[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {"PROPRANOLOL HYDROCHLORIDE"}

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


[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {GABAPENTIN}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': None, 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{GABAPENTIN}', '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}


[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {DIMETHICONE}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses relieves bloating, pressure or 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': '{"Stop use and ask a doctor if condition persists."}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Stop use and ask a doctor if condition persists. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}


[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {CARVEDILOL}

[Assistant] {'contraindications': '{"4 CONTRAINDICATIONS Carvedilol is contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of 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. Patients with severe hepatic impairment. Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol. 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 any component of this medication or other medications containing carvedilol. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS Most common adverse events ( 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 Glenmark Pharmaceuticals Inc., USA at 1(888)721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 patient populations 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). Heart Failure: 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 1 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 1. Adverse Events (%) Occurring More Frequently with 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 (n=765) Placebo (n=437) Carvedilol (n=1,156) Placebo (n=1,133) Body as a Whole Asthenia Fatigue Digoxin level increased Edema generalized Edema dependent 7 24 5 5 4 7 22 4 3 2 11 — 2 6 — 9 — 1 5 — Cardiovascular Bradycardia Hypotension Syncope Angina pectoris 9 9 3 2 1 3 3 3 10 14 8 6 3 8 5 4 Central Nervous System Dizziness Headache 32 8 19 7 24 5 17 3 Gastrointestinal Diarrhea Nausea Vomiting 12 9 6 6 5 4 5 4 1 3 3 2 Metabolic Hyperglycemia Weight increase BUN increased NPN increased Hypercholesterolemia Edema peripheral 12 10 6 6 4 2 8 7 5 5 3 1 5 12 — — 1 7 3 11 — — 1 6 Musculoskeletal Arthralgia 6 5 1 1 Respiratory Cough increased Rales 8 4 9 4 5 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: 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 greater than 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 greater than 1% but less than or equal to 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 greater than 1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension: 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. Most adverse events reported during therapy with carvedilol were of mild to moderate severity. In U.S. controlled clinical trials directly comparing carvedilol in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of subjects receiving carvedilol 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 increased 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. Table 2 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 2. Adverse Events (%) Occurring in U.S. Placebo-Controlled Hypertension Trials (Incidence ≥ 1%, Regardless of Causality) a Body System/ Adverse Event Carvedilol (n=1,142) Placebo (n=462) Cardiovascular Bradycardia Postural hypotension Peripheral edema 2 2 1 — — — Central Nervous System Dizziness Insomnia 6 2 5 1 Gastrointestinal Diarrhea 2 1 Hematologic Thrombocytopenia 1 — Metabolic Hypertriglyceridemia 1 — a Shown are events with rate > 1% rounded to nearest integer. 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, paroniria, 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 improvements in cardiac function induced by carvedilol led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol 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 patients; 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 carvedilol. 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 [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 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 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 co-administered with diltiazem. As with other β-blockers, if carvedilol is 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 Anesthesia If treatment with carvedilol 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 tablets 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 tablets 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 tablets 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 tablets are indicated for the management of essential hypertension [see Clinical Studies ( 14.3 , 14.4 )]. It 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 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, 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 is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol 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 abruptly even in patients treated only for hypertension or heart failure . 5.2 Bradycardia In clinical trials, carvedilol caused bradycardia in about 2% of hypertensive subjects, 9% of subjects with heart failure, and 6.5% of subjects with myocardial infarction and left ventricular dysfunction. If pulse rate drops below 55 beats per minute, the dosage should be reduced. 5.3 Hypotension In clinical trials of primarily mild-to-moderate heart failure, 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 subjects receiving carvedilol, 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 heart failure subjects 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 subjects receiving carvedilol, compared with 0.8% of placebo subjects. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, 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, 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 carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration ( 2 )]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. 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 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 may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is 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 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 carvedilol dosing 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 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 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 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 is 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. 