Professional Information — Propranolol Hydrochloride

Indications and Usage

Hypertension

Propranolol hydrochloride tablets, USP are indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Propranolol hydrochloride tablets, USP are not indicated in the management of hypertensive emergencies.

Angina Pectoris Due to Coronary Atherosclerosis

Propranolol hydrochloride tablets, USP are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris.

Atrial Fibrillation

Propranolol hydrochloride tablets, USP are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response.

Myocardial Infarction

Propranolol hydrochloride tablets, USP are indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable.

Migraine

Propranolol hydrochloride tablets, USP are indicated for the prophylaxis of common migraine headache. The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use.

Essential Tremor

Propranolol hydrochloride tablets, USP are indicated in the management of familial or hereditary essential tremor. Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs. It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement. Propranolol hydrochloride tablets, USP cause a reduction in the tremor amplitude, but not in the tremor frequency. Propranolol hydrochloride tablets, USP are not indicated for the treatment of tremor associated with Parkinsonism.

Hypertrophic Subaortic Stenosis

Propranolol hydrochloride tablets, USP improve NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.

Pheochromocytoma

Propranolol hydrochloride tablets, USP are indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors.

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 the 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.

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, and respiratory distress.

Respiratory: Bronchospasm.

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Autoimmune: Systemic lupus erythematosus (SLE).

Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol.

Genitourinary: Male impotence; Peyronie's disease.

Drug Interactions

Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes

Because propranolol's metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS ).

Substrates or Inhibitors of CYP2D6

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.

Substrates or Inhibitors of CYP1A2

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.

Substrates or Inhibitors of CYP2C19

Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, teniposide, and tolbutamide. No interaction was observed with omeprazole.

Inducers of Hepatic Drug Metabolism

Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.

Cardiovascular Drugs

Antiarrhythmics

The AUC of propafenone is increased by more than 200% by co-administration of propranolol.

The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two‑three fold increased blood concentration and greater degrees of clinical beta-blockade.

The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.

Calcium Channel Blockers

The mean C_max and AUC of propranolol are increased, respectively, by 50% and 30% by co‑administration of nisoldipine and by 80% and 47%, by co‑administration of nicardipine.

The mean C_max and AUC of nifedipine are increased by 64% and 79%, respectively, by co‑administration of propranolol.

Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of propranolol.

Non-Cardiovascular Drugs

Migraine Drugs

Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C_max by 37%) or rizatriptan (the AUC and C_max were increased by 67% and 75%, respectively).

Theophylline

Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.

Benzodiazepines

Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol.

The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

Neuroleptic Drugs

Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.

Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.

Anti-Ulcer Drugs

Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C_max by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.

Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics.

Lipid Lowering Drugs

Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.

Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.

Warfarin

Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

Alcohol

Concomitant use of alcohol may increase plasma levels of propranolol.

Use in Specific Populations

Geriatric

In a study of 12 elderly (62 to 79 years old) and 12 young (25 to 33 years old) healthy subjects, the clearance of S(-)-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life of both the R(+)- and S(-)-propranolol were prolonged in the elderly compared with the young (11 hours vs. 5 hours).

Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side-chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20 mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP-ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG-conjugation).

Gender

In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with another study, in which administration of testosterone cypionate confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of propranolol in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for propranolol showed any significant association with either estradiol or testosterone.

Race

A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(-)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively.

Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha₁ acid glycoprotein.

Renal Insufficiency

In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (C_max) of propranolol in the chronic renal failure group were 2 to 3-fold higher (161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure.

Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3-4 times higher and total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal function.

Chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance.

Propranolol is not significantly dialyzable.

Hepatic Insufficiency

Propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80 mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was increased 3-fold in comparison to controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours (see PRECAUTIONS ).

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 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:

Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80.

Propranolol hydrochloride is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration.

The inactive ingredients contained in propranolol hydrochloride tablets, USP are: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow #10 (10 mg, 40 mg and 80 mg tablets), FD&C Blue #1 (20 mg tablet), FD&C Blue #2 (40 mg tablet), FD&C Red #40 (60 mg tablet), FD&C Yellow #6 (10 mg and 80 mg tablets), magnesium stearate, and microcrystalline cellulose.

Clinical 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 agonist 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.

Mechanism of Action

The mechanism of the antihypertensive effect of propranolol has not been established. Factors that may contribute 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 antimigraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.

The specific mechanism of propranolol's antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved. A central effect is also possible. Clinical studies have demonstrated that propranolol is of benefit in exaggerated physiological and essential (familial) tremor.

How Supplied / Storage and Handling

Propranolol Hydrochloride Tablets, USP, 10 mg are orange, round, convex, scored tablets, debossed “54” bisect “82” on one side and debossed “V” on the reverse side. They are available as follows:

• Bottles of 100: 0603-5482-21
• Bottles of 1000: 0603-5482-32

Propranolol Hydrochloride Tablets, USP, 20 mg are blue, round, flat faced, beveled edge, scored tablets, debossed “54” bisect “83” on one side and debossed “V” on the reverse side. They are available as follows:

• Bottles of 100: 0603-5483-21
• Bottles of 1000: 0603-5483-32

Propranolol Hydrochloride Tablets, USP, 40 mg are green, round, convex, scored tablets, debossed “54” bisect “84” on one side and debossed “V” on the reverse side. They are available as follows:

• Bottles of 100: 0603-5484-21
• Bottles of 1000: 0603-5484-32

Propranolol Hydrochloride Tablets, USP, 60 mg are pink, round, convex, scored tablets, debossed “54” bisect “85” on one side and debossed “V” on the reverse side. They are available as follows:

• Bottles of 100: 0603-5485-21

Propranolol Hydrochloride Tablets, USP, 80 mg are yellow, round, convex, scored tablets, debossed “54” bisect “86” on one side and debossed “V” on the reverse side. They are available as follows:

• Bottles of 100: 0603-5486-21
• Bottles of 500: 0603-5486-28

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a well-closed, light-resistant container as defined in the USP.

Protect from light.