain <1% 2% Nervous System Disorders Headache 26% 34% Dizziness 5% 6% Tremor <1% 3% Infections and Infestations Nasopharyngitis 12% 13% Upper respiratory tract infection 8% 9% Sinusitis 4% 5% Psychiatric Disorders Insomnia 13% 20% Anxiety 5% 7% Abnormal dreams 2% 3% Agitation <1% 2% Musculoskeletal and Connective Tissue Disorders Myalgia 2% 3% Pain in extremity 2% 3% Respiratory, Thoracic, and Mediastinal Disorders Cough 3% 4% General Disorders and Administration Site Conditions Feeling jittery 2% 3% Skin and Subcutaneous Tissue Disorders Rash 2% 3% Metabolism and Nutrition Disorders Decreased appetite 1% 4% Reproductive System and Breast Disorders Dysmenorrhea <1% 2% Ear and Labyrinth Disorders Tinnitus <1% 3% Vascular Disorders Hypertension 0% 2% Changes in Body Weight Table 5 presents the incidence of body weight changes (≥5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight. Table 5: Incidence of Weight Gain or Weight Loss (≥5 lbs) in MDD Trials Using Bupropion HCl Sustained-Release Weight Change Bup r opion HCl Su stained-Release 300 mg/day ( n =339) Bup r opion HCl Su stained-Release 400 mg/day ( n =112) P lacebo ( n =347) Gained >5 lbs 3% 2% 4% Lost >5 lbs 14% 19% 6% Table 6 presents the incidence of body weight changes (≥5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥5 lbs, compared to the placebo group (11%). These were relatively long-term trials (up to 6 months). Table 6: Incidence of Weight Gain or Weight Loss (≥5 lbs) in SAD Trials Using Bupropion HCl Extended-release Weight Change Bup r opion HCl Extended-release 150 to 300 mg/day ( n =537) P lacebo ( n =511) Gained >5 lbs 11% 21% Lost >5 lbs 23% 11% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bupropion hydrochloride extended-release tablets (XL). 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. Body (General) Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise. Cardiovascular Postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism. Digestive Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer. Endocrine Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion. Hemic and Lymphatic Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Metabolic and Nutritional Glycosuria. Musculoskeletal Leg cramps, fever/rhabdomyolysis, and muscle weakness. Nervous System Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia. Respiratory Bronchospasm and pneumonia. Skin Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism, acute generalized exanthematous pustulosis. Special Senses Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis. Urogenital Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis."}', 'drug_interactions': '{"7 DRUG INTERACTIONS CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based on clinical exposure, but should not exceed the maximum recommended dose. ( 7.1 ) Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). Consider dose reduction when using with bupropion. ( 7.2 ) Drugs that lower seizure threshold: Dose bupropion hydrochloride extended-release tablets (XL) with caution. ( 5.3 , 7.3) Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with bupropion hydrochloride extended-release tablets (XL). ( 7.4 ) MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride extended-release tablets (XL). ( 7.6 ) Drug-laboratory test interactions: Bupropion hydrochloride extended-release tablets (XL) can cause false-positive urine test results for amphetamines. ( 7.7 ) 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-release Tablets (XL) Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL) and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see CLINICAL PHARMACOLOGY ( 12.3 )]. Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride extended-release tablets (XL) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [see CLINICAL PHARMACOLOGY ( 12.3 )]. Carbamazepine, Phenobarbital, Phenytoin: While not systemically studied, these drugs may induce metabolism of bupropion and may decrease bupropion exposure [see CLINICAL PHARMACOLOGY ( 12.3 )]. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. 7.2 Potential for Bupropion Hydrochloride Extended-release Tablets XL to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion hydrochloride extended-release tablets (XL) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, and flecainide). When used concomitantly with bupropion hydrochloride extended-release tablets (XL), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen), theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride extended-release tablets (XL) and such drugs may require increased doses of the drug [see CLINICAL PHARMACOLOGY ( 12.3 )]. 7.3 Drugs That Lower Seizure Threshold Use extreme caution when coadministering bupropion hydrochloride extended-release tablets (XL) with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of bupropion hydrochloride extended-release tablets (XL) and increase the dose gradually [see WARNINGS AND PRECAUTIONS ( 5.3 )]. 7.4 Dopaminergic Drugs (Levodopa and Amantadine) Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering bupropion hydrochloride extended-release tablets (XL) concomitantly with these drugs. 7.5 Use with Alcohol In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion hydrochloride extended-release tablets (XL). The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (XL) should be minimized or avoided. 7.6 MAO Inhibitors Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with bupropion hydrochloride extended-release tablets (XL). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL) before starting an MAOI antidepressant [see DOSAGE AND ADMINISTRATION ( 2.8 , 2.9 ) and CONTRAINDICATIONS ( 4 )]. 7.7 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Bupropion hydrochloride extended-release tablet (XL) is an aminoketone antidepressant, indicated for: treatment of major depressive disorder (MDD) ( 1.1 ) prevention of seasonal affective disorder (SAD) ( 1.2 ) 1.1 Major Depressive Disorder (MDD) Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The efficacy of the sustained-release formulation of bupropion in the maintenance treatment of MDD was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [see CLINICAL STUDIES ( 14.1 )]. 1.2 Seasonal Affective Disorder (SAD) Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD). The efficacy of bupropion hydrochloride extended-release tablets (XL) in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined in the DSM [see CLINICAL STUDIES ( 14.2 )]."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Events During Smoking Cessation: Postmarketing reports of serious or clinically significant neuropsychiatric adverse events have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients attempting to quit smoking with bupropion hydrochloride extended-release tablets (XL) for the occurrence of such symptoms and instruct them to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider if they experience such adverse events. ( 5.2 ) Seizure Risk: The risk is dose-related. Can minimize risk by limiting daily dose to 450 mg and gradually increasing the dose. Discontinue if seizure occurs. ( 4 , 5.3 , 7.3 ) Hypertension: Bupropion hydrochloride extended-release tablets (XL) can increase blood pressure. Monitor blood pressure before initiating treatment and periodically during treatment. ( 5.4 ) Activation of Mania/Hypomania: Screen patients for bipolar disorder and monitor for these symptoms. ( 5.5 ) Psychosis and Other Neuropsychiatric Reactions: Instruct patients to contact a healthcare professional if such reactions occur. ( 5.6 ) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.7 ) 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 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 (Selective Serotonin Reuptake Inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 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 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: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients A ge Range D rug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 years 14 additional cases 18 to 24 years 5 additional cases Decreases Compared to Placebo 25 to 64 years 1 fewer case ≥65 years 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug 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 [see BOXED WARNING and USE IN SPECIFIC POPULATIONS ( 8.4 )]. 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. 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion hydrochloride extended-release tablets (XL) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment Bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see ADVERSE REACTIONS ( 6.2 )]. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke. Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking bupropion hydrochloride extended-release tablets (XL) and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. The healthcare provider should evaluate the severity of the adverse events and the extent to which the patient is benefiting from treatment, and consider options including continued treatment under closer monitoring, or discontinuing treatment. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. 5.3 Seizure Bupropion hydrochloride extended-release tablets (XL) can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue bupropion hydrochloride extended-release tablets (XL) and do not restart treatment if the patient experiences a seizure. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with bupropion hydrochloride extended-release tablets (XL). bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see CONTRAINDICATIONS ( 4 )]. The following conditions can also increase the risk of seizure: concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), or use of illicit drugs (e.g., cocaine) or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin, use of anorectic drugs, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates. Incidence of Seizure with Bupropion Use The incidence of seizure with bupropion hydrochloride extended-release tablets (XL) have not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day. Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the bupropion hydrochloride extended-release tablets (XL) dose does not exceed 450 mg once daily and the titration rate is gradual. 5.4 Hypertension Treatment with bupropion hydrochloride extended-release tablets (XL) can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride extended-release tablets (XL), and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride extended-release tablets (XL) are used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see CONTRAINDICATIONS ( 4 )]. Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement. In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p=0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p=0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days. In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (CHF) (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled studies assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease. 5.5 Activation of Mania/Hypomania Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating bupropion hydrochloride extended-release tablets (XL), screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Bupropion hydrochloride extended-release tablets (XL) are not approved for the treatment of bipolar depression. 5.6 Psychosis and Other Neuropsychiatric Reactions Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Discontinue bupropion hydrochloride extended-release tablets (XL) if these reactions occur. 5.7 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including bupropion hydrochloride extended-release tablets (XL) may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.8 Hypersensitivity Reactions Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea, requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion hydrochloride extended-release tablets (XL) and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment. There are reports of arthralgia, myalgia, fever with rash and other symptoms of serum sickness suggestive of delayed hypersensitivity."}', 'overdosage': '{"10 OVERDOSAGE 10.1 Human Overdose Experience Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, ECG changes such as conduction disturbances or arrhythmias, mental status changes,clonus, myoclonus, and hyperreflexia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. 10.2 Overdosage Management Consult a Certified Poison Control Center for up-to-date guidance and advice. Call 1-800-222-1222 or refer to www.poison.org. There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose."}', 'active_flag': 'Y', 'generic_name': '{"BUPROPION 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). Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (XL) and counsel them in its appropriate use. A patient Medication Guide about \\"Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,\\" \\"Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,\\" and \\"What Other Important Information Should I Know About bupropion hydrochloride extended-release tablets (XL)?\\" are available for bupropion hydrochloride extended-release tablets (XL). Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Advise patients regarding the following issues and to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets (XL). Suicidal Thoughts and Behaviors Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient\'s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient\'s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment Although bupropion hydrochloride extended-release tablets (XL) are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN ® which is approved for this use. Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking bupropion. Instruct patients to discontinue bupropion hydrochloride extended-release tablets (XL) and contact a healthcare professional if they experience such symptoms [see WARNINGS AND PRECAUTIONS ( 5.2 ) and ADVERSE REACTIONS ( 6.2 )]. Severe Allergic Reactions Educate patients on the symptoms of hypersensitivity and to discontinue bupropion hydrochloride extended-release tablets (XL) if they have a severe allergic reaction. Seizure Instruct patients to discontinue and not restart bupropion hydrochloride extended-release tablets (XL) if they experience a seizure while on treatment. Advise patients that the excessive use or the abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid the use of alcohol. Angle-Closure Glaucoma Patients should be advised that taking bupropion hydrochloride extended-release tablets (XL) 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 ( 5.7 )]. Bupropion-Containing Products Educate patients that bupropion hydrochloride extended-release tablets (XL) contains the same active ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (XL) should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation, WELLBUTRIN, the immediate-release formulation, and APLENZIN ® , a bupropion hydrobromide formulation). In addition, there are a number of generic bupropion HCl products for the immediate, sustained, and extended-release formulations. Potential for Cognitive and Motor Impairment Advise patients that any CNS-active drug like bupropion hydrochloride extended-release tablets (XL) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that Bupropion hydrochloride extended-release tablets (XL) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion hydrochloride extended-release tablets (XL) treatment may lead to decreased alcohol tolerance. Concomitant Medications Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs, because bupropion hydrochloride extended-release tablets (XL) and other drugs may affect each other\'s metabolism. Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with bupropion hydrochloride extended-release tablets (XL). Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to bupropion hydrochloride extended-release tablets (XL) during pregnancy [see USE IN SPECIFIC POPULATIONS ( 8.1 )]. Administration Information Instruct patients to swallow bupropion hydrochloride extended-release tablets (XL) whole so that the release rate is not altered. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets (XL) should be administered in the morning and may be taken with or without food. Residual Inert Matrix Tablet Patients receiving bupropion hydrochloride extended-release tablets (XL) may notice an inert matrix passing in the stool. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet. The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited Goa 403 722 INDIA. Revised: April 2022 ID#: 270244"}', '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 register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/. Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data). There are risks to the mother associated with untreated depression (see Clinical Considerations). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. When given to pregnant rabbits during organogenesis, non-dose-related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater (see Animal Data). The estimated background risk for major birth defects and miscarriage are unknown for the indicated population. All pregnancies have a background rate 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: A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy 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 to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. Data Human Data: Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database, which has a limited number of exposed cases with cardiovascular malformations, and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted odds ratio (OR) = 2.6; 95% CI 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find an increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. Animal Data In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 10 and 6 times the MRHD, respectively, on a mg/m 2 basis). There was no evidence of fetal malformations in rats. When given to pregnant rabbits during organogenesis, nondose-related increases in incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m 2 basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m 2 basis) and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less. In a pre-and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the MRHD on a mg/m 2 basis) from embryonic implantation through lactation had no effect on pup growth or development."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established. When considering the use of bupropion hydrochloride extended-release tablets (XL) in a child or adolescent, balance the potential risks with the clinical need [see BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5.1 )]."}', 'geriatric_use': '{"8.5 Geriatric Use Of the approximately 6000 patients who participated in clinical trials with bupropion hydrochloride sustained-release tablets (depression and smoking cessation studies), 275 were ≥65 years old and 47 were ≥75 years old. In addition, several hundred patients ≥65 years of age participated in clinical trials using the immediate-release formulation of bupropion hydrochloride (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see DOSAGE AND ADMINISTRATION ( 2.7 ), USE IN SPECIFIC POPULATIONS ( 8.6 ), and CLINICAL PHARMACOLOGY ( 12.3 )]."}'}

{SIROLIMUS}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{SIROLIMUS}', '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}

{ALPRAZOLAM}

{'contraindications': '{"4 CONTRAINDICATIONS Alprazolam orally disintegrating tablets are contraindicated in patients with acute narrow angle glaucoma. Alprazolam orally disintegrating tablets can exacerbate narrow angle closure. Alprazolam orally disintegrating tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy. Alprazolam orally disintegrating tablets are contraindicated in patients treated with potent CYP3A4 inhibitors (e.g., ketoconazole and itraconazole), because these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) and can increase alprazolam exposures [see Clinical Pharmacology ( 12.3 ), Warnings and Precautions ( 5.9 ), and Drug Interactions ( 7.4 )]. Acute narrow angle glaucoma. Alprazolam can exacerbate narrow angle closure ( 4 ). Concomitant Use with potent CYP3A inhibitors (e.g., ketoconazole and itraconazole). Can increase the serum concentration of alprazolam ( 4 )."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Anxiety Disorder : The most common adverse reactions (greater than or equal to 5% and ~twice the rate of placebo) were sedation, and hypotension. Panic Disorder : The most common adverse reactions included sedation, impaired coordination, dysarthria, and increased libido ( 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 Trial Experience The most commonly reported (greater than or equal to 5% and ~ twice the rate of placebo) adverse reactions with alprazolam treatment are: sedation, impaired coordination, dysarthria, and increased libido. The data cited in the two tables below are estimates of adverse reactions occurring in patients who participated in clinical trials under the following conditions: relatively short duration (four weeks) placebo-controlled clinical studies with dosages up to 4 mg per day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg per day of alprazolam in patients with panic disorder, with or without agoraphobia. 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. Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the adverse reaction incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce dry mouth in others.) Table 1: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Generalized Anxiety Disorder (>2% and at a rate greater than placebo) GENERALIZED ANXIETY DISORDER Body System/Adverse Reaction Treatment-Emergent Symptom Incidence a ALPRAZOLAM (%) N=565 PLACEBO (%) N=505 Central Nervous System Sedation 41 22 Lightheadedness 21 19 Dizziness 2 1 Akathisia 2 1 Gastrointestinal Dry Mouth 15 13 Increased Salivation 4 2 Cardiovascular Hypotension 5 2 Cutaneous Dermatitis/Allergy 4 3 a Events reported by 1% or more of alprazolam patients are included. In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, 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 Reported in Placebo-Controlled Trials of Alprazolam in Panic Disorder (>2 % and greater than placebo) PANIC DISORDER Body System/Adverse Reaction Treatment-Emergent Symptom Incidence a Central Nervous System ALPRAZOLAM (%) N=1388 PLACEBO (%) N=1231 Sedation 77 43 Fatigue and Tiredness 49 42 Impaired Coordination 40 18 Irritability 33 30 Memory Impairment 33 22 Cognitive Disorder 29 21 Dysarthria 23 6 Decreased Libido 14 8 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 Constipation 26 15 Increased Salivation 6 4 Cutaneous Rash 11 8 Other Increased Appetite 33 23 Decreased Appetite 28 24 Weight Gain 27 18 Weight Loss 23 17 Micturition Difficulties 12 9 Menstrual Disorders 10 9 Sexual Dysfunction 7 4 Incontinence 2 1 a Events reported by 1% or more of alprazolam patients are included. In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, 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. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients [see Warnings and Precautions ( 5.4 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing 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. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia, and galactorrhea."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Alprazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, alcohol and other drugs that produce CNS depression ( 7.1 ). The formulation requires an acidic environment to dissolve; therefore, drugs or diseases that cause dry mouth or raise stomach pH may slow disintegration or dissolution, resulting in decreased absorption ( 7.2 ). Drugs which inhibit the hydroxylation catalyzed by cytochrome P450 3A (CYP3A) metabolic pathway can decrease the clearance of alprazolam and increase the serum concentration ( 7.4 ). 7.1 Use with Other CNS Depressants 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation. If alprazolam orally disintegrating tablets are coadministered with other psychotropic agents or anticonvulsant drugs, carefully consider the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, alcohol and other drugs which themselves produce CNS depression. 7.2 Drugs Effecting Salivary Flow and Stomach pH Because alprazolam orally disintegrating tablets disintegrate in the presence of saliva, and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption. 7.3 Use with Imipramine and Desipramine The steady state plasma concentrations of imipramine and desipramine can increase by approximately 30% and 20%, respectively, when administered concomitantly with alprazolam in doses up to 4 mg per day. The clinical significance of these changes is unknown. 7.4 Drugs that Inhibit Alprazolam Metabolism via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway can have a profound effect on the clearance of alprazolam [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 )] . 7.5 Drugs Demonstrated to be CYP3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Alprazolam Use caution during coadministration of Alprazolam and the following drugs: Fluoxetine — Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance. Propoxyphene — Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%. Oral Contraceptives — Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%. 7.6 Drugs and Other Substances Demonstrated to be CYP3A Inhibitors on the Basis of Clinical Studies Involving Benzodiazepines Metabolized Similarly to Alprazolam or on the Basis of In Vitro Studies with Alprazolam or Other Benzodiazepines Use caution during the coadministration of Alprazolam and the following : Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction between alprazolam and the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction between alprazolam and the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state doses of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction between benzodiazepines and the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine [see Warnings and Precautions ( 5.8 )] . 7.7 Inducers of CYP3A Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Alprazolam orally disintegrating tablets are a benzodiazepine indicated for: The treatment of generalized anxiety disorder ( 1.1 ). The efficacy of alprazolam was demonstrated in 5 short-term, placebo-controlled trials ( 14 ). The treatment of panic disorder, with or without agoraphobia ( 1.2 ). The efficacy of alprazolam in the treatment of panic disorder was established in 2 short-term, placebo-controlled trials ( 14 ). 1.1 Generalized Anxiety Disorder Alprazolam orally disintegrating tablets, USP are indicated for the treatment of generalized anxiety disorder. The efficacy of alprazolam in the treatment of generalized anxiety disorder was demonstrated in 5 short-term, placebo-controlled trials [see Clinical Studies ( 14.1 )] . 1.2 Panic Disorder Alprazolam orally disintegrating tablets, USP are also indicated for the treatment of panic disorder, with or without agoraphobia. The efficacy of alprazolam in the treatment of panic disorder was established in 2 short-term, placebo-controlled trials [see Clinical Studies ( 14.2 )] . Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to 4 months in duration for generalized anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Suicide: As with other psychotropic medications, use precautions with respect to administration of the drug and size of the prescription, especially in patients who are severely depressed or in patients where there is reason to expect concealed suicidal ideation or plans ( 5.4 ). Status Epilepticus and Seizure: can occur during discontinuation of alprazolam ( 5.5 ). CNS Depression and Impaired Cognitive and Motor Performance: caution patients against engaging in hazardous occupations or activities requiring complete mental alertness, until they are reasonably certain that alprazolam treatment does not affect them adversely. Caution patients about the use of alcohol and other CNS depressant drugs during treatment with alprazolam ( 5.7 ). Neonatal Sedation and Withdrawal Syndrome: Alprazolam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal ( 5.8 , 8.1 ). Interdose anxiety symptoms: can occur at prescribed maintenance doses. Consider dividing the daily dose into more frequent administrations ( 5.10 ). Patients with Concomitant Illness: In the elderly or debilitated patients, the smallest effective dose is recommended to preclude the development of ataxia or oversedation. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam ( 5.12 ). 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 orally disintegrating tablets, 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 orally disintegrating tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam orally disintegrating tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam orally disintegrating tablets 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 orally disintegrating tablets 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 orally disintegrating tablets, lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Alprazolam orally disintegrating tablets 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 )] . 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 per day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients, 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 per day had more difficulty tapering to zero dose than those treated with less than 4 mg per day. The importance of dose and the risks of Alprazolam as a treatment for panic disorder Because the management of panic disorder often requires the use of average daily doses of alprazolam above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with alprazolam compared to placebo-treated patients. Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline. 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. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71% to 93% of patients treated with alprazolam tapered completely off therapy compared to 89% to 96% of placebo-treated patients. In a controlled postmarketing discontinuation study of panic disorder patients, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 mg to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24 to 72 hours after discontinuation [see Dosage and Administration ( 2 )] . To discontinue treatment in patients taking alprazolam, the dosage should be reduced gradually. Decrease the daily dosage of alprazolam by no more than 0.5 mg every three days [see Dosage and Administration ( 2.3 )] . Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. 5.4 Suicide and Overdose As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. 5.5 Status Epilepticus Withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. 5.6 CNS Depression and Impaired Performance Because alprazolam has CNS depressant effects and has the potential to impair judgment, cognition, and motor performance, caution patients against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, until they are reasonably certain that alprazolam treatment does not affect them adversely. Caution patients about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam. 5.7 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression. 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 orally disintegrating tablets during pregnancy or labor for signs of sedation and monitor neonates exposed to Alprazolam orally disintegrating tablets during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.9 Alprazolam 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. Consequently, alprazolam should be avoided in patients receiving potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class. The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A. Potent CYP3A Inhibitors Azole antifungal agents— Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended [see CONTRAINDICATIONS ( 4 )]. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam Consider dose reduction of alprazolam during coadministration with the following drugs: Nefazodone — Coadministration of nefazodone increased alprazolam concentration two-fold. Fluvoxamine — Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance. Cimetidine — Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%. Other drugs possibly affecting alprazolam metabolism Other drugs possibly affect alprazolam metabolism by inhibition of CYP3A [see Drug Interactions ( 7.6 )]. 5.10 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 of alprazolam. 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. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations [see Dosage and Administration ( 2 )]. 5.11 Uricosuric Effect Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam. 5.12 Use in Patients with Concomitant Illness It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients [see Dosage and Administration ( 2 )] . The usual precautions in treating patients with impaired renal, hepatic or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. A decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam [see Clinical Pharmacology ( 12 )] . 5.13 Risks in Patients with Phenylketonuria Phenylketonuric patients should be informed that alprazolam orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 0.25 mg, 0.5 mg, 1 mg and 2 mg orally disintegrating tablet contains 2.52 mg, 5.04 mg, 5.04 mg and 10.08 mg of phenylalanine, respectively [see Description ( 11.1 )] ."}', '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 a poison center (1-800-222-1222), poisoncontrol.org, or 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 Inform patients and caregivers that potentially fatal additive effects may occur if alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider [ see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 ) ]. Abuse, Misuse, and Addiction Inform patients that the use of Alprazolam orally disintegrating 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 ) and Drug Abuse and Dependence ( 9.2 )]. Withdrawal Reactions Inform patients that the continued use of Alprazolam orally disintegrating tablets may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Alprazolam orally disintegrating 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 orally disintegrating tablets may require a slow taper [see Warnings and Precautions ( 5.3 ) and Drug Abuse and Dependence ( 9.3 )] . Use/Handling Alprazolam Orally Disintegrating Tablets To assure safe and effective use of benzodiazepines, all patients prescribed alprazolam orally disintegrating tablets should be provided with the following guidance. Do not remove Alprazolam orally disintegrating tablets from the blister until just prior to dosing. With dry hands, open the blister, remove the tablet, and immediately place on the tongue to dissolve and be swallowed with the saliva. The tablet may also be taken with water. Store at room temperature in a dry place. Protect from moisture. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines. Alprazolam orally disintegrating tablets are not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication. Inform your physician if you are nursing. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc. Do not increase the dose even if you think the medication “does not work anymore” without consulting your physician. Benzodiazepines, even after relatively short-term use at the doses recommended, may produce emotional and/or physical dependence. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur even after relatively short-term use at the doses recommended. You should follow a gradual dosage tapering schedule. Pregnancy: Advise pregnant females that use of Alprazolam orally disintegrating tablets late in pregnancy can result in sedation, (respiratory depression, withdrawal symptoms, 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 orally disintegrating tablets during pregnancy [see Use in Specific Populations ( 8.1 )] . 10. Phenylketonurics: Phenylketonuric patients should be informed that alprazolam orally disintegrating tablets contain phenylalanine (a component of aspartame). Each 0.25 mg, 0.5 mg, 1 mg and 2 mg orally disintegrating tablet contains 2.52 mg, 5.04 mg, 5.04 mg and 10.08 mg of phenylalanine, respectively [see Description ( 11.1 )] . 11. Lactation: Advise patients that breastfeeding is not recommended during treatment with Alprazolam orally disintegrating tablets [see Use in Specific Populations ( 8.2 )] . Dispense with Medication Guide available at: www.parpharm.com . Distributed by: PAR PHARMACEUTICAL Chestnut Ridge, NY 10977"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medication, including Alprazolam orally disintegrating tablets, 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/pregnancyregistry/ . Risk Summary Neonates born to mothers using benzodiazepines late stages 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 drug 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, 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 in individuals below 18 years of age have not been studied."}', 'geriatric_use': '{"8.5 Geriatric Use The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug, compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation [see Clinical Pharmacology ( 12 ) and Dosage and Administration ( 2 )]. Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects."}'}

{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 and ADVERSE REACTIONS )"}', 'adverse_reactions': '{"ADVERSE REACTIONS The following adverse reactions have been identified during post approval use of hydrocodone bitartrate 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 )."}', '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), and 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 an 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 hydrocodone bitartrate and acetaminophen tablets 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 contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and acetaminophen tablets expose 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 and 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 1-800-503-0784, 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 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 ). 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 ). 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 ). 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 and 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, and 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 and 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 are 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 the 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 )."}', '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 ). Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). 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. 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 and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider ( see WARNINGS and 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 bitartrate and acetaminophen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate 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 and 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 and 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 and 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 and 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), and 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 6000 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 1500 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 breastfeeding 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': '{"Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). 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. 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 and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider ( see WARNINGS and 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 bitartrate and acetaminophen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate 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 and 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 and 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 and 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 and CLINICAL PHARMACOLOGY )."}', '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. 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."}'}

{MENTHOL,"METHYL SALICYLATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"For the temporary relief of minor aches and pains of muscles and joints associated with simple backache, arthritis, strains, bruises and sprains"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"MENTHOL 10%, METHYL SALICYLATE 15%"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop Use and ask a doctor Conditions worsens or does not improve within 7 days Symptoms clear up and occur again within a few days Excessive skin irritation develops A temporary burning sensation may occur upon application, but generally disappears in a few days"}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only Do not use: On wounds or damaged, broken, (open) or irritated skin With a heating pad Ask a doctor before use if you are pregnant or breast feeding. When using this product Avoid contact with eyes or mucous membrane Do not bandage tightly"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DONEPEZIL HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Cardiovascular Conditions [see Warnings and Precautions ( 5.2 )] • Nausea and Vomiting [see Warnings and Precautions ( 5.3 )] • Peptic Ulcer Disease and GI Bleeding [see Warnings and Precautions ( 5.4 )] • Genitourinary Conditions [see Warnings and Precautions ( 5.6 )] • Neurological Conditions: Seizures [see Warnings and Precautions ( 5.7 )] • Pulmonary Conditions [see Warnings and Precautions ( 5.8 )] Most common adverse reactions in clinical studies of donepezil hydrochloride are nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 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. Donepezil hydrochloride has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days. Mild to Moderate Alzheimer’s Disease Adverse Reactions Leading to Discontinuation The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table 1. Table 1. Most Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo (n=355) % 5 mg/day Donepezil Hydrochloride (n=350) % 10 mg/day Donepezil Hydrochloride (n=315) % Nausea 1 1 3 Diarrhea 0 <1 3 Vomiting <1 <1 2 Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse reactions may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15- and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse reactions were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. See Table 2 for a comparison of the most common adverse reactions following one and six week titration regimens. Table 2. Comparison of Rates of Adverse Reactions in Mild to Moderate Patients Titrated to 10 mg/day over 1 and 6 Weeks No titration One week titration Six week titration Adverse Reaction Placebo (n=315) % 5 mg/day (n=311) % 10 mg/day (n=315) 5 10 mg/day (n=269) % Nausea 6 5 19 6 Diarrhea 5 8 15 9 Insomnia 6 6 14 6 Fatigue 3 4 8 3 Vomiting 3 3 8 5 Muscle cramps 2 6 8 3 Anorexia 2 3 7 3 Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age. Table 3. Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in Mild to Moderate Alzheimer’s Disease Adverse Reaction Placebo (n=355) % Donepezil Hydrochloride (n=747) % Percent of Patients with any Adverse Reaction 72 74 Nausea 6 11 Diarrhea 5 10 Headache 9 10 Insomnia 6 9 Pain, various locations 8 9 Dizziness 6 8 Accident 6 7 Muscle Cramps 2 6 Fatigue 3 5 Vomiting 3 5 Anorexia 2 4 Ecchymosis 3 4 Abnormal Dreams 0 3 Depression <1 3 Weight Loss 1 3 Arthritis 1 2 Frequent Urination 1 2 Somnolence <1 2 Syncope 1 2 Severe Alzheimer\'s Disease Severe Alzheimer’s Disease (donepezil hydrochloride 5 mg/day and 10 mg/day) Donepezil hydrochloride has been administered to over 600 patients with severe Alzheimer’s disease during clinical trials of at least 6 months duration, including three double-blind, placebo-controlled trials, two of which had an open label extension.\u200b Adverse Reactions Leading to Discontinuation The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride patients and at twice or more the incidence seen in placebo, were anorexia (2% vs. 1% placebo), nausea (2% vs. <1% placebo), diarrhea (2% vs. 0% placebo) and urinary tract infection (2% vs. 1% placebo). Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride’s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification. Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. Table 4. Adverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s Disease Body System/Adverse Reaction Placebo (n=392) % Donepezil Hydrochloride (n=501) % Percent of Patients with any Adverse Reaction 73 81 Accident 12 13 Infection 9 11 Diarrhea 3 4 Anorexia 2 3 Vomiting 2 3 Nausea 1 2 Insomnia <1 2 Ecchymosis 2 3 Headache 1 2 Pain 1 2 Back Pain 4 10 Eczema 4 8 Hallucinations 4 8 Hostility 2 6 Increase in Creatine Phosphokinase 2 5 Nervousness 1 3 Fever 1 2 Chest Pain <1 2 Confusion 4 5 Dehydration 2 3 Depression 2 3 Dizziness 1 3 Emotional Lability 1 2 Hemorrhage 1 2 Hyperlipemia 1 2 Personality Disorder 1 2 Somnolence 1 2 Personality Disorder 1 2 Syncope 2 3 Urinary Incontinence 1 2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of donepezil 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. Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes."}', 'drug_interactions': '{"7 DRUG INTERACTIONS • Cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications ( 7.1 ). • A synergistic effect may be expected with concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists ( 7.2 ). 7.1 Use with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. 7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Donepezil hydrochloride is indicated for the treatment of dementia of the Alzheimer\'s type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer\'s disease. Donepezil hydrochloride is an acetylcholinesterase inhibitor indicated for the treatment of dementia of the Alzheimer\'s type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer\'s Disease ( 1 )."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia ( 5.1 ). • Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as bradycardia or heart block ( 5.2 ). • Donepezil hydrochloride can cause vomiting. Patients should be observed closely at initiation of treatment and after dose increases ( 5.3 ). • Patients should be monitored closely for symptoms of active or occult gastrointestinal (GI) bleeding, especially those at increased risk for developing ulcers ( 5.4 ). • Cholinomimetics may cause bladder outflow obstructions ( 5.6 ). • Cholinomimetics are believed to have some potential to cause generalized convulsions ( 5.7 ). • Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease ( 5.8 ). 5.1 Anesthesia Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.2 Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of donepezil hydrochloride. 5.3 Nausea and Vomiting Donepezil hydrochloride, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. Although in most cases, these effects have been transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil hydrochloride, patients should be observed closely at the initiation of treatment and after dose increases. 5.4 Peptic Ulcer Disease and GI Bleeding Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of donepezil hydrochloride in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. 5.6 Genitourinary Conditions Although not observed in clinical trials of donepezil hydrochloride, cholinomimetics may cause bladder outflow obstruction. 5.7 Neurological Conditions: Seizures Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer\'s disease. 5.8 Pulmonary Conditions Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease."}', 'overdosage': '{"10 OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature."}', 'active_flag': 'Y', 'generic_name': '{"DONEPEZIL 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 (Patient Information). Instruct patients and caregivers to take donepezil hydrochloride only once per day, as prescribed. Instruct patients and caregivers that donepezil hydrochloride can be taken with or without food. Advise patients and caregivers that donepezil hydrochloride may cause nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and decreased appetite. Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant. Dispense with Patient Information available at: www.solcohealthcare.com/medguide/donepezil-tablets.pdf Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Xunqiao, Linhai, Zhejiang, 317024, China Distributed by: Solco Healthcare US, LLC Somerset, NJ 08873, USA Revised: 03/2022 200145-02 DONEPEZIL HYDROCHLORIDE PATIENT PACKAGE INSERT Donepezil (doe NEP e zil) Hydrochloride Tablets, USP • Tablets: 5 mg and 10 mg Dispense with Patient Information available at: www.solcohealthcare.com/medguide/donepezil-tablets.pdf Read this Patient Information that comes with donepezil hydrochloride before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about Alzheimer’s disease or treatment for it. If you have questions, ask the doctor or pharmacist. What is donepezil hydrochloride? Donepezil hydrochloride comes as donepezil hydrochloride film-coated tablets in dosage strengths of 5 mg and 10 mg. Donepezil hydrochloride is a prescription medicine to treat mild, moderate and severe Alzheimer’s disease. Donepezil hydrochloride can help with mental function and with doing daily tasks. Donepezil hydrochloride does not work the same in all people. Some people may: • Seem much better • Get better in small ways or stay the same • Get worse over time but slower than expected • Not change and then get worse as expected Donepezil hydrochloride does not cure Alzheimer\'s disease. All patients with Alzheimer\'s disease get worse over time, even if they take donepezil hydrochloride. Donepezil hydrochloride has not been approved as a treatment for any medical condition in children. Who should not take donepezil hydrochloride? Do not take donepezil hydrochloride if you are allergic to any of the ingredients in donepezil hydrochloride tablets or to medicines that contain piperidines. Ask your doctor if you are not sure. See the end of this leaflet for a list of ingredients in donepezil hydrochloride tablets. What should I tell my doctor before taking donepezil hydrochloride? Tell the doctor about all of your present or past health problems and conditions. Include: • Any heart problems including problems with irregular, slow, or fast heartbeats • Asthma or lung problems • A seizure • Stomach ulcers • Difficulty passing urine • Liver or kidney problems • Trouble swallowing tablets • Present pregnancy or plans to become pregnant. It is not known if donepezil hydrochloride can harm an unborn baby. • Present breast-feeding. It is not known if donepezil hydrochloride passes into breast milk. Talk to your doctor about the best way to feed your baby if you take donepezil hydrochloride. Tell the doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Donepezil hydrochloride and other medicines may affect each other. Be particularly sure to tell the doctor if you take aspirin or medicines called nonsteroidal anti-inflammatory drugs (NSAIDs). There are many NSAID medicines, both prescription and non-prescription. Ask the doctor or pharmacist if you are not sure if any of your medicines are NSAIDs. Taking NSAIDs and donepezil hydrochloride together may make you more likely to get stomach ulcers. Donepezil hydrochloride taken with certain medicines used for anesthesia may cause side effects. Tell the responsible doctor or dentist that you take donepezil hydrochloride before you have: • surgery • medical procedures • dental surgery or procedures Know the medicines that you take. Keep a list of all your medicines. Show it to your doctor or pharmacist before you start a new medicine. How should you take donepezil hydrochloride? • Take donepezil hydrochloride exactly as prescribed by the doctor. Do not stop donepezil hydrochloride or change the dose yourself. Talk with your doctor first. • Take donepezil hydrochloride one time each day. Donepezil hydrochloride can be taken with or without food. • If you miss giving the patient a dose of donepezil hydrochloride, just wait. Take only the next dose at the usual time. Do not take 2 doses at the same time. • If donepezil hydrochloride is missed for 7 days or more, talk with your doctor before starting again. • If you take too much donepezil hydrochloride at one time, call your doctor or poison control center, or go to the emergency room right away. What are the possible side effects of donepezil hydrochloride? Donepezil hydrochloride may cause the following serious side effects: • slow heartbeat and fainting. This happens more often in people with heart problems. Call your doctor right away if you feel faint or lightheaded while taking donepezil hydrochloride. • more stomach acid. This raises the chance of ulcers and bleeding. The risk is higher for people who have ulcers, or take aspirin or other NSAIDs. • worsening of lung problems in people with asthma or other lung disease. • seizures. • difficulty passing urine. Call your doctor right away if you have: • fainting. • heartburn or stomach pain that is new or won\'t go away. • nausea or vomiting, blood in the vomit, dark vomit that looks like coffee grounds. • bowel movements or stools that look like black tar. • new or worse asthma or breathing problems. • seizures. • difficulty passing urine. The most common side effects of donepezil hydrochloride are: • nausea • diarrhea • not sleeping well • vomiting • muscle cramps • feeling tired • not wanting to eat These side effects may get better after you take donepezil hydrochloride for a while. This is not a complete list of side effects with donepezil hydrochloride. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to Solco Healthcare U. S., LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088. How should donepezil hydrochloride be stored? Store donepezil hydrochloride at room temperature between 59° to 86°F (15° to 30°C). Keep donepezil hydrochloride and all medicines out of the reach of children. General information about donepezil hydrochloride Medicines are sometimes prescribed for conditions that are not mentioned in this Patient Information Leaflet. Do not use donepezil hydrochloride for a condition for which it was not prescribed. Do not give donepezil hydrochloride to other people, even if they have the same symptoms or condition. It may harm them. This leaflet summarizes the most important information about donepezil hydrochloride. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about donepezil hydrochloride that is written for health professionals. What are the ingredients in Donepezil Hydrochloride Tablets, USP? Active ingredient: donepezil hydrochloride Inactive ingredients: Donepezil Hydrochloride 5 mg and 10 mg film-coated tablets: lactose monohydrate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, corn starch, croscarmellose sodium. The film of 5 mg tablets coating contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, and FD&C blue. The film of 10 mg tablets coating contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, iron oxide yellow and iron oxide red. Rx Only Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Xunqiao, Linhai, Zhejiang, 317024, China Distributed by: Solco Healthcare US, LLC Somerset, NJ 08873, USA Revised: 03/2022 Rx Only"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of donepezil hydrochloride in pregnant women. In animal studies, developmental toxicity was not observed when donepezil was administered to pregnant rats and rabbits during organogenesis, but administration to rats during the latter part of pregnancy and throughout lactation resulted in increased stillbirths and decreased offspring survival at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. The background risks of major birth defects and miscarriage for the indicated population are unknown. Data Animal Data Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 16 times the maximum recommended human dose [MRHD] of 10 mg/day on a mg/m2 basis) and 10 mg/kg/day (approximately 20 times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose. The no-effect dose of 3 mg/kg/day is approximately 3 times the MRHD on a mg/m2 basis."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use Alzheimer\'s disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with donepezil hydrochloride was 73 years; 80% of these patients were between 65 and 84 years old, and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old."}'}

