Inderal

What is Inderal and how is it used?

Inderal is a prescription medicine used to treat the symptoms high blood pressure (hypertension), migraine, chest pain (angina), heart rhythm disorders, and other circulatory conditions, as a preventative of heart attacks and to reduce migraines. Inderal may be used alone or with other medications.

Inderal belongs to a class of drugs called Antidysrhythmics, II, Beta-Blockers, Nonselective, Antianginal Agents, Antimigraine Agents.

What are the possible side effects of Inderal?

Inderal may cause serious side effects including:

• slow or uneven heartbeats,
• lightheadedness,
• wheezing,
• trouble breathing,
• shortness of breath,
• swelling,
• rapid weight gain,
• sudden weakness,
• vision problems,
• loss of coordination (especially in a child with hemangioma in the face or head),
• cold feeling in your hands and feet,
• depression,
• confusion,
• hallucinations,
• nausea,
• upper stomach pain,
• itching,
• tired feeling,
• loss of appetite,
• dark urine,
• clay-colored stools,
• yellowing of the skin or eyes (jaundice),
• headache,
• hunger,
• weakness,
• sweating,
• irritability,
• dizziness,
• fast heart rate,
• feeling jittery,
• pale skin,
• blue or purple skin,
• fussiness,
• crying,
• not wanting to eat,
• feeling cold,
• drowsiness,
• weak or shallow breathing,
• seizures (convulsions),
• loss of consciousness,
• fever,
• sore throat,
• swelling in your face or tongue,
• burning in your eyes, and
• skin pain followed by a red or purple skin rash that spreads and causes blistering and peeling

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Inderal include:

• nausea,
• vomiting,
• diarrhea,
• constipation,
• stomach cramps,
• decreased sex drive,
• impotence,
• difficulty having an orgasm,
• sleep problems (insomnia), and
• feeling tired

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Inderal. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This product's label may have been revised after this insert was used in production. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-888-383-1733

DESCRIPTION

Inderal® (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.

Inderal (propranolol) is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration.

The inactive ingredients contained in Inderal (propranolol) Tablets are: lactose, magnesium stearate, microcrystalline cellulose, and stearic acid. In addition, Inderal (propranolol) 10 mg and 80 mg Tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; Inderal (propranolol) 20 mg Tablets contain FD&C Blue No. 1; Inderal (propranolol) 40 mg Tablets contain FD&C Blue No. 1, FD&C Yellow No. 6, and D&C Yellow No. 10; Inderal (propranolol) 60 mg Tablets contain D&C Red No. 30.

INDICATIONS

Hypertension

Inderal is indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Inderal is not indicated in the management of hypertensive emergencies.

Angina Pectoris Due to Coronary Atherosclerosis

Inderal is indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris.

Atrial Fibrillation

Inderal is indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response.

Myocardial Infarction

Inderal is indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable.

Migraine

Inderal 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

Inderal 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. Inderal causes a reduction in the tremor amplitude, but not in the tremor frequency. Inderal is not indicated for the treatment of tremor associated with Parkinsonism.

Hypertrophic Subaortic Stenosis

Inderal improves NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.

Pheochromocytoma

Inderal 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 Inderal 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 Inderal, 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 Inderal 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 Inderal 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 bid. 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 Inderal 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, Inderal 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 Inderal 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 Inderal three or four times daily before meals and at bedtime.

Pheochromocytoma

The usual dosage is 60 mg Inderal 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.

HOW SUPPLIED

Inderal®
(propranolol hydrochloride) Tablets

INDERAL 10—Each hexagonal-shaped, orange, scored tablet, embossed with an "I" and imprinted with "INDERAL 10," contains 10 mg propranolol hydrochloride, in bottles of 100 (NDC 24090) and 5,000 (NDC 24090-421-88).

Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F).

