PROPRANOLOL HYDROCHLORIDE

Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol’s metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6,1A2, 2C19), coadministration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS ). Substrates or Inhibitors of CYP2D6 Blood levels and/ or toxicity of propranolol may be increased by coadministration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole. Substrates or Inhibitors of CYP1A2 Blood levels and/ or toxicity of propranolol may be increased by coadministration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. Substrates or Inhibitors of CYP2C19 Blood levels and/ or toxicity of propranolol may be increased by coadministration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole. Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by coadministration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations. Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% by coadministration of propranolol. The metabolism of propranolol is reduced by coadministration of quinidine, leading to a two-three fold increased blood concentration and greater degrees of clinical beta-blockade. The metabolism of lidocaine is inhibited by coadministration of propranolol, resulting in a 25% increase in lidocaine concentrations. Calcium Channel Blockers The mean C max and AUC of propranolol are increased respectively, by 50% and 30% by coadministration of nisoldipine and by 80% and 47%, by coadministration of nicardipine. The mean C max and AUC of nifedipine are increased by 64% and 79%, respectively, by coadministration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol. Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C max by 37%) or rizatriptan (the AUC and C max were increased by 67% and 75%, respectively). Theophylline Coadministration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by coadministration of propranolol. Neuroleptic Drugs Coadministration of long-acting propranolol at doses greater than or equal to 160mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%. Coadministration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level. Anti-Ulcer Drugs Coadministration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C max by 46% and 35%, respectively. Coadministration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations. Coadministration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol’s pharmacokinetics. Lipid Lowering Drugs Coadministration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. Coadministration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin. Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time. Alcohol Concomitant use of alcohol may increase plasma levels of propranolol.

INDICATIONS AND USAGE Hypertension Propranolol hydrochloride tablets are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride is not indicated in the management of hypertensive emergencies. Angina Pectoris Due to Coronary Atherosclerosis Propranolol hydrochloride tablets are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris. Atrial Fibrillation Propranolol hydrochloride tablets are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response. Myocardial Infarction Propranolol is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable. Migraine Propranolol is indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use. Essential Tremor Propranolol is indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol causes a reduction in the tremor amplitude, but not in the tremor frequency. Propranolol is not indicated for the treatment of tremor associated with Parkinsonism. Hypertrophic Subaortic Stenosis Propranolol improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis. Pheochromocytoma Propranolol is indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors.

DOSAGE AND ADMINISTRATION General Because of the variable bioavailability of propranolol, the dose should be individualized based on response. Hypertension The usual initial dosage is 40 mg propranolol hydrochloride twice daily, whether used alone or added to a diuretic. Dosage may be increased gradually until adequate blood pressure control is achieved. The usual maintenance dosage is 120 mg to 240 mg per day. In some instances a dosage of 640 mg a day may be required. The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks. While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12-hour dosing interval. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. If control is not adequate, a larger dose, or 3-times-daily therapy may achieve better control. Angina Pectoris Total daily doses of 80 mg to 320 mg propranolol hydrochloride when administered orally, twice a day, three times a day, or four times a day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG. If treatment is to be discontinued, reduce dosage gradually over a period of several weeks. (See WARNINGS ) Atrial Fibrillation The recommended dose is 10 mg to 30 mg propranolol hydrochloride three or four times daily before meals and at bedtime. Myocardial Infarction In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1- month to 60 mg to 80 mg t.i.d. as tolerated. The recommended daily dosage is 180 mg to 240 mg propranolol hydrochloride per day in divided doses. Although a t.i.d. regimen was used in BHAT and a q.i.d. regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a t.i.d. or b.i.d. regimen (see PHARMACODYNAMICS AND CLINICAL EFFECTS ). The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established. However, higher dosages may be needed to effectively treat coexisting diseases such as angina or hypertension (see above). Migraine The initial dose is 80 mg propranolol hydrochloride daily in divided doses. The usual effective dose range is 160 mg to 240 mg per day. The dosage may be increased gradually to achieve optimum migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, propranolol hydrochloride therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks. Essential Tremor The initial dosage is 40 mg propranolol hydrochloride twice daily. Optimum reduction of essential tremor is usually achieved with a dose of 120 mg per day. Occasionally, it may be necessary to administer 240 mg to 320 mg per day. Hypertrophic Subaortic Stenosis The usual dosage is 20 mg to 40 mg propranolol hydrochloride three or four times daily before meals and at bedtime. Pheochromocytoma The usual dosage is 60 mg propranolol hydrochloride daily in divided doses for three days prior to surgery as adjunctive therapy to alpha-adrenergic blockade. For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade.

ADVERSE REACTIONS The following adverse events were observed and have been reported in patients using propranolol. Cardiovascular Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type. Central Nervous System Light-headedness, mental depression manifested by insomnia, lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium and decreased performance on neuropsychometrics. For immediate-release formulations, fatigue, lethargy and vivid dreams appear dose-related. Gastrointestinal Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. Allergic Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm and respiratory distress. Respiratory Bronchospasm. Hematologic Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Autoimmune Systemic lupus erythematosus (SLE). Skin and mucous membranes Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol. Genitourinary Male impotence; Peyronie’s disease. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.