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}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"Patient Package Insert Carvedilol (kar´ve dil ol) Tablets, USP Read the Patient Information that comes with carvedilol tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about carvedilol tablets, ask your doctor or pharmacist. What are Carvedilol Tablets? Carvedilol tablets are a prescription medicine that belongs to a group of medicines called “beta-blockers”. Carvedilol tablets are used, often with other medicines, for the following conditions: • to treat patients with certain types of heart failure • to treat patients who had a heart attack that worsened how well the heart pumps • to treat patients with high blood pressure (hypertension) Carvedilol tablets are not approved for use in children under 18 years of age. Who should not take Carvedilol Tablets? Do not take carvedilol tablets if you: • have severe heart failure and are hospitalized in the intensive care unit or require certain intravenous medications that help support circulation (inotropic medications). • are prone to asthma or other breathing problems. • have a slow heartbeat or a heart that skips a beat (irregular heartbeat). • have liver problems. • are allergic to any of the ingredients in carvedilol tablets. The active ingredient is carvedilol. See the end of this leaflet for a list of all the ingredients in carvedilol tablets. What should I tell my doctor before taking Carvedilol Tablets? Tell your doctor about all of your medical conditions, including if you: • have asthma or other lung problems (such as bronchitis or emphysema). • have problems with blood flow in your feet and legs (peripheral vascular disease). Carvedilol tablets can make some of your symptoms worse. • have diabetes. • have thyroid problems. • have a condition called pheochromocytoma. • have had severe allergic reactions. • are pregnant or trying to become pregnant. It is not known if carvedilol is safe for your unborn baby. You and your doctor should talk about the best way to control your high blood pressure during pregnancy. • are breastfeeding. It is not known if carvedilol passes into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking carvedilol tablets. • are scheduled for surgery and will be given anesthetic agents. • are scheduled for cataract surgery and have taken or are currently taking carvedilol tablets. • are taking prescription or over-the-counter medicines, vitamins, and herbal supplements. Carvedilol and certain other medicines can affect each other and cause serious side effects. Carvedilol may affect the way other medicines work. Also, other medicines may affect how well carvedilol works. Keep a list of all the medicines you take. Show this list to your doctor and pharmacist before you start a new medicine. How should I take Carvedilol Tablets? It is important for you to take your medicine every day as directed by your doctor. If you stop taking carvedilol tablets suddenly, you could have chest pain and/or a heart attack. If your doctor decides that you should stop taking carvedilol tablets, your doctor may slowly lower your dose over a period of time before stopping it completely. • Take carvedilol tablets exactly as prescribed. Your doctor will tell you how many tablets to take and how often. In order to minimize possible side effects, your doctor might begin with a low dose and then slowly increase the dose. • Do not stop taking carvedilol tablets and do not change the amount of carvedilol tablets you take without talking to your doctor. • Tell your doctor if you gain weight or have trouble breathing while taking carvedilol tablets. • Take carvedilol tablets with food. • If you miss a dose of carvedilol tablets, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time. • If you take too many carvedilol tablets, call your doctor or poison control center right away. What should I avoid while taking Carvedilol Tablets? • Carvedilol tablets can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms. What are possible side effects of Carvedilol Tablets? • Low blood pressure (which may cause dizziness or fainting when you stand up). If these happen, sit or lie down right away and tell your doctor. • Tiredness. If you feel tired or dizzy you should not drive, use machinery, or do anything that needs you to be alert. • Slow heartbeat. • Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels. • Carvedilol tablets may hide some of the symptoms of low blood sugar, especially a fast heartbeat. • Carvedilol tablets may mask the symptoms of hyperthyroidism (overactive thyroid). • Worsening of severe allergic reactions. • Rare but serious allergic reactions (including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing) have happened in patients who were on carvedilol tablets. These reactions can be life-threatening. Other side effects of carvedilol tablets include shortness of breath, weight gain, diarrhea, and fewer tears or dry eyes that become bothersome if you wear contact lenses. Call your doctor if you have any side effects that bother you or don’t go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Carvedilol Tablets? • Store carvedilol tablets at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container. • Safely, throw away carvedilol tablets that are out of date or no longer needed. • Keep carvedilol tablets and all medicines out of the reach of children. General Information about Carvedilol Tablets Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use carvedilol tablets for a condition for which it was not prescribed. Do not give carvedilol tablets to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about carvedilol tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about carvedilol tablets that is written for healthcare professionals. You can also find out more about carvedilol tablets by calling 1 (888) 721-7115. This call is free. What are the ingredients in Carvedilol Tablets? Active Ingredient: carvedilol. Inactive Ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone and titanium dioxide. Carvedilol tablets, USP come in the following strengths: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg. What is high blood pressure (hypertension)? Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. Carvedilol tablets can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure may lower your chance of having a stroke or heart attack. Manufactured by: Glenmark Pharmaceuticals Ltd. India Manufactured for: Glenmark Pharmaceuticals Inc., USA Mahwah, NJ 07430 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com September 2019"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Available data regarding use of carvedilol 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 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 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 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."}'}