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

INDERAL 20—Each hexagonal-shaped, blue, scored tablet, embossed with an "I" and imprinted with "INDERAL 20," contains 20 mg propranolol hydrochloride, in bottles of 100 (NDC 24090-422-88).

Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F).

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

Protect from light.

Use carton to protect contents from light.

INDERAL 40—Each hexagonal-shaped, green, scored tablet, embossed with an "I" and imprinted with "INDERAL 40," contains 40 mg propranolol hydrochloride, in bottles of 100 (NDC 24090) and 5,000 (NDC 24090-424-88).

Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F).

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

Protect from light.

Use carton to protect contents from light.

INDERAL 60—Each hexagonal-shaped, pink, scored tablet, embossed with an "I" and imprinted with "INDERAL 60," contains 60 mg propranolol hydrochloride, in bottles of 100 (NDC 24090-426-88).

Store at controlled room temperature 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F).

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

INDERAL 80—Each hexagonal-shaped, yellow, scored tablet, embossed with an "I" and imprinted with "INDERAL 80," contains 80 mg propranolol hydrochloride, in bottles of 100 (NDC 24090-428-88).

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]

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

Manufactured for Akrimax Pharmaceuticals, LLC Cranford, NJ 07016. By Wyeth Pharmaceuticals, Inc. Philadelphia, PA 19101. Marketed and Distributed by Akrimax Pharmaceuticals, LLC Cranford, NJ 07016. Revised 11/10

SIDE EFFECTS

The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency. Within each category, adverse reactions are listed in decreasing order of severity. Although many side effects are mild and transient, some require discontinuation of therapy.

Propranolol hydrochloride (Inderal® (propranolol) )

Cardiovascular: Congestive heart failure; hypotension; intensification of AV block; bradycardia; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type; paresthesia of hands.

Central Nervous System: Reversible mental depression progressing to catatonia; mental depression manifested by insomnia, lassitude, weakness, fatigue; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, decreased performance on neuropsychometrics; hallucinations; visual disturbances; vivid dreams; light-headedness. Total daily doses above 160 mg (when administered as divided doses of greater than 80 mg each) may be associated with an increased incidence of fatigue, lethargy, and vivid dreams.

Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation.

Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; laryngospasm and respiratory distress; pharyngitis and agranulocytosis; fever combined with aching and sore throat; erythematous rash.

Respiratory: Bronchospasm.

Hematologic: Agranulocytosis; nonthrombocytopenic purpura; thrombocytopenic purpura.

Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.

Miscellaneous: Male impotence. Alopecia, LE-like reactions, psoriasiform rashes, dry eyes, and Peyronie's disease have been reported rarely. Oculomucocutaneous reactions involving the skin, serous membranes, and conjunctivae reported for a beta blocker (practolol) have not been associated with propranolol.

Skin: Stevens-Johnson Syndrome; toxic epidermal necrolysis; exfoliative dermatitis; erythema multiforme; urticaria.

Hydrochlorothiazide

Cardiovascular: Orthostatic hypotension (may be aggravated by alcohol, barbiturates or narcotics).

Central Nervous System: Dizziness, vertigo, headache, xanthopsia, paresthesias.

Gastrointestinal: Pancreatitis; jaundice (intrahepatic cholestatic jaundice); sialadenitis; anorexia, nausea, vomiting, gastric irritation, cramping, diarrhea, constipation.

Hypersensitivity: Anaphylactic reactions; necrotizing angiitis (vasculitis, cutaneous vasculitis); respiratory distress including pneumonitis; fever; urticaria, rash, purpura, photosensitivity.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

Miscellaneous: Hyperglycemia, glycosuria; hyperuricemia; muscle spasm; weakness; restlessness; transient blurred vision.

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

DRUG INTERACTIONS

Propranolol hvdrochloride (Inderal® (propranolol) )

Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if Inderide is administered. The added catecholamine-blocking action may produce an excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.

Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel blocking drug, especially intravenous verapamil, for both agents may depress myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant intravenous use of a beta blocker and verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.

Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.

Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.

Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.

Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.

Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels of both drugs.

Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.

Thyroxine may result in a lower than expected TS concentration when used concomitantly with propranolol.

Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing blood levels.

Theophylline clearance is reduced when used concomitantly with propranolol.

Hydrochlorothiazide

Thiazide drugs may increase the responsiveness to tubocurarine.

Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Hypokalemia may develop during concomitant use of corticosteroids or ACTH.

Drug/Laboratory Test Interactions

Hydrochlorothiazide

Thiazides may decrease serum FBI levels without signs of thyroid disturbance.

Thiazides should be discontinued before carrying out tests for parathyroid function (see "PRECAUTIONS—General").

WARNINGS

Propranolol hydrochloride (Inderal® (propranolol) )

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol and hydrochlorothiazide (see "ADVERSE REACTIONS").

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Propranolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle (i.e., that of supporting the strength of myocardial contractions). In patients already receiving digitalis, the positive inotropic action of digitalis may be reduced by propranolol's negative inotropic effect.

Patients Without a History of Heart Failure: Continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. In rare instances, this has been observed during propranolol therapy. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given additional diuretic, and the response observed closely: a) if cardiac failure continues, despite adequate digitalization and diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the patient closely followed until threat of cardiac failure is over.

Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema): PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Propranolol should be administered with caution since it may block 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 in labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage of insulin. Hypoglycemic attack may be accompanied by a precipitous elevation of blood pressure in patients on propranolol.

Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has been found after this type of drug therapy and prolonged physical exertion and has occurred in renal insufficiency, both during dialysis and sporadically, in patients on propranolol.

Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients on propranolol.

Thyrotoxicosis: Beta 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: Several cases have been reported in which, after propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand pacemaker. In one case this resulted after an initial dose of 5 mg propranolol.

Skin 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").

Hydrochlorothiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects of the drug may develop.

Thiazides should also be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic-blocking drugs.

Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Acute Myopia and Secondary Angle-closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

PRECAUTIONS

General

Propranolol hvdrochloride (Inderal®)

Propranolol should be used with caution in patients with impaired hepatic or renal function. Inderide is not indicated for the treatment of hypertensive emergencies.

Risk of anaphylactic reaction. 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.

Hydrochlorothiazide

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content.

Any chloride deficit is generally mild, and usually does not require specific treatment except under extraordinary circumstances (as in liver or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Diabetes mellitus which has been latent may become manifest during thiazide administration. The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen.

Laboratory Tests

Propranolol hvdrochloride (Inderal® (propranolol) )

Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase, alkaline phosphatase, lactate dehydrogenase.

Hydrochlorothiazide

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic or mutagenic potential or for potential to adversely affect fertility.

Propranolol hydrochloride (Inderal® (propranolol) )

In dietary administration studies in which mice and rats were treated with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis.

In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, 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).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay (S.typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell (mutagenicity) and Aspergillus nidulans non-disjunction assays.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Pregnancy: Pregnancy Category C

Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on pregnancy in animals. Nor are there adequate and well-controlled studies of propranolol, hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Propranolol hydrochloride (Inderal® (propranolol) )

In a series of reproduction and developmental toxicology studies, propranolol was given to ratsby gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day ( > 30 times the dose of propranolol contained in the maximum recommended human daily dose of Inderide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity (reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths). Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day ( > 45 times the dose of propranolol contained in the maximum recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was noted.

Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in human 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 these infants at birth should be available.

Hydrochlorothiazide

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats at doses of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

Nursing Mothers

Propranolol hydrochloride (Inderal®)

Propranolol is excreted in human milk. Caution should be exercised when Inderide is administered to a nursing woman.

Hydrochlorothiazide

Thiazides appear in breast milk. If the use of drug is deemed essential, the patient should stop nursing.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Inderide 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 decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

OVERDOSE

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 50150 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.