{"FLUTICASONE PROPIONATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Temporarily relieves these symptoms of hay fever or other upper respiratory allergies: • nasal congestion • runny nose • sneezing • itchy nose • itchy, watery eyes"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"FLUTICASONE PROPIONATE"}', 'route': '{NASAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • you have, or come into contact with someone who has, chicken pox, measles or tuberculosis • your symptoms do not get better within 7 days of starting use or you get new symptoms such as severe facial pain or thick nasal discharge. You may have something more than allergies, such as an infection. • you get a constant whistling sound from your nose. This may be a sign of damage inside your nose. • you get an allergic reaction to this product. Seek medical help right away. • you get new changes to your vision that develop after starting this product • you have severe or frequent nosebleeds"}', 'do_not_use': '{"Do not use • in children under 4 years of age • to treat asthma • if you have an injury or surgery to your nose that is not fully healed • if you have ever had an allergic reaction to this product or any of the ingredients"}', 'when_using': '{"When using this product • the growth rate of some children may be slower • stinging or sneezing may occur for a few seconds right after use • do not share this bottle with anyone else as this may spread germs • remember to tell your doctor about all the medicines you take, including this one"}', 'warnings': '{"Warnings Only for use in the nose. Do not spray into your eyes or mouth. Do not use • in children under 4 years of age • to treat asthma • if you have an injury or surgery to your nose that is not fully healed • if you have ever had an allergic reaction to this product or any of the ingredients Ask a doctor before use if you have or had glaucoma or cataracts Ask a doctor or pharmacist before use if you are taking • medicine for HIV infection (such as ritonavir) • a steroid medicine for asthma, allergies or skin rash • ketoconazole pills (medicine for fungal infection) When using this product • the growth rate of some children may be slower • stinging or sneezing may occur for a few seconds right after use • do not share this bottle with anyone else as this may spread germs • remember to tell your doctor about all the medicines you take, including this one Stop use and ask a doctor if • you have, or come into contact with someone who has, chicken pox, measles or tuberculosis • your symptoms do not get better within 7 days of starting use or you get new symptoms such as severe facial pain or thick nasal discharge. You may have something more than allergies, such as an infection. • you get a constant whistling sound from your nose. This may be a sign of damage inside your nose. • you get an allergic reaction to this product. Seek medical help right away. • you get new changes to your vision that develop after starting this product • you have severe or frequent nosebleeds 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}

{'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}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"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."}', '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 has ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': '{"When using this product do not exceed recommended dose (see overdose warning)"}', '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 • 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. 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 has ever had an allergic reaction to this product or any of its ingredients 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 When using this product do not exceed recommended dose (see overdose warning) 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. 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 even if you do not notice any signs or symptoms."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DOXYCYCLINE HYCLATE"}

{'contraindications': '{"CONTRAINDICATIONS This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines."}', 'adverse_reactions': '{"ADVERSE REACTIONS Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development (see WARNINGS). Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS). Renal toxicity: Rise in BUN has been reported and is apparently dose related (see WARNINGS). Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS). Other: Bulging fontanels in infants and intracranial hypertension in adults (see WARNINGS). Blood: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline for injection and other antibacterial drugs, doxycycline for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible 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. Doxycycline is indicated in infections caused by the following microorganisms: Rickettsiae (Rocky Mountain spotted fever, typhus fever, and the typhus group, Q fever, rickettsialpox and tick fevers). Mycoplasma pneumoniae (PPLO, Eaton Agent). Agents of psittacosis and ornithosis. Agents of lymphogranuloma venereum and granuloma inguinale. The spirochetal agent of relapsing fever ( Borrelia recurrentis ). The following gram-negative microorganisms: Haemophilus ducreyi ( chancroid ), Yersinia pestis Francisella tularensis, Bartonella bacilliformis, Bacteroides species, Vibrio cholerae and Campylobacte fetus, Brucella species ( in conjunction with streptomycin). Because many strains of the following groups of microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli, Enterobacter aerogenes, Shigella species, Acinetobacter species, Haemophilus influenzae (respiratory infections), Klebsiella species (respiratory and urinary infections). Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Streptococcus species Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive. For upper respiratory infections due to group A beta-hemolytic streptococci, penicillin is the usual drug of choice, including prophylaxis of rheumatic fever. Streptococcus pneumoniae, Staphylococcus aureus , respiratory skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections. Anthrax due to Bacillus anthracis , including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis . When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to: Neisseria gonorrhoeae and N. meningitidis, Treponema pallidum and Treponema pallidum subspecie s pertenue (syphilis and yaws), Listeria monocytogenes, Clostridium species, Fusobacterium fusiforme (Vincent\'s infection), Actinomyces species . In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. Doxycycline is indicated in the treatment of trachoma, although the infectious agent is not always eliminated, as judged by immunofluorescence."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{DOXYCYCLINE}', 'route': '{INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, 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 the use of antibacterial drugs. 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 use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline (see ADVERSE REACTIONS). If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted. Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function."}', 'precautions': '{"PRECAUTIONS General As with other antibacterial drugs, use of doxycycline may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, doxycycline should be discontinued and appropriate therapy instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy, when indicated. Prescribing doxycycline in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. All infections due to group A beta-hemolytic streptococci should be treated for at least 10 days. Information For Patients Patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered (see WARNINGS). that the use of doxycycline might increase the incidence of vaginal candidiasis. Patients should be counseled that antibacterial drugs, including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline is prescribed to treat a bacterial infection, patients should be told 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 doxycycline or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible. Laboratory Tests In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. Drug Interactions Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective. Usage in Pregnancy (see WARNINGS about use during tooth development.) Doxycycline for injection has not been studied in pregnant patients. It should not be used in pregnant women unless, in the judgment of the physician, it is essential for the welfare of the patient. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Usage in Children The use of doxycycline for injection in children under 8 years is not recommended because safe conditions for its use have not been established. Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies (see WARNINGS and DOSAGE AND ADMINISTRATION). As with other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Tetracyclines are present in the milk of lactating women who are taking a drug in this class."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ORPHENADRINE CITRATE"}

{'contraindications': '{"CONTRAINDICATIONS Contraindicated in patients with glaucoma, pyloric or duodenal obstruction, stenosing peptic ulcers, prostatic hypertrophy or obstruction of the bladder neck, cardio-spasm (megaesophagus) and myasthenia gravis. Contraindicated in patients who have demonstrated a previous hypersensitivity to the drug."}', 'adverse_reactions': '{"ADVERSE REACTIONS Adverse reactions of orphenadrine citrate are mainly due to the mild anti-cholinergic action of orphenadrine citrate and are usually associated with higher dosage. Dryness of the mouth is usually the first adverse effect to appear. When the daily dose is increased, possible adverse effects include tachycardia, palpitation, urinary hesitancy or retention, blurred vision, dilatation of pupils, increased ocular tension, weakness, nausea, vomiting, headache, dizziness, constipation, drowsiness, hypersensitivity reactions, pruritus, hallucinations, agitation, tremor, gastric irritation and rarely urticaria and other dermatoses. Infrequently, an elderly patient may experience some degree of mental confusion. These adverse reactions can usually be eliminated by reduction in dosage. Very rare cases of aplastic anemia associated with the use of orphenadrine tablets have been reported. No causal relationship has been established. 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."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Orphenadrine citrate extended-release tablets are indicated as an adjunct to rest, physical therapy and other measures for the relief of discomfort associated with acute painful musculo skeletal conditions."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Orphenadrine citrate is toxic when overdosed and typically induces anticholinergic effects. [3] In a review of orphenadrine toxicity, the minimum lethal dose was found to be 2 to 3 grams for adults; however, the range of toxicity is variable and unpredictable. [4] Treatment for orphenadrine citrate overdose is evacuation of stomach contents (when necessary), charcoal at repeated doses, intensive monitoring and appropriate supportive treatment of any emergent anticholinergic effects. [5]"}', 'active_flag': 'Y', 'generic_name': '{"ORPHENADRINE CITRATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Some patients may experience transient episodes of light-headedness, dizziness or syncope. Orphenadrine citrate may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; ambulatory patients should therefore be cautioned accordingly."}', 'precautions': '{"PRECAUTIONS Confusion, anxiety and tremors have been reported in few patients receiving propoxyphene and orphenadrine concomitantly. As these symptoms may be simply due to an additive effect, reduction of dosage and/or discontinuation of one or both agents is recommended in such cases. Orphenadrine citrate should be used with caution in patients with tachycardia, cardiac decompensation, coronary insufficiency, cardiac arrhythmias. Safety of continuous long-term therapy with orphenadrine citrate has not been established. Therefore, if orphenadrine citrate is prescribed for prolonged use, periodic monitoring of blood, urine and liver function values is recommended."}', 'information_for_patients': None, 'pregnancy': '{"PREGNANCY Animal reproduction studies have not been conducted with orphenadrine citrate. It is also not known whether orphenadrine citrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Orphenadrine citrate should be given to a pregnant woman only if clearly needed."}', 'pediatric_use': '{"PEDIATRIC USE Safety and effectiveness in pediatric patients have not been established."}', 'geriatric_use': None}

{DOCOSANOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses treats cold sores/fever blisters on the face or lips shortens healing time and duration of symptoms: tingling, pain, burning, and/or itching"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{DOCOSANOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if your cold sore gets worse or the cold sore is not healed within 10 days"}', 'do_not_use': '{"Do not use if you are allergic to any ingredient in this product"}', 'when_using': '{"When using this product apply only to the affected areas do not use in or near the eyes avoid applying directly inside your mouth do not share this product with anyone. This may spread the infection."}', 'warnings': '{"Warnings Allergy Alert This product may cause a severe allergic reaction. Symptoms may include: hives facial swelling wheezing/difficulty breathing shock rash If an allergic reaction occurs, stop use and seek medical help right away. For external use only Do not use if you are allergic to any ingredient in this product When using this product apply only to the affected areas do not use in or near the eyes avoid applying directly inside your mouth do not share this product with anyone. This may spread the infection. Stop use and ask a doctor if your cold sore gets worse or the cold sore is not healed within 10 days 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}

{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 myelopoieses (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 antineutrophilic 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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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. β-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 in the first trimester of pregnancy. If methimazole is 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 in the first trimester of pregnancy, it may be appropriate to use other agents in pregnant women requiring treatment for hyperthyroidism. If methimazole is used, the lowest possible dose to control the maternal disease should be given. Agranulocytosis Agranulocytosis is a potentially 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, pruritus, 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 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. β-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 is 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 post-marketing reports of severe liver injury in pediatric patients treated with propylthiouracil, methimazole is the preferred choice when an anti-thyroid 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 is 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 post-marketing reports of severe liver injury in pediatric patients treated with propylthiouracil, methimazole is the preferred choice when an anti-thyroid drug is required for a pediatric patient [see DOSAGE AND ADMINISTRATION ] ."}', 'geriatric_use': None}

{"SALICYLIC ACID"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses for the treatment of acne."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"SALICYLIC ACID"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': '{"When using this product • skin irritation and dryness is more likely to occur if you use another topical acne medication at the same time. If irritation occurs only use one topical acne medication at a time. • avoid contact with eyes. If contact occurs, flush thoroughly with water."}', 'warnings': '{"Warnings For external use only"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{NONOXYNOL-9}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use for the prevention of pregnancy"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{NONOXYNOL-9}', 'route': '{VAGINAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if you or your partner get burning, itching, a rash, or other irritation of the vagina or penis"}', 'do_not_use': '{"Do not use if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control"}', 'when_using': '{"When using this product you may get vaginal irritation (burning, itching or a rash)"}', 'warnings': '{"Warnings For Vaginal Use Only Not for rectal (anal) use Sexually transmitted disease (STDs) alert This product does not protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner. Do not use if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control When using this product you may get vaginal irritation (burning, itching or a rash) Stop use and ask a doctor if you or your partner get burning, itching, a rash, or other irritation of the vagina or penis 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}

{"CHLORHEXIDINE GLUCONATE"}

{'contraindications': '{"Chlorhexidine gluconate oral rinse should not be used by persons who are known to be hypersensitive to chlorhexidine gluconate or other formula ingredients."}', 'adverse_reactions': '{"The most common side effects associated with chlorhexidine gluconate oral rinses are: 1) an increase in staining of teeth and other oral surfaces; 2) an increase in calculus formation; and 3) an alteration in taste perception; see WARNINGS and PRECAUTIONS. Oral irritation and local allergy-type symptoms have been spontaneously reported as side effects associated with the use of chlorhexidine gluconate rinse. The following oral mucosal side effects were reported during placebo-controlled adult clinical trials: aphthous ulcer, grossly obvious gingivitis, trauma, ulceration, erythema, desquamation, coated tongue, keratinization, geographic tongue, mucocele, and short frenum. Each occurred at a frequency of less than 1%. Among post marketing reports, the most frequently reported oral mucosal symptoms associated with chlorhexidine gluconate oral rinse are stomatitis, gingivitis, glossitis, ulcer, dry mouth, hypesthesia, glossal edema, and paresthesia. Minor irritation and superficial desquamation of the oral mucosa have been noted in patients using chlorhexidine gluconate oral rinse. There have been cases of parotid gland swelling and inflammation of the salivary glands (sialadenitis) reported in patients using chlorhexidine gluconate oral rinse."}', 'drug_interactions': None, 'indications_and_usage': '{"Chlorhexidine gluconate oral rinse is indicated for use between dental visits as part of a professional program for the treatment of gingivitis as characterized by redness and swelling of the gingivae, including gingival bleeding upon probing. Chlorhexidine gluconate oral rinse has not been tested among patients with acute necrotizing ulcerative gingivitis (ANUG). For patients having coexisting gingivitis and periodontitis, see PRECAUTIONS."}', 'warnings_and_cautions': None, 'overdosage': '{"Ingestion of 1 or 2 ounces of chlorhexidine gluconate oral rinse by a small child (~10 kg body weight) might result in gastric distress, including nausea, or signs of alcohol intoxication. Medical attention should be sought if more than 4 ounces of chlorhexidine gluconate oral rinse is ingested by a small child or if signs of alcohol intoxication develop."}', 'active_flag': 'Y', 'generic_name': '{"CHLORHEXIDINE GLUCONATE 0.12% ORAL RINSE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"The effect of chlorhexidine gluconate oral rinse on periodontitis has not been determined. An increase in supragingival calculus was noted in clinical testing in chlorhexidine gluconate oral rinse users compared with control users. It is not known if chlorhexidine gluconate oral rinse use results in an increase in subgingival calculus. Calculus deposits should be removed by a dental prophylaxis at intervals not greater than six months. Anaphylaxis, as well as serious allergic reactions, have been reported during postmarketing use with dental products containing chlorhexidine. SEE CONTRAINDICATIONS."}', 'precautions': '{"General: 1. For patients having coexisting gingivitis and periodontitis, the presence or absence of gingival inflammation following treatment with chlorhexidine gluconate oral rinse should not be used as a major indicator of underlying periodontitis. 2. Chlorhexidine gluconate oral rinse can cause staining of oral surfaces, such as tooth surfaces, restorations, and the dorsum of the tongue. Not all patients will experience a visually significant increase in toothstaining. In clinical testing, 56% of chlorhexidine gluconate oral rinse users exhibited a measurable increase in facial anterior stain, compared to 35% of control users after six months; 15% of chlorhexidine gluconate oral rinse users developed what was judged to be heavy stain, compared to 1% of control users after six months. Stain will be more pronounced in patients who have heavier accumulations of unremoved plaque. Stain resulting from use of chlorhexidine gluconate oral rinse does not adversely affect health of the gingivae or other oral tissues. Stain can be removed from most tooth surfaces by conventional professional prophylactic techniques. Additional time may be required to complete the prophylaxis. Discretion should be used when prescribing to patients with anterior facial restorations with rough surfaces or margins. If natural stain cannot be removed from these surfaces by a dental prophylaxis, patients should be excluded from chlorhexidine gluconate oral rinse treatment if permanent discoloration is unacceptable. Stain in these areas may be difficult to remove by dental prophylaxis and on rare occasions may necessitate replacement of these restorations. 3. Some patients may experience an alteration in taste perception while undergoing treatment with chlorhexidine gluconate oral rinse. Rare instances of permanent taste alteration following chlorhexidine gluconate oral rinse use have been reported via post-marketing product surveillance."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy: Teratogenic Effects Pregnancy Category B Reproduction studies have been performed in rats and rabbits at chlorhexidine gluconate doses up to 300 mg/kg/day and 40 mg/kg/day, respectively, and have not revealed evidence of harm to the fetus. However, adequate and well-controlled studies in pregnant women have not been done. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed."}', 'pediatric_use': '{"Clinical effectiveness and safety of chlorhexidine gluconate oral rinse have not been established in children under the age of 18."}', 'geriatric_use': None}

{ACETAMINOPHEN,"DEXTROMETHORPHAN HYDROBROMIDE","DOXYLAMINE SUCCINATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves common cold/flu symptoms: ▪ cough due to minor throat and bronchial irritation ▪ sore throat ▪ headache ▪ minor aches and pains ▪ fever ▪ runny nose and sneezing"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ACETAMINOPHEN, DEXTROMETHORPHAN HBR, DOXYLAMINE SUCCINATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if ▪ pain or cough gets worse or lasts more than 7 days ▪ fever gets worse or lasts more than 3 days ▪ redness or swelling is present ▪ new symptoms occur ▪ cough comes back or occurs with rash or headache that lasts. 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. ▪ if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. ▪ if you have ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': '{"When using this product ▪ excitability may occur, especially in children ▪ marked drowsiness may occur ▪ avoid alcoholic drinks ▪ be careful when driving a motor vehicle or operating machinery ▪ alcohol, sedatives, and tranquilizers may increase drowsiness"}', 'warnings': '{"Warnings Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take • more than 4 doses in 24 hours, which is the maximum daily amount for this product • with other drugs containing acetaminophen • 3 or more alcoholic drinks every day while using this product 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. 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 you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. ▪ 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 ▪ glaucoma ▪ cough that occurs with too much phlegm (mucus) ▪ a breathing problem such as emphysema or chronic bronchitis ▪ trouble urinating due to an enlarged prostate gland ▪ persistent or chronic cough as occurs with smoking, asthma, or emphysema ▪ a sodium-restricted diet Ask a doctor or pharmacist before use if you are ▪ taking sedatives or tranquilizers ▪ taking the blood thinning drug warfarin When using this product ▪ excitability may occur, especially in children ▪ marked drowsiness may occur ▪ avoid alcoholic drinks ▪ be careful when driving a motor vehicle or operating machinery ▪ alcohol, sedatives, and tranquilizers may increase drowsiness Stop use and ask a doctor if ▪ pain or cough gets worse or lasts more than 7 days ▪ fever gets worse or lasts more than 3 days ▪ redness or swelling is present ▪ new symptoms occur ▪ cough comes back or occurs with rash or headache that lasts. 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}

{"ATORVASTATIN CALCIUM TRIHYDRATE"}

{'contraindications': '{"4 CONTRAINDICATIONS • Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels • Hypersensitivity to Any Component of This Medication • Pregnancy [see Use in Specific Populations ( 8.1 , 8.3 )]. • Lactation [see Use in Specific Populations ( 8.2 )] . • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 ). • Hypersensitivity to any component of this medication ( 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: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Liver enzyme abnormalities [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc., at 1-866-924-6266 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, the 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 the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin vs. 7,311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin in placebo controlled trials (n=8,755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%). Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8,755), from seventeen placebo-controlled trials. Table 2: Clinical Adverse Reactions Occurring in ≥ 2% in Patients Treated with any Dose of Atorvastatin and at an Incidence Greater than Placebo Regardless of Causality (% of Patients). Adverse Reaction Adverse Reaction ≥ 2% in any dose greater than placebo Any dose N=8,755 10 mg N=3,908 20 mg N=188 40 mg N=604 80 mg N=4,055 Placebo N=7,311 Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2 Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3 Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9 Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6 Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3 Nausea 4.0 3.7 3.7 7.1 3.8 3.5 Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6 Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3.0 Myalgia 3.5 3.6 5.9 8.4 2.7 3.1 Insomnia 3.0 2.8 1.1 5.3 2.8 2.9 Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 Other adverse reactions reported in placebo-controlled studies include: Body as a whole : malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system : musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system : transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system : nightmare; Respiratory system: epistaxis; Skin and appendages : urticaria; Special senses : vision blurred, tinnitus; Urogenital system: white blood cells urine positive. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) In ASCOT [see Clinical Studies ( 14.1 )] involving 10,305 participants (age range 40 to 80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up. Collaborative Atorvastatin Diabetes Study (CARDS) In CARDS [see Clinical Studies ( 14.1 )] involving 2,838 subjects (age range 39 to 77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported. Treating to New Targets Study (TNT) In TNT [see Clinical Studies ( 14.1 )] involving 10,001 subjects (age range 29 to 78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%). Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL) In IDEAL [see Clinical Studies ( 14.1 )] involving 8,888 subjects (age range 26 to 80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin 80 mg/day (n=4,439) or simvastatin 20 mg to 40 mg daily (n=4,449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4,731 subjects (age range 21 to 92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with atorvastatin 80 mg (n=2,365) or placebo (n=2,366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions ( 5.6 )] . In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2,365, 9.2% vs. 274/2,366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2,365, 2.3% vs. 33/2,366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin vs. 2 (4%) placebo]. There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%). Adverse Reactions from Clinical Studies of Atorvastatin in Pediatric Patients In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin 10 mg to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Special Populations ( 8.4 ) and Clinical Studies ( 14.6 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atorvastatin. 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 associated with atorvastatin therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, and pancreatitis and interstitial lung disease. 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, 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 (one day to years) and symptom resolution (median of 3 weeks)."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Drug Interactions that may Increase the Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7.1 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid modifying doses of niacin, colchicine Consider the risk/benefit of concomitant use with atorvastatin • Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin ( 7 ). • Rifampin should be simultaneously co-administered with atorvastatin ( 7.2 ). • Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased ( 7.3 ). • Digoxin: Patients should be monitored appropriately ( 7.3 ). 7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 3 includes a list of drugs that may increase exposure to atorvastatin calcium and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. Table 3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology ( 12.3 )]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology ( 12.3 )]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention: ● Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. ● In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. ● In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg. ● In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration ( 2.6 )]. ● Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. ● Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology ( 12.3 )]. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [see Dosage and Administration ( 2.6 )]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin. 7.2 Drug Interactions that may Decrease Exposure to Atorvastatin Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them. Table 4: Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin and rifampin simultaneously. 7.3 Atorvastatin Effects on Other Drugs Table 5 presents atorvastatin\'s effect on other drugs and instructions for preventing or managing them. Table 5: Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology ( 12.3 )]. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin. Digoxin Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor patients taking digoxin appropriately."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet. Atorvastatin calcium tablets are an HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to: • Reduce the risk of MI, stroke, revascularization procedures, and angina in adult patients without CHD, but with multiple risk factors ( 1.1 ). • Reduce the risk of MI and stroke in adult patients with type 2 diabetes without CHD, but with multiple risk factors ( 1.1 ). • Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in adult patients with CHD ( 1.1 ). • Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( 1.2 ). • Reduce elevated TG in adult patients with hypertriglyceridemia and primary dysbetalipoproteinemia ( 1.2 ). • Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) ( 1.2 ). • Reduce elevated total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) after failing an adequate trial of diet therapy ( 1.2 ). Limitations of Use: Atorvastatin calcium tablets have not been studied in Fredrickson Types I and V dyslipidemias ( 1.3 ). 1.1 Prevention of Cardiovascular Disease in Adults In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to: • Reduce the risk of myocardial infarction • Reduce the risk of stroke • Reduce the risk for revascularization procedures and angina In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to: • Reduce the risk of myocardial infarction • Reduce the risk of stroke In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: • Reduce the risk of non-fatal myocardial infarction • Reduce the risk of fatal and non-fatal stroke • Reduce the risk for revascularization procedures • Reduce the risk of hospitalization for CHF • Reduce the risk of angina 1.2 Hyperlipidemia Atorvastatin calcium tablets are indicated: • As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb); • As an adjunct to diet for the treatment of adult patients with elevated serum TG levels ( Fredrickson Type IV); • For the treatment of adult patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet; • To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; • As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients,10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present: 1. LDL-C remains ≥ 190 mg/dL or 2. LDL-C remains ≥ 160 mg/dL and: ▪ there is a positive family history of premature cardiovascular disease or ▪ two or more other CVD risk factors are present in the pediatric patient 1.3 Limitations of Use Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson Types I and V)."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Myopathy and Rhabdomyolysis: Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of 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. Atorvastatin therapy should be discontinued if myopathy is diagnosed or suspected ( 2.6 5.1 , 8.5 ). • 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. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.3 ). • A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin 80 mg group vs. placebo ( 5.6 ). 5.1 Myopathy and Rhabdomyolysis Atorvastatin may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including atorvastatin. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin dosage [see Drug Interactions ( 7.1 )]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Atorvastatin exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin is not recommended. Atorvastatin dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration ( 2.6 )] . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin coadministered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interaction s ( 7.1 )] . Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin [see Drug Interactions ( 7.1 )]. Discontinue atorvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if atorvastatin is discontinued. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the atorvastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 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 different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM. 5.3 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on two or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10 mg, 20 mg, 40 mg, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin. It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin [see Contraindications ( 4 )]. 5.4 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. 5.5 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of two male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. 5.6 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions ( 6.1 )] ."}', 'overdosage': '{"10 OVERDOSAGE There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance."}', 'active_flag': 'Y', 'generic_name': '{"ATORVASTATIN CALCIUM, FILM COATED"}', '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 taking atorvastatin calcium tablets should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment. Patients should be advised about substances they should not take concomitantly with atorvastatin [ see Warnings and Precautions ( 5.1 )] . Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking atorvastatin calcium tablets. 17.1 Muscle Pain All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium tablets. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium tablets and if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 17.3 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 )]. 17.4 Lactation Advise women not to breastfeed during treatment with atorvastatin calcium tablets [see Contraindications ( 4 ) and Use in Specific Populations ( 8.2 )]. The brand names listed are trademarks of their respective owners and are not trademark of the Graviti Pharmaceuticals Private Limited. Manufactured by: Graviti Pharmaceuticals Private Limited. Telangana-502307, India Manufactured for: Biocon Pharma Inc., Iselin, NJ 08830-3009 USA Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320"}', 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"PRAMOXINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"INDICATION: Use for the temporary relief of pain and itching associated with hemorrhoids."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"PRAMOXINE HYDROCHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{""}', 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS: Do not exceed the recommended daily dosage unless directed by a physician. If condition worsens or does not improve within 7 days, consult a physician. In case of rectal bleeding, consult a physician promptly. Do not put this product into the rectum by using fingers or any mechanical device or applicator. Certain persons can develop allergic reactions to ingredients in this product. If the symptom being treated does not subside or if redness, irritation, swelling, pain or other symptoms develop or increase, discontinue use immediately and consult a physician. Do not use in the eyes or nose. Do not apply to large areas of the body."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ARIPIPRAZOLE}

