Indications and Usage
Hypertension
Propranolol Hydrochloride Extended-Release Capsules 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 Extended-Release Capsules are not indicated in the management of hypertensive emergencies.
Angina Pectoris Due to Coronary Atherosclerosis
Propranolol Hydrochloride Extended-Release Capsules are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris.
Migraine
Propranolol Hydrochloride Extended-Release Capsules 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 improve NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.
Dosage and Administration
General
Propranolol hydrochloride extended-release capsules provide propranolol hydrochloride in a sustained-release capsule for administration once daily. If patients are switched from propranolol hydrochloride tablets to propranolol hydrochloride extended-release capsules, care should be taken to assure that the desired therapeutic effect is maintained. Propranolol hydrochloride extended-release capsules should not be considered a simple mg-for-mg substitute for propranolol hydrochloride tablets. Propranolol hydrochloride extended-release capsules have different kinetics and produce lower blood levels. Retitration may be necessary, especially to maintain effectiveness at the end of the 24-hour dosing interval.
Hypertension
The usual initial dosage is 80 mg propranolol hydrochloride extended-release capsules once daily, whether used alone or added to a diuretic. The dosage may be increased to 120 mg once daily or higher until adequate blood pressure control is achieved. The usual maintenance dosage is 120 to 160 mg once daily. In some instances a dosage of 640 mg may be required. The time needed for full hypertensive response to a given dosage is variable and may range from a few days to several weeks.
Angina Pectoris
Starting with 80 mg propranolol hydrochloride extended-release capsules once daily, dosage should be gradually increased at three- to seven-day intervals until optimal response is obtained. Although individual patients may respond at any dosage level, the average optimal dosage appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding 320 mg per day have not been established.
If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks (see “ WARNINGS ”).
Migraine
The initial oral dose is 80 mg propranolol hydrochloride extended-release capsules once daily. The usual effective dose range is 160 to 240 mg once daily. The dosage may be increased gradually to achieve optimal migraine prophylaxis. If a satisfactory response is not obtained within four to six weeks after reaching the maximal dose, propranolol hydrochloride extended-release capsules therapy should be discontinued. It may be advisable to withdraw the drug gradually over a period of several weeks depending on the patient's age, comorbidity, and dose of propranolol hydrochloride extended-release capsules.
Hypertrophic Subaortic Stenosis
The usual dosage is 80 to 160 mg propranolol hydrochloride extended-release capsules once daily.
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
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, and 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 psoriasisiform 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
All drug interaction studies were conducted with propranolol. There are no data on drug interactions with propranolol hydrochloride extended-release capsules.
Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes
Because propranolol’s metabolism involves multiple pathways in the Cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or affect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS ).
Substrates or Inhibitors of CYP2D6
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.
Substrates or Inhibitors of CYP1A2
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.
Substrates or Inhibitors of CYP2C19
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.
Inducers of Hepatic Drug Metabolism
Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.
Cardiovascular Drugs
Antiarrhythmics
The AUC of propafenone is increased by more than 200% by co-administration of propranolol.
The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two to three fold increased blood concentration and greater degrees of clinical beta-blockade.
The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.
Calcium Channel Blockers
The mean C maxand AUC of propranolol are increased respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine.
The mean C maxand AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol.
Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.
Non-Cardiovascular Drugs
Migraine Drugs
Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C maxby 37%) or rizatriptan (the AUC and C maxwere increased by 67% and 75%, respectively).
Theophylline
Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.
Benzodiazepines
Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol.
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.
Neuroleptic Drugs
Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.
Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.
Anti-Ulcer Drugs
Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C maxby 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1,200 mg) may result in a decrease in propranolol concentrations.
Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol’s pharmacokinetics.
Lipid Lowering Drugs
Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.
Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.
Warfarin
Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.
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 to 150 mcg/kg intravenously followed by continuous drip of 1 to 5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing.
The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.
Description
Propranolol hydrochloride, USP is a synthetic beta-adrenergic receptor-blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride, (±)-. Its molecular and structural formulae are:
C 16H 21NO 2·HCl
Propranolol hydrochloride, USP is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80.
Propranolol Hydrochloride Extended-Release Capsules, USP are formulated to provide a sustained release of propranolol hydrochloride, USP. Propranolol Hydrochloride Extended-Release Capsules, USP are available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
- Each 60 mg capsule contains 60 mg propranolol hydrochloride, USP (equivalent to 52.60 mg of propranolol).
- Each 80 mg capsule contains 80 mg propranolol hydrochloride, USP (equivalent to 70.14 mg of propranolol).
- Each 120 mg capsule contains 120 mg propranolol hydrochloride, USP (equivalent to 105.21 mg of propranolol).
- Each 160 mg capsule contains 160 mg propranolol hydrochloride, USP (equivalent to 140.28 mg of propranolol).
The inactive ingredients contained in Propranolol Hydrochloride Extended-Release Capsules, USP are: empty hard gelatin capsules, ethylcellulose, hydroxypropyl cellulose, hypromellose, sugar spheres, and talc.
The capsule shell contains FD&C blue 1, FD&C red 3 (60 mg, 80 mg and 120 mg), gelatin, and titanium dioxide.
The imprinting ink contains black iron oxide, potassium hydroxide and shellac.
These capsules comply with USP Dissolution Test 6.
chemical-structureClinical Pharmacology
General
Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor-stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
Propranolol hydrochloride extended-release capsules should not be considered a simple mg-for-mg substitute for conventional propranolol and the blood levels achieved do not match (are lower than) those of two to four times daily dosing with the same dose (see DOSAGE AND ADMINISTRATION ). When changing to propranolol hydrochloride extended-release capsules from conventional propranolol, a possible need for retitration upwards should be considered, especially to maintain effectiveness at the end of the dosing interval. In most clinical settings, however, such as hypertension or angina where there is little correlation between plasma levels and clinical effect, propranolol hydrochloride extended-release capsules have been therapeutically equivalent to the same mg dose of conventional propranolol hydrochloride as assessed by 24-hour effects on blood pressure and on 24-hour exercise responses of heart rate, systolic pressure, and rate pressure product.
Mechanism of Action
The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat variable.
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity.
Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
The mechanism of the anti-migraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
How Supplied / Storage and Handling
Propranolol Hydrochloride Extended-Release Capsules, USP
80 mg: Each capsule (Capsule # 3), opaque light blue cap printed with in black ink and opaque light blue body printed with 106 in black ink, contains 80 mg of propranolol hydrochloride, USP (equivalent to 70.14 mg of propranolol).
NDC: 70518-3552-00
PACKAGING: 90 in 1 BOTTLE PLASTIC
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]
Protect from light, moisture, freezing, and excessive heat. Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure.
Keep this and all medication out of the reach of children.
Repackaged and Distributed By:
Remedy Repack, Inc.
625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762