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.

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 Inderal (propranolol) is of benefit in exaggerated physiological and essential (familial) tremor.

Pharmacokinetics And Drug Metabolism

Absorption

Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose.

Administration of protein-rich foods increase the bioavailability of propranolol by about 50% with no change in time to peak concentration, plasma binding, half-life, or the amount of unchanged drug in the urine.

Distribution

Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alphai acid glycoprotein). The binding is enantiomer-selective. The S(-)-enantiomer is preferentially bound to alpha₁ glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg.

Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.

Metabolism and Elimination

Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol.

In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.

Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.

In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and of naphthyloxyactic acid significantly lower in EMs than PMs.

The plasma half-life of propranolol is from 3 to 6 hours.

Enantiomers

Propranolol is a racemic mixture of two enantiomers, R(+) and S(-). The S(-)-enantiomer is approximately 100 times as potent as the R(+)-enantiomer in blocking beta adrenergic receptors. In normal subjects receiving oral doses of racemic propranolol, S(-)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic metabolism. Clearance of the pharmacologically active S(-)-propranolol is lower than R(+)-propranolol after intravenous and oral doses.

Special Populations

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).

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).

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.

Pharmacodynamics And Clinical Effects

Hypertension

In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other antihypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained.

Angina Pectoris

In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time.

Atrial Fibrillation

In a report examining the long-term (5-22 months) efficacy of propranolol, 10 patients, aged 27 to 80, with atrial fibrillation and ventricular rate >120 beats per minute despite digitalis, received propranolol up to 30 mg t.i.d. Seven patients (70%) achieved ventricular rate reduction to <100 beats per minute.

Myocardial Infarction

The Beta-Blocker Heart Attack Trial (BHAT) was a National Heart, Lung and Blood Institute-sponsored multicenter, randomized, double-blind, placebo-controlled trial conducted in 31 U.S. centers (plus one in Canada) in 3,837 persons without history of severe congestive heart failure or presence of recent heart failure; certain conduction defects; angina since infarction, who had survived the acute phase of myocardial infarction. Propranolol was administered at either 60 or 80 mg t.i.d. based on blood levels achieved during an initial trial of 40 mg t.i.d. Therapy with Inderal (propranolol) , begun 5 to 21 days following infarction, was shown to reduce overall mortality up to 39 months, the longest period of follow-up. This was primarily attributable to a reduction in cardiovascular mortality. The protective effect of Inderal (propranolol) was consistent regardless of age, sex, or site of infarction. Compared with placebo, total mortality was reduced 39% at 12 months and 26% over an average follow-up period of 25 months. The Norwegian Multicenter Trial in which propranolol was administered at 40 mg q.i.d. gave overall results which support the findings in the BHAT.

Although the clinical trials used either t.i.d. or q.i.d. dosing, clinical, pharmacologic, and pharmacokinetic data provide a reasonable basis for concluding that b.i.d. dosing with propranolol should be adequate in the treatment of postinfarction patients.

Migraine

In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or 4 times daily. The headache unit index, a composite of the number of days with headache and the associated severity of the headache, was significantly reduced for patients receiving propranolol as compared to those on placebo.

Essential Tremor

In a 2 week, double-blind, parallel, placebo-controlled study of 9 patients with essential or familial tremor, propranolol, at a dose titrated as needed from 40-80 mg t.i.d. reduced tremor severity compared to placebo.

Hypertrophic Subaortic Stenosis

In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral propranolol 40-80 mg t.i.d. was administered and patients were followed for up to 17 months. Propranolol was associated with improved NYHA class for most patients.

Pheochromocytoma

In an uncontrolled series of 3 patients with norepinephrine-secreting pheochromocytoma who were pretreated with an alpha adrenergic blocker (prazosin), perioperative use of propranolol at doses of 40-80 mg t.i.d. resulted in symptomatic blood pressure control.

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.