{'contraindications': '{"4 CONTRAINDICATIONS Aripiprazole is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6.2)]. Known hypersensitivity to aripiprazole (4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS 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 following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)] Cerebrovascular Adverse Events, Including Stroke [see Warnings and Precautions (5.2)] Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.3)] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)] Tardive Dyskinesia [see Warnings and Precautions (5.5)] Metabolic Changes [see Warnings and Precautions (5.6)] Pathological Gambling and Other Compulsive Behaviors [see Warnings and Precautions (5.7)] Orthostatic Hypotension [see Warnings and Precautions (5.8)] Falls [see Warnings and Precautions (5.9)] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.10)] Seizures/Convulsions [see Warnings and Precautions (5.11)] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)] Body Temperature Regulation [see Warnings and Precautions (5.13)] Suicide [see Warnings and Precautions (5.14)] Dysphagia [see Warnings and Precautions (5.15)] The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased. Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, other indications, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, andwho had approximately 7,619 patient-years of exposure to oral aripiprazole and 749 patients with exposure to aripiprazole injection. A total of 3,390 patients were treated with oral aripiprazole for at least 180 days and 1,933 patients treated with oral aripiprazole had at least one year of exposure. Aripiprazole has been evaluated for safety in 1,686 pediatric patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, autistic disorder, or Tourette’s disorder or another indication and who had approximately 1,342 patient-years of exposure to oral aripiprazole. A total of 959 pediatric patients were treated with oral aripiprazole for at least 180 days and 556 pediatric patients treated with oral aripiprazole had at least one year of exposure. The conditions and duration of treatment with aripiprazole tablets included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure. Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) were (6.1): • Adult patients with schizophrenia: akathisia • Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor • Pediatric patients (6 to 17 years) with autistic disorder: sedation, fatigue, vomiting, somnolence, tremor, pyrexia, drooling, decreased appetite, salivary hypersecretion, extrapyramidal disorder, and lethargy • Pediatric patients (6 to 18 years) with Tourette’s disorder: sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, increased appetite To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Adult Patients with Schizophrenia The following findings are based on a pool of five placebo-controlled trials (four 4 week and one 6 week) in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Commonly Observed Adverse Reactions The only commonly observed adverse reaction associated with the use of aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%). Less Common Adverse Reactions in Adults Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in another indication), including only those reactions that occurred in 2% or more of patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset. Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral Aripiprazole System Organ Class Preferred Term Percentage of Patients Reporting Reaction * Aripiprazole (n=1,843) Placebo (n=1,166) Eye Disorders Blurred Vision 3 1 Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 * Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Pediatric Patients (13 to 17 years) with Schizophrenia The following findings are based on one 6-week, placebo-controlled trial in which oral aripiprazole was administered in doses ranging from 2 to 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in adolescent patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor. Pediatric Patients (6 to 17 years) with Autistic Disorder The following findings are based on two 8 week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 to 15 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with autistic disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 20. Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction Preferred Term Aripiprazole (n=212) Placebo (n=101) Sedation 21 4 Fatigue 17 2 Vomiting 14 7 Somnolence 10 4 Tremor 10 0 Pyrexia 9 1 Drooling 9 0 Decreased Appetite 7 2 Salivary Hypersecretion 6 1 Extrapyramidal Disorder 6 0 Lethargy 5 0 Pediatric Patients (6 to 18 years) with Tourette’s Disorder The following findings are based on one 8 week and one 10 week, placebo-controlled trials in which oral aripiprazole was administered in doses of 2 to 20 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between aripiprazole-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of aripiprazole in pediatric patients with Tourette\'s disorder (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) are shown in Table 21. Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette’s Disorder Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction Aripiprazole Placebo Preferred Term (n=121) (n=72) Sedation 13 6 Somnolence 13 1 Nausea 11 4 Headache 10 3 Nasopharyngitis 9 0 Fatigue 8 0 Increased Appetite 7 1 Less Common Adverse Reactions in Pediatric Patients (6 to 18 years) with Schizophrenia, Another Indication, Autistic Disorder, or Tourette’s Disorder Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in one indication, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette’s disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with aripiprazole (doses ≥2 mg/day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo. Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral Aripiprazole Percentage of Patients Reporting Reaction * System Organ Class Preferred Term Aripiprazole (n=732) Placebo (n=370) Eye Disorders Blurred Vision 3 0 Gastrointestinal Disorders Abdominal Discomfort 2 1 Vomiting 8 7 Nausea 8 4 Diarrhea 4 3 Salivary Hypersecretion 4 1 Abdominal Pain Upper 3 2 Constipation 2 2 General Disorders and Administration Site Conditions Fatigue 10 2 Pyrexia 4 1 Irritability 2 1 Asthenia 2 1 Infections and Infestations Nasopharyngitis 6 3 Investigations Weight Increased 3 1 Metabolism and Nutrition Disorders Increased Appetite 7 3 Decreased Appetite 5 4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 2 1 Muscle Rigidity 2 1 Nervous System Disorders Somnolence 16 4 Headache 12 10 Sedation 9 2 Tremor 9 1 Extrapyramidal Disorder 6 1 Akathisia 6 4 Drooling 3 0 Lethargy 3 0 Dizziness 3 2 Dystonia 2 1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 2 1 Skin and Subcutaneous Disorders Rash 2 1 * Adverse reactions reported by at least 2% of pediatric patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. Dose-Related Adverse Reactions Schizophrenia Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral aripiprazole to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5%; 10 mg, 13%; 30 mg, 21.6%); somnolence (incidences were placebo, 6%; 10 mg, 11%; 30 mg, 21.6%); and tremor (incidences were placebo, 2%; 10 mg, 2%; 30 mg, 11.8%). Autistic Disorder In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22%; 15 mg, 18.5%). Tourette’s Disorder In a study of pediatric patients (7 to 17 years of age) with Tourette’s disorder, no common adverse reaction(s) had a dose response relationship. Extrapyramidal Symptoms Schizophrenia In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for aripiprazole-treated patients was 9% vs. 6% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, –0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Simpson Angus Rating Scale (aripiprazole, 0.24; placebo, –0.29). Similarly, in a long-term (26 week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between aripiprazole and placebo. Autistic Disorder In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 3% vs. 9% for placebo. In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between aripiprazole and placebo (Aripiprazole, 0.1; placebo, – 0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the aripiprazole and placebo groups. Tourette’s Disorder In the short-term, placebo-controlled trials in Tourette’s disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for aripiprazole-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for aripiprazole-treated patients was 4% vs. 6% for placebo. In the pediatric (6 to 18 years) short-term Tourette’s disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for aripiprazole and placebo. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Additional Findings Observed in Clinical Trials Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials The adverse reactions reported in a 26 week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for aripiprazole tablets vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of aripiprazole tablets. In addition, in a long-term (52 weeks), active-controlled study, the incidence of tremor was 5% (40/859) for aripiprazole. Other Adverse Reactions Observed During Clinical Trial Evaluation of Aripiprazole The following listing does not 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients: Adults - Oral Administration • Blood and Lymphatic System Disorders: rare - thrombocytopenia • Cardiac Disorders: infrequent - bradycardia, palpitations, rare - atrial flutter, cardio-respiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure • Eye Disorders: infrequent - photophobia; rare - diplopia • Gastrointestinal Disorders: infrequent - gastroesophageal reflux disease • General Disorders and Administration Site Conditions: frequent - asthenia; infrequent - peripheral edema, chest pain; rare - face edema • Hepatobiliary Disorders: rare - hepatitis, jaundice • Immune System Disorders: rare - hypersensitivity • Injury, Poisoning, and Procedural Complications: infrequent - fall; rare – heat stroke • Investigations: frequent – blood prolactin decreased, weight decreased, infrequent - hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare - blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased • Metabolism and Nutrition Disorders: frequent - anorexia; rare - hypokalemia, hyponatremia, hypoglycemia • Musculoskeletal and Connective Tissue Disorders: infrequent - muscular weakness, muscle tightness; rare - rhabdomyolysis, mobility decreased • Nervous System Disorders: infrequent - parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, bradykinesia; rare - akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; <1/10,000 patients – choreoathetosis • Psychiatric Disorders: infrequent - aggression, loss of libido, delirium; rare - libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking • Renal and Urinary Disorders: rare - urinary retention, nocturia • Reproductive System and Breast Disorders: infrequent - erectile dysfunction; rare - gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism • Respiratory, Thoracic, and Mediastinal Disorders: infrequent - nasal congestion, dyspnea • Skin and Subcutaneous Tissue Disorders: infrequent - rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare - urticaria • Vascular Disorders: infrequent - hypotension, hypertension Pediatric Patients - Oral Administration Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below. • Eye Disorders: infrequent - oculogyric crisis • Gastrointestinal Disorders: infrequent - tongue dry, tongue spasm • Investigations: frequent - blood insulin increased • Nervous System Disorders: infrequent - sleep talking • Renal and Urinary Disorders: frequent - enuresis • Skin and Subcutaneous Tissue Disorders: infrequent - hirsutism 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of aripiprazole. 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: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hiccups, oculogyric crisis, and pathological gambling."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Dosage adjustment due to drug interactions (7.1): Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks 7.1 Drugs Having Clinically Important Interactions with Aripiprazole Table 25: Clinically Important Drug Interactions with Aripiprazole: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see Dosage and Administration (2.7)]. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology (12.3)]. With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see Dosage and Administration (2.7)]. Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions (5.8)]. Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see Warnings and Precautions (5.8)] Monitor sedation and blood pressure. Adjust dose accordingly. 7.2 Drugs Having No Clinically Important Interactions with Aripiprazole Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam. In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [see Clinical Pharmacology (12.3)] ."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Aripiprazole is indicated for the treatment of: • Schizophrenia • Irritability Associated with Autistic Disorder • Treatment of Tourette’s Disorder Aripiprazole is an atypical antipsychotic. The oral formulations are indicated for: • Schizophrenia (14.1) • Irritability Associated with Autistic Disorder (14.4) • Treatment of Tourette’s disorder (14.5)"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities) (5.2) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4) Tardive Dyskinesia: Discontinue if clinically appropriate (5.5) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain (5.6) Hyperglycemia/Diabetes Mellitus: Monitor glucose regularly in patients with and at risk for diabetes (5.6) Dyslipidemia: Undesirable alterations in lipid levels have been observed in patients treated with atypical antipsychotics (5.6) Weight Gain: Weight gain has been observed with atypical antipsychotic use. Monitor weight (5.6) Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation (5.7) Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.8) Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics including aripiprazole. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of aripiprazole should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.10) Seizures/Convulsions: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.11) Potential for Cognitive and Motor Impairment: Use caution when operating machinery (5.12) Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients (5.14) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Increased Mortality Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning]. Safety Experience in Elderly Patients with Psychosis Associated with Alzheimer’s Disease In three, 10 week, placebo-controlled studies of aripiprazole in elderly patients with psychosis associated with Alzheimer’s disease (n=938; mean age: 82.4 years; range: 56 to 99 years), the adverse reactions that were reported at an incidence of ≥3% and aripiprazole incidence at least twice that for placebo were lethargy [placebo 2%, aripiprazole 5%], somnolence (including sedation) [placebo 3%, aripiprazole 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, aripiprazole 5%], excessive salivation [placebo 0%, aripiprazole 4%], and lightheadedness [placebo 1%, aripiprazole 4%]. The safety and efficacy of aripiprazole in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with aripiprazole, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see Boxed Warning ]. 5.2 Cerebrovascular Adverse Events, Including Stroke In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78 to 88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ]. 5.3 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 to 24 years) with 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 years; there was a reduction with antidepressants compared to placebo in adults aged 65 years 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 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 1,000 patients treated) are provided in Table 5. Table 5: Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer case No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug 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 MDD 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. 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for aripiprazole should be written for the smallest quantity of tablets 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 aripiprazole is not approved for use in treating depression in the pediatric population. 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS occurred during aripiprazole treatment in the worldwide clinical database. 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) 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 pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 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 uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported. 5.5 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, aripiprazole should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, drug discontinuation should be considered. However, some patients may require treatment with aripiprazole despite the presence of the syndrome. 5.6 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia/Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole [see Adverse Reactions (6.1, 6.2)]. Although fewer patients have been treated with aripiprazole, it is not known if this more limited experience is the sole reason for the paucity of such reports. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies which did not include aripiprazole suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics included in these studies. Because aripiprazole was not marketed at the time these studies were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Adults In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or another indication, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1,057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 6 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days). Table 6: Changes in Fasting Glucose from Placebo-Controlled Monotherapy Trials in Adult Patients Fasting Glucose Category Change (at least once) from Baseline Treatment Arm n/N % Normal to High (<100 mg/dL to ≥126 mg/dL) Aripiprazole 31/822 3.8 Placebo 22/605 3.6 Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL Aripiprazole 31/176 17.6 Placebo 13/142 9.2 At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively]. Pediatric Patients and Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication (10 to 17 years), the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123). In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in aripiprazole -treated patients (–0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (–0.6 mg/dL; N=33). In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette’s disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in aripiprazole-treated patients (0.79 mg/dL; N=90) was not significantly different than in placebo-treated patients (–1.66 mg/dL; N=58). Table 8 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and another indication (median exposure of 42 to 43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 year) with Tourette’s Disorder (median exposure 57 days). Table 8: Changes in Fasting Glucose from Placebo-Controlled Trials in Pediatric and Adolescent Patients Category Change (at least once) from Baseline Indication Treatment Arm n/N % Fasting Glucose Normal to High (<100 mg/dL to ≥126 mg/dL) Pooled Schizophrenia and Another Indication Aripiprazole 2/236 0.8 Placebo 2/110 1.8 Irritability Associated with Autistic Disorder Aripiprazole 0/73 0 Placebo 0/32 0 Tourette’s Disorder Aripiprazole 3/88 3.4 Placebo 1/58 1.7 Fasting Glucose Borderline to High (≥100 mg/dL to <126 mg/dL to ≥126 mg/dL) Pooled Schizophrenia and Another Indication Aripiprazole 1/22 4.5 Placebo 0/12 0 Irritability Associated with Autistic Disorder Aripiprazole 0/9 0 Placebo 0/1 0 Tourette’s Disorder Aripiprazole 0/11 0 Placebo 0/4 0 At 12 weeks in the pooled adolescent schizophrenia and other indication trials, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively]. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients. Adults Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and another indication monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days). Table 9: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Adults Treatment Arm n/N % Total Cholesterol Normal to High (<200 mg/dL to ≥240 mg/dL) Aripiprazole 34/1,357 2.5 Placebo 27/973 2.8 Fasting Triglycerides Normalto High (<150 mg/dL to ≥200 mg/dL) Aripiprazole 40/539 7.4 Placebo 30/431 7 Fasting LDL Cholesterol Normal to High (<100 mg/dL to ≥160 mg/dL) Aripiprazole 2/332 0.6 Placebo 2/268 0.7 HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) Aripiprazole 121/1,066 11.4 Placebo 99/794 12.5 In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively. Pediatric Patients and Adolescents Table 11 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days), and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days). Table 11: Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients in Schizophrenia and Another Indication Treatment Arm n/N % Total Cholesterol Normal to High (<170 mg/dL to ≥200 mg/dL) Aripiprazole 3/220 1.4 Placebo 0/116 0 Fasting Triglycerides Normalto High (<150 mg/dL to ≥200 mg/dL) Aripiprazole 7/187 3.7 Placebo 4/85 4.7 HDL Cholesterol Normal to Low (≥40 mg/dL to <40 mg/dL) Aripiprazole 27/236 11.4 Placebo 22/109 20.2 In monotherapy trials of adolescents with schizophrenia and pediatric patients with another indication, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10%), respectively. Table 12 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder. Table 12: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients with Autistic Disorder Treatment Arm n/N % Total Cholesterol Aripiprazole 1/95 1.1 Normal to High (<170 mg/dL to ≥200 mg/dL) Placebo 0/34 0 Fasting Triglycerides Aripiprazole 0/75 0 Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 0/30 0 HDL Cholesterol Aripiprazole 9/107 8.4 Normal to Low (≥40 mg/dL to <40 mg/dL) Placebo 5/49 10.2 Table 13 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette’s Disorder. Table 13: Changes in Blood Lipid Parameters from Placebo-Controlled Trials in Pediatric Patients with Tourette’s Disorder Treatment Arm n/N % Total Cholesterol Aripiprazole 1/85 1.2 Normal to High (<170 mg/dL to ≥200 mg/dL) Placebo 0/46 0 Fasting Triglycerides Aripiprazole 5/94 5.3 Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 2/55 3.6 HDL Cholesterol Aripiprazole 4/108 3.7 Normal to Low (≥40 mg/dL to <40 mg/dL) Placebo 2/67 3.0 Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Adults In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and another indication, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients. Table 14 shows the percentage of adult patients with weight gain ≥7% of body weight by indication. Table 14 : Percentage of Patients from Placebo-Controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight Indication Treatment Arm N Patients n (%) Weight gain ≥7% of body weight Schizophrenia * Aripiprazole 852 69 (8.1) Placebo 379 12 (3.2) Other Indication † Aripiprazole 719 16 (2.2) Placebo 598 16 (2.7) * 4 to 6 weeks duration. † 3 weeks duration. Pediatric Patients and Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication(10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients. In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in aripiprazole -treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients. In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette’s Disorder with median exposure of 57 days, the mean change in body weight in aripiprazole -treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients. Table 15 shows the percentage of pediatric and adolescent patients with weight gain ≥7% of body weight by indication. Table 15: Percentage of Patients from Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain ≥7% of Body Weight Indication Treatment Arm N Patients n (%) Weight gain ≥7% of body weight Pooled Schizophrenia and Another Indication * Aripiprazole 381 20 (5.2) Placebo 187 3 (1.6) Irritability Associated with Autistic Disorder † Aripiprazole 209 55 (26.3) Placebo 98 7 (7.1) Tourette’s Disorder ‡ Aripiprazole 105 21 (20) Placebo 66 5 (7.6) * 4 to 6 weeks duration † 8 weeks duration. ‡ 8 to 10 weeks duration. In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with another indication(10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with aripiprazole. After 26 weeks, 32.8% of patients gained ≥7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD. In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with aripiprazole. The mean change in weight z-score was 0.26 SDs for patients receiving >9 months of treatment. When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth. 5.7 Pathological Gambling and Other Compulsive Behaviors Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges. 5.8 Orthostatic Hypotension Aripiprazole may cause orthostatic hypotension, perhaps due to its α 1 -adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2,467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral aripiprazole included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0%), and syncope (0.2%, 0%) [see Adverse Reactions (6.1)] The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%), in pediatric oral aripiprazole-treated patients aged 6 to 18 years (0.4%, 1%). Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Drug Interactions (7.1)] . 5.9 Falls Antipsychotics, including aripiprazole, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.10 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of aripiprazole at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue aripiprazole in patients with severe neutropenia (absolute neutrophil count <1,000/mm 3 ) and follow their WBC counts until recovery. 5.11 Seizures/Convulsions In short-term, placebo-controlled trials, seizures/convulsions occurred in 0.1% (3/2,467) of adult patients treated with oral aripiprazole, in 0.1% (1/732) of pediatric patients (6 to 18 years). As with other antipsychotic drugs, aripiprazole should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. 5.12 Potential for Cognitive and Motor Impairment Aripiprazole, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2,467) treated with oral aripiprazole (11%, 6%), in pediatric patients ages 6 to 17 years (n=611; 24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2,467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral aripiprazole in short-term, placebo-controlled trials. Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with aripiprazole does not affect them adversely. 5.13 Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see Adverse Reactions (6.2)]. 5.14 Suicide The possibility of a suicide attempt is inherent in psychotic illnesses and close supervision of high-risk patients should accompany drug therapy. Prescriptions for aripiprazole should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see Adverse Reactions (6.1, 6.2)]. 5.15 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)] ."}', 'overdosage': '{"10 OVERDOSAGE MedDRA terminology has been used to classify the adverse reactions. 10.1 Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. 10.2 Management of Overdosage No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of aripiprazole, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of aripiprazole, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis : Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins."}', 'active_flag': 'Y', 'generic_name': '{ARIPIPRAZOLE}', '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). Discuss the following issues with patients prescribed Aripiprazole: Clinical Worsening of Depression and Suicide Risk Patients, their families, and caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Warnings and Precautions (5.3)]. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with aripiprazole and should counsel them in its appropriate use. A patient Medication Guide including information about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for aripiprazole. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. It should be noted that aripiprazole tablets are not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder. Pathological Gambling and Other Compulsive Behaviors Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Warnings and Precautions (5.7)] . Interference with Cognitive and Motor Performance Because aripiprazole may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that aripiprazole therapy does not affect them adversely [see Warnings and Precautions (5.12)] . Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)] . Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)] . Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with aripiprazole. Advise patients that aripiprazole may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to aripiprazole during pregnancy [see Use in Specific Populations (8.1)]. Medication Guide available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-9797. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. Bedminster, NJ 07921, USA Revision: 03/2024"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) . Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see Clinical Considerations). In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (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. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and 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 risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. Animal Data In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. In pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the MRHD of 30 mg/day based on mg/m 2 body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the MRHD of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the MRHD; this dose also caused maternal toxicity. In pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the MRHD of 30 mg/day based on mg/m 2 body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the MRHD. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD. In pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the MRHD of 30 mg/day based on mg/m 2 body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossificationwere observed at 19 times the MRHD; this dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD. In rats treated orally with aripiprazole peri- and postnatally from gestation Day 17 through postpartum Day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the MRHD of 30 mg/day based on mg/m 2 body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the MRHD. An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose. In rats injected intravenously with aripiprazole from gestation Day 6 through lactation Day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the MRHD of 30 mg/day based on mg/m 2 body surface area, increased stillbirths were observed at 3 and 6 times the MRHD; and decreases in early postnatal pup weight and survival were observed at 6 times the MRHD; these doses also caused some maternal toxicity. There were no effects on postnatal behavioral and reproductive development."}', 'pediatric_use': '{"8.4 Pediatric Use The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see Clinical Pharmacology (12.3)] . Schizophrenia Safety and effectiveness in pediatric patients with schizophrenia were established in a 6 week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see Dosage and Administration (2.1), Adverse Reactions (6.1), and Clinical Studies (14.1)]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Bipolar I Disorder Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Irritability Associated with Autistic Disorder Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8 week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see Indications and Usage (1), Dosage and Administration (2.4), Adverse Reactions (6.1), and Clinical Studies (14.4)] . A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as >25% improvement on the ABC-I subscale, and a CGI-I rating of “much improved” or “very much improved”) on aripiprazole for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16 week, double-blind phase where they were randomized to either continue aripiprazole treatment or switch to placebo. In this trial, the efficacy of aripiprazole for the maintenance treatment of irritability associated with autistic disorder was not established. Tourette’s Disorder Safety and effectiveness of aripiprazole in pediatric patients with Tourette’s Disorder were established in one 8 week (aged 7 to 17 years) and one 10 week trial (aged 6 to 18 years) in 194 pediatric patients [see Dosage and Administration (2.5), Adverse Reactions (6.1), and Clinical Studies (14.5)] . Maintenance efficacy in pediatric patients has not been systematically evaluated. Juvenile Animal Studies Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2 month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2 month recovery period."}', 'geriatric_use': '{"8.5 Geriatric Use No dosage adjustment is recommended for elderly patients [see Boxed Warning, Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] . Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1,073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia or other indications did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Aripiprazole is not approved for the treatment of patients with psychosis associated with Alzheimer’s disease [see Boxed Warning and Warnings and Precautions (5.1)]."}'}

{ACETAMINOPHEN,"PHENYLEPHRINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves these symptoms associated with hay fever or other respiratory allergies, and the common cold: minor aches and pains headache nasal congestion sinus congestion and pressure helps decongest sinus openings and passages promotes sinus drainage helps clear nasal passages temporarily reduces fever"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"ACETAMINOPHEN AND PHENYLEPHRINE HCL"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur pain or nasal congestion gets worse or lasts more than 7 days new symptoms occur fever gets worse or lasts more than 3 days redness or swelling is present 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. if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. if you have ever had an allergic reaction to this product or any of its ingredients"}', 'when_using': '{"When using this product do not exceed recommended dosage."}', '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 Allergy alert: Acetaminophen may cause severe skin reactions. Symptoms may include: blisters rash skin reddening If a skin reaction occurs, stop use and seek medical help right away. 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 you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. 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 difficulty in urination due to enlargement of the prostate gland heart disease diabetes thyroid disease high blood pressure Ask a doctor or pharmacist before use if you are taking the blood thinning drug warfarin. When using this product do not exceed recommended dosage. Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur pain or nasal congestion gets worse or lasts more than 7 days new symptoms occur fever gets worse or lasts more than 3 days redness or swelling is present 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. In case of accidental overdose, get medical help or contact a Poison Control Center right away. Prompt 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}

{"GONORRHEAL URETHRAL SECRETION HUMAN"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Rx Only*"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"GONORRHEAL URETHRAL SECRETION HUMAN"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist for more than 3 days or worsen"}', 'do_not_use': None, 'when_using': None, 'warnings': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DESMOPRESSIN ACETATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Desmopressin nasal spray is contraindicated in patients with: Known hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray. Severe allergic reactions and anaphylaxis have been reported [see Adverse Reactions ( 6 )] . Renal impairment defined as estimated creatinine clearance (CLcr) by Cockcroft-Gault equation less than 50 mL/min [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Hyponatremia or a history of hyponatremia [see Warnings and Precautions ( 5.1 )]. Known hypersensitivity to desmopressin acetate or to any of the components of desmopressin nasal spray ( 4 , 6 ) Patients with renal impairment (creatinine clearance below 50 mL/min) ( 4 , 8.6 , 12.3 ) Hyponatremia or a history of hyponatremia ( 4 , 5.1 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious reactions are described below and elsewhere in the labeling: Hyponatremia [see Warnings and Precautions ( 5.1 )]. Altered Absorption in Patients with Changes in Nasal Mucosa [see Warnings and Precautions ( 5.2 )]. The following adverse reactions have been identified during post-approval use of desmopressin acetate. 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: Increase in blood pressure, headache, nasal congestion, rhinitis, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and abdominal cramps. Water intoxication with hyponatremia Hyponatremic convulsions associated with concomitant use of the following medications: oxybutinin and imipramine [see Drug Interactions ( 7.1 )] . Severe allergic reactions and anaphylaxis [see Contraindications ( 4 )] Adverse reactions that have been identified in patients administered desmopressin nasal spray are headache, nasal congestion, rhinitis, nosebleed, sore throat, cough, upper respiratory infections, nausea, flushing, and mild abdominal cramps ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch"}', 'drug_interactions': '{"7 DRUG INTERACTIONS Drugs that Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium ( 7.1 ) Other Vasoconstrictors: Concomitant use may elevate blood pressure and require a reduction in desmopressin nasal spray dosage ( 7.2 ) 7.1 Other Drugs that may Increase Risk of Hyponatremia The concomitant administration of desmopressin nasal spray with other drugs that may increase the risk of water intoxication with hyponatremia, (e.g., tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine, oxybutynin and carbamazepine) requires more frequent serum sodium monitoring [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6 )]. 7.2 Other Vasoconstrictors Desmopressin acetate can elevate blood pressure. Use of large doses of desmopressin nasal spray with other vasoconstrictors may require a reduction of the desmopressin dosage [see Adverse Reactions ( 6 )]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Desmopressin nasal spray is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in adults and pediatric patients 4 years of age and older Limitations of Use: Desmopressin nasal spray is not indicated for: Treatment of nephrogenic diabetes insipidus, Treatment of primary nocturnal enuresis [see Warnings and Precautions ( 5.1 )], Use in patients with conditions that compromise the intranasal route of administration (e.g., severe nasal congestion and blockage, nasal mucosa atrophy, severe atrophic rhinitis, recent nasal surgery such as transsphenoidal hypophysectomy) [see Warnings and Precautions ( 5.2 )]. Use in patients with an impaired level of consciousness, Use in patients requiring doses less than 10 mcg or doses that are not multiples of 10 mcg [see Dosage Forms and Strengths ( 3 )]. Desmopressin nasal spray is a vasopressin analog indicated as antidiuretic replacement therapy in the management of central diabetes insipidus for adults and pediatric patients 4 years of age and older ( 1 ) Limitations of Use: Desmopressin nasal spray is not indicated for: Treatment of nephrogenic diabetes insipidus ( 1 ) Treatment of primary nocturnal enuresis ( 1 , 5.1 ) Use in patients with conditions that compromise intranasal route of administration ( 1 , 5.2 ) Use in patients with an impaired level of consciousness ( 1 ) Use in patients requiring doses less than 10 mcg or doses that are not multiples of 10 mcg ( 1 , 3 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Hyponatremia: Instruct patients about proper fluid restriction and monitor serum sodium as needed ( 2.1 , 5.1 ) Altered Absorption in Patients with Nasal Mucosa Abnormalities: May occur with chronic administration, and require use of other formulations instead ( 5.2 ) 5.1 Hyponatremia Excessive fluid intake when urine output is limited by the antidiuretic effect of desmopressin may lead to water intoxication with hyponatremia. Cases of hyponatremia have been reported from postmarketing experience in patients treated with desmopressin acetate. Unless properly diagnosed and treated, hyponatremia can be fatal. All patients receiving desmopressin nasal spray should be observed for the following signs or symptoms associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium, weight gain, restlessness, fatigue, lethargy, disorientation, depressed reflexes, loss appetite, irritability, muscle weakness, muscle spasms or cramps and abnormal mental status such as hallucinations, decreased consciousness, and confusion. Severe symptoms due to an extreme decrease in serum sodium and plasma osmolality may include one or a combination of the following: seizure, coma, and/or respiratory arrest. In order to decrease the risk of water intoxication with hyponatremia, fluid restriction is recommended. Careful fluid intake restriction is particularly important in pediatric and geriatric patients because these patients are at greater risk of developing hyponatremia [see Use in Specific Populations ( 8.4 , 8.5 )] . More frequent monitoring of serum sodium levels is recommended in the following patients: those with conditions associated with fluid and electrolyte imbalance, such as cystic fibrosis, heart failure, renal disorders, habitual or psychogenic polydipsia or those taking concomitant drugs that may cause hyponatremia [see Drug Interactions ( 7.1 )]. Desmopressin nasal spray is not an indicated formulation for the treatment of primary nocturnal enuresis due to a higher risk of hyponatremia and hyponatremic convulsions with the use of the nasal spray formulation compared to desmopressin tablets seen in postmarketing reports [see Indications and Usage ( 1 )]. 5.2 Altered Absorption in Patients With Nasal Mucosa Abnormalities Chronic administration of desmopressin nasal spray may result in changes to nasal mucosa. Nasal mucosa abnormalities (such as scarring and edema) due to chronic administration, or due to other causes (nasal blockage, nasal mucosal atrophy, severe atrophic rhinitis, recent nasal surgery such as transsphenoidal hypophysectomy) may cause erratic, unreliable absorption. Avoid use of desmopressin nasal spray in such patients [see Indications and Usage ( 1 )] and consider use of other formulations of desmopressin acetate given by other routes of administration."}', 'overdosage': '{"10 OVERDOSAGE Signs of desmopressin acetate overdosage may include confusion, drowsiness, continuing headache, problems with passing urine, and rapid weight gain due to fluid retention [see Warnings and Precautions ( 5.1 )]. In case of overdosage, reduce the dosage, decrease the frequency of administration, or discontinue desmopressin nasal spray. There is no known specific antidote for desmopressin acetate."}', 'active_flag': 'Y', 'generic_name': '{"DESMOPRESSIN ACETATE"}', '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) Administration Inform caregivers for pediatric patients that administration should be supervised to ensure the patient receives the prescribed dose. Inform patients that the pump must be primed prior to first use and again if not used for greater than one week. Inform patients that the desmopressin nasal spray bottle delivers 50 sprays of 10 mcg each following the initial 4 priming pumps. Inform patients to discard any solution remaining after 50 sprays since the amount delivered thereafter may be substantially less than 10 mcg of drug. Monitoring Educate patients about the signs and symptoms of hyponatremia and advise them to contact a healthcare provider if such symptoms occur. Discuss downward adjustment of fluid intake and monitoring of urine output with patients. APOTEX INC. Desmopressin Nasal Spray, USP 10 mcg/ 0.1 mL Manufactured by Apotex Inc. Toronto, Ontario Canada M9L 1T9 Manufactured for Apotex Corp. Weston, Florida 33326 September 2022"}', 'pregnancy': '{"8.1 Pregnancy Risk summary Prolonged experience with desmopressin in pregnant women over several decades, based on the available published data and case reports, did not identify a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In addition, in vitro studies with human placenta demonstrate poor placental transfer of desmopressin. No adverse developmental outcomes were observed in animal reproduction studies with administration of desmopressin during organogenesis to pregnant rats and rabbits at doses approximately <1 and 38 times, respectively, the maximum recommended human dose based on body surface area (mg/m 2 ) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. 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 Animal Data Desmopressin acetate at up to 50 ng/kg/day was given by subcutaneous injection to pregnant rats, from gestation day 1 to 20 during the period of early embryonic development and organogenesis without teratogenic effects. Desmopressin acetate at up to 10 mcg/kg/day was given to pregnant rabbits by subcutaneous injection from gestation day 6 to 18 during fetal organogenesis without teratogenic effects. These doses of desmopressin acetate represent approximately <1 times (rat) and 38 times (rabbit) the maximum recommended human dose based on body surface area (mg/m 2 )."}', 'pediatric_use': '{"8.4 Pediatric Use Desmopressin nasal spray is indicated as antidiuretic replacement therapy in the management of central diabetes insipidus in pediatric patients 4 years of age and older. Desmopressin nasal spray is not indicated in pediatric patients less than 4 years of age. Use of desmopressin nasal spray in pediatric patients 4 years of age and older is supported by evidence from adults and pediatric patients with central diabetes insipidus. Use in pediatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )]."}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of desmopressin nasal spray 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 a low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection, and monitoring renal function is recommended [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 )]. Use of desmopressin nasal spray in geriatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings and Precautions ( 5.1 )]."}'}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses hand sanitizer to help reduce bacteria on the skin."}', '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."}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only. Flammable. Keep away from heat and flame. When using this product, avoid contact with face, eyes and broken skin. In case of eye contact, flush with plenty of water and seek medical advice."}', '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': '{"For handwashing to decrease bacteria on the skin 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 and redness develop and persist for more than 72 hours."}', 'do_not_use': None, 'when_using': None, 'warnings': '{"For external use only. Flammable, keep away from fire or flame. Do not use in the eyes. In case of contact, rinse eyes thoroughly with water."}', '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': '{"Uses: Hand sanitizer to help reduce bacteria that potentially can cause disease. For use when soap and water not available."}', '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 rash occurs. These may be signs of a serious condition."}', 'do_not_use': '{"Do not use: On children less than 2 months of age On open skin wounds"}', 'when_using': '{"When using this product, keep out of eyes, ears, and mouth. In case of contact with eyes, rinse eyes thoroughly with water."}', 'warnings': '{"Warnings: For external use only. Flammable. Keep away from heat or flame."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{AMMONIA}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses To prevent or treat fainting."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"AMMONIA INHALANTS"}', 'route': '{"RESPIRATORY (INHALATION)"}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only. Do not use if you have breathing problems such as asthma or emphysema. Stop use and ask a doctor if condition persists."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"PSEUDOEPHEDRINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves nasal congestion due to the common cold, hay fever or other upper respiratory allergies temporarily relieves sinus congestion and pressure"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"PSEUDOEPHEDRINE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever"}', 'do_not_use': '{"Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson\'s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product."}', 'when_using': '{"When using this product do not exceed recommended dosage"}', 'warnings': '{"Warnings Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson\'s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. Ask a doctor before use if you have heart disease high blood pressure thyroid disease diabetes trouble urinating due to an enlarged prostate gland When using this product do not exceed recommended dosage Stop use and ask a doctor if nervousness, dizziness, or sleeplessness occur symptoms do not improve within 7 days or occur with a fever 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}

{CAPSAICIN}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses Temporarily relieves minor aches and pains of muscles and joints due to: • arthritis • simple backache • strains • bruises • sprains"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{CAPSAICIN}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': '{"Do not use • On wounds, cuts, damaged or infected skin • On eyes, mouth, genitals, or any other mucous membranes Allergy Alert: if you are allergic to capsicum or chili peppers or any inactive ingredient of this product, contact a doctor before use."}', 'when_using': '{"Whe n us ing this product • You may experience a burning sensation. The intensity of this reaction varies among individuals and may be severe. With regular use, this sensation generally disappears after several days. • Avoid contact with the eyes, lips, nose and mucous membranes • Do not tightly wrap or bandage the treated area • Do not apply heat to the treated area immediately before or after use"}', 'warnings': '{"Warnings For external use only . Use only as directed or as directed by a health care professional Read all warnings and directions before use. Discontinue use at least one hour prior to bath, shower, or swimming; do not use immediately after bath, shower, or swimming. Do not use • On wounds, cuts, damaged or infected skin • On eyes, mouth, genitals, or any other mucous membranes Allergy Alert: if you are allergic to capsicum or chili peppers or any inactive ingredient of this product, contact a doctor before use. Whe n us ing this product • You may experience a burning sensation. The intensity of this reaction varies among individuals and may be severe. With regular use, this sensation generally disappears after several days. • Avoid contact with the eyes, lips, nose and mucous membranes • Do not tightly wrap or bandage the treated area • Do not apply heat to the treated area immediately before or after use Stop use and as k a physician: • If pregnant or breast feeding • If condition worsens, or if symptoms persist for more than 7 days or clear up and occur again within a few days, discontinue use of this product and consult a physician. • If severe burning persists or blistering occurs Keep out of reach of children and pets . If swallowed, get medical help or contact a Poison Control Center immediately."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ATENOLOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{ATENOLOL}', '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}

{"VALACYCLOVIR HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Valacyclovir tablets are contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3) ]. \xadHypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir, or any component of the formulation. (4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1) ] . Acute Renal Failure [see Warnings and Precautions (5.2) ] . Central Nervous System Effects [see Warnings and Precautions (5.3) ] . The most common adverse reactions reported in at least 1 indication by >10% of adult patients treated with valacyclovir hydrochloride and observed more frequently with valacyclovir hydrochloride compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in >10% of pediatric patients <18 years of age was headache. The most common adverse reactions reported in at least one indication by >10% of adult patients treated with valacyclovir hydrochloride and more commonly than in patients treated with placebo are headache, nausea, and abdominal pain. (6.1) The only adverse reaction occurring in >10% of pediatric patients <18 years of age was headache. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Adult Patients 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. Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving valacyclovir hydrochloride 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (>2 x ULN) were 1.8% for patients receiving valacyclovir hydrochloride compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups. Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2. Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by ≥5% of patients receiving valacyclovir hydrochloride 500 mg twice daily for 3 days (n = 402), valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%). For the incidence of laboratory abnormalities see Table 2. Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram once daily (n = 269), valacyclovir hydrochloride 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2. Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for valacyclovir hydrochloride (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively. Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving valacyclovir hydrochloride 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%). Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving valacyclovir hydrochloride 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2. Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations a Data were not collected prospectively. LLN = Lower limit of normal. ULN = Upper limit of normal. Laboratory Abnormality Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression Valacyclovir Hydrochloride 1 gram 3 times daily (n = 967) Placebo (n = 195) Valacyclovir Hydrochloride 1 gram twice daily (n = 1,194) Valacyclovir Hydrochloride 500 mg twice daily (n = 1,159) Placebo (n = 439) Valacyclovir Hydrochloride 1 gram once daily (n = 269) Valacyclovir Hydrochloride 500 mg once daily (n = 266) Placebo (n =134) Hemoglobin (<0.8 x LLN) White blood cells (<0.75 x LLN) Platelet count (<100,000/mm 3 ) AST (SGOT) (>2 x ULN) Serum creatinine (>1.5 x ULN) 0.8% 1.3% 1% 1% 0.2% 0% 0.6% 1.2% 0% 0% 0.3% 0.7% 0.3% 1% 0.7% 0.2% 0.6% 0.1% a 0% 0% 0.2% 0.7% 0.5% 0% 0% 0.7% 0.4% 4.1% 0% 0.8% 0.8% 1.1% 3.8% 0% 0.8% 1.5% 1.5% 3% 0% 6.2 Clinical Trials Experience in Pediatric Patients The safety profile of valacyclovir hydrochloride has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five of these pediatric patients, 12 to <18 years of age, received oral tablets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults. Pediatric Patients 12 to <18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving valacyclovir hydrochloride 2 grams twice daily for 1 day, or valacyclovir hydrochloride 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%). Pediatric Patients 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed. 6.3 Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of valacyclovir hydrochloride. 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 valacyclovir hydrochloride. General: Facial edema, hypertension, tachycardia. Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4) ]. CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors [see Warnings and Precautions (5.3) , Use in Specific Populations (8.5) , (8.6) ]. Eye: Visual abnormalities. Gastrointestinal: Diarrhea. Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis. Renal: Renal failure, renal pain (may be associated with renal failure) [see Warnings and Precautions (5.2) , Use in Specific Populations (8.5) , (8.6) ]. Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5.1) ]. Skin: Erythema multiforme, rashes including photosensitivity, alopecia."}', 'drug_interactions': '{"7 DRUG INTERACTIONS No clinically significant drug-drug or drug-food interactions with valacyclovir hydrochloride are known [see Clinical Pharmacology (12.3) ]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Valacyclovir hydrochloride is a nucleoside analogue DNA polymerase inhibitor indicated for: Adult Patients (1.1) Cold Sores (Herpes Labialis) Genital Herpes Treatment in immunocompetent patients (initial or recurrent episode) Suppression in immunocompetent or HIV-infected patients Reduction of transmission Herpes Zoster Pediatric Patients (1.2) Cold Sores (Herpes Labialis) Chickenpox Limitations of Use (1.3) The efficacy and safety of valacyclovir tablets have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. 1.1 Adult Patients Cold Sores (Herpes Labialis): Valacyclovir tablets are indicated for treatment of cold sores (herpes labialis). The efficacy of valacyclovir tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Genital Herpes: Initial Episode: Valacyclovir tablets are indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir tablets when initiated more than 72 hours after the onset of signs and symptoms has not been established. Recurrent Episodes: Valacyclovir tablets are indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with valacyclovir tablets when initiated more than 24 hours after the onset of signs and symptoms has not been established. Suppressive Therapy: Valacyclovir tablets are indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults. The efficacy and safety of valacyclovir tablets for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-infected patients have not been established. Reduction of Transmission: Valacyclovir tablets are indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of valacyclovir tablets for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of valacyclovir tablets for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] Sexually Transmitted Diseases Treatment Guidelines ). Herpes Zoster: Valacyclovir tablets are indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of valacyclovir tablets when initiated more than 72 hours after the onset of rash and the efficacy and safety of valacyclovir tablets for treatment of disseminated herpes zoster have not been established. 1.2 Pediatric Patients Cold Sores (Herpes Labialis): Valacyclovir tablets are indicated for the treatment of cold sores (herpes labialis) in pediatric patients ≥12 years of age. The efficacy of valacyclovir tablets initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Chickenpox: Valacyclovir tablets are indicated for the treatment of chickenpox in immunocompetent pediatric patients 2 to <18 years of age. Based on efficacy data from clinical studies with oral acyclovir, treatment with valacyclovir tablets should be initiated within 24 hours after the onset of rash [see Clinical Studies (14.4) ]. 1.3 Limitations of Use The efficacy and safety of valacyclovir tablets have not been established in: Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count ≥100 cells/mm 3 . Patients <12 years of age with cold sores (herpes labialis). Patients <2 years of age or ≥18 years of age with chickenpox. Patients <18 years of age with genital herpes. Patients <18 years of age with herpes zoster. Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Has occurred in patients with advanced HIV disease and in allogenic bone marrow transplant and renal transplant patients receiving 8 grams per day of valacyclovir hydrochloride in clinical trials. Discontinue treatment if clinical symptoms and laboratory findings consistent with TTP/HUS occur. (5.1) Acute renal failure: May occur in elderly patients (with or without reduced renal function), patients with underlying renal disease who receive higher than recommended doses of valacyclovir hydrochloride for their level of renal function, patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients and reduce dosage in patients with renal impairment. (2.4 , 5.2) Central nervous system adverse reactions (e.g., agitation, hallucinations, confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with underlying renal disease who receive higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Use with caution in elderly patients and reduce dosage in patients with renal impairment. (2.4 , 5.3) 5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir hydrochloride at doses of 8 grams per day. Treatment with valacyclovir hydrochloride should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur. 5.2 Acute Renal Failure Cases of acute renal failure have been reported in: Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir hydrochloride to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.4) , Use in Specific Populations (8.5) ]. Patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Dosage reduction is recommended when administering valacyclovir hydrochloride to patients with renal impairment [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) ]. Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir hydrochloride to patients receiving potentially nephrotoxic drugs. Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4) , Adverse Reactions (6.3) ]. 5.3 Central Nervous System Effects Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of valacyclovir hydrochloride for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. Valacyclovir hydrochloride should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3) , Use in Specific Populations (8.5 , 8.6) ]."}', 'overdosage': '{"10 OVERDOSAGE Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5) , (8.6) ]. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4) ]."}', 'active_flag': 'Y', 'generic_name': '{"VALACYCLOVIR 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 See FDA-Approved Patient Labeling . 17.1 Importance of Adequate Hydration Patients should be advised to maintain adequate hydration. 17.2 Cold Sores (Herpes Labialis) Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that valacyclovir hydrochloride is not a cure for cold sores. 17.3 Genital Herpes Patients should be informed that valacyclovir hydrochloride is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with valacyclovir hydrochloride. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists. Valacyclovir hydrochloride has not been shown to reduce transmission of sexually transmitted infections other than HSV-2. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year’s duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months’ duration in HIV-infected patients. 17.4 Herpes Zoster There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. 17.5 Chickenpox Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 04/12 AV 09/14 (P) AvPAK"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies of valacyclovir hydrochloride or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. Valacyclovir hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits, respectively, revealed no evidence of teratogenicity."}', 'pediatric_use': '{"8.4 Pediatric Use Valacyclovir hydrochloride is indicated for treatment of cold sores in pediatric patients ≥12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age [see Indications and Usage (1.2) , Dosage and Administration (2.2) ]. The use of valacyclovir hydrochloride for treatment of cold sores is based on 2 double‑blind, placebo‑controlled clinical trials in healthy adults and adolescents (≥12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1) ]. The use of valacyclovir hydrochloride for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox [see Dosage and Administration (2.2) , Adverse Reactions (6.2) , Clinical Pharmacology (12.3) , Clinical Studies (14.4) ]. The efficacy and safety of valacyclovir have not been established in pediatric patients: <12 years of age with cold sores <18 years of age with genital herpes <18 years of age with herpes zoster <2 years of age with chickenpox for suppressive therapy following neonatal HSV infection. The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies. Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age with clinically suspected varicella-zoster virus (VZV) infection [see Dosage and Administration (2.2) , Adverse Reactions (6.2) , Clinical Pharmacology (12.3) , Clinical Studies (14.4) ]. Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir oral suspension. In infants and children 3 months to <6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to <3 months of age, mean acyclovir exposures resulting from a 25 mg/kg dose were higher (C max : ↑30%, AUC: ↑60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir. Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (C max : ↓20%, AUC: ↓33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: ↑16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children 1 to <12 years of age with recurrent genital herpes."}', 'geriatric_use': '{"8.5 Geriatric Use Of the total number of subjects in clinical studies of valacyclovir hydrochloride, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events [see Dosage and Administration (2.4) , Warnings and Precautions (5.2 , 5.3) , Clinical Pharmacology (12.3) ]."}'}

