propranolol HCl 80 MG Oral Tablet

Generic Name: PROPRANOLOL HYDROCHLORIDE
Brand Name: Propranolol Hydrochloride
  • Substance Name(s):
  • PROPRANOLOL HYDROCHLORIDE

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 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 additional therapies, including 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 T4 and reverse T3 and decreasing T3.

Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-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.

Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed.

In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure.

DRUG INTERACTIONS

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, 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‑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 Cmax 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 Cmax 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 Cmax by 37%) or rizatriptan (the AUC and Cmax 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 Cmax 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.

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.

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.

This is the formula for Propranolol Hydrochloride.

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.

HOW SUPPLIED

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.

GERIATRIC USE

Geriatric In a study of 12 elderly (62-79 years old) and 12 young (25-33 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).

MECHANISM OF ACTION

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.

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.

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.

PREGNANCY

Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride 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 received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression.

Adequate facilities for monitoring such infants at birth should be available.

Propranolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers Propranolol is excreted in human milk.

Caution should be exercised when propranolol is administered to a nursing woman.

INACTIVE INGREDIENTS

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.

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.