{"NALTREXONE HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Naltrexone hydrochloride is contraindicated in: Patients receiving opioid analgesics. Patients currently dependent on opioids, including those currently maintained on opiate agonists [e.g., methadone) or partial agonists (e.g., buprenorphine). Patients in acute opioid withdrawal (see WARNINGS ). Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids. Any individual with a history of sensitivity to naltrexone hydrochloride or any other components of this product. It is not known if there is any cross-sensitivity with naloxone or the phenanthrene containing opioids."}', 'adverse_reactions': '{"ADVERSE REACTIONS During two randomized, double-blind, placebo-controlled 12 week trials to evaluate the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcohol dependence, most patients tolerated naltrexone hydrochloride well. In these studies, a total of 93 patients received naltrexone hydrochloride at a dose of 50 mg once daily. Five of these patients discontinued naltrexone hydrochloride because of nausea. No serious adverse events were reported during these two trials. While extensive clinical studies evaluating the use of naltrexone hydrochloride in detoxified, formerly opioid-dependent individuals failed to identify any single, serious untoward risk of naltrexone hydrochloride use, placebo-controlled studies employing up to fivefold higher doses of naltrexone hydrochloride (up to 300 mg per day) than that recommended for use in opiate receptor blockade have shown that naltrexone hydrochloride causes hepatocellular injury in a substantial proportion of patients exposed at higher doses (see WARNINGS and PRECAUTIONS: Laboratory Tests ). Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence does not incriminate naltrexone hydrochloride, used at any dose, as a cause of any other serious adverse reaction for the patient who is “opioid-free.” It is critical to recognize that naltrexone hydrochloride can precipitate or exacerbate abstinence signs and symptoms in any individual who is not completely free of exogenous opioids. Patients with addictive disorders, especially opioid addiction, are at risk for multiple numerous adverse events and abnormal laboratory findings, including liver function abnormalities . Data from both controlled and observational studies suggest that these abnormalities, other than the dose-related hepatotoxicity described above, are not related to the use of naltrexone hydrochloride. Among opioid-free individuals, naltrexone hydrochloride administration at the recommended dose has not been associated with a predictable profile of serious adverse or untoward events. However, as mentioned above, among individuals using opioids, naltrexone hydrochloride may cause serious withdrawal reactions (see CONTRAINDICATIONS , WARNINGS , DOSAGE AND ADMINISTRATION ). Reported Adverse Events Naltrexone hydrochloride has not been shown to cause significant increases in complaints in placebo-controlled trials in patients known to be free of opioids for more than 7 to 10 days. Studies in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid withdrawal-like symptom complex consisting of tearfulness, mild nausea, abdominal cramps, restlessness, bone or joint pain, myalgia, and nasal symptoms. This may represent the unmasking of occult opioid use, or it may represent symptoms attributable to naltrexone. A number of alternative dosing patterns have been recommended to try to reduce the frequency of these complaints. Alcoholism In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone hydrochloride, the following new-onset adverse reactions occurred in 2% or more of the patients: nausea (10%), headache (7%), dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting (3%), anxiety (2%) and somnolence (2%). Depression, suicidal ideation, and suicidal attempts have been reported in all groups when comparing naltrexone, placebo, or controls undergoing treatment for alcoholism. RATE RANGES OF NEW ONSET EVENTS Naltrexone Placebo Depression 0 to 15% 0 to 17% Suicide Attempt/Ideation 0 to 1% 0 to 3% Although no causal relationship with naltrexone hydrochloride is suspected, physicians should be aware that treatment with naltrexone hydrochloride does not reduce the risk of suicide in these patients (see PRECAUTIONS ). Opioid Addiction The following adverse reactions have been reported both at baseline and during the naltrexone hydrochloride clinical trials in opioid addiction at an incidence rate of more than 10%: Difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint and muscle pain, and headache. The incidence was less than 10% for: Loss of appetite, diarrhea, constipation, increased thirst, increased energy, feeling down, irritability, dizziness, skin rash, delayed ejaculation, decreased potency, and chills. The following events occurred in less than 1% of subjects: Respiratory: Nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath. Cardiovascular: Nose bleeds, phlebitis, edema, increased blood pressure, non-specific ECG changes, palpitations, tachycardia. Gastrointestinal: Excessive gas, hemorrhoids, diarrhea, ulcer. Musculoskeletal: Painful shoulders, legs or knees; tremors, twitching. Genitourinary: Increased frequency of, or discomfort during, urination; increased or decreased sexual interest. Dermatologic: Oily skin, pruritus, acne, athlete’s foot, cold sores, alopecia. Psychiatric: Depression, paranoia, fatigue, restlessness, confusion, disorientation, hallucinations, nightmares, bad dreams. Special senses: Eyes-blurred, burning, light sensitive, swollen, aching, strained; ears-“clogged”, aching, tinnitus. General: Increased appetite, weight loss, weight gain, yawning, somnolence, fever, dry mouth, head “pounding”, inguinal pain, swollen glands, “side” pains, cold feet, “hot spells.” Postmarketing Experience: Data collected from postmarketing use of naltrexone hydrochloride show that most events usually occur early in the course of drug therapy and are transient. It is not always possible to distinguish these occurrences from those signs and symptoms that may result from a withdrawal syndrome. Events that have been reported include anorexia, asthenia, chest pain, fatigue, headache, hot flushes, malaise, changes in blood pressure, agitation, dizziness, hyperkinesia, nausea, vomiting, tremor, abdominal pain, diarrhea, palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia, nervousness, somnolence, abnormal thinking, dyspnea, rash, increased sweating, vision abnormalities, and idiopathic thrombocytopenic purpura. In some individuals the use of opioid antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of such changes is not fully understood. Adverse events, including withdrawal symptoms and death, have been reported with the use of naltrexone hydrochloride in ultra rapid opiate detoxification programs. The cause of death in these cases is not known (see WARNINGS ). Laboratory Tests: In a placebo controlled study in which naltrexone hydrochloride was administered to obese subjects at a dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day), 19% (5/26) of naltrexone hydrochloride recipients and 0% (0/24) of placebo-treated patients developed elevations of serum transaminases (i.e., peak ALT values ranging from 121 to 532; or 3 to 19 times their baseline values) after three to eight weeks of treatment. The patients involved were generally clinically asymptomatic, and the transaminase levels of all patients on whom follow-up was obtained returned to (or toward) baseline values in a matter of weeks. Transaminase elevations were also observed in other placebo controlled studies in which exposure to naltrexone hydrochloride at doses above the amount recommended for the treatment of alcoholism or opioid blockade consistently produced more numerous and more significant elevations of serum transaminases than did placebo. Transaminase elevations occurred in 3 of 9 patients with Alzheimer\'s Disease who received naltrexone hydrochloride (at doses up to 300 mg/day) for 5 to 8 weeks in an open clinical trial."}', 'drug_interactions': '{"Drug Interactions Studies to evaluate possible interactions between naltrexone hydrochloride and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of naltrexone hydrochloride and other drugs is required. The safety and efficacy of concomitant use of naltrexone hydrochloride and disulfiram is unknown, and the concomitant use of two potentially hepatotoxic medications is not ordinarily recommended unless the probable benefits outweigh the known risks. Lethargy and somnolence have been reported following doses of naltrexone hydrochloride and thioridazine. Patients taking naltrexone hydrochloride may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid analgesics. In an emergency situation when opioid analgesia must be administered to a patient receiving naltrexone hydrochloride, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see PRECAUTIONS )."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Naltrexone hydrochloride tablets are indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. Naltrexone hydrochloride has not been shown to provide any therapeutic benefit except as part of an appropriate plan of management for the addictions."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE There is limited clinical experience with naltrexone hydrochloride overdosage in humans. In one study, subjects who received 800 mg daily naltrexone hydrochloride for up to one week showed no evidence of toxicity. In the mouse, rat and guinea pig, the oral LD50s were 1,100 to 1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone hydrochloride (generally ≥1,000 mg/kg) produced salivation, depression/reduced activity, tremors, and convulsions. Mortalities in animals due to high-dose naltrexone hydrochloride administration usually were due to clonic-tonic convulsions and/or respiratory failure. Treatment of Overdosage In view of the lack of actual experience in the treatment of naltrexone hydrochloride overdose, patients should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date information."}', 'active_flag': 'Y', 'generic_name': '{"NALTREXONE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Vulnerability to Opioid Overdose After opioid detoxification, patients are likely to have reduced tolerance to opioids. As the blockade of exogenous opioids provided by naltrexone hydrochloride wanes and eventually dissipates completely, patients who have been treated with naltrexone hydrochloride may respond to lower doses of opioids than previously used, just as they would shortly after completing detoxification. This could result in potentially life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes have been reported in patients after discontinuing treatment. Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after naltrexone hydrochloride treatment is discontinued. It is important that patients inform family members, and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose (see PRECAUTIONS, Information for Patients ). There is also the possibility that a patient who is treated with naltrexone hydrochloride could overcome the opioid blockade effect of naltrexone hydrochloride. Although naltrexone hydrochloride is a potent antagonist, the blockade produced by naltrexone hydrochloride is surmountable. The plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade. This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids. Any attempt by a patient to overcome the antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose. Patients should be told of the serious consequences of trying to overcome the opioid blockade (see PRECAUTIONS, Information for Patients ). Precipitated Opioid Withdrawal The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal syndrome can be severe enough to require hospitalization. Symptoms of withdrawal have usually appeared within five minutes of ingestion of naltrexone hydrochloride and have lasted for up to 48 hours. Mental status changes including confusion, somnolence and visual hallucinations have occurred. Significant fluid losses from vomiting and diarrhea have required intravenous fluid administration. Review of postmarketing cases of precipitated opioid withdrawal in association with naltrexone treatment has identified cases with symptoms of withdrawal severe enough to require hospital admission, and in some cases, management in the intensive care unit. To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or exacerbation of a preexisting subclinical withdrawal syndrome, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting naltrexone hydrochloride treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short-acting opioids. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks. If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate by the healthcare provider, monitor the patient closely in an appropriate medical setting where precipitated withdrawal can be managed. In every case, healthcare providers should always be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Patients should be made aware of the risks associated with precipitated withdrawal and encouraged to give an accurate account of last opioid use. Patients treated for alcohol dependence with naltrexone hydrochloride should also be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone hydrochloride. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids. Hepatotoxicity Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone hydrochloride exposure during the clinical development program and in the postmarketing period. Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials and postmarketing period. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including preexisting alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury. Patients should be warned of the risk of hepatic injury and advised to seek medical attention if they experience symptoms of acute hepatitis. Use of naltrexone hydrochloride should be discontinued in the event of symptoms and/or signs of acute hepatitis. Depression and Suicidality Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone hydrochloride used in the treatment of opioid dependence. No causal relationship has been demonstrated. In the literature, endogenous opioids have been theorized to contribute to a variety of conditions. Alcohol-and opioid-dependent patients, including those taking naltrexone hydrochloride, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with naltrexone hydrochloride should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider. Ultra Rapid Opioid Withdrawal: Safe use of naltrexone hydrochloride in ultra rapid opiate detoxification programs has not been established (see ADVERSE REACTIONS )."}', 'precautions': '{"PRECAUTIONS General When Reversal of Naltrexone Hydrochloride Blockade is Required for Pain Management: In an emergency situation in patients receiving fully blocking doses of naltrexone hydrochloride, a suggested plan of management is regional analgesia, conscious sedation with a benzodiazepine, use of non-opioid analgesics or general anesthesia. In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged. A rapidly acting opioid analgesic which minimizes the duration of respiratory depression is preferred. The amount of analgesic administered should be titrated to the needs of the patient. Non-receptor mediated actions may occur and should be expected (e.g., facial swelling, itching, generalized erythema, or bronchoconstriction) presumably due to histamine release. Irrespective of the drug chosen to reverse naltrexone hydrochloride blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation. Special Risk Patients Renal Impairment: Naltrexone hydrochloride and its primary metabolite are excreted primarily in the urine, and caution is recommended in administering the drug to patients with renal impairment. Hepatic Impairment: An increase in naltrexone AUC of approximately 5-and 10-fold in patients with compensated and decompensated liver cirrhosis, respectively, compared with subjects with normal liver function has been reported. These data also suggest that alterations in naltrexone bioavailability are related to liver disease severity. Information for Patients It is recommended that the prescribing physician relate the following information to patients being treated with naltrexone hydrochloride: You have been prescribed naltrexone hydrochloride tablets as part of the comprehensive treatment for your alcoholism or drug dependence. You should carry identification to alert medical personnel to the fact that you are taking naltrexone hydrochloride. A naltrexone hydrochloride medication card may be obtained from your physician and can be used for this purpose. Carrying the identification card should help to ensure that you can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the treating physician that you are receiving naltrexone hydrochloride therapy. You should take naltrexone hydrochloride as directed by your physician. Advise patients that if they previously used opioids, they may be more sensitive to lower doses of opioids and at risk of accidental overdose should they use opioids after naltrexone hydrochloride treatment is discontinued or temporarily interrupted. It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose. Advise patients that because naltrexone hydrochloride can block the effects of opioids, patients will not perceive any effect if they attempt to self-administer heroin or any other opioid drug in small doses while on naltrexone hydrochloride tablets. Further, emphasize that administration of large doses of heroin or any other opioid to try to bypass the blockade and get high while on naltrexone hydrochloride may lead to serious injury, coma, or death. Patients on naltrexone hydrochloride tablets may not experience the expected effects from opioid-containing analgesic, antidiarrheal, or antitussive medications. Patients should be off all opioids, including opioid-containing medicines, for a minimum of 7 to 10 days before starting naltrexone hydrochloride tablets in order to avoid precipitation of opioid withdrawal. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks. Ensure that patients understand that withdrawal precipitated by administration of an opioid antagonist may be severe enough to require hospitalization if they have not been opioid-free for an adequate period of time, and is different from the experience of spontaneous withdrawal that occurs with discontinuation of opioid in a dependent individual. Advise patients that they should not take naltrexone hydrochloride tablets if they have any symptoms of opioid withdrawal. Advise all patients, including those with alcohol dependence, that it is imperative to notify healthcare providers of any recent use of opioids or any history of opioid dependence before starting naltrexone hydrochloride to avoid precipitation of opioid withdrawal. Advise patients that naltrexone hydrochloride tablets may cause liver injury. Patients should immediately notify their physician if they develop symptoms and/or signs of liver disease. Advise patients that they may experience depression while taking naltrexone hydrochloride tablets. It is important that patients inform family members and the people closest to the patient that they are taking naltrexone hydrochloride and that they should call a doctor right away should they become depressed or experience symptoms of depression. Advise patients that naltrexone hydrochloride has been shown to be effective only when used as part of a treatment program that includes counseling and support. Advise patients that dizziness may occur with naltrexone hydrochloride treatment, and they should avoid driving or operating heavy machinery until they have determined how naltrexone hydrochloride affects them. Advise patients to notify their physician if they: become pregnant or intend to become pregnant during treatment with naltrexone hydrochloride. are breast-feeding. experience other unusual or significant side effects while on naltrexone hydrochloride therapy. Laboratory Tests Naltrexone hydrochloride does not interfere with thin-layer, gas-liquid, and high pressure liquid chromatographic methods which may be used for the separation and detection of morphine, methadone or quinine in the urine. Naltrexone hydrochloride may or may not interfere with enzymatic methods for the detection of opioids depending on the specificity of the test. Please consult the test manufacturer for specific details. Drug Interactions Studies to evaluate possible interactions between naltrexone hydrochloride and drugs other than opiates have not been performed. Consequently, caution is advised if the concomitant administration of naltrexone hydrochloride and other drugs is required. The safety and efficacy of concomitant use of naltrexone hydrochloride and disulfiram is unknown, and the concomitant use of two potentially hepatotoxic medications is not ordinarily recommended unless the probable benefits outweigh the known risks. Lethargy and somnolence have been reported following doses of naltrexone hydrochloride and thioridazine. Patients taking naltrexone hydrochloride may not benefit from opioid containing medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid analgesics. In an emergency situation when opioid analgesia must be administered to a patient receiving naltrexone hydrochloride, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged (see PRECAUTIONS ). Carcinogenesis, Mutagenesis and Impairment of Fertility The following statements are based on the results of experiments in mice and rats. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-β-naltrexol are unknown. In a two-year carcinogenicity study in rats, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (600 mg/m 2 /day; 16 times the recommended therapeutic dose, based on body surface area) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day (600 mg/m 2 /day) was 4% but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice. There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli . However, no evidence of genotoxic potential was observed in a range of other in vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in vivo mouse micronucleus assay. Naltrexone (100 mg/kg/day [600 mg/m 2 /day] PO; 16 times the recommended therapeutic dose, based on body surface area) caused a significant increase in pseudopregnancy in the rat. A decrease in the pregnancy rate of mated female rats also occurred. There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known. Pregnancy Teratogenic Effects: Pregnancy Category C: Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥ 30 mg/kg/day (180 mg/m 2 /day; 5 times the recommended therapeutic dose, based on body surface area) and to rabbits at oral doses ≥ 60 mg/kg/day (720 mg/m 2 /day; 18 times the recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (32 and 65 times the recommended therapeutic dose, respectively, based on body surface area). Rats do not form appreciable quantities of the major human metabolites, 6-β-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known. There are no adequate and well-controlled studies in pregnant women. Naltrexone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery Whether or not naltrexone hydrochloride affects the duration of labor and delivery is unknown. Nursing Mothers In animal studies, naltrexone and 6-β-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone. Whether or not naltrexone hydrochloride is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when naltrexone hydrochloride is administered to a nursing woman. Pediatric Use The safe use of naltrexone hydrochloride in pediatric patients younger than 18 years old has not been established."}', 'information_for_patients': '{"Information for Patients It is recommended that the prescribing physician relate the following information to patients being treated with naltrexone hydrochloride: You have been prescribed naltrexone hydrochloride tablets as part of the comprehensive treatment for your alcoholism or drug dependence. You should carry identification to alert medical personnel to the fact that you are taking naltrexone hydrochloride. A naltrexone hydrochloride medication card may be obtained from your physician and can be used for this purpose. Carrying the identification card should help to ensure that you can obtain adequate treatment in an emergency. If you require medical treatment, be sure to tell the treating physician that you are receiving naltrexone hydrochloride therapy. You should take naltrexone hydrochloride as directed by your physician. Advise patients that if they previously used opioids, they may be more sensitive to lower doses of opioids and at risk of accidental overdose should they use opioids after naltrexone hydrochloride treatment is discontinued or temporarily interrupted. It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose. Advise patients that because naltrexone hydrochloride can block the effects of opioids, patients will not perceive any effect if they attempt to self-administer heroin or any other opioid drug in small doses while on naltrexone hydrochloride tablets. Further, emphasize that administration of large doses of heroin or any other opioid to try to bypass the blockade and get high while on naltrexone hydrochloride may lead to serious injury, coma, or death. Patients on naltrexone hydrochloride tablets may not experience the expected effects from opioid-containing analgesic, antidiarrheal, or antitussive medications. Patients should be off all opioids, including opioid-containing medicines, for a minimum of 7 to 10 days before starting naltrexone hydrochloride tablets in order to avoid precipitation of opioid withdrawal. Patients transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks. Ensure that patients understand that withdrawal precipitated by administration of an opioid antagonist may be severe enough to require hospitalization if they have not been opioid-free for an adequate period of time, and is different from the experience of spontaneous withdrawal that occurs with discontinuation of opioid in a dependent individual. Advise patients that they should not take naltrexone hydrochloride tablets if they have any symptoms of opioid withdrawal. Advise all patients, including those with alcohol dependence, that it is imperative to notify healthcare providers of any recent use of opioids or any history of opioid dependence before starting naltrexone hydrochloride to avoid precipitation of opioid withdrawal. Advise patients that naltrexone hydrochloride tablets may cause liver injury. Patients should immediately notify their physician if they develop symptoms and/or signs of liver disease. Advise patients that they may experience depression while taking naltrexone hydrochloride tablets. It is important that patients inform family members and the people closest to the patient that they are taking naltrexone hydrochloride and that they should call a doctor right away should they become depressed or experience symptoms of depression. Advise patients that naltrexone hydrochloride has been shown to be effective only when used as part of a treatment program that includes counseling and support. Advise patients that dizziness may occur with naltrexone hydrochloride treatment, and they should avoid driving or operating heavy machinery until they have determined how naltrexone hydrochloride affects them. Advise patients to notify their physician if they: become pregnant or intend to become pregnant during treatment with naltrexone hydrochloride. are breast-feeding. experience other unusual or significant side effects while on naltrexone hydrochloride therapy."}', 'pregnancy': '{"Pregnancy Teratogenic Effects: Pregnancy Category C: Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥ 30 mg/kg/day (180 mg/m 2 /day; 5 times the recommended therapeutic dose, based on body surface area) and to rabbits at oral doses ≥ 60 mg/kg/day (720 mg/m 2 /day; 18 times the recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (32 and 65 times the recommended therapeutic dose, respectively, based on body surface area). Rats do not form appreciable quantities of the major human metabolites, 6-β-naltrexol; therefore, the potential reproductive toxicity of the metabolite in rats is not known. There are no adequate and well-controlled studies in pregnant women. Naltrexone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"Pediatric Use The safe use of naltrexone hydrochloride in pediatric patients younger than 18 years old has not been established."}', 'geriatric_use': None}

{SPIRONOLACTONE}

{'contraindications': '{"4 CONTRAINDICATIONS Spironolactone tablets are contraindicated in the patients with: • Hyperkalemia • Addison’s disease • Concomitant use of eplerenone Spironolactone Tablets are contraindicated in patients with ( 4 ): • Hyperkalemia • Addison’s disease • Concomitant use of eplerenone"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hyperkalemia [see Warnings and Precautions ( 5.1 )] • Hypotension and Worsening Renal Function [see Warnings and Precautions ( 5.2 )] • Electrolyte and Metabolic Abnormalities [see Warnings and Precautions ( 5.3 )] • Gynecomastia [see Warnings and Precautions ( 5.4 )] • Impaired neurological function/ coma in patients with hepatic impairment, cirrhosis and ascites [ see Use in Specific Populations (8.7) ] The following adverse reactions associated with the use of spironolactone were identified in clinical trials or postmarketing reports. Because these reactions were 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. Digestive: Gastric bleeding, ulceration, gastritis, diarrhea and cramping, nausea, vomiting. Reproductive: Decreased libido, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain. Hematologic: Leukopenia (including agranulocytosis), thrombocytopenia. Hypersensitivity: Fever, urticaria, maculopapular or erythematous cutaneous eruptions, anaphylactic reactions, vasculitis. Metabolism: Hyperkalemia, electrolyte disturbances [ see Warnings and Precautions (5.1 , 5.3 ) ] , hyponatremia, hypovolemia. Musculoskeletal : Leg cramps. Nervous system/psychiatric: Lethargy, mental confusion, ataxia, dizziness, headache, drowsiness. Liver/biliary: A very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality, have been reported with spironolactone administration. Renal: Renal dysfunction (including renal failure). Skin: Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), alopecia, pruritis. The most common adverse reaction with spironolactone tablets treatment is gynecomastia ( 5.4 , 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"7 DRUG INTERACTIONS • Agents increasing serum potassium: Concomitant administration can lead to hyperkalemia ( 5.1 , 7.1 ). • Lithium: Increased risk of lithium toxicity ( 7.2 ). • NSAIDs: May reduce the diuretic, natriuretic and antihypertensive effect of spironolactone tablets ( 7.3 ). • Digoxin: Spironolactone tablets can interfere with radioimmunologic assays of digoxin exposure ( 7.4 ). • Cholestyramine: Hyperkalemic metabolic acidosis has been reported with concomitant use ( 7.5 ). • Acetylsalicylic Acid (ASA): ASA may reduce the efficacy of spironolactone tablets ( 7.6 ). • Abiraterone: May increase prostate-specific antigen (PSA) levels ( 7.7 ). 7.1 Drugs and Supplements Increasing Serum Potassium Concomitant administration of spironolactone tablets with potassium supplementation or drugs that can increase potassium may lead to severe hyperkalemia. In general, discontinue potassium supplementation in heart failure patients who start spironolactone tablets [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Check serum potassium levels when ACE inhibitor or ARB therapy is altered in patients receiving spironolactone tablets. Examples of drugs that can increase potassium include: • ACE inhibitors • angiotensin receptor blockers • non-steroidal anti-inflammatory drugs (NSAIDs) • heparin and low molecular weight heparin • trimethoprim 7.2 Lithium Like other diuretics, spironolactone tablets reduces the renal clearance of lithium, thus increasing the risk of lithium toxicity. Monitor lithium levels periodically when spironolactone tablets are coadministered [ see Clinical Pharmacology (12.3) ] . 7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) In some patients, the administration of an NSAID can reduce the diuretic, natriuretic, and antihypertensive effect of diuretics. Therefore, when spironolactone tablets and NSAIDs are used concomitantly, monitor closely to determine if the desired effect of the diuretic is obtained [ see Clinical Pharmacology (12.3) ] . 7.4 Digoxin Spironolactone and its metabolites interfere with radioimmunoassays for digoxin and increase the apparent exposure to digoxin. It is unknown to what extent, if any, spironolactone may increase actual digoxin exposure. In patients taking concomitant digoxin, use an assay that does not interact with spironolactone. 7.5 Cholestyramine Hyperkalemic metabolic acidosis has been reported in patients given spironolactone tablets concurrently with cholestyramine. 7.6 Acetylsalicylic Acid Acetylsalicylic acid may reduce the efficacy of spironolactone. Therefore, when spironolactone tablets and acetylsalicylic acid are used concomitantly, spironolactone tablets may need to be titrated to higher maintenance dose and the patient should be observed closely to determine if the desired effect is obtained [ see Clinical Pharmacology (12.3 ) ] 7.7 Abiraterone Spironolactone binds to the androgen receptor and may increase prostate-specific antigen (PSA) levels in abiraterone-treated prostate cancer patients. Concomitant use of spironolactone and abiraterone is not recommended."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Spironolactone tablets are an aldosterone antagonist indicated for: • The treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and to reduce the need for hospitalization for heart failure ( 1.1 ). • Use as an add-on therapy for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.2 ). • The management of edema in adult patients who are cirrhotic when edema is not responsive to fluid and sodium restrictions and in the setting of nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response ( 1.3 ). • Treatment of primary hyperaldosternism for: ( 1.4 ). • Short-term preoperative treatment • Long-term maintenance for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery and patients with bilateral micro or macronodular adrenal hyperplasia 1.1 Heart Failure Spironolactone tablets are indicated for treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure. Spironolactone tablets are usually administered in conjunction with other heart failure therapies. 1.2 Hypertension Spironolactone tablets are indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. 1.3 Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome Spironolactone tablets are indicated for the management of edema in the following settings: • Cirrhosis of the liver when edema is not responsive to fluid and sodium restriction. • Nephrotic syndrome when treatment of the underlying disease, restriction of fluid and sodium intake, and the use of other diuretics produce an inadequate response. Because it increases serum potassium, spironolactone tablets may be useful for treating edema when administration of other diuretics has caused hypokalemia. 1.4 Primary Hyperaldosteronism Spironolactone tablets are indicated in the following settings: • Short-term preoperative treatment of patients with primary hyperaldosteronism. • Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery. • Long-term maintenance therapy for patients with bilateral micro or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism)."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Hyperkalemia: Monitor serum potassium within one week of initiation and regularly thereafter ( 5.1 ). • Hypotension and Worsening Renal Function: Monitor volume status and renal function periodically ( 5.2 ). Electrolyte and Metabolic Abnormalities: Monitor serum electrolytes, uric acid and blood glucose periodically ( 5.3 ). • Gynecomastia: Spironolactone tablets can cause gynecomastia ( 5.4 ). 5.1 Hyperkalemia Spironolactone tablets can cause hyperkalemia. This risk is increased by impaired renal function or concomitant potassium supplementation, potassium-containing salt substitutes or drugs that increase potassium, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers [see Drug Interactions (7.1) ] . Monitor serum potassium within 1 week of initiation or titration of spironolactone tablets and regularly thereafter. More frequent monitoring may be needed when spironolactone tablets are given with other drugs that cause hyperkalemia or in patients with impaired renal function. If hyperkalemia occurs, decrease the dose or discontinue spironolactone tablets and treat hyperkalemia. 5.2 Hypotension and Worsening Renal Function Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically. 5.3 Electrolyte and Metabolic Abnormalities In addition to causing hyperkalemia, spironolactone tablets can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can occur and rarely gout is precipitated. Monitor serum electrolytes, uric acid and blood glucose periodically. 5.4 Gynecomastia Spironolactone tablets can cause gynecomastia. In the Randomized Spironolactone Evaluation Study, patients with heart failure treated with a mean dose of 26 mg of spironolactone once daily, about 9% of the male subjects developed gynecomastia. The risk of gynecomastia increases in a dose-dependent manner with an onset that varies widely from 1-2 months to over a year. Gynecomastia is usually reversible."}', 'overdosage': '{"10 OVERDOSAGE The oral LD 50 of spironolactone tablets is greater than 1000 mg/kg in mice, rats, and rabbits. Acute overdosage of spironolactone tablets may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Rarely, instances of hyponatremia, hyperkalemia, or hepatic coma may occur in patients with severe liver disease, but these are unlikely due to acute overdosage. Hyperkalemia may occur, especially in patients with impaired renal function. Treatment: Induce vomiting or evacuate the stomach by lavage. There is no specific antidote. Treatment is supportive to maintain hydration, electrolyte balance, and vital functions. Patients who have renal impairment may develop hyperkalemia. In such cases, discontinue spironolactone tablets."}', 'active_flag': 'Y', 'generic_name': '{SPIRONOLACTONE}', '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 who receive spironolactone tablets should be advised to avoid potassium supplements and foods containing high levels of potassium, including salt substitutes. 1. Distributed by: Sun Pharmaceutical Industries, Inc. 2. Cranbury, NJ 08512 Rev 12, December 2022"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Based on mechanism of action and findings in animal studies, spironolactone may affect sex differentiation of the male during embryogenesis (see Data) . Rat embryofetal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Limited available data from published case reports and case series did not demonstrate an association of major malformations or other adverse pregnancy outcomes with spironolactone . There are risks to the mother and fetus associated with heart failure, cirrhosis and poorly controlled hypertension during pregnancy ( see Clinical Considerations ) . Because of the potential risk to the male fetus due to anti-androgenic properties of spironolactone and animal data, avoid spironolactone in pregnant women or advise a pregnant woman of the potential risk to a male 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 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 congestive heart failure are at increased risk for preterm birth. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Clinical classification of heart disease may worsen with pregnancy and lead to maternal death. Closely monitor pregnant patients for destabilization of their heart failure. Pregnant women with symptomatic cirrhosis generally have poor outcomes including hepatic failure, variceal hemorrhage, preterm delivery, fetal growth restriction and maternal death. Outcomes are worse with coexisting esophageal varices. Pregnant women with cirrhosis of the liver should be carefully monitored and managed accordingly. Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Data Animal Data Teratology studies with spironolactone tablets have been carried out in mice and rabbits at doses of up to 20 mg/kg/day. On a body surface area basis, this dose in the mouse is substantially below the maximum recommended human dose and, in the rabbit, approximates the maximum recommended human dose. No teratogenic or other embryotoxic effects were observed in mice, but the 20 mg/kg dose caused an increased rate of resorption and a lower number of live fetuses in rabbits. Because of its antiandrogenic activity and the requirement of testosterone for male morphogenesis, spironolactone tablets may have the potential for adversely affecting sex differentiation of the male during embryogenesis. When administered to rats at 200 mg/kg/day between gestation days 13 and 21 (late embryogenesis and fetal development), feminization of male fetuses was observed. Offspring exposed during late pregnancy to 50 and 100 mg/kg/day doses of spironolactone tablets exhibited changes in the reproductive tract including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction, that persisted into adulthood. Spironolactone tablets has known endocrine effects in animals including progestational and antiandrogenic effects."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use Spironolactone tablets are 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, monitor renal function."}'}

{NIFEDIPINE}

{'contraindications': '{"CONTRAINDICATIONS Known hypersensitivity reaction to nifedipine."}', 'adverse_reactions': '{"ADVERSE REACTIONS In multiple-dose United States and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of nifedipine. Adverse Effect Nifedipine (%) (N=226) Placebo (%) (N=235) Dizziness, lightheadedness, giddiness 27 15 Flushing, heat sensation 25 8 Headache 23 20 Weakness 12 10 Nausea, heartburn 11 8 Muscle cramps, tremor 8 3 Peripheral edema 7 1 Nervousness, mood changes 7 4 Palpitation 7 5 Dyspnea, cough, wheezing 6 3 Nasal congestion, sore throat 6 8 There is also a large uncontrolled experience in over 2,100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The most common adverse events were: Incidence Approximately 10% Cardiovascular: peripheral edema Central Nervous System: dizziness or lightheadedness Gastrointestinal: nausea Systemic: headache and flushing, weakness Incidence Approximately 5% Cardiovascular: transient hypotension Incidence 2% or Less Cardiovascular: palpitation Respiratory: nasal and chest congestion, shortness of breath Gastrointestinal: diarrhea, constipation, cramps, flatulence Musculoskeletal: inflammation, joint stiffness, muscle cramps Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties Incidence Approximately 0.5% Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose), erythromelalgia Incidence Less Than 0.5% Hematologic: thrombocytopenia, anemia, leukopenia, purpura Gastrointestinal: allergic hepatitis Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia CNS: depression, paranoid syndrome Special Senses: transient blindness at the peak of plasma level, tinnitus Urogenital: nocturia, polyuria Other: arthritis with ANA (+), exfoliative dermatitis, gynecomastia Musculoskeletal: myalgia Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally of mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of nifedipine therapy was associated with an increase in anginal pain, possibly due to associated hypotension. Transient unilateral loss of vision has also occurred. In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients. In a subgroup of over 1,000 patients receiving nifedipine with concomitant beta blocker therapy, the pattern and incidence of adverse experiences were not different from that of the entire group of nifedipine treated patients. (See PRECAUTIONS . ) In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina pectoris (about 10% of the total patient population), dizziness or lightheadedness, peripheral edema, headache, or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150. In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': '{"Drug Interactions: Beta-adrenergic blocking agents: (See INDICATIONS AND USAGE and WARNINGS . ) Experience in over 1,400 patients in a non-comparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina. Long-acting nitrates: Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination. Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and since there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Quinidine: There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine). Coumarin anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain. Cimetidine: A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at 1,000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised. Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy. CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir may result in increased exposure to nifedipine when co-administered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications."}', 'indications_and_usage': '{"INDICATIONS AND USAGE I. Vasospastic Angina Nifedipine is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta blockers. II. Chronic Stable Angina (Classical Effort-Associated Angina) Nifedipine is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina), nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients are incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs. (See WARNINGS . )"}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, and judicious use of calcium infusion, pressor agents, and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial."}', 'active_flag': 'Y', 'generic_name': '{NIFEDIPINE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Excessive Hypotension Although, in most patients, the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment. Although patients have rarely experienced excessive hypotension on nifedipine alone, this may be more common in patients on concomitant beta blocker therapy. Although not approved for this purpose, nifedipine capsules have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe cases of profound hypotension, myocardial infarction, and death when immediate-release nifedipine was used in this way. Nifedipine capsules should not be used for the acute reduction of blood pressure. Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient\'s condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery. Increased Angina and/or Myocardial Infarction Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration, and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established. Several well-controlled, randomized trials studied the use of immediate-release nifedipine in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo. Nifedipine capsules should not be administered within the first week or two after myocardial infarction, and they should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent). Use in Essential Hypertension Nifedipine and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension, although nifedipine capsules have not been approved for this purpose and no properly controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. Nifedipine capsules should not be used for the control of essential hypertension. Beta Blocker Withdrawal Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and nifedipine initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine. Congestive Heart Failure Rarely, patients, usually those receiving a beta blocker, have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve."}', 'precautions': '{"PRECAUTIONS General: Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure. (See WARNINGS . ) Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients treated with nifedipine. This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction. Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have been reported. Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro . Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and an increase in bleeding time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated. Positive direct Coombs Test with/without hemolytic anemia has been reported but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined. Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect, in certain cases, rare, reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some. Drug Interactions: Beta-adrenergic blocking agents: (See INDICATIONS AND USAGE and WARNINGS . ) Experience in over 1,400 patients in a non-comparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina. Long-acting nitrates: Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination. Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and since there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Quinidine: There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine). Coumarin anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain. Cimetidine: A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at 1,000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised. Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy. CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir may result in increased exposure to nifedipine when co-administered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications. Other Interactions Grapefruit Juice: Co-administration of nifedipine with grapefruit juice resulted in approximately a doubling in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations most likely result from inhibition of CYP 3A4 related first-pass metabolism. Avoid ingestion of grapefruit and grapefruit juice while taking nifedipine. Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 5 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro . In vivo mutagenicity studies were negative. Pregnancy: Pregnancy Category C: Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Nifedipine administration was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (5 to 50 times) than the maximum recommended human dose of 120 mg/day. On a mg/m 2 basis, some doses were higher and some were lower than the maximum recommended human dose but all were within an order of magnitude of it. The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. Nifedipine should be used during pregnancy only if the potential benefit justifies the potential risk. Lactation: Nifedipine is transferred through breast milk. Nifedipine should be used during breast-feeding only if the potential benefit justifies the potential risk. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Use in pediatric population is not recommended. Geriatric Use: Age appears to have a significant effect on the pharmacokinetics of nifedipine. The clearance is decreased resulting in a higher AUC in the elderly. These changes are not due to changes in renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics )."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy: Pregnancy Category C: Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Nifedipine administration was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (5 to 50 times) than the maximum recommended human dose of 120 mg/day. On a mg/m 2 basis, some doses were higher and some were lower than the maximum recommended human dose but all were within an order of magnitude of it. The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. Nifedipine should be used during pregnancy only if the potential benefit justifies the potential risk. Lactation: Nifedipine is transferred through breast milk. Nifedipine should be used during breast-feeding only if the potential benefit justifies the potential risk."}', 'pediatric_use': '{"Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Use in pediatric population is not recommended."}', 'geriatric_use': '{"Geriatric Use: Age appears to have a significant effect on the pharmacokinetics of nifedipine. The clearance is decreased resulting in a higher AUC in the elderly. These changes are not due to changes in renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics )."}'}

{LORATADINE}

{'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 • itchy, watery eyes • sneezing • itching of the nose or throat"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{LORATADINE}', '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."}', 'when_using': '{"When using this product do not take more than directed. Taking more than directed may cause drowsiness."}', 'warnings': '{"Warnings Do not use 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 or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. 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}

{"RANITIDINE HYDROCHLORIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves heartburn associated with acid indigestion and sour stomach prevents heartburn associated with acid indigestion and sour stomach brought on by eating or drinking certain foods and beverages"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{RANITIDINE}', '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 ranitidine 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 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."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"SODIUM CHLORIDE"}

{'contraindications': None, 'adverse_reactions': '{"ADVERSE REACTIONS Reactions which may occur because of this solution, added drugs or the technique of reconstitution or administration include febrile response, local tenderness, abscess, tissue necrosis or infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection and extravasation. If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate countermeasures, and if possible, retrieve and save the remainder of the unused vehicle for examination."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE This parenteral preparation is indicated only for diluting or dissolving drugs for intravenous, intramuscular or subcutaneous injection, according to instructions of the manufacturer of the drug to be administered."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Use only as a diluent or solvent. This parenteral preparation is unlikely to pose a threat of carbohydrate, sodium chloride or fluid overload except possibly in neonates or very small infants. In the event these should occur, re-evaluate the patient and institute appropriate corrective measures. See PRECAUTIONS and ADVERSE REACTIONS ."}', 'active_flag': 'Y', 'generic_name': '{"SODIUM CHLORIDE"}', 'route': '{INTRAMUSCULAR,INTRAVENOUS,SUBCUTANEOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': '{"PRECAUTIONS Consult the manufacturer\'s instructions for choice of vehicle, appropriate dilution or volume for dissolving the drugs to be injected, including the route and rate of injection. Inspect reconstituted (diluted or dissolved) drugs for clarity (if soluble) and freedom from unexpected precipitation or discoloration prior to administration. Pregnancy: Animal reproduction studies have not been conducted with 0.9% Sodium Chloride Injection, USP. It is also not known whether sodium chloride injection containing additives can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium chloride injection containing additives should be given to a pregnant woman only if clearly needed. Pediatric Use: The safety and effectiveness in the pediatric population are based on the similarity of the clinical conditions of the pediatric and adult populations. In neonates or very small infants the volume of fluid may affect fluid and electrolyte balance. Drug Interactions Some drugs for injection may be incompatible in a given vehicle, or when combined in the same vehicle or in a vehicle containing benzyl alcohol. Consult with pharmacist, if available. Use aseptic technique for single or multiple entry and withdrawal from all containers. When diluting or dissolving drugs, mix thoroughly and use promptly. Do not store reconstituted solutions of drugs for injection unless otherwise directed by the manufacturer of the solute. Do not use unless the solution is clear and seal intact. Do not reuse single-dose containers, discard unused portion."}', '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: For hand washing to decrease bacteria on the skin. 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 rash appears and lasts."}', 'do_not_use': None, 'when_using': '{"When using this product do not use in or near the eyes. In case of contact, rinse eyes thoroughly with water."}', 'warnings': '{"Warnings: Not recommended for infants. Flammable. Keep away from fire or flame. For external use only. Avoid contact with broken skin."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{COLCHICINE}

{'contraindications': '{"4 CONTRAINDICATIONS Patients with renal or hepatic impairment should not be given colchicine with drugs that inhibit both P\xad glycoprotein and CYP3A4 inhibitors [See Drug Interactions ( 7 )]. Combining these dual inhibitors with colchicine in patients with renal or hepatic impairment has resulted in life-threatening or fatal colchicine toxicity. Patients with both renal and hepatic impairment should not be given colchicine. • Patients with renal or hepatic impairment should not be given colchicine in conjunction with drugs that inhibit both P-gp and CYP3A4 ( 4 ). • Patients with both renal and hepatic impairment should not be given colchicine ( 4 )."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Gastrointestinal disorders are the most common adverse reactions with colchicine. They are often the first signs of toxicity and may indicate that the colchicine dose needs to be reduced or therapy stopped. These include diarrhea, nausea, vomiting, and abdominal pain. Colchicine has been reported to cause neuromuscular toxicity, which may present as muscle pain or weakness [see Warnings and Precautions ( 5.4 )]. Toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous system. These most often occur with excessive accumulation or overdosage [see Overdosage ( 10 )]. The following reactions have been reported with colchicine. These have been generally reversible by interrupting treatment or lowering the dose of colchicine: D i gestive : abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting N eurological : sensory motor neuropathy D ermatological : alopecia, maculopapular rash, purpura, rash H e m atological : leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia H epatobiliary : elevated AST, elevated ALT Musculoskeletal : myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis R eproductive : azoospermia, oligospermia The most commonly reported adverse reactions with colchicine are gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal pain ( 6 ). 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."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp), and the CYP3A4 metabolizing enzyme. Fatal drug interactions have been reported when colchicine is administered with clarithromycin, a dual inhibitor of CYP3A4 and P-glycoprotein. Toxicities have also been reported when colchicine is administered with inhibitors of CYP3A4 that may not be potent inhibitors of P-gp (e.g., grapefruit juice, erythromycin, verapamil), or inhibitors of P-gp that may not be potent inhibitors of CYP3A4 (e.g., cyclosporine). Patients with renal or hepatic impairment should not be given colchicine with drugs that inhibit both P\xad glycoprotein and CYP3A4 [See Contraindications ( 4 )]. Combining these dual inhibitors with colchicine in patients with renal and hepatic impairment has resulted in life-threatening or fatal colchicine toxicity. Physicians should ensure that patients are suitable candidates for treatment with colchicine and remain alert for signs and symptoms of toxic reactions associated with increased colchicine exposure due to drug interactions. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine should be discontinued immediately. • Coadministration of P-gp or CYP3A4 inhibitors or inhibitors of both P-gp and CYP3A4 (e.g., clarithromycin or cyclosporine) have been reported to lead to colchicine toxicity. The potential for drug-drug interactions must be considered prior to and during therapy. • Concomitant use of colchicine and inhibitors of CYP3A4 or P-gp should be avoided if possible. If coadministration of colchicine and an inhibitor of CYP3A4 or P-gp is necessary, the dose of colchicine should be reduced and the patient should be monitored carefully for colchicine toxicity ( 7 , 12.3 ). 7.1 CYP3A4 The concomitant use of colchicine and CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, grapefruit juice, erythromycin, verapamil, etc.) should be avoided due to the potential for serious and life-threatening toxicity [See Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12 )]. If coadministration of colchicine and a CYP3A4 inhibitor is necessary, the dose of colchicine should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [See Clinical Pharmacology ( 12 )]. 7.2 P-glycoprotein The concomitant use of colchicine and inhibitors of P-glycoprotein (e.g. clarithromycin, ketoconazole, cyclosporine, etc.) should be avoided due to the potential for serious and life-threatening toxicity [See Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12 )]. If coadministration of colchicine and a P-gp inhibitor is necessary, the dose of colchicine should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [See C linical Pharmacology ( 12 )]. 7.3 HMG-CoA Reductase Inhibitors and Fibrates Some drugs such as HMG-CoA reductase inhibitors and fibrates may increase the risk of myopathy when combined with colchicine. Complaints of muscle pain or weakness could be an indication to check serum creatinine kinase levels for signs of myopathy. 7.4 Drug-Drug Interaction Studies Four pharmacokinetic studies evaluated the effects of coadministration of voriconazole (200 mg BID), fluconazole (200 mg QD), cimetidine (800 mg BID), and propafenone (225 mg BID) on systemic levels of colchicine. Colchicine can be administered with these drugs at the tested doses without a need for dose adjustment. However, these results should not be extrapolated to other coadministered drugs [See Drug-Drug Interactions ( 7.1 , 7.2 ) and Pharmacokinetics ( 12.3 )]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Colchicine Capsules are indicated for prophylaxis of gout flares in adults. Limitations of use: The safety and effectiveness of colchicine for acute treatment of gout flares during prophylaxis has not been studied. Colchicine is not an analgesic medication and should not be used to treat pain from other causes. • Colchicine Capsule is indicated for prophylaxis of gout flares in adults ( 1 ). Limitations of use: The safety and effectiveness of colchicine for acute treatment of gout flares during prophylaxis has not been studied. Colchicine is not an analgesic medication and should not be used to treat pain from other causes."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Fatal overdoses have been reported with colchicine in adults and children. Keep colchicine out of the reach of children ( 5.1 , 10 ). • Blood dyscrasias : myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported ( 5.2 ). • Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ). • D rug interaction with dual P-gp and CYP3A4 inhibitors : Coadministration of colchicine with dual P-gp and CYP3A4 inhibitors has resulted in life- threatening interactions and death ( 5.3 , 7 ) • N e u romuscular toxicity : Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine ( 5.4 , 7 ). 5.1 Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [See Overdosage ( 10 )]. Colchicine should be kept out of the reach of children. 5.2 Blood Dyscrasias Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses. 5.3 Interactions with CYP3A4 and P-gp Inhibitors Because colchicine is a substrate for both the CYP3A4 metabolizing enzyme and the P-glycoprotein efflux transporter, inhibition of either of these pathways may lead to colchicine-related toxicity. Inhibition of both CYP3A4 and P-gp by dual inhibitors such as clarithromycin has been reported to produce life-threatening or fatal colchicine toxicity due to significant increases in systemic colchicine levels. Therefore, concomitant use of colchicine and inhibitors of CYP3A4 or P-glycoprotein should be avoided [See Drug Interactions ( 7 )]. If avoidance is not possible, reduced daily dose should be considered and the patient should be monitored closely for colchicine toxicity. Use of colchicine in conjunction with drugs that inhibit both P-gp and CYP3A4 is contraindicated in patients with renal or hepatic impairment [See Contraindications ( 4 )]. 5.4 Neuromuscular Toxicity Neuromuscular toxicity and rhabdomyolysis have been reported from chronic treatment with colchicine in therapeutic doses, especially in combination with other drugs known to cause this effect. Patients with impaired renal function and elderly patients (even those with normal renal and hepatic function) are at increased risk. Once colchicine treatment is ceased, the symptoms generally resolve within 1 week to several months."}', 'overdosage': '{"10 OVERDOSAGE The dose of colchicine that would induce significant toxicity for an individual is unknown. Fatalities have been reported in patients after ingesting a dose as low as 7 mg over a 4-day period, while other patients have reportedly survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder adverse reactions, such as gastrointestinal symptoms, whereas those who ingested from 0.5 to 0.8 mg/kg had more severe adverse reactions, including myelosuppression. There was 100% mortality among patients who ingested more than 0.8 mg/kg. The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its associated consequences. Death usually results from respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion. Treatment of colchicine overdose should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by hemodialysis [See Pharmacokinetics ( 12.3 )]."}', 'active_flag': 'Y', 'generic_name': '{COLCHICINE}', '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). Dosing Instructions If a dose of colchicine is missed, advise the patient to take the dose as soon as possible and then return to the normal dosing schedule. However, if a dose is skipped, the patient should not double the next dose. Fatal Overdose Advise the patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. Colchicine should be kept out of the reach of children. Blood Dyscrasias Advise patients that bone marrow depression with agranulocytosis, aplastic anemia, and thrombocytopenia may occur with colchicine. Drug and Food Interactions Advise patients that many drugs or other substances may interact with colchicine and some interactions could be fatal. Therefore, patients should report to their healthcare provider all of the current medications they are taking, and check with their healthcare provider before starting any new medications, including short-term medications such as antibiotics. Patients should also be advised to report the use of non-prescription medication or herbal products. Grapefruit and grapefruit juice may also interact and should not be consumed during treatment with colchicine. Neuromuscular Toxicity Advise patients that muscle pain or weakness, tingling or numbness in fingers or toes may occur with colchicine alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue colchicine and seek medical evaluation immediately. Dispense with Medication Guide available at: www.parpharm.com/products."}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Category C . There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. Developmental studies in animals were not conducted with colchicine, however published animal reproduction and development studies with colchicine demonstrated embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. Colchicine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."}', 'pediatric_use': '{"8.4 Pediatric Use Gout is rare in pediatric patients; the safety and effectiveness of colchicine in pediatric patients has not been evaluated in controlled studies."}', 'geriatric_use': '{"8.5 Geriatric Use Because of the increased incidence of decreased renal function in the elderly population, and the higher incidence of other co-morbid conditions in the elderly population requiring the use of other medications, reducing the dosage of colchicine when elderly patients are treated with colchicine should be carefully considered."}'}

{"TELOTRISTAT ETHYL"}

{'contraindications': '{"4 CONTRAINDICATIONS None. None. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse reactions (≥5%) are nausea, headache, increased GGT, depression, flatulence, decreased appetite, peripheral edema, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics LLC at 1-844-334-4035 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. Xermelo was studied in a double-blind, placebo-controlled clinical trial of 90 patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea. Patients reported between 4 to 12 bowel movements daily despite the use of SSA therapy at a stable dose for at least 3 months [see Clinical Studies ( 14 )] . Placebo or Xermelo 250 mg was administered three times daily for 12 weeks. Concomitant anti-diarrheal medications (e.g., loperamide) were used by 43% (36% and 51% in the placebo and Xermelo group, respectively), pancreatic enzyme replacement medications by 39% (36% and 42% in the placebo and Xermelo group, respectively), and opioid analgesics by 29% (24% and 33% in the placebo and Xermelo group, respectively) of patients during the 12-week double-blind period of the trial. Table 1 below lists adverse reactions occurring at an incidence of at least 5% in the Xermelo group (N=45) and at an incidence greater than placebo (N=45) during the 12-week placebo-controlled period of the trial. Table 1: Percent Common Adverse Reactions a by Treatment Group at 12-Weeks in a Double-Blind Placebo-Controlled Clinical Trial of Patients with Carcinoid Syndrome Diarrhea a incidence of at least 5% in the Xermelo group and at an incidence greater than placebo b including depression, depressed mood and decreased interest Adverse Reaction Xermelo 250 mg Three Times Daily, N=45 (%) Placebo, N=45 (%) Nausea 13 11 Headache 11 4 Increased gamma-glutamyl-transferase (GGT) 9 0 Depression b 9 7 Peripheral edema 7 2 Flatulence 7 2 Decreased appetite 7 4 Pyrexia 7 4 In another placebo-controlled clinical trial of patients with carcinoid syndrome diarrhea and less than 4 bowel movements per day, the following additional adverse reactions, not listed in Table 1 , of abdominal pain (including upper and lower abdominal pain, abdominal distention and gastrointestinal pain) and constipation were reported in at least 5% of patients in the Xermelo treated group and at an incidence greater than placebo [see Warnings and Precautions ( 5.1 )] . Less Common Adverse Reactions : The following is a list of adverse reactions occurring in less than 5% of patients receiving Xermelo during the 12-week placebo-controlled period of the clinical trial: Investigations : increased alkaline phosphatase, increased alanine aminotransferase, and increased aspartate aminotransferase. Fecaloma was reported in one patient treated with Xermelo during the 36-week open-label extension period following the 12-week double-blind period of the trial."}', 'drug_interactions': '{"7 DRUG INTERACTIONS CYP3A4 Substrates (e.g., midazolam): Efficacy of concomitant drugs may be decreased; monitor for suboptimal efficacy and consider increasing the dose of the concomitant drug. ( 7.1 ) 7.1 CYP3A4 Substrates Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP3A4 substrates (e.g., midazolam) by decreasing their systemic exposure. Monitor for suboptimal efficacy and consider increasing the dose for concomitant CYP3A4 substrates, if necessary [see Clinical Pharmacology ( 12.3 )] . 7.2 Short-Acting Octreotide Concurrent administration of short-acting octreotide with Xermelo significantly decreased the systemic exposure of telotristat ethyl and telotristat, the active metabolite. If treatment with short-acting octreotide is needed in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administration of Xermelo [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] ."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. Xermelo is a tryptophan hydroxylase inhibitor indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Constipation: Xermelo reduces bowel movement frequency; monitor patients for constipation and/or severe persistent or worsening abdominal pain. Discontinue Xermelo if severe constipation or abdominal pain develops. ( 5.1 ) 5.1 Constipation Xermelo reduces bowel movement frequency. In a 12-week, placebo-controlled trial, in which patients had 4 or greater bowel movements per day, 2 out of 45 patients treated with a higher than recommended dosage of Xermelo reported constipation. In one patient the constipation was serious, resulting in hospitalization. During the 36-week extension period with higher than the recommended dosage, 10 of 115 patients reported constipation: one developed intestinal perforation and one developed obstruction. In another 12-week, placebo-controlled trial in which patients had less than 4 bowel movements per day, 4 out of 25 patients treated with the recommended dosage of Xermelo reported constipation. Given that patients with metastatic carcinoid tumors may have impaired integrity of the gastrointestinal tract wall, monitor for the development of constipation and/or severe, persistent, or worsening abdominal pain in patients taking Xermelo. Discontinue Xermelo if severe constipation or severe persistent or worsening abdominal pain develops [see Dosage and Administration ( 2 ), Adverse Reactions ( 6.1 )] ."}', 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"TELOTRISTAT ETHYL"}', '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 patients: If they experience severe constipation or severe persistent or worsening abdominal pain, to discontinue Xermelo and contact their healthcare provider [see Warnings and Precautions ( 5.1 )] . To take Xermelo with food [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . When short-acting octreotide is used in combination with Xermelo, administer short-acting octreotide at least 30 minutes after administering Xermelo [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . If a dose is missed, take the next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose. Distributed by: Lexicon Pharmaceuticals, Inc. The Woodlands, TX 77381"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no human data with Xermelo use in pregnant women to inform a drug-associated risk. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral telotristat ethyl to rats during organogenesis at doses up to 750 mg/kg/day (approximately 9 times the exposure at the RHD [recommended human dose]). Treatment of pregnant rabbits with oral telotristat ethyl during organogenesis produced maternal toxicity and post-implantation loss at doses of 250 mg/kg/day or higher (approximately 15 times the exposure at the RHD), and reduced fetal weight at 500 mg/kg/day (approximately 33 times the exposure at the RHD). In a pre-/postnatal development study, an increased incidence of mortality in rat offspring was observed during postnatal days 0 to 4 at the maternal oral dose of 500 mg/kg/day (approximately 5 times the exposure at the RHD), given during organogenesis through lactation [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 Animal data An embryo-fetal development study performed in rats with oral telotristat ethyl at doses up to 750 mg/kg/day (approximately 9 times the AUC [area under the plasma concentration-time curve] for the active metabolite at the RHD) during organogenesis produced no harm to embryo-fetal development. In pregnant rabbits treated orally with telotristat ethyl during organogenesis, an increased incidence of post-implantation loss at doses of 250 and 500 mg/kg/day (approximately 15 times the AUC for the active metabolite at RHD) and a decrease in fetal weight at 500 mg/kg/day (approximately 33 times the AUC for the active metabolite at the RHD) was observed. The adverse effects on embryo-fetal development were associated with maternal toxicity (impaired weight gain and/or mortality) at 250 and 500 mg/kg/day. No adverse effects on embryo-fetal development were observed at 125 mg/kg/day (approximately 5 times the AUC for the active metabolite at the RHD). A pre-/postnatal development study was conducted in rats using oral administration of 100, 200, and 500 mg/kg/day telotristat ethyl during organogenesis through lactation. An increased incidence of pup mortality was observed during postnatal days 0 to 4 at the maternal dose of 500 mg/kg/day (approximately 5 times the AUC for the active metabolite at the RHD). No developmental abnormalities or effects on growth, learning and memory, or reproductive performance were observed through maturation of offspring at maternal doses of up to 500 mg/kg/day in surviving offspring."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of Xermelo in pediatric patients have not been established."}', 'geriatric_use': '{"8.5 Geriatric Use Of 45 patients in a clinical trial of Xermelo, 19 (42%) patients were 65 years of age 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 differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out."}'}

{DIAZEPAM}

{'contraindications': '{"CONTRAINDICATIONS Diazepam Tablets USP are contraindicated in patients with a known hypersensitivity to this drug and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Diazepam is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. It may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow-angle glaucoma."}', 'adverse_reactions': '{"ADVERSE REACTIONS Side effects most commonly reported were drowsiness, fatigue, muscle weakness, and ataxia. The following have also been reported: Central Nervous System: confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo Gastrointestinal System: constipation, nausea, gastrointestinal disturbances Special Senses: blurred vision, diplopia, dizziness Cardiovascular System: hypotension Psychiatric and Paradoxical Reactions: stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly. Urogenital System: incontinence, changes in libido, urinary retention Skin and Appendages: skin reactions Laboratories: elevated transaminases and alkaline phosphatase Other: changes in salivation, including dry mouth, hypersalivation Antegrade amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior. Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after diazepam therapy and are of no known significance. Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy. Postmarketing Experience Injury, Poisoning and Procedural Complications There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcohol), and in the elderly. 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': '{"Drug Interactions Centrally Acting Agents If diazepam is to be combined with other centrally acting agents, careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants. Alcohol Concomitant use with alcohol is not recommended due to enhancement of the sedative effect. Antacids Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The lower peak concentrations appear due to a slower rate of absorption, with the time required to achieve peak concentrations on average 20 - 25 minutes greater in the presence of antacids. However, this difference was not statistically significant. Compounds Which Inhibit Certain Hepatic Enzymes There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole. Phenytoin There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam."}', 'indications_and_usage': '{"INDICATIONS Diazepam Tablets USP are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. Diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma); spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia); athetosis; and stiff-man syndrome. Oral diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. The effectiveness of diazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Overdose of benzodiazepines is usually manifested by central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, confusion, and lethargy. In more serious cases, symptoms may include ataxia, diminished reflexes, hypotonia, hypotension, respiratory depression, coma (rarely), and death (very rarely). Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored. Management of Overdosage Following overdose with oral benzodiazepines, general supportive measures should be employed including the monitoring of respiration, pulse, and blood pressure. Vomiting should be induced (within 1 hour) if the patient is conscious. Gastric lavage should be undertaken with the airway protected if the patient is unconscious. Intravenous fluids should be administered. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiac function in intensive care. General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures. Dialysis is of limited value. As with the management of intentional overdosage with any drug, it should be considered that multiple agents may have been ingested. Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. Caution should be observed in the use of flumazenil in epileptic patients treated with benzodiazepines. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS , should be consulted prior to use. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE )."}', 'active_flag': 'Y', 'generic_name': '{DIAZEPAM}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Diazepam is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since diazepam has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy. As with other agents which have anticonvulsant activity, when diazepam is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of diazepam in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures. Pregnancy An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested. There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m 2 basis). Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis. Rodent studies have indicated that prenatal exposure to diazepam doses similar to those used clinically can produce long-term changes in cellular immune responses, brain neurochemistry, and behavior. In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug. Labor and Delivery Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants). Nursing Mothers Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving diazepam."}', 'precautions': '{"PRECAUTIONS General If diazepam is to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed - particularly with known compounds that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants (see Drug Interactions ). The usual precautions are indicated for severely depressed patients or those in whom there is any evidence of latent depression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary. Psychiatric and paradoxical reactions are known to occur when using benzodiazepines (see ADVERSE REACTIONS ). Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly. A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see DRUG ABUSE AND DEPENDENCE ). In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated). Some loss of response to the effects of benzodiazepines may develop after repeated use of diazepam for a prolonged time. Information for Patients To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy. As is true of most CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle. Drug Interactions Centrally Acting Agents If diazepam is to be combined with other centrally acting agents, careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants. Alcohol Concomitant use with alcohol is not recommended due to enhancement of the sedative effect. Antacids Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The lower peak concentrations appear due to a slower rate of absorption, with the time required to achieve peak concentrations on average 20 - 25 minutes greater in the presence of antacids. However, this difference was not statistically significant. Compounds Which Inhibit Certain Hepatic Enzymes There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole. Phenytoin There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam. Carcinogenesis, Mutagenesis, Impairment of Fertility In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m 2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. The data currently available are inadequate to determine the mutagenic potential of diazepam. Reproduction studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 16 times the MRHD on a mg/m 2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 13 times the MRHD on a mg/m 2 basis). Pregnancy Category D (see WARNINGS: Pregnancy ). Pediatric Use Safety and effectiveness in pediatric patients below the age of 6 months have not been established. Geriatric Use In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated). Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions 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 Insufficiency Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis. In such patients, a 2- to 5- fold increase in mean half-life has been reported. Delayed elimination has also been reported for the active metabolite desmethyldiazepam. Benzodiazepines are commonly implicated in hepatic encephalopathy. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations: Hepatic Insufficiency )."}', 'information_for_patients': '{"Information for Patients To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing this drug. The risk of dependence increases with duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy. As is true of most CNS-acting drugs, patients receiving diazepam should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle."}', 'pregnancy': '{"Pregnancy An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested. There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. In addition, children born to mothers receiving benzodiazepines on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m 2 basis). Cleft palate and encephalopathy are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis. Rodent studies have indicated that prenatal exposure to diazepam doses similar to those used clinically can produce long-term changes in cellular immune responses, brain neurochemistry, and behavior. In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug.","Pregnancy Category D (see WARNINGS: Pregnancy )."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness in pediatric patients below the age of 6 months have not been established."}', 'geriatric_use': '{"Geriatric Use In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated). Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions 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."}'}

{"SULFUR IODIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Nasal Discharge During Cold And Flu Convalescence*"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"SULFUR IODIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist for more than 3 days or worsen"}', 'do_not_use': None, 'when_using': None, 'warnings': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{PREDNISONE}

{'contraindications': '{"CONTRAINDICATIONS Systemic fungal infections and known hypersensitivity to components."}', 'adverse_reactions': '{"ADVERSE REACTIONS Fluid and Electrolyte Disturbances Sodium retention Fluid retention Congestive heart failure in susceptible patients Potassium loss Hypokalemic alkalosis Hypertension Musculoskeletal Muscle weakness Steroid myopathy Loss of muscle mass Osteoporosis Vertebral compression fractures Aseptic necrosis of femoral and humeral heads Pathologic fracture of long bones Gastrointestinal Peptic ulcer with possible perforation and hemorrhage Pancreatitis Abdominal distention Ulcerative esophagitis Dermatologic Impaired wound healing Thin fragile skin Petechiae and ecchymoses Facial erythema Increased sweating May suppress reactions to skin tests Metabolic Negative nitrogen balance due to protein catabolism Neurological Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment Convulsions Vertigo Headache Endocrine Menstrual irregularities Development of Cushingoid state Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness Suppression of growth in children Decreased carbohydrate tolerance Manifestations of latent diabetes mellitus Increased requirements for insulin or oral hypoglycemic agents in diabetics Ophthalmic Posterior subcapsular cataracts Increased intraocular pressure Glaucoma Exophthalmos Additional Reactions Urticaria and other allergic, anaphylactic or hypersensitivity reactions"}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Prednisone tablets are indicated in the following conditions: 1. Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance) Congenital adrenal hyperplasia Hypercalcemia associated with cancer Nonsuppurative thyroiditis 2. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Acute nonspecific tenosynovitis Acute gouty arthritis Post-traumatic osteoarthritis Synovitis of osteoarthritis Epicondylitis 3. Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis 4. Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoides Severe psoriasis Severe seborrheic dermatitis 5. Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Drug hypersensitivity reactions 6. Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic corneal marginal ulcers Herpes zoster ophthalmicus Anterior segment inflammation Diffuse posterior uveitis and choroiditis Sympathetic ophthalmia Allergic conjunctivitis Keratitis Chorioretinitis Optic neuritis Iritis and iridocyclitis 7. Respiratory Diseases Symptomatic sarcoidosis Loeffler\'s syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Aspiration pneumonitis 8. Hematologic Disorders Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia 9. Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood 10. Edematous States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus 11. Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis 12. Nervous System Acute exacerbations of multiple sclerosis 13. Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{PREDNISONE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated. Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Usage in pregnancy : Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers or women of child bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy, should be carefully observed for signs of hypoadrenalism. Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response. The use of prednisone tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate anti-tuberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chickenpox and measles, for example, can have a more serious or even fatal course in children on immunosuppressant corticosteroids. In such children, or in adults who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered."}', 'precautions': '{"PRECAUTIONS General Precautions Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.) Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Since concurrent use of these agents results in a mutual inhibition of metabolism, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Information for the Patient Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice."}', 'information_for_patients': '{"Information for the Patient Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to obtain medical advice."}', 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ALCOHOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses • Hand sanitizer to help reduce bacteria on the skin. For use when soap and water are not available."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"HAND SANITIZER WIPES ALOE AND EUCALYPTUS SCENT"}', '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 fire or flame Do not store in car. Do not use in children less than 12 months of age Do not use on open skin wounds 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 doctor if irritation or redness develop"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"AMANTADINE HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Amantadine hydrochloride tablets are contraindicated in patients with known hypersensitivity to amantadine hydrochloride or to any of the other ingredients in amantadine hydrochloride tablets."}', 'adverse_reactions': '{"ADVERSE REACTIONS The adverse reactions reported most frequently at the recommended dose of amantadine hydrochloride (5 to 10%) are: nausea, dizziness (lightheadedness), and insomnia. Less frequently (1 to 5%) reported adverse reactions are: depression, anxiety and irritability, hallucinations, confusion, anorexia, dry mouth, constipation, ataxia, livedo reticularis, peripheral edema, orthostatic hypotension, headache, somnolence, nervousness, dream abnormality, agitation, dry nose, diarrhea and fatigue. Infrequently (0.1 to 1%) occurring adverse reactions are: congestive heart failure, psychosis, urinary retention, dyspnea, skin rash, vomiting, weakness, slurred speech, euphoria, thinking abnormality, amnesia, hyperkinesia, hypertension, decreased libido, and visual disturbance, including punctate subepithelial or other corneal opacity, corneal edema, decreased visual acuity, sensitivity to light, and optic nerve palsy. Rare (less than 0.1%) occurring adverse reactions are: instances of convulsion, leukopenia, neutropenia, eczematoid dermatitis, oculogyric episodes, suicidal attempt, suicide, and suicidal ideation (see WARNINGS ). Other adverse reactions reported during postmarketing experience with amantadine hydrochloride usage include: Nervous System/Psychiatric - coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, and tremor. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech; Cardiovascular - cardiac arrest, arrhythmias including malignant arrhythmias, hypotension, and tachycardia; Respiratory - acute respiratory failure, pulmonary edema, and tachypnea; Gastrointestinal - dysphagia; Hematologic - leukocytosis; agranulocytosis Special Senses - keratitis and mydriasis; Skin and Appendages - pruritus and diaphoresis; Miscellaneous - neuroleptic malignant syndrome (see WARNINGS ), allergic reactions including anaphylactic reactions, edema and fever. Laboratory Test - elevated: CPK, BUN, serum creatinine, alkaline phosphatase, LDH, bilirubin, GGT, SGOT, and SGPT. To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Amantadine hydrochloride tablets are indicated for the prophylaxis and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Amantadine hydrochloride tablets are also indicated in the treatment of parkinsonism and drug-induced extrapyramidal reactions. Influenza A Prophylaxis Amantadine hydrochloride tablets are indicated for chemoprophylaxis against signs and symptoms of influenza A virus infection. Because amantadine hydrochloride tablets do not completely prevent the host immune response to influenza A infection, individuals who take this drug may still develop immune responses to natural disease or vaccination and may be protected when later exposed to antigenically related viruses. Following vaccination during an influenza A outbreak, amantadine hydrochloride tablets prophylaxis should be considered for the 2- to 4-week time period required to develop an antibody response. Influenza A Treatment Amantadine hydrochloride tablets are also indicated in the treatment of uncomplicated respiratory tract illness caused by influenza A virus strains especially when administered early in the course of illness. There are no well-controlled clinical studies demonstrating that treatment with amantadine hydrochloride tablets will avoid the development of influenza A virus pneumonitis or other complications in high risk patients. There is no clinical evidence indicating that amantadine hydrochloride tablets are effective in the prophylaxis or treatment of viral respiratory tract illnesses other than those caused by influenza A virus strains. The following points should be considered before initiating treatment or prophylaxis with amantadine hydrochloride tablets: Amantadine hydrochloride tablets are not a substitute for early vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use amantadine hydrochloride tablets. Parkinson’s Disease/Syndrome Amantadine hydrochloride tablets are indicated in the treatment of idiopathic Parkinson’s disease (Paralysis Agitans), postencephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the nervous system by carbon monoxide intoxication. It is indicated in those elderly patients believed to develop parkinsonism in association with cerebral arteriosclerosis. In the treatment of Parkinson’s disease, amantadine hydrochloride tablets are less effective than levodopa, (-)-3-(3,4- dihydroxyphenyl)-L-alanine, and its efficacy in comparison with the anticholinergic antiparkinson drugs has not yet been established. Drug-Induced Extrapyramidal Reactions Amantadine hydrochloride tablets are indicated in the treatment of drug-induced extrapyramidal reactions. Although anticholinergic-type side effects have been noted with amantadine hydrochloride tablets when used in patients with drug-induced extrapyramidal reactions, there is a lower incidence of these side effects than that observed with the anticholinergic antiparkinson drugs."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Deaths have been reported from overdose with amantadine hydrochloride. The lowest reported acute lethal dose was 1 gram. Because some patients have attempted suicide by overdosing with amantadine, prescriptions should be written for the smallest quantity consistent with good patient management. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including adult respiratory distress syndrome - ARDS) have been reported; renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, agitation, aggressive behavior, hypertonia, hyperkinesia, ataxia, gait abnormality, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucinations, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred. There is no specific antidote for an overdose of amantadine hydrochloride. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult 2 at 1- to 2-hour intervals and 0.5 mg doses in a child 3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of amantadine hydrochloride. Since the excretion rate of amantadine hydrochloride increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. The blood pressure, pulse, respiration and temperature should be monitored. The patient should be observed for hyperactivity and convulsions; if required, sedation, and anticonvulsant therapy should be administered. The patient should be observed for the possible development of arrhythmias and hypotension; if required, appropriate antiarrhythmic and antihypotensive therapy should be given. Electrocardiographic monitoring may be required after ingestion, since malignant tachyarrhythmias can appear after overdose. Care should be exercised when administering adrenergic agents, such as isoproterenol, to patients with a amantadine hydrochloride overdose, since the dopaminergic activity of amantadine hydrochloride has been reported to induce malignant arrhythmias. The blood electrolytes, urine pH and urinary output should be monitored. If there is no record of recent voiding, catheterization should be done."}', 'active_flag': 'Y', 'generic_name': '{AMANTADINE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Deaths Deaths have been reported from overdose with amantadine hydrochloride. The lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to the anticholinergic effects of amantadine. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension (see OVERDOSAGE ). Deaths due to drug accumulation (overdosage) have been reported in patients with renal impairment, who were prescribed higher than recommended doses of Amantadine Hydrochloride for their level of renal function (see DOSAGE AND ADMINISTRATION; Dosage For Impaired Renal Function and OVERDOSAGE ). Suicide Attempts Suicide attempts, some of which have been fatal, have been reported in patients treated with amantadine hydrochloride, many of whom received short courses for influenza treatment or prophylaxis. The incidence of suicide attempts is not known and the pathophysiologic mechanism is not understood. Suicide attempts and suicidal ideation have been reported in patients with and without prior history of psychiatric illness. Amantadine hydrochloride can exacerbate mental problems in patients with a history of psychiatric disorders or substance abuse. Patients who attempt suicide may exhibit abnormal mental states which include disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, and somnolence or insomnia. Because of the possibility of serious adverse effects, caution should be observed when prescribing amantadine hydrochloride tablets to patients being treated with drugs having CNS effects, or for whom the potential risks outweigh the benefit of treatment. CNS Effects Patients with a history of epilepsy or other “seizures” should be observed closely for possible increased seizure activity. Patients receiving amantadine hydrochloride tablets who note central nervous system effects or bluallergic reactions including rring of vision should be cautioned against driving or working in situations where alertness and adequate motor coordination are important. Other Patients with a history of congestive heart failure or peripheral edema should be followed closely as there are patients who developed congestive heart failure while receiving amantadine hydrochloride tablets. Patients with Parkinson’s disease improving on amantadine hydrochloride tablets should resume normal activities gradually and cautiously, consistent with other medical considerations, such as the presence of osteoporosis or phlebothrombosis. Because amantadine hydrochloride tablets have anticholinergic effects and may cause mydriasis, it should not be given to patients with untreated angle closure glaucoma."}', 'precautions': '{"PRECAUTIONS Amantadine hydrochloride should not be discontinued abruptly in patients with Parkinson’s disease since a few patients have experienced a parkinsonian crisis, i.e., a sudden marked clinical deterioration, when this medication was suddenly stopped. The dose of anticholinergic drugs or of amantadine hydrochloride should be reduced if atropine-like effects appear when these drugs are used concurrently. Abrupt discontinuation may also precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression and slurred speech. Neuroleptic Malignant Syndrome (NMS) Sporadic cases of possible Neuroleptic Malignant Syndrome (NMS) have been reported in association with dose reduction or withdrawal of amantadine hydrochloride therapy. Therefore, patients should be observed carefully when the dosage of amantadine hydrochloride 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; neurologic findings including muscle rigidity, involuntary movements, altered consciousness; mental status changes; other disturbances such as autonomic dysfunction, tachycardia, tachypnea, hyper- or hypotension; laboratory findings such as creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum myoglobin. 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. Renal disease Because amantadine hydrochloride is mainly excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older (see DOSAGE AND ADMINISTRATION; Dosage for Impaired Renal Function ). Liver disease Care should be exercised when administering amantadine hydrochloride to patients with liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine hydrochloride, though a specific relationship between the drug and such changes has not been established. Impulse Control/Compulsive Behaviors Postmarketing reports suggest that patients treated with anti- Parkinson medications can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and other intense urges. Patients may be unable to control these urges while taking one or more of the medications that are generally used for the treatment of Parkinson’s disease and that increase central dopaminergic tone, including amantadine hydrochloride. 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 their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with amantadine hydrochloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking amantadine hydrochloride. 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 amantadine hydrochloride tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Other The dose of amantadine hydrochloride may need careful adjustment in patients with congestive heart failure, peripheral edema, or orthostatic hypotension. Care should be exercised when administering amantadine hydrochloride to patients with a history of recurrent eczematoid rash, or to patients with psychosis or severe psychoneurosis not controlled by chemotherapeutic agents. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Amantadine hydrochloride has not been shown to prevent such complications. Information for Patients Patients should be advised of the following information: Blurry vision and/or impaired mental acuity may occur. Gradually increase physical activity as the symptoms of Parkinson’s disease improve. Avoid excessive alcohol usage, since it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness and orthostatic hypotension. Avoid getting up suddenly from a sitting or lying position. If dizziness or lightheadedness occurs, notify physician. Notify physician if mood/mental changes, swelling of extremities, difficulty urinating and/or shortness of breath occur. Do not take more medication than prescribed because of the risk of overdose. If there is no improvement in a few days, or if medication appears less effective after a few weeks, discuss with a physician. Consult physician before discontinuing medication. Seek medical attention immediately if it is suspected that an overdose of medication has been taken. Drug Interactions Careful observation is required when amantadine hydrochloride is administered concurrently with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. Coadministration of thioridazine has been reported to worsen the tremor in elderly patients with Parkinson’s disease, however, it is not known if other phenothiazines produce a similar response. Coadministration of Dyazide (triamterene/hydrochlorothiazide) resulted in a higher plasma amantadine concentration in a 61-year-old man receiving amantadine hydrochloride 100 mg TID for Parkinson’s disease. 1 It is not known which of the components of Dyazide contributed to the observation or if related drugs produce a similar response. Coadministration of quinine or quinidine with amantadine was shown to reduce the renal clearance of amantadine by about 30%. The concurrent use of amantadine hydrochloride with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of amantadine hydrochloride, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of amantadine hydrochloride. Carcinogenesis and Mutagenesis Long-term in vivo animal studies designed to evaluate the carcinogenic potential of amantadine hydrochloride have not been performed. In several in vitro assays for gene mutation, amantadine hydrochloride did not increase the number of spontaneously observed mutations in four strains of Salmonella typhimurium (Ames Test) or in a mammalian cell line (Chinese Hamster Ovary cells) when incubations were performed either with or without a liver metabolic activation extract. Further, there was no evidence of chromosome damage observed in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with and without metabolic activation) or in an in vivo mouse bone marrow micronucleus test (140 to 550 mg/kg; estimated human equivalent doses of 11.7 to 45.8 mg/kg based on body surface area conversion). Impairment of Fertility The effect of amantadine on fertility has not been adequately tested, that is, in a study conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. In a three litter, non-GLP, reproduction study in rats, amantadine hydrochloride at a dose of 32 mg/kg/day (equal to the maximum recommended human dose on a mg/m 2 basis) administered to both males and females slightly impaired fertility. There were no effects on fertility at a dose level of 10 mg/kg/day (or 0.3 times the maximum recommended human dose on a mg/m 2 basis); intermediate doses were not tested. Failed fertility has been reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks prior to, and during the IVF cycle. Pregnancy The effect of amantadine on embryofetal and peri-postnatal development has not been adequately tested, that is, in studies conducted under Good Laboratory Practice (GLP) and according to current recommended methodology. However, in two non-GLP studies in rats in which females were dosed from 5 days prior to mating to Day 6 of gestation or on Days 7 to 14 of gestation, amantadine hydrochloride produced increases in embryonic death at an oral dose of 100 mg/kg (or 3 times the maximum recommended human dose on a mg/m 2 basis). In the non-GLP rat study in which females were dosed on Days 7 to14 of gestation, there was a marked increase in severe visceral and skeletal malformations at oral doses of 50 and 100 mg/kg (or 1.5 and 3 times, respectively, the maximum recommended human dose on a mg/m 2 basis). The no-effect dose for teratogenicity was 37 mg/kg (equal to the maximum recommended human dose on a mg/m 2 basis). The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate and well-controlled studies in pregnant women. Human data regarding teratogenicity after maternal use of amantadine is scarce. Tetralogy of Fallot and tibial hemimelia (normal karyotype) occurred in an infant exposed to amantadine during the first trimester of pregnancy (100 mg P.O. for 7 days during the 6th and 7th week of gestation). Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was associated with maternal exposure to amantadine (100 mg/d) administered during the first 2 weeks of pregnancy. Amantadine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus. Nursing Mothers Amantadine hydrochloride is excreted in human milk. Use is not recommended in nursing mothers. Pediatric Use The safety and efficacy of amantadine hydrochloride in newborn infants and infants below the age of 1 year have not been established. Usage in the Elderly Because amantadine hydrochloride is primarily excreted in the urine, it accumulates in the plasma and in the body when renal function declines. Thus, the dose of amantadine hydrochloride should be reduced in patients with renal impairment and in individuals who are 65 years of age or older. The dose of amantadine hydrochloride may need reduction in patients with congestive heart failure, peripheral edema, or orthostatic hypotension (see DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CEFAZOLIN SODIUM"}

{'contraindications': '{"CONTRAINDICATIONS Cefazolin for Injection IS CONTRAINDICATED IN PATIENTS WITH KNOWN ALLERGY TO THE CEPHALOSPORIN GROUP OF ANTIBIOTICS."}', 'adverse_reactions': '{"ADVERSE REACTIONS The following reactions have been reported: Gastrointestinal Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia, and pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS ). Nausea and vomiting have been reported rarely. Allergic Anaphylaxis, eosinophilia, itching, drug fever, skin rash, Stevens-Johnson syndrome. Hematologic Neutropenia, leukopenia, thrombocytopenia, thrombocythemia. Hepatic Transient rise in SGOT, SGPT, and alkaline phosphatase levels has been observed. As with other cephalosporins, reports of hepatitis have been received. Renal As with other cephalosporins, reports of increased BUN and creatinine levels, as well as renal failure, have been received. Local Reactions Rare instances of phlebitis have been reported at site of injection. Pain at the site of injection after intramuscular administration has occurred infrequently. Some induration has occurred. Other Reactions Genital and anal pruritus (including vulvar pruritus, genital moniliasis, and vaginitis). To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ."}', 'drug_interactions': '{"Drug Interactions Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Cefazolin for Injection, USP is indicated in the treatment of the following serious infections due to susceptible organisms: Respiratory Tract Infections: Due to S. pneumoniae, Klebsiella species, H. influenzae, S. aureus (penicillin-sensitive and penicillin-resistant), and group A beta-hemolytic streptococci . Injectable benzathine penicillin is considered to be the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefazolin for Injection is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of Cefazolin for Injection in the subsequent prevention of rheumatic fever are not available at present. Urinary Tract Infections: Due to E. coli, P. mirabilis, Klebsiella species, and some strains of enterobacter and enterococci . Skin and Skin Structure Infections: Due to S. aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci, and other strains of streptococci. Biliary Tract Infections: Due to E. coli, various strains of streptococci, P. mirabilis, Klebsiella species, and S. aureus. Bone and Joint Infections: Due to S. aureus. Genital Infections: (i.e., prostatitis, epididymitis) due to E. coli, P. mirabilis, Klebsiella species, and some strains of enterococci . Septicemia: Due to S. pneumoniae, S. aureus (penicillin-sensitive and penicillin-resistant), P. mirabilis, E. coli and Klebsiella species. Endocarditis: Due to S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci. Perioperative Prophylaxis: The prophylactic administration of Cefazolin for Injection preoperatively, intraoperatively and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those older than 70 years, with acute cholecystitis, obstructive jaundice, or common duct bile stones). The perioperative use of Cefazolin for Injection may also be effective in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty). The prophylactic administration of Cefazolin for Injection should usually be discontinued within a 24 hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of Cefazolin for Injection may be continued for 3 to 5 days following the completion of surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that appropriate therapy may be instituted (see DOSAGE AND ADMINISTRATION ). To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection, USP and other antibacterial drugs, Cefazolin for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible 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."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{CEFAZOLIN}', 'route': '{INTRAMUSCULAR,INTRAVENOUS}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS BEFORE THERAPY WITH CEFAZOLIN FOR INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFAZOLIN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFAZOLIN FOR INJECTION OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, IV FLUIDS, IV ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefazolin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an oral antibacterial drug clinically effective against C. difficile colitis."}', 'precautions': '{"PRECAUTIONS General Prolonged use of Cefazolin for Injection may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. When Cefazolin for Injection is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required (see DOSAGE AND ADMINISTRATION ). As with other β-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function (see DOSAGE AND ADMINISTRATION ). Cefazolin for Injection, as with all cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Prescribing Cefazolin for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Drug Interactions Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels. Drug/Laboratory Test Interactions A false positive reaction for glucose in the urine may occur with Benedict\'s solution, Fehling’s solution or with CLINITEST ® tablets, but not with enzyme-based tests such as CLINISTIX ® . Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery. Information for Patients Patients should be counseled that antibacterial drugs including Cefazolin for Injection, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin for Injection is prescribed to treat a bacterial infection, patients should be told 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 Cefazolin for Injection or other antibacterial drugs in the future. Carcinogenesis/Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of Cefazolin for Injection have not been performed. Pregnancy Teratogenic Effects Pregnancy Category B Reproduction studies have been performed in rats, mice and rabbits at doses up to 25 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Cefazolin for Injection . 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. Labor and Delivery When cefazolin has been administered prior to caesarean section, drug levels in cord blood have been approximately one quarter to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus. Nursing Mothers Cefazolin for Injection is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when Cefazolin for Injection is administered to a nursing woman. Pediatric Use Safety and effectiveness for use in premature infants and neonates have not been established. See DOSAGE AND ADMINISTRATION for recommended dosage in pediatric patients older than 1 month. Geriatric Use Of the 920 subjects who received Cefazolin for Injection in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness 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. 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 (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': '{"Information for Patients Patients should be counseled that antibacterial drugs including Cefazolin for Injection, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin for Injection is prescribed to treat a bacterial infection, patients should be told 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 Cefazolin for Injection or other antibacterial drugs in the future."}', 'pregnancy': '{"Pregnancy Teratogenic Effects Pregnancy Category B Reproduction studies have been performed in rats, mice and rabbits at doses up to 25 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Cefazolin for Injection . 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."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness for use in premature infants and neonates have not been established. See DOSAGE AND ADMINISTRATION for recommended dosage in pediatric patients older than 1 month."}', 'geriatric_use': '{"Geriatric Use Of the 920 subjects who received Cefazolin for Injection in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness 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. 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 (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION )."}'}

{OXAPROZIN}

{'contraindications': '{"4 CONTRAINDICATIONS OXAPROZIN CAPSULES is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin 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 CABG surgery [ see Warnings and Precautions (5.1) ] Known hypersensitivity to oxaprozin 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 clinically significant adverse reactions are described elswhere in 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 (incidence > 3%) are: constipation, diarrhea, dyspepsia, nausea, rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Solubiomix, LLC at 1-844-551-9911 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 reaction data were derived from patients who received oxaprozin, the active component of OXAPROZIN CAPSULES, in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2253 patients who took 1,200 mg to 1800 mg of the active component of OXAPROZIN CAPSULES per day in clinical trials. Of these, 1721 patients were treated for at least 1 month, 971 patients for at least 3 months, and 366 patients for more than 1 year. Incidence Greater than 1% : In clinical trials of oxaprozin, the active component of OXAPROZIN CAPSULES, or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%. Cardiovascular system: edema. Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting. Hematologic system : anemia, increased bleeding time. Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache. Skin and appendages: pruritus, rash. Special senses: tinnitus. Urogenital system: abnormal renal function, dysuria or frequency. Incidence Greater than 1%: The following adverse reactions were reported in clinical trials or in patients taking other NSAIDs. Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis. Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis. Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including liver failure, stomatitis, hemorrhoidal or rectal bleeding. Hematologic system: aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, purpura, thrombocytopenia, leukopenia. Metabolic system: hyperglycemia, weight changes. Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness. Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression. Skin: alopecia, angioedema, urticaria, photosensitivity, sweat. Special senses: blurred vision, conjunctivitis, hearing decrease. Urogenital: cystitis, hematuria, increase in menstrual flow, oliguria/ polyuria, proteinuria, renal insufficiency, decreased menstrual flow. Adverse Reactions in Pediatric Patients with Juvenile Rheumatoid Arthritis In a 3-month open label study in 59 pediatric patients with juvenile rheumatoid arthritis treated with oxaprozin, the active component of OXAPROZIN CAPSULES, adverse events were reported by 58% of patients. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Of 30 patients who continued treatment for more than 3 months (19 to 48 weeks range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and five of those discontinued treatment. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxaprozin, the active component of OXAPROZIN 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. Body as a whole: serum sickness. Digestive system : hepatitis, pancreatitis. Hematologic system : agranulocytosis, pancytopenia. Skin: pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell\'s syndrome). Urogenital : acute interstitial nephritis, nephrotic syndrome, acute renal failure."}', 'drug_interactions': '{"7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with oxaprozin [ see Clinical Pharmacology (12.3) ]. Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis Clinical Impact: Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin 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 OXAPROZIN CAPSULES with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and 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 OXAPROZIN CAPSULES and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.12) ]. OXAPROZIN CAPSULES 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 ACE inhibitors, 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 OXAPROZIN CAPSULES and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES 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 oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES 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) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate. Intervention: During concomitant use of OXAPROZIN CAPSULES and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of OXAPROZIN CAPSULES and cyclosporine may increase cyclosporine\'s nephrotoxicity. Intervention: During concomitant use of OXAPROZIN CAPSULES and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of oxaprozin 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 oxaprozin with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of OXAPROZIN CAPSULES and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of OXAPROZIN CAPSULES 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. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with OXAPROZIN CAPSULES may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of OXAPROZIN CAPSULES with corticosteroids for signs of bleeding [ see Warnings and Precautions (5.2) ]. Glyburide Clinical Impact: While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. Intervention: During concomitant use of OXAPROZIN CAPSULES and glyburide, monitor patient\'s blood glucose in the beginning phase of cotherapy. Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]) : Monitor patients for bleeding who are concomitantly taking OXAPROZIN CAPSULES with drugs that interfere with hemostasis. Concomitant use of OXAPROZIN CAPSULES and analgesic doses of aspirin is not generally recommended ( 7 ) Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with OXAPROZIN CAPSULES may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs : Concomitant use with OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 ) Laboratory Test Interactions False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking OXAPROZIN CAPSULES. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of OXAPROZIN CAPSULES therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish OXAPROZIN CAPSULES from benzodiazepines."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE OXAPROZIN CAPSULES is indicated: For relief of the signs and symptoms of osteoarthritis For relief of the signs and symptoms of rheumatoid arthritis For relief of the signs and symptoms of juvenile rheumatoid arthritis OXAPROZIN CAPSULES is a non-steroidal anti-inflammatory drug indicated for: Relief of signs and symptoms of Osteoarthritis (OA) ( 1 ) Relief of signs and symptoms of Rheumatoid Arthritis (RA) ( 1 ) Relief of signs and symptoms of Juvenile Rheumatoid Arthritis (JRA) ( 1 )"}', '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 OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES 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 : OXAPROZIN CAPSULES is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES, between about 20 to 30 weeks in pregnancy 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 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 cyclooxygenase-2 (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 oxaprozin, 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 OXAPROZIN CAPSULES in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If OXAPROZIN CAPSULES is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including OXAPROZIN CAPSULES, 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-times 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, antiplatelet drugs (such as 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 OXAPROZIN CAPSULES 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 alanine aminotransferase (ALT) or aspartate aminotransferase (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 oxaprozin. 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), discontinue OXAPROZIN CAPSULES immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including OXAPROZIN CAPSULES, 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) ]. 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 oxaprozin 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 OXAPROZIN CAPSULES in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES in patients with advanced renal disease. The renal effects of OXAPROZIN CAPSULES may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating OXAPROZIN CAPSULES. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of OXAPROZIN CAPSULES [ see Drug Interactions (7) ] . Avoid the use of OXAPROZIN CAPSULES in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If OXAPROZIN CAPSULES 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 Oxaprozin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to oxaprozin 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, OXAPROZIN CAPSULES is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4) ]. When OXAPROZIN CAPSULES 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 oxaprozin, 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 OXAPROZIN CAPSULES at the first appearance of skin rash or any other sign of hypersensitivity. OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES. 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 OXAPROZIN CAPSULES and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including OXAPROZIN CAPSULES, in pregnant women at about 30 weeks gestation and later. NSAIDs, including OXAPROZIN CAPSULES, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age [ see Use in Specific Populations (8.1) ]. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including OXAPROZIN CAPSULES, 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 OXAPROZIN CAPSULES use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if OXAPROZIN CAPSULES treatment extends beyond 48 hours. Discontinue OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including OXAPROZIN CAPSULES, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), 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 OXAPROZIN CAPSULES 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 complete blood count (CBC) and a chemistry profile periodically [ see Warnings and Precautions (5.2 , 5.3 , 5.6) ]. 5.15 Photosensitivity Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials."}', '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 grams to 100 grams in adults, 1 gram 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': '{OXAPROZIN}', '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 OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES, 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 OXAPROZIN CAPSULES and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES until they talk to their healthcare provider [ see Drug Interactions (7) ]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.solubiomix.net. Manufactured for: Ayrurax, LLC Fairhope, AL 36532"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Use of NSAIDs, including OXAPROZIN CAPSULES, 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 OXAPROZIN CAPSULES use between about 20 and 30 weeks of gestation, and avoid OXAPROZIN CAPSULES 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 OXAPROZIN CAPSULES, 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, oral administration of oxaprozin to pregnant rabbits at doses 0.1 times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses 0.2 times and 1.6 times the maximum recommended human dose, respectively, revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at a dose 1.6 times the maximum recommended human dose (based on body surface area). 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 oxaprozin, 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 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 OXAPROZIN CAPSULES, 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 OXAPROZIN CAPSULES treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue OXAPROZIN CAPSULES and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of OXAPROZIN CAPSULES during labor or delivery. In animal studies, NSAIDS, including oxaprozin, 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 full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Teratology studies with oxaprozin were performed in mice, rats, and rabbits in pregnant animals administered oral doses up to 200 mg/kg/day, 200 mg/kg/day, and 30 mg/kg/day, respectively, during the period of organogenesis. In rabbits, malformations were observed at doses greater than or equal to 7.5 mg/kg/day of oxaprozin (0.1 times the maximum recommended human daily dose [MRHD] of 1,200 mg based on body surface area). However, in mice and rats, no drug-related developmental abnormalities or embryo-fetal toxicity were observed at doses up to 50 and 200 mg/kg/day of oxaprozin, respectively (0.2 times and 1.6 times the maximum recommended human daily dose of 1200 mg based on a body surface area comparison, respectively). In fertility/reproductive studies in rats, 200 mg/kg/day oxaprozin was orally administered to female rats for 14 days prior to mating through lactation day (LD) 2, or from gestation day (GD) 15 through LD 2 and the females were mated with males treated with 200 mg/kg/day oxaprozin for 60 days prior to mating. Oxaprozin administration resulted in failure to deliver and a reduction in live birth index at 200 mg/kg/day (1.6 times the maximum recommended human daily dose of 1,200 mg based on a body surface area comparison)."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness of oxaprozin, the active component of the OXAPROZIN CAPSULES, have been established for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6 to 16 years. Use of oxaprozin for this indication is supported by evidence from one open label study in 59 pediatric JRA patients and evidence from adequate and well controlled studies in adult rheumatoid arthritis patients.[ see Clinical Studies (14.1, 14.2,14.3) ]. Gastrointestinal symptoms occurred in pediatric patients at a higher incidence than those historically seen in controlled studies in adults. Of 30 patients in the pediatric JRA trial who continued treatment more than 3 months (19 to 48 weeks range total treatment duration), nine experienced rash on sun-exposed areas of the skin and five of those discontinued treatment [ see Adverse Reactions (6.1) ]. Safety and effectiveness of OXAPROZIN CAPSULES in pediatric patients below the age of 6 years of age have not been established."}', '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) ]. No adjustment of the dose of OXAPROZIN CAPSULES is necessary in the elderly, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging [ see Clinical Pharmacology (12.3) ]. Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% 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 elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Although selected elderly patients in controlled clinical trials tolerated oxaprozin as well as younger patients, caution should be exercised in treating the elderly. OXAPROZIN CAPSULES is substantially excreted by the kidney, and the risk of toxic reactions to OXAPROZIN CAPSULES 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 Warnings and Precautions (5.6) ]."}'}

{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}

{CHLOROXYLENOL}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use for handwashing to decrease bacteria on the skin"}', '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: hands only When using this product • do not get into eyes. If contact occurs, rinse eyes thoroughly with water. Stop use and ask a doctor if • irritation and redness develop • 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}

{"SEPIA OFFICINALIS JUICE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Bloating And Lower Back Pain During Menstruation*"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"SEPIA OFFICINALIS JUICE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist for more than 3 days or worsen"}', 'do_not_use': None, 'when_using': None, 'warnings': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"DOXYLAMINE SUCCINATE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use • helps to reduce difficulty in falling asleep"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"DOXYLAMINE SUCCINATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • sleeplessness persists continuously for more than two weeks. Insomnia may be a symptom of serious underlying medical illness."}', 'do_not_use': '{"Do not use in children under 12 years of age"}', 'when_using': '{"When using this product • avoid alcoholic beverages • take only at bedtime"}', 'warnings': '{"Warnings Do not use in children under 12 years of age Ask a doctor before use if you have • a breathing problem such as asthma, emphysema or chronic bronchitis • glaucoma • trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are taking any other drugs When using this product • avoid alcoholic beverages • take only at bedtime Stop use and ask a doctor if • sleeplessness persists continuously for more than two weeks. Insomnia may be a symptom of serious underlying medical illness. 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}

{"BENDAMUSTINE HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS VIVIMUSTA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, dehydrated alcohol, or monothioglycerol [see Warnings and Precautions (5.4)] History of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, dehydrated alcohol, or monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions. (4, 5.4)"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labelling: • Myelosuppression [see Warnings and Precautions (5.1)] • Infections [see Warnings and Precautions (5.2)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)] • Anaphylaxis and Infusion-Related Reactions [see Warnings and Precautions (5.4)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] • Skin Reactions [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Other Malignancies [see Warnings and Precautions (5.8)] • Extravasation Injury [see Warnings and Precautions (5.9)] • Adverse reactions (> 5%) during infusion and within 24 hours post-infusion are nausea, and fatigue. (6.1) • Most common adverse reactions (≥15%) for CLL are anemia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, hyperbilirubinemia, pyrexia, nausea, vomiting. (6.1) • Most common adverse reactions (≥15%) for NHL are lymphopenia, leukopenia, anemia neutropenia, thrombocytopenia, nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased dyspnea, rash, and stomatitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Slayback Pharma at 1-844-566-2505 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. Chronic Lymphocytic Leukemia (CLL) The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% were male, 100% were White, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%). Table 2 summarizes the adverse reactions, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 2: Non-Hematologic Adverse Reactions that Occurred in at Least 5% of Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Adverse Reaction Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) All Grades n (%) Grade 3 or 4 n (%) All Grades n (%) Grade 3 or 4 n (%) Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 Hematology laboratory abnormalities are described in Table 3. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil. Bilirubin elevation occurred in 34% of patients, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with bendamustine hydrochloride may also have changes in their creatinine levels. Table 3: Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Laboratory Abnormality Bendamustine Hydrochloride (N=150) Chlorambucil (N=141) All Grades n (%) Grade 3 or 4 n (%) All Grades n (%) Grade 3 or 4 n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Non-Hodgkin Lymphoma (NHL) The data described below reflect exposure to bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age; 60% were male; 89% were White, 7% were Black, 3% were Hispanic, 1% were other, and <1% were Asian. These patients received bendamustine hydrochloride at a dose of 120 mg/m 2 intravenously on Days 1 and 2 for up to eight 21-day cycles. In both studies, serious adverse reactions, were reported in 37% of patients receiving bendamustine hydrochloride. The most frequent serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion-related reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Non-hematologic adverse reactions are shown in Table 4. Table 4: Non-Hematologic Adverse Reactions that Occurred in at Least 5% of Patients who Received Bendamustine Hydrochloride in the NHL Studies Bendamustine Hydrochloride (N=176*) Adverse Reaction All Grades n(%) Grade 3 or 4 n(%) Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac Disorders Tachycardia 13 (7) 0 Gastrointestinal disorders Nausea 132 (75) 7 (4) Vomiting 71 (40) 5 (3) Diarrhea 65 (37) 6 (3) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 1 (<1) Abdominal pain 22 (13) 2 (1) Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 0 Dry mouth 15 (9) 1 (<1) Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) 0 General disorders and administration site conditions Fatigue 101 (57) 19 (11) Pyrexia 59 (34) 3 (2) Chills 24 (14) 0 Edema peripheral 23 (13) 1 (<1) Asthenia 19 (11) 4 (2) Chest pain 11 (6) 1 (<1) Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) 0 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile neutropenia 11 (6) 11 (6) Oral candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorder Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each body system category. Hematologic toxicities, based on laboratory values and CTC grade, in patients with NHL treated in both single arm studies combined are described in Table 5. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in patients with NHL who were treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 5: Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies Hematology Variable Bendamustine Hydrochloride All Grades (%) Grade 3 or 4 (%) Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bendamustine 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. Blood and lymphatic systems disorders: Pancytopenia. Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation. General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling). Immune system disorders: Anaphylaxis. Infections and infestations: Pneumocystis jiroveci pneumonia, progressive multifocal leukoencephalopathy (PML). Respiratory, thoracic and mediastinal disorders: Pneumonitis. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and non-melanoma skin cancer (NMSC)."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Consider alternative therapies that are not CYP1A2 inducers or inhibitors during treatment with VIVIMUSTA. (7.1) 7.1 Effect of Other Drugs on VIVIMUSTA CYP1A2 Inhibitors The coadministration of VIVIMUSTA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with VIVIMUSTA [see Clinical Pharmacology (12.3)]. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with VIVIMUSTA. CYP1A2 Inducers The coadministration of VIVIMUSTA with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of VIVIMUSTA [see Clinical Pharmacology (12.3)]. Consider alternative therapies that are not CYP1A2 inducers during treatment with VIVIMUSTA."}', 'indications_and_usage': '{"1 INDICATIONS & USAGE VIVIMUSTA is an alkylating drug indicated for treatment of patients with: • Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. (1.1) • Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. (1.2) 1.1 Chronic Lymphocytic Leukemia (CLL) VIVIMUSTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 1.2 Non-Hodgkin Lymphoma (NHL) VIVIMUSTA is indicated for the treatment of adult patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Myelosuppression : Delay or reduce dose, and restart treatment based on ANC and platelet count recovery. (5.1) • Infections : Monitor for fever and other signs of infection or reactivation of infections and treat promptly. (5.2) • Progressive multifocal leukoencephalopathy (PML) : Monitor for new or worsening neurological, cognitive or behavioral signs or symptoms suggestive of PML. (5.3) • Anaphylaxis and Infusion-Related Reactions : Severe anaphylactic reactions have occurred. Monitor clinically and discontinue drug for severe reactions. Pre-medicate in subsequent cycles for milder reactions. (5.4) • Tumor Lysis Syndrome : May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk. (5.5) • Skin Reactions : Discontinue for severe skin reactions. Cases of SJS, DRESS and TEN, some fatal, have been reported. (5.6). • Hepatotoxicity : Monitor liver chemistry tests prior to and during treatment. (5.7) • Other Malignancies : Pre-malignant and malignant diseases have been reported. (5.8) • Extravasation Injury : Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration. (5.9) • Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. (5.10, 8.1) 5.1 Myelosuppression VIVIMUSTA causes myelosuppression. Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies [see Adverse Reactions (6.1)] . Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia and pneumonia from an opportunistic infection (CMV). Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Delay the next cycle of therapy if ANC less than 1 x 10 9 /L or platelet count less than 75 x 10 9 /L [see Dosage and Administration (2.1, 2.2)]. 5.2 Infections Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following VIVIMUSTA treatment to contact healthcare provider immediately if they have symptoms or signs of infection. Patients treated with VIVIMUSTA are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Implement appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration. 5.3 Progressive Multifocal Leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab [see Adverse Reactions (6.2)] . Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold VIVIMUSTA treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.4 Anaphylaxis and Infusion-Related Reactions Infusion-related reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion-related reactions after their first cycle of therapy. Do not rechallenge patients who experienced Grade 3 or worse allergic-type reactions. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion-related reactions. Discontinue VIVIMUSTA for patients with Grade 4 infusion-related reactions. Consider discontinuation for Grade 3 infusion-related reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Administer vigorous hydration and monitor blood chemistry, particularly potassium and uric acid levels at baseline and closely during treatment with VIVIMUSTA. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)]. 5.6 Skin Reactions Fatal and serious skin reactions have been reported with bendamustine hydrochloride treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash. Events occurred when bendamustine hydrochloride was given as a single agent and in combination with other anticancer agents or allopurinol. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue VIVIMUSTA. 5.7 Hepatotoxicity Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients [see Warnings and Precautions (5.2)]. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during treatment with VIVIMUSTA. 5.8 Other Malignancies Pre-malignant and malignant diseases have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, bronchial carcinoma, and non-melanoma skin cancer including basal cell carcinoma and squamous cell carcinoma [see Adverse Reactions (6.2)] . Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with VIVIMUSTA. 5.9 Extravasation Injury Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting VIVIMUSTA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of VIVIMUSTA. 5.10 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and the drug\'s mechanism of action, VIVIMUSTA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with VIVIMUSTA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with VIVIMUSTA and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]."}', 'overdosage': '{"10 OVERDOSAGE The intravenous lethal dose 50 (LD 50 ) of bendamustine hydrochloride is 240 mg/m 2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m 2 . Three of four patients who received this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for bendamustine hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs."}', 'active_flag': 'Y', 'generic_name': '{"BENDAMUSTINE HYDROCHLORIDE"}', '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 Myelosuppression Inform patients of the likelihood that bendamustine hydrochloride will cause a decrease in white blood cells, platelets, and red blood cells and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1)]. Progressive Multifocal Leukoencephalopathy (PML) Inform patients to immediately contact their healthcare provider if they experience confusion, memory loss, trouble thinking, difficulty talking or walking, vision loss or other neurological or cognitive symptoms [see Warnings and Precautions (5.3) ]. Anaphylaxis and Infusion-Related Reactions Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.4)]. Skin Reactions Advise patients that a rash or itching may occur during treatment with VIVIMUSTA. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions (5.6)] . Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.7)] . Fatigue Advise patients that VIVIMUSTA may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect [see Adverse Reactions (6.1)]. Nausea and Vomiting Advise patients that VIVIMUSTA may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided [see Adverse Reactions (6.1)]. Diarrhea Advise patients that VIVIMUSTA may cause diarrhea. Patients should report diarrhea to the healthcare provider so that symptomatic treatment may be provided [see Adverse Reactions (6.1)]. Non-melanoma Skin Cancer (NMSC) Advise patients to undergo regular skin cancer screenings, and to report any suspicious skin changes to their healthcare provider [see Warnings and Precautions (5.8)] . 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 (5.10), Use in Specific Populations (8.1, 8.3), and Nonclinical Toxicology (13.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with VIVIMUSTA and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with VIVIMUSTA and for 3 months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. Lactation Advise females not to breastfeed during treatment with VIVIMUSTA and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise males of reproductive potential that VIVIMUSTA may impair fertility [see Use in Specific Populations (8.3)]. Manufactured for: Slayback Pharma LLC Princeton, NJ 08540. Manufactured at: Corden Pharma Latina S.p.A. 04013 Sermoneta (LT), Italy."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a 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 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 Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m 2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride in mice on gestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m 2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m 2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration. Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats."}', 'pediatric_use': '{"8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1-19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient. The safety profile in these patients was consistent with that seen in adults and no new safety signals were identified. The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area."}', 'geriatric_use': '{"8.5 Geriatric Use No overall differences in safety were observed between patients ≥65 years of age and younger patients. Efficacy was lower in patients 65 and over with CLL receiving bendamustine hydrochloride based upon an overall response rate of 47% for patients 65 and over and 70% for younger patients. Progression free survival was also longer in younger patients with CLL receiving bendamustine (19 months vs. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients."}'}

{HYDROCHLOROTHIAZIDE}

{'contraindications': '{"CONTRAINDICATIONS Hydrochlorothiazide capsules are contraindicated in patients with anuria. Hypersensitivity to this product or other sulfonamide derived drugs is also contraindicated."}', 'adverse_reactions': '{"ADVERSE REACTIONS The adverse reactions associated with hydrochlorothiazide have been shown to be dose related. In controlled clinical trials, the adverse events reported with doses of 12.5 mg hydrochlorothiazide once daily were comparable to placebo. The following adverse reactions have been reported for doses of hydrochlorothiazide 25 mg and greater and, within each category, are listed in the order of decreasing severity. Body as a whole: Weakness. Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs). Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia. Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. Metabolic: Electrolyte imbalance (see PRECAUTIONS ), hyperglycemia, glycosuria, hyperuricemia. Musculoskeletal: Muscle Spasm. Nervous System/Psychiatric: Vertigo, paresthesia, dizziness, headache, restlessness. Renal : Renal failure, renal dysfunction, interstitial nephritis (see WARNINGS ). Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia. Special Senses: Transient blurred vision, xanthopsia. Urogenital: Impotence. Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn."}', 'drug_interactions': '{"Drug Interactions When given concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur. Antidiabetic drugs - (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs - additive effect or potentiation. Cholestyramine and colestipol resins - Cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroid, ACTH – intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant. Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and greatly increase the risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide. Non-steroidal anti-inflammatory drugs - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. When hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained. Drug/Laboratory Test Interactions - Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS , General)."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Hydrochlorothiazide capsules are indicated in the management of hypertension either as the sole therapeutic agent, or in combination with other antihypertensives. Unlike potassium sparing combination diuretic products, hydrochlorothiazide capsules may be used in those patients in whom the development of hyperkalemia cannot be risked, including patients taking ACE inhibitors. 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 pathological causes or from the physiologic and mechanical consequences of pregnancy. Diuretics are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. 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 which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which 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 which is not relieved by rest. In these cases a short course of diuretics may provide relief and may be appropriate."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. In the event of overdosage, symptomatic and supportive measures should be employed. Emesis should be induced or gastric lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat."}', 'active_flag': 'Y', 'generic_name': '{HYDROCHLOROTHIAZIDE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. Diabetes and Hypoglycemia : Latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose. Renal Disease : Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate azotemia."}', 'precautions': '{"PRECAUTIONS Electrolyte and Fluid Balance Status In published studies, clinically significant hypokalemia has been consistently less common in patients who received 12.5 mg of hydrochlorothiazide than in patients who received higher doses. Nevertheless, periodic determination of serum electrolytes should be performed in patients who may be at risk for the development of hypokalemia. Patients should be observed for signs of fluid or electrolyte disturbances, i.e. hyponatremia, hypochloremic alkalosis, and hypokalemia and hypomagnesemia. Warning signs or symptoms of fluid and electrolyte imbalance include 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. Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroid or adrenocorticotropic hormone (ACTH) or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium rich foods. Dilutional hyponatremia is life-threatening and may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than salt administration, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics. Impaired Hepatic Function Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease. Parathyroid Disease Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy. Drug Interactions When given concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur. Antidiabetic drugs - (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs - additive effect or potentiation. Cholestyramine and colestipol resins - Cholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Corticosteroid, ACTH – intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine) - possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - possible increased responsiveness to the muscle relaxant. Lithium - generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and greatly increase the risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with hydrochlorothiazide. Non-steroidal anti-inflammatory drugs - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. When hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained. Drug/Laboratory Test Interactions - Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS , General). Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an unspecified concentration. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation. Pregnancy Teratogenic Effects Pregnancy Category B: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. 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. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Nursing Mothers Thiazides are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Elderly Use A greater blood pressure reduction and an increase in side effects may be observed in the elderly (i.e., >65 years) with hydrochlorothiazide. Starting treatment with the lowest available dose of hydrochlorothiazide (12.5 mg) is therefore recommended. If further titration is required, 12.5 mg increments should be utilized."}', 'information_for_patients': None, 'pregnancy': '{"Pregnancy Teratogenic Effects Pregnancy Category B: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus. 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. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness in pediatric patients have not been established."}', 'geriatric_use': None}

{DIMETHICONE}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use relieves bloating, pressure and fullness commonly referred to as gas"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{SIMETHICONE}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Keep out of reach of children"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{ERYTHROMYCIN}

{'contraindications': '{"CONTRAINDICATIONS Erythromycin is contraindicated in patients with known hypersensitivity to this antibiotic. Erythromycin is contraindicated in patients taking terfenadine, astemizole, cisapride, pimozide, ergotamine, or dihydroergotamine (see PRECAUTIONS - Drug Interactions ). Do not use erythromycin concomitantly with HMG CoA reductase inhibitors (statins) that are extensively metabolized by CYP 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see PRECAUTIONS - Drug Interactions )."}', 'adverse_reactions': '{"ADVERSE REACTIONS The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhea and anorexia. Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver function test results may occur (see WARNINGS ). Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS ). Erythromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsade de pointes (see WARNINGS ). Allergic reactions ranging from urticaria to anaphylaxis have occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely. There have been reports of interstitial nephritis coincident with erythromycin use. There have been reports of pancreatitis and convulsions. There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency and in patients receiving high doses of erythromycin."}', 'drug_interactions': '{"Drug Interactions Theophylline Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy. There have been published reports suggesting that when oral erythromycin is given concurrently with theophylline there is a significant decrease in erythromycin serum concentrations of approximately 35 percent. The mechanism by which this interaction occurs is unknown. The decrease in erythromycin concentrations due to co-administration of theophylline could result in subtherapeutic concentrations of erythromycin. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class. Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels. There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to interactions of erythromycin with oral anticoagulants may be more pronounced in the elderly. Erythromycin is a substrate and inhibitor of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Co-administration of erythromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving erythromycin. The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. The following CYP3A based drug interactions have been observed with erythromycin products in post-marketing experience: Ergotamine/dihydroergotamine Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including central nervous system. Concomitant administration of erythromycin with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS ). Triazolobenzodiazepines (such as triazolam and alprazolam) and related benzodiazepines Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. HMG-CoA Reductase Inhibitors Erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (for example, lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly (see CONTRAINDICATIONS ). Sildenafil (Viagra) Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered. (See Viagra package insert.) There have been spontaneous or published reports of CYP3A based interactions of erythromycin with carbamazepine, cyclosporine, tacrolimus, alfentanil, disopyramide, bromocriptine, rifabutin, quinidine methylprednisolone, cilostazol, and vinblastine. Concomitant administration of erythromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS ). In addition, there have been reports of interactions of erythromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. Erythromycin has been reported to significantly alter the metabolism of the nonsedating antihistamines terfenadine and astemizole when taken concomitantly. Rare cases of serious cardiovascular adverse events, including electrocardiographic QT/QT c interval prolongation, cardiac arrest, torsades de pointes, and other ventricular arrhythmias, have been observed (see CONTRAINDICATIONS ). In addition, deaths have been reported rarely with concomitant administration of terfenadine and erythromycin. There have been post-marketing reports of drug interactions when erythromycin was co-administered with cisapride, resulting in QT prolongation, cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and torsades de pointes, most likely due to the inhibition of hepatic metabolism of cisapride by erythromycin. Fatalities have been reported (see CONTRAINDICATIONS ). Colchicine Colchicine is a substrate for both CYP3A4 and the efflux transporter P-glycoprotein (P-gp). Erythromycin is considered a moderate inhibitor of CYP3A4. A significant increase in colchicine plasma concentration is anticipated when co-administered with moderate CYP3A4 inhibitors such as erythromycin. If co-administration of colchicine and erythromycin is necessary, the starting dose of colchicine may need to be reduced, and the maximum colchicine dose should be lowered. Patients should be monitored for clinical symptoms of colchicine toxicity (see WARNINGS )."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Erythromycin is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the diseases listed below: Upper respiratory tract infections of mild to moderate degree caused by Streptococcus pyogenes, Streptococcus pneumoniae, or Haemophilus influenzae (when used concomitantly with adequate doses of sulfonamides, since many strains of H. influenzae are not susceptible to the erythromycin concentrations ordinarily achieved) (see appropriate sulfonamide labeling for prescribing information). Lower respiratory tract infections of mild to moderate severity caused by Streptococcus pneumoniae or Streptococcus pyogenes. Listeriosis caused by Listeria monocytogenes. Pertussis (whooping cough) caused by Bordetella pertussis. Erythromycin is effective in eliminating the organism from the nasopharynx of infected individuals rendering them noninfectious. Some clinical studies suggest that erythromycin may be helpful in the prophylaxis of pertussis in exposed susceptible individuals. Respiratory tract infections due to Mycoplasma pneumoniae. Skin and skin structure infections of mild to moderate severity caused by Streptococcus pyogenes or Staphylococcus aureus (resistant staphylococci may emerge during treatment). Diphtheria: Infections due to Corynebacterium diphtheria e, as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers. Erythrasma: In the treatment of infections due to Corynebacterium minutissimum . Syphilis caused by Treponema pallidum : Erythromycin is an alternate choice of treatment for primary syphilis in penicillin-allergic patients. In primary syphilis, spinal fluid examinations should be done before treatment and as part of follow-up after therapy. Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only). Extraenteric amebiasis requires treatment with other agents. Acute pelvic inflammatory disease caused by Neisseria gonorrhoea e: Erythromycin lactobionate for injection, USP followed by erythromycin base orally, as an alternative drug in treatment of acute pelvic inflammatory disease caused by N. gonorrhoeae in female patients with a history of sensitivity to penicillin. Patients should have a serologic test for syphilis before receiving erythromycin as treatment of gonorrhea and a follow-up serologic test for syphilis after 3 months. Erythromycins are indicated for the treatment of the following infections caused by Chlamydia trachomati s: conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections during pregnancy. When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of uncomplicated urethral, endocervical, or rectal infections in adults due to Chlamydia trachomati s. When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of nongonococcal urethritis caused by Ureaplasma urealyticum . Legionnaires\' Disease caused by Legionella pneumophila . Although no controlled clinical efficacy studies have been conducted, in vitro and limited preliminary clinical data suggest that erythromycin may be effective in treating Legionnaires\' Disease. Prophylaxis Prevention of Initial Attacks of Rheumatic Fever Penicillin is considered by the American Heart Association to be the drug of choice in the prevention of initial attacks of rheumatic fever (treatment of Streptococcus pyogenes infections of the upper respiratory tract, e.g., tonsillitis or pharyngitis). Erythromycin is indicated for the treatment of penicillin-allergic patients. 1 The therapeutic dose should be administered for ten days. Prevention of Recurrent Attacks of Rheumatic Fever Penicillin or sulfonamides are considered by the American Heart Association to be the drugs of choice in the prevention of recurrent attacks of rheumatic fever. In patients who are allergic to penicillin and sulfonamides, oral erythromycin is recommended by the American Heart Association in the long-term prophylaxis of streptococcal pharyngitis (for the prevention of recurrent attacks of rheumatic fever). 1 To reduce the development of drug-resistant bacteria and maintain the effectiveness of erythromycin delayed-release capsules, USP and other antibacterial drugs, erythromycin delayed-release capsules, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible 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."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE In case of overdosage, erythromycin should be discontinued. Overdosage should be handled with the prompt elimination of unabsorbed drug and all other appropriate measures. Erythromycin is not removed by peritoneal dialysis or hemodialysis."}', 'active_flag': 'Y', 'generic_name': '{ERYTHROMYCIN}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Hepatotoxicity There have been reports of hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, occurring in patients receiving oral erythromycin products. QT Prolongation Erythromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving erythromycin. Fatalities have been reported. Erythromycin should be avoided in patients with known prolongation of the QT interval, patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval. Syphilis in pregnancy There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen. Clostridium difficile -associated diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including erythromycin delayed-release capsules, USP, 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. Drug Interactions Serious adverse reactions have been reported in patients taking erythromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP3A4 (for example, verapamil, amlodipine, diltiazem) (see PRECAUTIONS, Drug Interactions ). There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine. This interaction is potentially life-threatening, and may occur while using both drugs at their recommended doses (see PRECAUTIONS, Drug Interactions ). Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels. (See package insert for lovastatin.)"}', 'precautions': '{"PRECAUTIONS General Prescribing erythromycin delayed-release capsules, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Since erythromycin is principally excreted by the liver, caution should be exercised when erythromycin is administered to patients with impaired hepatic function (see CLINICAL PHARMACOLOGY and WARNINGS .) Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving erythromycin therapy. There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. In one cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5 percent) developed symptoms of non bilious vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. A possible dose-response effect was described with an absolute risk of IHPS of 5.1 percent for infants who took erythromycin for 8 to 14 days and 10 percent for infants who took erythromycin for 15 to 21 days. 2 Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or neonatal Chlamydia trachomatis infections), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs. Prolonged or repeated use of erythromycin may result in an overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, erythromycin should be discontinued and appropriate therapy instituted. When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy. Information for Patients Patients should be counseled that antibacterial drugs including erythromycin delayed-release capsules, USP should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When erythromycin delayed-release capsules, USP are prescribed to treat a bacterial infection, patients should be told 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 erythromycin delayed-release capsules, USP or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Drug Interactions Theophylline Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy. There have been published reports suggesting that when oral erythromycin is given concurrently with theophylline there is a significant decrease in erythromycin serum concentrations of approximately 35 percent. The mechanism by which this interaction occurs is unknown. The decrease in erythromycin concentrations due to co-administration of theophylline could result in subtherapeutic concentrations of erythromycin. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class. Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels. There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to interactions of erythromycin with oral anticoagulants may be more pronounced in the elderly. Erythromycin is a substrate and inhibitor of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Co-administration of erythromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving erythromycin. The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. The following CYP3A based drug interactions have been observed with erythromycin products in post-marketing experience: Ergotamine/dihydroergotamine Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including central nervous system. Concomitant administration of erythromycin with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS ). Triazolobenzodiazepines (such as triazolam and alprazolam) and related benzodiazepines Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. HMG-CoA Reductase Inhibitors Erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (for example, lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly (see CONTRAINDICATIONS ). Sildenafil (Viagra) Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered. (See Viagra package insert.) There have been spontaneous or published reports of CYP3A based interactions of erythromycin with carbamazepine, cyclosporine, tacrolimus, alfentanil, disopyramide, bromocriptine, rifabutin, quinidine methylprednisolone, cilostazol, and vinblastine. Concomitant administration of erythromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS ). In addition, there have been reports of interactions of erythromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. Erythromycin has been reported to significantly alter the metabolism of the nonsedating antihistamines terfenadine and astemizole when taken concomitantly. Rare cases of serious cardiovascular adverse events, including electrocardiographic QT/QT c interval prolongation, cardiac arrest, torsades de pointes, and other ventricular arrhythmias, have been observed (see CONTRAINDICATIONS ). In addition, deaths have been reported rarely with concomitant administration of terfenadine and erythromycin. There have been post-marketing reports of drug interactions when erythromycin was co-administered with cisapride, resulting in QT prolongation, cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and torsades de pointes, most likely due to the inhibition of hepatic metabolism of cisapride by erythromycin. Fatalities have been reported (see CONTRAINDICATIONS ). Colchicine Colchicine is a substrate for both CYP3A4 and the efflux transporter P-glycoprotein (P-gp). Erythromycin is considered a moderate inhibitor of CYP3A4. A significant increase in colchicine plasma concentration is anticipated when co-administered with moderate CYP3A4 inhibitors such as erythromycin. If co-administration of colchicine and erythromycin is necessary, the starting dose of colchicine may need to be reduced, and the maximum colchicine dose should be lowered. Patients should be monitored for clinical symptoms of colchicine toxicity (see WARNINGS ). Drug/Laboratory test interactions Erythromycin interferes with the fluorometric determination of urinary catecholamines. Carcinogenesis, Mutagenesis and Impairment of Fertility Long-term (2-year) oral studies conducted in rats with erythromycin base did not provide evidence of tumorigenicity. Mutagenicity studies have not been conducted. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25 percent of diet. Pregnancy Teratogenic Effects There was no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25 percent of diet) prior to and during mating, during gestation, and through weaning of two successive litters. 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. Labor and Delivery The effect of erythromycin on labor and delivery is unknown. Nursing Mothers Erythromycin is excreted in human milk. Caution should be exercised when erythromycin is administered to a nursing woman. Pediatric Use See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION . Geriatric Use Clinical studies with erythromycin delayed-release capsules, USP 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 the decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients (see WARNINGS ). Elderly patients may experience increased effects of oral anticoagulant therapy while undergoing treatment with erythromycin (see PRECAUTIONS, Drug Interactions .) erythromycin delayed-release capsules, USP do not contain sodium."}', 'information_for_patients': '{"Information for Patients Patients should be counseled that antibacterial drugs including erythromycin delayed-release capsules, USP should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When erythromycin delayed-release capsules, USP are prescribed to treat a bacterial infection, patients should be told 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 erythromycin delayed-release capsules, USP or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible."}', 'pregnancy': '{"Pregnancy Teratogenic Effects There was no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25 percent of diet) prior to and during mating, during gestation, and through weaning of two successive litters. 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."}', 'pediatric_use': '{"Pediatric Use See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ."}', 'geriatric_use': '{"Geriatric Use Clinical studies with erythromycin delayed-release capsules, USP 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 the decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients (see WARNINGS ). Elderly patients may experience increased effects of oral anticoagulant therapy while undergoing treatment with erythromycin (see PRECAUTIONS, Drug Interactions .) erythromycin delayed-release capsules, USP do not contain sodium."}'}

{"CARVEDILOL PHOSPHATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Carvedilol Phosphate extended-release capsules are contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of immediate-release carvedilol. Second- or third-degree AV block. Sick sinus syndrome. Severe bradycardia (unless a permanent pacemaker is in place). Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating Carvedilol Phosphate extended-release capsules. Patients with severe hepatic impairment. Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of Carvedilol Phosphate extended-release capsules. Bronchial asthma or related bronchospastic conditions. ( 4 ) Second- or third-degree AV block. ( 4 ) Sick sinus syndrome. ( 4 ) Severe bradycardia (unless permanent pacemaker in place). ( 4 ) Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy. ( 4) Severe hepatic impairment. ( 2.4 , 4 ) History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of Carvedilol Phosphate extended-release capsules. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The safety profile of Carvedilol Phosphate extended-release was similar to that observed for immediate-release carvedilol. Most common adverse events seen with immediate-release carvedilol. ( 6.1 ): Heart failure and left ventricular dysfunction following myocardial infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥5%): Dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Woodward Pharma Services LLC at 1-844-200-7910 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. Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these populations reflecting the use of either Carvedilol Phosphate extended-release capsules or immediate-release carvedilol tablets are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). Carvedilol Phosphate extended-release capsules has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol tablets and 2 weeks of Carvedilol Phosphate extended-release capsules) clinical trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with Carvedilol Phosphate extended-release capsules in this small, short-term trial was generally similar to that observed with immediate-release carvedilol tablets. Differences in safety would not be expected based on the similarity in plasma levels for Carvedilol Phosphate extended-release capsules and immediate-release carvedilol. Heart Failure The following information describes the safety experience in heart failure with immediate-release carvedilol. Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with carvedilol for up to 5.9 years (mean 4.8 years). Both in U.S. clinical trials in mild-to-moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial). Table 2 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in U.S. placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of greater than 3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild-to-moderate heart failure and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of carvedilol observed in the long-term COMET trial was generally similar to that observed in the U.S. Heart Failure Trials. Table 2. Adverse Events (%) Occurring More Frequently with Immediate-Release Carvedilol than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in U.S. Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality) Body System/Adverse Event Mild-to-Moderate HF Severe HF Carvedilol Placebo Carvedilol Placebo (n = 765) (n = 437) (n = 1,156) (n = 1,133) Body as a Whole Asthenia 7 7 11 9 Fatigue 24 22 — — Digoxin level increased 5 4 2 1 Edema generalized 5 3 6 5 Edema dependent 4 2 — — Cardiovascular Bradycardia 9 1 10 3 Hypotension 9 3 14 8 Syncope 3 3 8 5 Angina pectoris 2 3 6 4 Central Nervous System Dizziness 32 19 24 17 Headache 8 7 5 3 Gastrointestinal Diarrhea 12 6 5 3 Nausea 9 5 4 3 Vomiting 6 4 1 2 Metabolic Hyperglycemia 12 8 5 3 Weight increase 10 7 12 11 BUN increased 6 5 — — NPN increased 6 5 — — Hypercholesterolemia 4 3 1 1 Edema peripheral 2 1 7 6 Musculoskeletal Arthralgia 6 5 1 1 Respiratory Cough increased 8 9 5 4 Rales 4 4 4 2 Vision Vision abnormal 5 2 — — Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol in either the U.S. placebo-controlled trials in subjects with mild-to-moderate heart failure or in subjects with severe heart failure in the COPERNICUS trial. Incidence greater than 1% to less than or equal to 3% Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema. Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension. Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia. Gastrointestinal: Melena, periodontitis. Liver and Biliary System: SGPT increased, SGOT increased. Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased. Musculoskeletal: Muscle cramps. Platelet, Bleeding and Clotting: Prothrombin decreased, purpura, thrombocytopenia. Psychiatric: Somnolence. Reproductive, male: Impotence. Special Senses: Blurred vision. Urinary System: Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction Following Myocardial Infarction The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol. Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively. The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the U.S. heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in >3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation >1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension Carvedilol Phosphate extended-release capsules were evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with Carvedilol Phosphate extended-release capsules was generally similar to that observed with immediate-release carvedilol tablets. The overall rates of discontinuations due to adverse events were similar between Carvedilol Phosphate extended-release capsules and placebo. Table 3. Adverse Events (%) Occurring More Frequently with Carvedilol Phosphate extended-release capsules than with Placebo in Subjects with Hypertension (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality) Adverse Event Carvedilol Phosphate extended-release capsules (n = 253) Placebo (n = 84) Nasopharyngitis 4 0 Dizziness 2 1 Nausea 2 0 Edema peripheral 2 1 Nasal congestion 1 0 Paresthesia 1 0 Sinus congestion 1 0 Diarrhea 1 0 Insomnia 1 0 The following information describes the safety experience in hypertension with immediate-release carvedilol. Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In U.S. controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of carvedilol subjects discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo-controlled trials was found to increase with increasing dose of carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg as single or divided doses. Table 4 shows adverse events in U.S. placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality and that were more frequent in drug-treated subjects than placebo-treated subjects. Table 4. Adverse Events (% Occurrence) in U.S. Placebo-Controlled Hypertension Trials with Immediate-Release Carvedilol Tablets (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality) Shown are events with rate >1% rounded to nearest integer. Adverse Event Carvedilol (n = 1,142) Placebo (n = 462) Cardiovascular Bradycardia 2 — Postural hypotension 2 — Peripheral edema 1 — Central Nervous System Dizziness 6 5 Insomnia 2 1 Gastrointestinal Diarrhea 2 1 Hematologic Thrombocytopenia 1 — Metabolic Hypertriglyceridemia 1 — Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events not described above were reported as possibly or probably related to carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension or heart failure. Incidence greater than 0.1% to less than or equal to 1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions (6.2) ] . Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paranoia, emotional lability. Respiratory System: Asthma [see Contraindications (4) ] . Reproductive, male: Decreased libido. Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses: Tinnitus. Urinary System: Micturition frequency increased. Autonomic Nervous System: Dry mouth, sweating increased. Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia. Hematologic: Anemia, leukopenia. The following events were reported in less than or equal to 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes. Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol. Rates of transaminase elevations (2- to 3-times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with carvedilol had lower values for hepatic transaminases than subjects treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol therapy has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive subjects; fasting serum glucose was not evaluated in the heart failure clinical trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of immediate-release carvedilol tablets or Carvedilol Phosphate extended-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. Blood and Lymphatic System Disorders Aplastic anemia. Immune System Disorders Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria). Renal and Urinary Disorders Urinary incontinence. Respiratory, Thoracic, and Mediastinal Disorders Interstitial pneumonitis. Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme."}', 'drug_interactions': '{"7 DRUG INTERACTIONS CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease carvedilol levels. ( 7.1 , 7.5 ) Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia. ( 7.2 ) Cyclosporine or digoxin levels may increase. ( 7.3 , 7.4 ) Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. ( 7.4 ) Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction. ( 7.6 ) Verapamil- or diltiazem-type calcium channel blockers may affect ECG and/or blood pressure. ( 7.7 ) Insulin and oral hypoglycemics action may be enhanced. ( 7.8 ) 7.1 CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical Pharmacology (12.3) ] . Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer. 7.2 Hypotensive Agents Patients taking a β-blocker and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with a β-blocker may cause hypotension and bradycardia. When concomitant treatment with a β-blocker and clonidine is to be terminated, the β-blocker should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage. 7.3 Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate. 7.4 Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia . Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Carvedilol Phosphate extended-release capsules [see Clinical Pharmacology (12.5) ] . 7.5 Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5) ] . Cimetidine increased area under the curve (AUC) by about 30% but caused no change in C max [see Clinical Pharmacology (12.5) ] . 7.6 Amiodarone Amiodarone and its metabolite desethyl amiodarone, inhibitors of CYP2C9, and P-glycoprotein increased concentrations of the S(-) enantiomer of carvedilol by at least 2-fold [see Clinical Pharmacology (12.5) ] . The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with Carvedilol Phosphate extended-release capsules may enhance the β–blocking activity, resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other. 7.7 Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol is coadministered with diltiazem. As with other β-blockers, if Carvedilol Phosphate extended-release capsules are to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. 7.8 Insulin or Oral Hypoglycemics β-blockers may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6) ] . 7.9 Proton Pump Inhibitors There is no clinically meaningful increase in AUC and C max with concomitant administration of Carvedilol Phosphate extended-release capsules with pantoprazole. 7.10 Anesthesia If treatment with Carvedilol Phosphate extended-release capsules is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see Overdosage (10) ] ."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Carvedilol Phosphate extended-release capsules are an alpha-/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure. ( 1.1 ) left ventricular dysfunction following myocardial infarction in clinically stable patients. ( 1.2 ) hypertension. ( 1.3 ) 1.1 Heart Failure Carvedilol Phosphate extended-release capsules are indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Drug Interactions (7.4) , Clinical Studies (14.1) ] . 1.2 Left Ventricular Dysfunction following Myocardial Infarction Carvedilol Phosphate extended-release capsules are indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure) [see Clinical Studies (14.2) ] . 1.3 Hypertension Carvedilol Phosphate extended-release capsules are indicated for the management of essential hypertension [see Clinical Studies (14.3 , 14.4) ] . They can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2) ] ."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS In clinical trials of Carvedilol Phosphate extended-release capsules in subjects with hypertension (338 subjects) and in subjects with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of immediate-release carvedilol. Therefore, the information included within this section is based on data from controlled clinical trials with Carvedilol Phosphate extended-release capsules as well as immediate-release carvedilol tablets. Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. ( 5.1 ) Bradycardia, hypotension, worsening heart failure/fluid retention may occur. Reduce the dose as needed. ( 5.2 , 5.3 , 5.4 ) Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers. ( 4 ) However, if deemed necessary, use with caution and at lowest effective dose. ( 5.5 ) Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. ( 5.6 ) 5.1 Cessation of Therapy Patients with coronary artery disease, who are being treated with Carvedilol Phosphate extended-release capsules, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with angina following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of Carvedilol Phosphate extended-release capsules is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol Phosphate extended-release capsules should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol Phosphate extended-release capsules be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with Carvedilol Phosphate extended-release capsules abruptly even in patients treated only for hypertension or heart failure. 5.2 Bradycardia In clinical trials with immediate-release carvedilol, bradycardia was reported in about 2% of hypertensive subjects, 9% of subjects with heart failure, and 6.5% of subjects with myocardial infarction with left ventricular dysfunction. Bradycardia was reported in 0.5% of subjects receiving Carvedilol Phosphate extended-release capsules in a trial of subjects with heart failure and subjects with myocardial infarction and left ventricular dysfunction. There were no reports of bradycardia in the clinical trial of Carvedilol Phosphate extended-release capsules in hypertension. However, if pulse rate drops below 55 beats per minute, the dosage of Carvedilol Phosphate extended-release capsules should be reduced. 5.3 Hypotension In clinical trials of primarily mild-to-moderate heart failure with immediate-release carvedilol, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of carvedilol subjects, compared with 0.4% of placebo subjects. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of subjects with heart failure receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of carvedilol subjects, compared with 0.8% of placebo subjects. In a trial comparing subjects with heart failure switched to Carvedilol Phosphate extended-release capsules or maintained on immediate-release carvedilol tablets, there was a 2-fold increase in the combined incidence of hypotension, syncope, or dizziness in elderly subjects (older than 65 years) switched from the highest dose of immediate-release carvedilol (25 mg twice daily) to Carvedilol Phosphate extended-release capsules 80 mg once daily [see Dosage and Administration (2) , Use in Specific Populations (8.5) ] . In the clinical trial of Carvedilol Phosphate extended-release capsules in hypertensive subjects, syncope was reported in 0.3% of subjects receiving Carvedilol Phosphate extended-release capsules compared with 0% of subjects receiving placebo. There were no reports of postural hypotension in this trial. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects receiving immediate-release carvedilol, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects. In the CAPRICORN trial of survivors of an acute myocardial infarction with left ventricular dysfunction, hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects. Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur. 5.4 Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased, and the dose of Carvedilol Phosphate extended-release capsules should not be advanced until clinical stability resumes [see Dosage and Administration (2) ] . Occasionally it is necessary to lower the dose of Carvedilol Phosphate extended-release capsules or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, Carvedilol Phosphate extended-release capsules. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with immediate-release carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients\' underlying disease than to treatment with carvedilol. 5.5 Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis, emphysema) should, in general, not receive β-blockers. Carvedilol Phosphate extended-release capsules may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol Phosphate extended-release capsules are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized. In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that Carvedilol Phosphate extended-release capsules be used with caution. The dosing recommendations should be followed closely, and the dose should be lowered if any evidence of bronchospasm is observed during up-titration. 5.6 Glycemic Control in Type 2 Diabetes In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia or diabetic patients receiving insulin or oral hypoglycemic agents should be cautioned about these possibilities. In patients with heart failure and diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when dosing with Carvedilol Phosphate extended-release capsules is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted. In a trial designed to examine the effects of immediate-release carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies (14.4) ] . 5.7 Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals. 5.8 Deterioration of Renal Function Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors, it is recommended that renal function be monitored during up-titration of Carvedilol Phosphate Extended-release and the drug discontinued or dosage reduced if worsening of renal function occurs. 5.9 Major Surgery Chronically administered β-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. 5.10 Thyrotoxicosis β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm. 5.11 Pheochromocytoma In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having pheochromocytoma. 5.12 Prinzmetal\'s Variant Angina Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal\'s variant angina. There has been no clinical experience with carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of Carvedilol Phosphate extended-release capsules to patients suspected of having Prinzmetal\'s variant angina. 5.13 Risk of Anaphylactic Reaction While taking β-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. 5.14 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (Carvedilol Phosphate extended-release capsules are an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient\'s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery."}', 'overdosage': '{"10 OVERDOSAGE Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur. The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. The following agents may be administered: For excessive bradycardia: Atropine, 2 mg IV. To support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg per hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect. If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended. NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol. There is no experience of overdosage with Carvedilol Phosphate extended-release capsules. Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered."}', 'active_flag': 'Y', 'generic_name': '{"CARVEDILOL PHOSPHATE"}', '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 taking Carvedilol Phosphate extended-release capsules should be advised of the following: Patients should not interrupt or discontinue using Carvedilol Phosphate extended-release capsules without a physician\'s advice. Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath. Patients may experience a drop in blood pressure when standing, resulting in dizziness and, rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur. If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks. Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted. Patients should not crush or chew Carvedilol Phosphate extended-release capsules. Patients should take Carvedilol Phosphate extended-release capsules with food. Diabetic patients should report any changes in blood sugar levels to their physician. Contact lens wearers may experience decreased lacrimation. The other brand listed is a trademark owned by or licensed to its owner and is not owned by or licensed to the Woodward Pharma Services LLC. The maker of this brand is not affiliated with and does not endorse Woodward Pharma Services LLCGSK or its products."}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Available data regarding use of Carvedilol Phosphate extended-release capsules in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy. The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate (see Clinical Considerations ). In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses (see Data ) . Oral administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations are 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: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly. Data Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post-implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m 2 ) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m 2 ). In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m 2 ) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m 2 ); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m 2 ). In a pre- and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg per kg per day (approximately 32 times the MRHD as mg per m 2 ), and pup mortality and delays in physical growth/development were observed at 60 mg per kg per day (10 times the MRHD as mg per m 2 ) in the absence of maternal toxicity. The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m 2 ). Carvedilol was present in fetal rat tissue."}', 'pediatric_use': '{"8.4 Pediatric Use Effectiveness of carvedilol in patients younger than 18 years has not been established. In a double-blind trial, 161 children (mean age: 6 years; range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction less than 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with immediate-release carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%)."}', 'geriatric_use': '{"8.5 Geriatric Use The initial clinical trials of Carvedilol Phosphate extended-release capsules in subjects with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects aged 65 years or older to determine whether they respond differently from younger patients. A randomized trial (n = 405) comparing subjects with mild to severe heart failure switched to Carvedilol Phosphate extended-release capsules or maintained on immediate-release carvedilol tablets included 220 subjects who were aged 65 years or older. In this elderly subgroup, the combined incidence of dizziness, hypotension, or syncope was 24% (18/75) in subjects switched from the highest dose of immediate-release carvedilol tablets (25 mg twice daily) to the highest dose of Carvedilol Phosphate extended-release capsules (80 mg once daily) compared with 11% (4/36) in subjects maintained on immediate-release carvedilol tablets (25 mg twice daily). When switching from the higher doses of immediate-release carvedilol tablets to Carvedilol Phosphate extended-release capsules, a lower starting dose is recommended for elderly patients [see Dosage and Administration (2.5) ] . The following information is available for trials with immediate-release carvedilol. Of the 765 subjects with heart failure randomized to carvedilol in U.S. clinical trials, 31% (235) were aged 65 years or older, and 7.3% (56) were aged 75 years or older. Of the 1,156 subjects randomized to carvedilol in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were aged 65 years or older, and 15% (174) were aged 75 years or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were aged 65 years or older. Of the 975 subjects with myocardial infarction randomized to carvedilol in the CAPRICORN trial, 48% (468) were aged 65 years or older, and 11% (111) were aged 75 years or older. Of the 2,065 hypertensive subjects in U.S. clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were aged 65 years or older. Of 3,722 subjects receiving immediate-release carvedilol in hypertension clinical trials conducted worldwide, 24% were aged 65 years or older. With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figures 2 and 4 ) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out."}'}

{MUPIROCIN}

{'contraindications': '{"4 CONTRAINDICATIONS Mupirocin ointment is contraindicated in patients with known hypersensitivity to mupirocin or any of the excipients of mupirocin ointment. Known hypersensitivity to mupirocin or any of the excipients of mupirocin ointment. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Severe Allergic Reactions [see Warnings and Precautions ( 5.1 )] Eye Irritation [see Warnings and Precautions ( 5.2 )] Local Irritation [see Warnings and Precautions ( 5.3 )] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.4 )] The most frequent adverse reactions (at least 1%) were burning, stinging or pain, and itching. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888)721-7115 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. The following local adverse reactions were reported by at least 1% of subjects in connection with the use of mupirocin ointment in clinical trials: burning, stinging, or pain in 1.5% of subjects; itching in 1% of subjects. Rash, nausea, erythema, dry skin, tenderness, swelling, contact dermatitis, and increased exudate were reported in less than 1% of subjects. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of mupirocin ointment. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal relationship to mupirocin ointment. Immune System Disorders Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash [see Warnings and Precautions ( 5.1 )] ."}', 'drug_interactions': None, 'indications_and_usage': '{"1 INDICATIONS AND USAGE Mupirocin ointment is indicated for the topical treatment of impetigo due to susceptible isolates of Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). Mupirocin ointment is an RNA synthetase inhibitor antibacterial indicated for the topical treatment of impetigo due to susceptible isolates of Staphylococcus aureus and Streptococcus pyogenes. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Severe Allergic Reactions: Anaphylaxis, urticaria, angioedema, and generalized rash have been reported in patients treated with formulations of mupirocin, including mupirocin ointment. ( 5.1 ) Eye Irritation: Avoid contact with eyes. ( 5.2 ) Local Irritation: Discontinue in the event of sensitization or severe local irritation. ( 5.3 ) Clostridium difficile -Associated Diarrhea (CDAD): If diarrhea occurs, evaluate patients for CDAD. ( 5.4 ) Potential for Microbial Overgrowth: Prolonged use may result in overgrowth of nonsusceptible microorganisms, including fungi. ( 5.5 ) Risk Associated with Mucosal Use: Mupirocin ointment is not formulated for use on mucosal surfaces. A separate formulation, BACTROBAN nasal ointment, is available for intranasal use. ( 5.6 ) Risk of Polyethylene Glycol Absorption: Mupirocin ointment should not be used where absorption of large quantities of polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment. ( 5.7 ) Risk Associated with Use at Intravenous Sites: Mupirocin ointment should not be used with intravenous cannulae or at central intravenous sites because of the potential to promote fungal infections and antimicrobial resistance. ( 5.8 ) 5.1 Severe Allergic Reactions Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash, have been reported in patients treated with formulations of mupirocin, including mupirocin ointment [see Adverse Reactions ( 6.2 )]. 5.2 Eye Irritation Avoid contact with the eyes. In case of accidental contact, rinse well with water. 5.3 Local Irritation In the event of a sensitization or severe local irritation from mupirocin ointment, usage should be discontinued, and appropriate alternative therapy for the infection instituted. 5.4 Clostridium difficile -Associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents 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 drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.5 Potential for Microbial Overgrowth As with other antibacterial products, prolonged use of mupirocin ointment may result in overgrowth of nonsusceptible microorganisms, including fungi [see Dosage and Administration ( 2 )]. 5.6 Risk Associated with Mucosal Use Mupirocin ointment is not formulated for use on mucosal surfaces. Intranasal use has been associated with isolated reports of stinging and drying. A separate formulation, BACTROBAN ® (mupirocin calcium) nasal ointment, is available for intranasal use. 5.7 Risk of Polyethylene Glycol Absorption Polyethylene glycol can be absorbed from open wounds and damaged skin and is excreted by the kidneys. In common with other polyethylene glycol-based ointments, mupirocin ointment should not be used in conditions where absorption of large quantities of polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment. 5.8 Risk Associated with Use at Intravenous Sites Mupirocin ointment should not be used with intravenous cannulae or at central intravenous sites because of the potential to promote fungal infections and antimicrobial resistance."}', 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{MUPIROCIN}', '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). Advise the patient to administer mupirocin ointment as follows: Use mupirocin ointment only as directed by the healthcare provider. It is for external use only. Avoid contact of mupirocin ointment with the eyes. If mupirocin ointment gets in the eyes, rinse thoroughly with water. Do not use mupirocin ointment in the nose. Wash your hands before and after applying mupirocin ointment. Use a gauze pad or cotton swab to apply a small amount of mupirocin ointment to the affected area. The treated area may be covered by gauze dressing if desired. Report to the healthcare provider any signs of local adverse reactions. Mupirocin ointment should be stopped and the healthcare provider contacted if irritation, severe itching, or rash occurs. Report to the healthcare provider or go to the nearest emergency room if severe allergic reactions, such as swelling of the lips, face, or tongue, or wheezing occur [see Warnings and Precautions ( 5.1 )] . If impetigo has not improved in 3 to 5 days, contact the healthcare provider. Trademarks are the property of their respective owners. Manufactured by: Glenmark Pharmaceuticals Ltd. Colvale-Bardez, Goa 403 513, India Manufactured for: Glenmark Pharmaceuticals Inc., USA Mahwah, NJ 07430 Questions? 1 (888)721-7115 www.glenmarkpharma.com/usa July 2017 Glenmark"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk with mupirocin ointment in pregnant women. Systemic absorption of mupirocin through intact human skin is minimal following topical administration of mupirocin ointment [see Clinical Pharmacology ( 12.3 )] . No developmental toxicity was observed in rats or rabbits treated with mupirocin subcutaneously during organogenesis at doses of 160 or 40 mg per kg per day, respectively (22 and 11 times the human topical dose based on calculations of dose divided by the entire body surface area). The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data: Developmental toxicity studies have been performed with mupirocin administered subcutaneously to rats and rabbits at doses up to 160 mg per kg per day during organogenesis. This dose is 22 and 43 times, respectively, the human topical dose (approximately 60 mg mupirocin per day) based on calculations of dose divided by the entire body surface area. Maternal toxicity was observed (body weight loss/decreased body weight gain and reduced feeding) in both species with no evidence of developmental toxicity in rats. In rabbits, excessive maternal toxicity at the high dose precluded the evaluation of fetal outcomes. There was no developmental toxicity in rabbits at 40 mg per kg per day, 11 times the human topical dose based on calculations of dose divided by the entire body surface area. Mupirocin administered subcutaneously to rats in a pre-and postnatal development study (dosed during late gestation through lactation) was associated with reduced offspring viability in the early postnatal period at a dose of 106.7 mg per kg, in the presence of injection site irritation and/or subcutaneous hemorrhaging. This dose is 14 times the human topical dose based on calculations of dose divided by the entire body surface area. The no-observed adverse effect level in this study was 44.2 mg per kg per day, which is 6 times the human topical dose."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of mupirocin ointment have been established in the age range of 2 months to 16 years. Use of mupirocin ointment in these age-groups is supported by evidence from adequate and well-controlled trials of mupirocin ointment in impetigo in pediatric subjects studied as a part of the pivotal clinical trials [see Clinical Studies ( 14 )] ."}', 'geriatric_use': None}

{"LIDOCAINE HYDROCHLORIDE"}

{'contraindications': '{"CONTRAINDICATIONS Lidocaine HCl is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type."}', 'adverse_reactions': '{"ADVERSE REACTIONS Systemic Adverse experiences following the administration of lidocaine HCl are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported: Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine HCl is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Cardiovascular System Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest. Allergic Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in the multiple dose vials. Allergic reactions, including anaphylactic reactions, may occur as a result of sensitivity to lidocaine, but are infrequent. If allergic reactions do occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine. Neurologic The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10,440 patients who received lidocaine HCl for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration. Hematologic Methemoglobinemia.","Systemic Adverse experiences following the administration of lidocaine HCl are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported:","Central Nervous System CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine HCl is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.","Cardiovascular System Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.","Allergic Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in the multiple dose vials. Allergic reactions, including anaphylactic reactions, may occur as a result of sensitivity to lidocaine, but are infrequent. If allergic reactions do occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine.","Neurologic The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10,440 patients who received lidocaine HCl for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration.","Hematologic Methemoglobinemia."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Lidocaine HCl Injections are indicated for production of local anesthesia by infiltration techniques such as percutaneous injection and by peripheral nerve block techniques such as brachial plexus and intercostal, when the accepted procedures for these techniques as described in standard textbooks are observed."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS , WARNINGS , and PRECAUTIONS ). Management of Local Anesthetic Emergencies The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (eg, ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine HCl. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324) mg/kg (as the salt) in fasted female rats.","Management of Local Anesthetic Emergencies The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (eg, ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine HCl. The oral LD 50 of lidocaine HCl in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324) mg/kg (as the salt) in fasted female rats."}', 'active_flag': 'Y', 'generic_name': '{"LIDOCAINE HYDROCHLORIDE"}', 'route': '{INFILTRATION,PERINEURAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS LIDOCAINE HCl INJECTIONS FOR INFILTRATION AND NERVE BLOCK SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT AND THE PERSONNEL NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (see also ADVERSE REACTIONS and PRECAUTIONS ). 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. 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 lidocaine 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. 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. To avoid intravascular injection, aspiration should be performed before the local anesthetic solution is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided. Local anesthetic solutions containing antimicrobial preservatives (eg, methylparaben) should not be used for epidural or spinal anesthesia because the safety of these agents has not been established with regard to intrathecal injection, either intentional or accidental. Anaphylactic reactions may occur following administration of lidocaine hydrochloride (see ADVERSE REACTIONS ). In the case of severe reaction, discontinue the use of the drug."}', 'precautions': '{"PRECAUTIONS General The safety and effectiveness of lidocaine HCl depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Standard textbooks should be consulted for specific techniques and precautions for various regional anesthetic procedures. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS ). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Syringe aspirations should also be performed before and during each supplemental injection when using indwelling catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. Repeated doses of lidocaine HCl may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical condition. Lidocaine HCl should also be used with caution in patients with severe shock or heart block. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity. Since amide-type local anesthetics are metabolized by the liver, Lidocaine HCl Injection should be used with caution in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Lidocaine HCl Injection should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). Lidocaine HCl should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine HCl. Use in the Head and Neck Area Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. 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 ). Information for Patients 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 Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Drug/Laboratory Test Interactions The intramuscular injection of lidocaine HCl may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine HCl. 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, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, paraaminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of lidocaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine HCl. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine HCl to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place. \u200bLabor and Delivery Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY , Pharmacokinetics and Metabolism ). The potential for toxicity depends 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. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Paracervical or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides. 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 lidocaine HCl is administered to a nursing woman. Pediatric Use Dosages in pediatric patients should be reduced, commensurate with age, body weight and physical condition (see DOSAGE AND ADMINISTRATION ).","General The safety and effectiveness of lidocaine HCl depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Standard textbooks should be consulted for specific techniques and precautions for various regional anesthetic procedures. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS ). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Syringe aspirations should also be performed before and during each supplemental injection when using indwelling catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative. Repeated doses of lidocaine HCl may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical condition. Lidocaine HCl should also be used with caution in patients with severe shock or heart block. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity. Since amide-type local anesthetics are metabolized by the liver, Lidocaine HCl Injection should be used with caution in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Lidocaine HCl Injection should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). Lidocaine HCl should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine HCl.","Use in the Head and Neck Area Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. 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 ).","Information for Patients 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 Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.","Drug/Laboratory Test Interactions The intramuscular injection of lidocaine HCl may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine HCl. 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, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, paraaminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine","Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of lidocaine HCl in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted.","Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine HCl. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine HCl to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place.","\u200bLabor and Delivery Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY , Pharmacokinetics and Metabolism ). The potential for toxicity depends 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. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Paracervical or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.","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 lidocaine HCl is administered to a nursing woman.","Pediatric Use Dosages in pediatric patients should be reduced, commensurate with age, body weight and physical condition (see DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"BENZOYL PEROXIDE"}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses For the treatment of Acne. Reduces the severity of acne blemishes, acne pimples, blackheads, whiteheads and allows the skin to heal."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZOYL PEROXIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a physician if irritation becomes severe"}', 'do_not_use': '{"Do not use if you have very sensitive skin are sensitive to benzoyl peroxide"}', 'when_using': '{"When using this product skin irritation and dryness is more likely to occur if you use another topical acne medication at the same time. If irritation occurs, only use one topical acne medication at a time.","When using this product avoid unnecessary sun exposure and use a sunscreen avoid contact with hair and dyed fabrics, which may be bleached by this product avoid contact with the eyes, lips and mouth skin irritation may occur, characterized by redness, burning, itching, peeling, or possibly swelling. Irritation may be reduced by using the product less frequently or in a lower concentration"}', 'warnings': '{"Warnings For External Use Only. When using this product skin irritation and dryness is more likely to occur if you use another topical acne medication at the same time. If irritation occurs, only use one topical acne medication at a time. Do not use if you have very sensitive skin are sensitive to benzoyl peroxide When using this product avoid unnecessary sun exposure and use a sunscreen avoid contact with hair and dyed fabrics, which may be bleached by this product avoid contact with the eyes, lips and mouth skin irritation may occur, characterized by redness, burning, itching, peeling, or possibly swelling. Irritation may be reduced by using the product less frequently or in a lower concentration Stop use and ask a physician if irritation becomes severe Keep out of reach of children. If accidentally swallowed, seek medical help immediately or contact the Poison Control Center."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"ATORVASTATIN CALCIUM TRIHYDRATE"}

{'contraindications': '{"4 CONTRAINDICATIONS Active Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic Transaminase Levels Hypersensitivity To Any Component of This Medication Pregnancy [see Use in Specific Populations (8.1) ]. Lactation [see Use in Specific Populations (8.2) ]. Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4 ). Hypersensitivity to any component of this medication ( 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 and myopathy [see Warnings and Precautions (5.1) ] Liver enzyme abnormalities [see Warnings and Precautions (5.2) ] The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin calcium in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experiences Because clinical trials are conducted under widely varying conditions, the 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 the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin calcium and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin calcium in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%). Table 3 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Table 3. Clinical adverse reactions occurring in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Adverse Reaction* Any dose N=8755 10 mg N=3908 20 mg N=188 40 mg N=604 80 mg N=4055 Placebo N=7311 Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2 Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3 Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9 Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6 Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3 Nausea 4.0 3.7 3.7 7.1 3.8 3.5 Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6 Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3.0 Myalgia 3.5 3.6 5.9 8.4 2.7 3.1 Insomnia 3.0 2.8 1.1 5.3 2.8 2.9 Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 * Adverse Reaction > 2% in any dose greater than placebo Other adverse reactions reported in placebo-controlled studies include: Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) In ASCOT [see Clinical Studies (14.1) ] involving 10,305 participants (age range 40 to 80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin calcium was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up. Collaborative Atorvastatin Diabetes Study (CARDS) In CARDS [see Clinical Studies (14.1) ] involving 2,838 subjects (age range 39 to 77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with atorvastatin calcium 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported. Treating to New Targets Study (TNT) In TNT [see Clinical Studies (14.1) ] involving 10,001 subjects (age range 29 to 78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin calcium 10 mg daily (n=5006) or atorvastatin calcium 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%). Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL) In IDEAL [see Clinical Studies (14.1) ] involving 8,888 subjects (age range 26 to 80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin calcium 80 mg/day (n=4439) or simvastatin 20 to 40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4731 subjects (age range 21 to 92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with atorvastatin calcium 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions (5.5) ] . In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin calcium vs. 2 (4%) placebo]. There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin calcium 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin calcium 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin calcium 80 mg group (5.0%) than in the placebo group (4.0%). Adverse Reactions from Clinical Studies of Atorvastatin Calcium in Pediatric Patients In a 26-week controlled study in boys and postmenarchal girls with HeFH (ages 10 years to17 years) (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of Atorvastatin calcium 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apoB levels, was generally similar to that of placebo [see Use in Special Populations (8.4) and Clinical Studies(14.6) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atorvastatin calcium. 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 associated with atorvastatin calcium therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1) ]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, 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 The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin calcium ( 7 ). Digoxin: Patients should be monitored appropriately ( 7.8 ). Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased ( 7.9 ). Rifampin should be simultaneously co-administered with atorvastatin calcium ( 7.7 ). 7.1 Strong Inhibitors of CYP 3A4 Atorvastatin calcium is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin calcium with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4. Clarithromycin Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3) ] . Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Dosage and Administration (2.6) , and Warnings and Precautions (5.1) ]. Combination of Protease Inhibitors Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3) ] . Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin calcium should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of atorvastatin calcium should not exceed 20 mg and should be used with caution [see Dosage and Administration (2.6) and Warnings and Precautions (5.1) ] . In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin calcium should not exceed 40 mg and close clinical monitoring is recommended. Itraconazole Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3) ] . Therefore, in patients taking itraconazole, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1) ] . 7.2 Grapefruit Juice Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day). 7.3 Cyclosporine Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3) ] . The co-administration of atorvastatin calcium with cyclosporine should be avoided [see Warnings and Precautions (5.1) ] . 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin calcium with gemfibrozil should be avoided [see Warnings and Precautions (5.1) ] . 7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, atorvastatin calcium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) ] . 7.6 Niacin The risk of skeletal muscle effects may be enhanced when atorvastatin calcium is used in combination with niacin; a reduction in atorvastatin calcium dosage should be considered in this setting [see Warnings and Precautions (5.1) ] . 7.7 Rifampin or other Inducers of Cytochrome P450 3A4 Concomitant administration of atorvastatin calcium with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin calcium with rifampin is recommended, as delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. 7.8 Digoxin When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. 7.9 Oral Contraceptives Co-administration of atorvastatin calcium and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ] . These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin calcium. 7.10 Warfarin Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. 7.11 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet. Atorvastatin calcium tablet is an HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to: Reduce the risk of MI, stroke, revascularization procedures, and angina in adult patients without CHD, but with multiple risk factors ( 1.1 ). Reduce the risk of MI and stroke in adult patients with type 2 diabetes without CHD, but with multiple risk factors ( 1.1 ). Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in adult patients with CHD ( 1.1 ). Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( 1.2 ). Reduce elevated TG in adult patients with hypertriglyceridemia and primary dysbetalipoproteinemia ( 1.2 ). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) ( 1.2 ). Reduce elevated total-C, LDL-C, and apo B levels in pediatric patients 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) after failing an adequate trial of diet therapy ( 1.2 ). Limitations of Use: Atorvastatin calcium tablets has not been studied in Fredrickson Types I and V dyslipidemias ( 1.3 ). 1.1 Prevention of Cardiovascular Disease in Adults In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke Reduce the risk for revascularization procedures and angina In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina 1.2 Hyperlipidemia Atorvastatin calcium tablets are indicated: As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb); As an adjunct to diet for the treatment of adult patients with elevated serum TG levels ( Fredrickson Type IV); For the treatment of adult patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in pediatric patients, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains ≥ 190 mg/dL or b. LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient 1.3 Limitations of Use Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson Types I and V)."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of 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. Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected ( 5.1 , 8.5 ). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.2 ). A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs. placebo ( 5.5 ). 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin calcium and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. 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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin calcium. Atorvastatin calcium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with atorvastatin calcium and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs [ see Drug Interactions (7) ] . Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 2 [ see Dosage and Administration (2.6) , Drug Interactions (7), and Clinical Pharmacology (12.3) ] . Table 2. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily *Use with caution and with the lowest dose necessary (12.3) Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11) ] . Atorvastatin calcium therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). 5.2 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin calcium. It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin calcium. Atorvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin calcium [see Contraindications (4) ] . 5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin calcium. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin calcium does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. 5.4 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. 5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1) ] ."}', 'overdosage': '{"10 OVERDOSAGE There is no specific treatment for atorvastatin calcium overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance."}', 'active_flag': 'Y', 'generic_name': '{"ATORVASTATIN 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 Advisethe patient to read the FDA-approved patient labeling (Patient Information). Patients taking atorvastatin calcium should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment. Patients should be advised about substances they should not take concomitantly with atorvastatin [see Warnings and Precautions (5.1) ] . Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking atorvastatin calcium. 17.1 Muscle Pain All patients starting therapy with atorvastatin calcium should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium and if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 17.3 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) ] . 17.4 Lactation Advise women not to breastfeed during treatment with atorvastatin calcium [see Contraindications (4) and Use in Specific Populations (8.2) ]. Manufactured for: Cipla USA, Inc. 1560 Sawgrass Corporate Parkway Suite 130, Sunrise, FL 33323 Manufactured by: ScieGen Pharmaceuticals, Inc. Hauppauge, NY 11788 USA Rev: 10/17"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Atorvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥ 6 times the MRHD (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 atorvastatin calcium from observational studies, meta-analyses and case reports 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 HMG-CoA reductase inhibitors. 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 ≥3to 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 Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300mg/kg/day and 100mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300mg/kg/day or in rabbits at doses up to 100mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100mg/kg/day in rabbits, there was increased post-implantation loss, and at 100mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100mg/kg/dayand acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22times (225 mg/kg) the human exposure at the MRHD, based on AUC."}', 'pediatric_use': '{"8.4 Pediatric Use Heterozygous Familial Hypercholesterolemia (HeFH) The safety and effectiveness of atorvastatin calcium have been established in pediatric patients, 10 years to 17 years of age, with HeFH as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels when, after an adequate trial of diet therapy, the following are present: LDL-C ≥ 190 mg/dL, or LDL-C ≥ 160 mg/dL and a positive family history of FH, or premature CVD in a first, or second-degree relative, or two or more other CVD risk factors are present. Use of atorvastatin calcium for this indication is supported by evidence from [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.6) ]: A placebo-controlled clinical trial of 6 months duration in 187 boys and postmenarchal girls,10 years to 17 years of age. Patients treated with 10 mg or 20 mg daily atorvastatin calcium had an adverse reaction profile generally similar to that of patients treated with placebo. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls. A three year open-label uncontrolled trial that included 163 pediatric patients 10 to 15years of age with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of atorvastatin calcium in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations (8.1) , (8.3) ] . The long-term efficacy of atorvastatin calcium therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established. The safety and efficacy of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH. Homozygous Familial Hypercholesterolemia (HoFH) Clinical efficacy of atorvastatin calcium with dosages up to 80mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients [see Clinical Studies (14.5) ]."}', 'geriatric_use': '{"8.5 Geriatric Use Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) 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, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly."}'}

{PHENOBARBITAL}

{'contraindications': '{"CONTRAINDICATIONS Phenobarbital is contraindicated in patients who are hypersensitive to barbiturates. In such patients, severe hepatic damage can occur from ordinary doses and is usually associated with dermatitis and involvement of parenchymatous organs. A personal or familial history of acute intermittent porphyria represents one of the few absolute contraindications to the use of barbiturates. Phenobarbital is also contraindicated in patients with marked impairment of liver function, or respiratory disease in which dyspnea or obstruction is evident. It should not be administered to persons with known previous addiction to the sedative/hypnotic group, since ordinary doses may be ineffectual and may contribute to further addiction."}', 'adverse_reactions': '{"ADVERSE REACTIONS The following adverse reactions have been reported: CNS Depression: Residual sedation or “hangover”, drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as phenobarbital repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Like other non-analgesic hypnotic drugs, barbiturates, such as phenobarbital, when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffused myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued. Respiratory/Circulatory: Respiratory depression, apnea, circulatory collapse. Allergic: Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by phenobarbital and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of phenobarbital. Other: Nausea and vomiting; headache. 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 ."}', 'drug_interactions': '{"Drug Interactions: Phenobarbital in combination with alcohol, tranquilizers, and other central nervous system depressants has additive depressant effects, and the patient should be so advised. Patients taking this drug should be warned not to exceed the dosage recommended by their physician. Toxic effects and fatalities have occurred following overdoses of phenobarbital alone and in combination with other central nervous system depressants. Caution should be exercised in prescribing unnecessarily large amounts of phenobarbital for patients who have a history of emotional disturbances or suicidal ideation or who have misused alcohol and other CNS drugs (see OVERDOSAGE )."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Phenobarbital Tablets, USP are indicated for use as a sedative or anticonvulsant."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE The signs and symptoms of barbiturate poisoning are referable especially to the central nervous system and the cardiovascular system. Moderate intoxication resembles alcoholic inebriation. In severe intoxication, the patient is comatose, the level of reflex activity conforming in a general way to the intensity of the central depression. The deep reflexes may persist for some time despite coexistent coma. The Babinski sign is often positive. The EEG may be of the “burst-suppression” type, with brief periods of electrical silence. The pupils may be constricted and react to light, but late in the course of barbiturate poisoning they may show hypoxic paralytic dilatation. Respiration is affected early. Breathing may be either slow or rapid and shallow; Cheyne-Stokes rhythm may be present. Respiratory minute volume is diminished, and hypoxia and respiratory acidosis may develop. The blood pressure falls, owing partly to depression of medullary vasomotor centers; partly to a direct action of the drug on the myocardium, sympathetic ganglia, and vascular smooth muscle; partly to hypoxia. The patient thus develops a typical shock syndrome, with a weak and rapid pulse, cold and clammy skin, and a rise in the hematocrit. Respiratory complications (atelectasis, pulmonary edema, and bronchopneumonia) and renal failure are much dreaded and not infrequent concomitant of severe barbiturate poisoning. There is usually hypothermia, sometimes with temperatures as low as 32°C. Treatment: General management should consist of symptomatic and supportive therapy, including gastric lavage, administration of intravenous fluids, and maintenance of blood pressure, body temperature and adequate respiratory exchange. Dialysis will increase the rate of removal of barbiturates from the body fluids. Antibiotics may be required to control pulmonary complications."}', 'active_flag': 'Y', 'generic_name': '{PHENOBARBITAL}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS In small doses, the barbiturates may increase the reaction to painful stimuli. Taken by themselves, the barbiturates cannot be relied upon to relieve pain or even to produce sedation or sleep in the presence of severe pain."}', 'precautions': '{"PRECAUTIONS General Precautions: Barbiturates induce liver microsomal enzyme activity. This accelerates the biotransformation of various drugs and is probably part of the mechanism of the tolerance encountered with barbiturates. Phenobarbital, therefore, should be used with caution in patients with decreased liver function. This drug should also be administered cautiously to patients with a history of drug dependence or abuse (see DRUG ABUSE AND DEPENDENCE ). Phenobarbital may decrease the potency of coumarin anticoagulants; therefore, patients receiving such concomitant therapy should have more frequent prothrombin determinations. As with other sedatives and hypnotics, elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. The systemic effects of exogenous hydrocortisone and endogenous hydrocortisone (cortisol) may be diminished by phenobarbital. Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin. Information for Patients: Phenobarbital may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly. Drug Interactions: Phenobarbital in combination with alcohol, tranquilizers, and other central nervous system depressants has additive depressant effects, and the patient should be so advised. Patients taking this drug should be warned not to exceed the dosage recommended by their physician. Toxic effects and fatalities have occurred following overdoses of phenobarbital alone and in combination with other central nervous system depressants. Caution should be exercised in prescribing unnecessarily large amounts of phenobarbital for patients who have a history of emotional disturbances or suicidal ideation or who have misused alcohol and other CNS drugs (see OVERDOSAGE ). Usage in Pregnancy: Pregnancy Category B - Reproduction studies have been performed in animals and have revealed no evidence of impaired fertility or harm to the fetus due to phenobarbital. 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. Nursing Mothers: Caution should be exercised when phenobarbital is administered to a nursing woman."}', 'information_for_patients': '{"Information for Patients: Phenobarbital may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly."}', 'pregnancy': '{"Usage in Pregnancy: Pregnancy Category B - Reproduction studies have been performed in animals and have revealed no evidence of impaired fertility or harm to the fetus due to phenobarbital. 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."}', 'pediatric_use': None, 'geriatric_use': None}

{THALLIUM}

{'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Rx Only*"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{THALLIUM}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': '{"Stop use and ask a doctor if symptoms persist for more than 3 days or worsen"}', 'do_not_use': None, 'when_using': None, 'warnings': '{""}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{"CLONIDINE HYDROCHLORIDE"}

{'contraindications': '{"4 CONTRAINDICATIONS Clonidine hydrochloride extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Adverse Reactions (6) ] . History of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, angioedema. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail elsewhere in labeling: Hypotension/bradycardia [see Warnings and Precautions (5.1) ] Sedation and somnolence [see Warnings and Precautions (5.2) ] Rebound hypertension [see Warnings and Precautions (5.3) ] Allergic reactions [see Warnings and Precautions (5.4) ] Cardiac Conduction Abnormalities [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as monotherapy in ADHD: somnolence, fatigue, irritability, nightmare, insomnia, constipation, dry mouth. ( 6.1 ) Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as adjunct therapy to psychostimulant in ADHD: somnolence, fatigue, decreased appetite, dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xiamen LP Pharmaceutical Co,. Ltd. at 1-415-516-9498 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. Two clonidine hydrochloride extended-release tablets ADHD clinical studies (Study 1, CLON-301 and Study 2, CLON-302) evaluated 256 patients in two 8-week placebo-controlled studies. Additional pediatric use information for patients ages 6 to 17 years is approved for Concordia Pharmaceuticals Inc.’s KAPVAY (clonidine hydrochloride) extended-release tablets. However, due to Concordia Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Study 1: Fixed-dose Clonidine Hydrochloride Extended-Release Tablets Monotherapy Study 1 (CLON-301) was a short-term, multi-center, randomized, double-blind, placebo-controlled study of two fixed doses (0.2 mg/day or 0.4 mg/day) of clonidine hydrochloride extended-release tablets in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Most Common Adverse Reactions (incidence of ≥5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth. Adverse Events Leading to Discontinuation of Clonidine Hydrochloride Extended-Release Tablets –Five patients (7%) in the low dose group (0.2 mg), 15 patients (20%) in the high dose group (0.4 mg), and 1 patient in the placebo group (1%) reported adverse reactions that led to discontinuation. The most common adverse reactions that led to discontinuation were somnolence and fatigue. Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2. Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Treatment Period (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) PSYCHIATRIC DISORDERS Somnolence* Nightmare Emotional Disorder Aggression Tearfulness Enuresis Sleep Terror Poor Quality Sleep 38% 4% 4% 3% 1% 0% 3% 0% 31% 9% 4% 1% 3% 4% 0% 3% 4% 0% 1% 0% 0% 0% 0% 1% NERVOUS SYSTEM DISORDERS Headache Insomnia Tremor Abnormal Sleep-Related Event 20% 5% 1% 3% 13% 6% 4% 1% 16% 1% 0% 0% GASTROINTESTINAL DISORDERS Upper Abdominal Pain Nausea Constipation Dry Mouth 15% 4% 1% 0% 10% 5% 6% 5% 12% 3% 0% 1% GENERAL DISORDERS Fatigue† Irritability 16% 9% 13% 5% 1% 4% CARDIAC DISORDERS Dizziness Bradycardia 7% 0% 3% 4% 5% 0% INVESTIGATIONS Increased Heart Rate 0% 3% 0% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 3% 4% 4% * Somnolence includes the terms \\"somnolence\\" and \\"sedation\\". † Fatigue includes the terms \\"fatigue\\" and \\"lethargy\\". Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3. Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial - Taper Period* (Study 1) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets 0.2 mg/day N=76 Clonidine Hydrochloride Extended-Release Tablets 0.4 mg/day N=78 Placebo (N=76) Abdominal Pain Upper 0% 6% 3% Headache 5% 2% 3% Gastrointestinal Viral 0% 5% 0% Somnolence 2% 3% 0% Heart Rate Increased 0% 3% 0% Otitis Media Acute 3% 0% 0% * Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose Clonidine Hydrochloride Extended-Release Tablets as Adjunctive Therapy to Psychostimulants Study 2 (CLON-302) was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine hydrochloride extended-release tablets as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes during which clonidine hydrochloride extended-release tablets were initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most clonidine hydrochloride extended-release tablets treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Most Common Adverse Reactions (incidence of ≥5% and at least twice the rate of placebo): somnolence, fatigue, decreased appetite, dizziness. Adverse Events Leading to Discontinuation –There was one patient in the CLON+STM group (1%) who discontinued because of an adverse event (severe bradyphrenia, with severe fatigue). Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4. Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial - Treatment Period (Study 2) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets+STM (N=102) PBO+STM (N=96) PSYCHIATRIC DISORDERS Somnolence* Aggression Affect Lability Emotional Disorder 19% 2% 2% 2% 7% 1% 1% 0% GENERAL DISORDERS Fatigue† Irritability 14% 2% 4% 7% NERVOUS SYSTEM DISORDERS Headache Insomnia 7% 4% 12% 3% GASTROINTESTINAL DISORDERS Upper Abdominal Pain 7% 4% RESPIRATORY DISORDERS Nasal Congestion 2% 2% METABOLISM AND NUTRITION DISORDERS Decreased Appetite 6% 3% CARDIAC DISORDERS Dizziness 5% 1% * Somnolence includes the terms: \\"somnolence\\" and \\"sedation\\". † Fatigue includes the terms \\"fatigue\\" and \\"lethargy\\". Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5. Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial - Taper Period* (Study 2) Percentage of Patients Reporting Event Preferred Term Clonidine Hydrochloride Extended-Release Tablets+STM (N=102) PBO+STM (N=96) Nasal Congestion 4% 2% Headache 3% 1% Irritability 3% 2% Throat Pain 3% 1% Gastroenteritis Viral 2% 0% Rash 2% 0% * Taper Period: weeks 6-8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine hydrochloride extended-release tablets discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of clonidine hydrochloride extended-release tablets monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Effect on Blood Pressure and Heart Rate In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -8.8 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride extended-release tablets 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release tablets 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release tablets 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release tablets 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release tablets 0.4 mg/day. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clonidine hydrochloride extended-release 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. These events exclude those already mentioned in 6.1: Psychiatric: hallucinations Cardiovascular: Q-T prolongation"}', 'drug_interactions': '{"7 DRUG INTERACTIONS The following have been reported with other oral immediate release formulations of clonidine: Table 6 Clinically Important Drug Interactions Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Tricyclic antidepressants Increase blood pressure and may counteract clonidine’s hypotensive effects Monitor blood pressure and adjust as needed Antihypertensive drugs Potentiate clonidine’s hypotensive effects Monitor blood pressure and adjust as needed CNS depressants Potentiate sedating effects Avoid use Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Potentiate bradycardia and risk of AV block Avoid use • Sedating Drugs: Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. ( 7 ) • Tricyclic Antidepressants: May reduce the hypotensive effect of clonidine. ( 7 ) • Drugs Known to Affect Sinus Node Function or AV Nodal Conduction: Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects such as bradycardia and AV block. ( 7 ) • Antihypertensive drugs: Use caution when coadministered with c lonidine hydrochloride extended-release tablets. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Clonidine hydrochloride extended-release tablets are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see C linical Studies (14) ] . • Clonidine hydrochloride extended-release tablets are a centrally acting alpha 2 -adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS • Hypotension/bradycardia/syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure. Measure heart rate andblood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated. Advise patients to avoid becoming dehydrated or overheated. ( 5.1 ) • Somnolence/Sedation: Has been observed with clonidine hydrochloride extended-release tablets. Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to clonidine hydrochloride extended-release tablets. ( 5.2 ) • Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate slowly and monitor vital signs frequently. ( 5.5 ) 5.1 Hypotension/Bradycardia Treatment with clonidine hydrochloride extended-release tablets can cause dose-related decreases in blood pressure and heart rate [see Adverse Reactions (6.1) ] . Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate clonidine hydrochloride extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with clonidine hydrochloride extended-release tablets+stimulant versus 7% treated with placebo+stimulant reported somnolence. Before using clonidine hydrochloride extended-release tablets with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with clonidine hydrochloride extended-release tablets. Advise patients to avoid use with alcohol. 5.3 Rebound Hypertension Abrupt discontinuation of clonidine hydrochloride extended-release tablets can cause rebound hypertension. In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. No studies evaluating abrupt discontinuation of clonidine hydrochloride extended-release tablets in children with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of clonidine hydrochloride extended-release tablets in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue clonidine hydrochloride extended-release tablets therapy without consulting their physician due to the potential risk of withdrawal effects. 5.4 Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride extended-release tablets therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride extended-release tablets may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). 5.5 Cardiac Conduction Abnormalities The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There have been post-marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring IV atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine. Titrate clonidine hydrochloride extended-release tablets slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs."}', 'overdosage': '{"10 OVERDOSAGE Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. Treatment Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice."}', 'active_flag': 'Y', 'generic_name': '{"CLONIDINE 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 (Patient Information) Dosage and Administration Advise patients that clonidine hydrochloride extended-release tablets must be swallowed whole, never crushed, cut, or chewed, and may be taken with or without food. When initiating treatment, provide dosage escalation instructions [see Dosage and Administration (2.1) ] . Missed Dose If patients miss a dose of clonidine hydrochloride extended-release tablets, advise them to skip the dose and take the next dose as scheduled and not to take more than the prescribed total daily amount of clonidine hydrochloride extended-release tablets in any 24-hour period [see Dosage and Administration (2.4) ] . Hypotension/Bradycardia Advise patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, to avoid becoming dehydrated or overheated [see Warnings and Precautions (5.1) ] . Sedation and Somnolence Instruct patients to use caution when driving a car or operating hazardous machinery until they know how they will respond to treatment with clonidine hydrochloride extended-release tablets. Also advise patients to avoid the use of clonidine hydrochloride extended-release tablets with other centrally active depressants and with alcohol [see Warnings and Precautions (5.2) ] . Rebound Hypertension Advise patients not to discontinue clonidine hydrochloride extended-release tablets abruptly [see Warnings and Precautions (5.3) ] . Allergic Reactions Advise patients to discontinue clonidine hydrochloride extended-release tablets and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur, such as generalized rash, urticaria, or angioedema [see Warnings and Precautions (5.4) ] . Brands listed are the trademarks of their respective owners. Manufactured by: Xiamen LP Pharmaceutical Co., Ltd. 2010 Wengjiao West Road, Xiamen, Fujian 361027, China Distributed by: Prinston Pharmaceutical Inc. 2002 Eastpark Blvd, Cranbury, NJ 08512, USA Revised: x/2016"}', 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}

{EPINEPHRINE}

{'contraindications': '{"4 CONTRAINDICATIONS None. None. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS 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. Common adverse reactions to systemically administered epinephrine include anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism [see Warnings and Precautions (5.5)] . Cardiovascular Reactions Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [see Warnings and Precautions (5.5) and Drug Interactions (7)] . Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see Warnings and Precautions (5.5)] . Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.5)] . Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine. Reactions from Accidental Injection and/or Improper Technique Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.2)] . Adverse reactions experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. Lacerations, bent needles, and embedded needles have been reported when epinephrine injection has been injected into the thigh of young children who are uncooperative and kick or move during an injection [see Warnings and Precautions (5.2)] . Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.2)] . Skin and Soft Tissue Infections 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 (5.3)] . Adverse reactions to epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties. ( 6 ) 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': '{"7 DRUG INTERACTIONS Cardiac Glycosides, Diuretics, and Anti-arrhythmics Patients who receive epinephrine while concomitantly taking cardiac glycosides, diuretics, or anti-arrhythmics should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.5)] . Antidepressants, Monoamine Oxidase Inhibitors, Levothyroxine, and Antihistamines The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine. Beta-Adrenergic Blockers The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol. Alpha-Adrenergic Blockers The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentolamine. Ergot Alkaloids Ergot alkaloids may also reverse the pressor effects of epinephrine. Cardiac glycosides or diuretics: observe for development of cardiac arrhythmias. ( 7 ) Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines: potentiate effects of epinephrine. ( 7 ) Beta-adrenergic blocking drugs: antagonize cardiostimulating and bronchodilating effects of epinephrine. ( 7 ) Alpha-adrenergic blocking drugs: antagonize vasoconstricting and hypertensive effects of epinephrine. ( 7 ) Ergot alkaloids: may reverse the pressor effects of epinephrine. ( 7 )"}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Epinephrine injection is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which includes bees, wasps, hornets, yellow jackets and fire ants), and biting insects (e.g., triatoma, mosquitoes), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media), and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. Epinephrine injection is intended for immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Anaphylactic reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria, or angioedema. Epinephrine injection is intended for immediate administration as emergency supportive therapy only and is not a replacement or substitute for immediate medical care. Epinephrine injection is a non-selective alpha and beta-adrenergic receptor agonist, indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis. ( 1 )"}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS In conjunction with use, seek immediate medical or hospital care. ( 5.1 ) Do not inject intravenously, into buttock, or into digits, hands, or feet. ( 5.2 ) To minimize the risk of injection related injury, hold the child’s leg firmly in place and limit movement prior to and during injection when administering to young children. ( 5.2 ) 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. ( 5.3 ) The presence of a sulfite in this product should not deter use. ( 5.4 ) Administer with caution in patients with heart disease; may aggravate angina pectoris or produce ventricular arrhythmias. ( 5.5 ) 5.1 Emergency Treatment Epinephrine injection is intended for immediate administration as emergency supportive therapy and is not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision [see Indications and Usage (1), Dosage and Administration (2) and Patient Counseling Information (17)] . 5.2 Injection-Related Complications Epinephrine injection should only be injected into the anterolateral aspect of the thigh [see Dosage and Administration (2) and Patient Counseling Information (17)] . Do not inject intravenously Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to a sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Do not inject into buttock Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Additionally, injection into the buttock has been associated with the development of Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower the risk. Do not inject into digits, hands or feet Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. Treatment of such inadvertent administration should consist of vasodilation, in addition to further appropriate treatment of anaphylaxis [see Adverse Reactions (6)] . Hold leg firmly during injection Lacerations, bent needles, and embedded needles have been reported when epinephrine has been injected into the thigh of young children who are uncooperative and kick or move during an injection. To minimize the risk of injection related injury when administering, hold the child’s leg firmly in place and limit movement prior to and during injection. 5.3 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 (5.2)] . 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. 5.4 Allergic Reactions Associated with Sulfite The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive. Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium bisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. 5.5 Disease Interactions Some patients may be at greater risk for developing adverse reactions after epinephrine administration. Despite these concerns, it should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Therefore, patients with these conditions, and/or any other person who might be in a position to administer epinephrine injection to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used. Patients with Heart Disease Epinephrine should be administered with caution to patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias [see Drug Interactions (7) and Adverse Reactions (6)] . Other Patients and Diseases Epinephrine should be administered with caution to patients with hyperthyroidism, diabetes, elderly individuals, and pregnant women. Patients with Parkinson’s disease may notice a temporary worsening of symptoms."}', '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. Treatment consists of a rapidly acting vasodilators or alpha-adrenergic blocking drugs and/or respiratory support. Epinephrine overdosage can 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. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug such as propranolol. Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis, and kidney failure. Suitable corrective measures must be taken in such situations."}', 'active_flag': 'Y', 'generic_name': '{EPINEPHRINE}', 'route': '{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 See FDA-Approved Patient Labeling (Patient Information and Instructions for Use) A healthcare provider should review the patient instructions and operation of epinephrine injection, in detail, with the patient or caregiver. Epinephrine is essential for the treatment of anaphylaxis. Carefully instruct patients who are at risk of or with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens, as well as idiopathic and exercise-induced anaphylaxis, about the circumstances under which epinephrine should be used. Administration Instruct patients and/or caregivers in the appropriate use of epinephrine injection. Epinephrine injection should be injected into the middle of the outer thigh (through clothing if necessary). Instruct caregivers to hold the leg of young children firmly in place and limit movement prior to and during injection. Lacerations, bent needles, and embedded needles have been reported when epinephrine injection has been injected into the thigh of young children who are uncooperative and kick during an injection [see Warnings and Precautions (5.2)] . Advise patients to seek immediate medical care in conjunction with administration of epinephrine injection. Complete patient information, including dosage, directions for proper administration and precautions can be found inside each epinephrine injection carton. A printed label on the surface of epinephrine injection shows instructions for use and a diagram depicting the injection process. Training Instruct patients and/or caregivers to use the Trainer to familiarize themselves with the use of epinephrine injection in an allergic emergency. The Trainer may be used multiple times. Adverse Reactions Epinephrine may produce symptoms and signs that include 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 signs and symptoms usually subside rapidly, especially with rest, quiet, and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms [see Warnings and Precautions (5.5)] . Accidental Injection Advise patients to seek immediate medical care in the case of accidental injection. Since epinephrine is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an accidental injection to these areas [see Warnings and Precautions (5.2)] . Serious Infections at the Injection Site Rare cases of 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 (5.3)] . Pregnancy and Breastfeeding Inform patients that epinephrine injection has not been studied in pregnant women or breastfeeding mothers so the effects of epinephrine injection on pregnant women or breastfed infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations (8.1, 8.2)] . Storage and Handling Instruct patients to inspect the epinephrine solution visually through the viewing window periodically. Replace epinephrine injection, USP auto-injector if the epinephrine solution appears discolored (pinkish or brown), cloudy, or contains particles. Epinephrine is light sensitive, store in the outer case provided to protect it from light. Instruct patients that epinephrine injection, USP auto-injector must be properly disposed of once the blue caps have been removed or after use [see How Supplied/Storage and Handling (16)] . Complete patient information, including dosage, directions for proper administration and precautions are provided inside each epinephrine injection carton. Manufactured by: Hospira, Inc. McPherson, KS 67460 Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 © 2021 Amneal Pharmaceuticals LLC. All rights reserved. For inquiries call 1-877-835-5472 1871-03"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary There are no available human data on the use of epinephrine injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, epinephrine administered by the subcutaneous route to rabbits, mice, and hamsters during the period of organogenesis was teratogenic at doses 7 times and higher than the maximum recommended daily subcutaneous or intramuscular dose on a mg/m 2 basis ( see Data ). Epinephrine is the first-line medication of choice for the treatment of anaphylaxis during pregnancy in humans. Epinephrine should be used for treatment of anaphylaxis during pregnancy in the same manner as it is used in non-pregnant patients. 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 embryo/fetal risk: During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately 3 cases per 100,000 deliveries. Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. Data Animal Data In an embryofetal development study with rabbits dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including gastroschisis and embryonic lethality) at doses approximately 40 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 an embryofetal development study with mice dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including embryonic lethality) at doses approximately 8 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 4 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 an embryofetal development study with hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine was shown to be teratogenic at doses approximately 7 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)."}', 'pediatric_use': '{"8.4 Pediatric Use Epinephrine injection may be administered to pediatric patients at a dosage appropriate to body weight [see Dosage and Administration (2.1)] . 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. Since the dose of epinephrine delivered from epinephrine injection is fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary."}', 'geriatric_use': '{"8.5 Geriatric Use 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, epinephrine injection should be administered with caution in elderly individuals, who may be at greater risk for developing adverse reactions after epinephrine administration [see Warnings and Precautions (5.5) and Overdosage (10)] ."}'}