PROPRANOLOL HYDROCHLORIDE and HYDROCHLOROTHIAZIDE TABLETS, USP
40 mg/25 mg and 80 mg/25 mg

Propranolol hydrochloride and hydrochlorothiazide tablets, USP for oral administration combine two antihypertensive agents: propranolol hydrochloride, USP, a beta-adrenergic blocking agent, and hydrochlorothiazide, USP, a thiazide diuretic-antihypertensive. Propranolol hydrochloride and hydrochlorothiazide tablets, 40/25 contain 40 mg propranolol hydrochloride and 25 mg hydrochlorothiazide; propranolol hydrochloride and hydrochlorothiazide tablets, 80/25 contain 80 mg propranolol hydrochloride and 25 mg hydrochlorothiazide.

Propranolol hydrochloride is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is:

Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.81.

Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution; sparingly soluble in methanol; insoluble in ether, chloroform, benzene, and dilute mineral acids. Its chemical name is: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its structural formula is:

Propranolol hydrochloride and hydrochlorothiazide tablets, 40 mg/25 mg and 80 mg/25 mg are for oral administration and contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized cornstarch and sodium lauryl sulfate.

Propranolol hydrochloride is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.

Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is immediately metabolized by the liver on its first pass through the portal circulation.

Peak effect occurs in one to one-and-one-half hours. The biologic half-life is approximately four hours. Propranolol is not significantly dialyzable. There is no simple correlation between dose or plasma level and therapeutic effect, and the dose-sensitivity range, as observed in clinical practice, is wide. The principal reason for this is that sympathetic tone varies widely between individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether total beta blockade has been achieved, proper dosage requires titration.

The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action are (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. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been shown to cause a small increase in serum potassium concentration when used in the treatment of hypertensive patients. Propranolol hydrochloride decreases heart rate, cardiac output, and blood pressure.

Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional changes, sympathetic activity is detrimental to the patient. But there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function is maintained by virtue of sympathetic drive, which should be preserved. In the presence of AV block greater than first degree, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta blockade results in bronchial constriction by interfering with adrenergic bronchodilator activity, which should be preserved in patients subject to bronchospasm.

The proper objective of beta-blockade therapy is to decrease adverse sympathetic stimulation, but not to the degree that may impair necessary sympathetic support.

Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic closely related to chlorothiazide. The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not affect normal blood pressure.

Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency.

Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate. Onset of diuretic action of hydrochlorothiazide occurs in two hours, and the peak effect in about four hours. Its action persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.

Propranolol hydrochloride and hydrochlorothiazide tablets are indicated in the management of hypertension.

This fixed combination is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management.

Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; 4) congestive heart failure (see WARNINGS) unless the failure is secondary to a tachyarrhythmia treatable with propranolol.

Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs.

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

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.

Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol hydrochloride and hydrochlorothiazide tablets are not indicated for the treatment of hypertensive emergencies.

Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told that propranolol hydrochloride and hydrochlorothiazide may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.

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

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 the combination in pregnant women. Propranolol and hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of propranolol hydrochloride and hydrochlorothiazide 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.

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 uled in decreasing order of severity. Although many side effects are mild and transient, some require discontinuation of therapy.

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 of 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.

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.

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.

The propranolol hydrochloride component may cause bradycardia, cardiac failure, hypotension, or bronchospasm. Propranolol is not significantly dialyzable.

The hydrochlorothiazide component can be expected to cause diuresis. Lethargy of varying degree may appear and may progress to coma within a few hours, with minimal depression of respiration and cardiovascular function, and in the absence of significant serum electrolyte changes or dehydration. The mechanism of central nervous system depression with thiazide overdosage is unknown. Gastrointestinal irritation and hypermotility can occur, temporary elevation of BUN has been reported, and serum electrolyte changes could occur, especially in patients with impairment of renal function.

The oral LD₅₀ dosages in rats and mice for propranolol, hydrochlorothiazide and combined propranolol/hydrochlorothiazide (40/25, 80/25) are 364 to 533 mg/kg, greater than 2,750 to 5,000 mg/kg, and 538 to 845 mg/kg, respectively.

The following measures should be employed:

General: If ingestion is, or may have been, recent, evacuate gastric spans, taking care to prevent pulmonary aspiration.

Bradycardia: Administer atropine (0.25 to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.

Cardiac Failure: Digitalization and diuretics.

Hypotension: Vasopressors, e.g., levarterenol or epinephrine.

Bronchospasm: Administer isoproterenol and aminophylline.

Stupor or Coma: Administer supportive therapy as clinically warranted.

Gastrointestinal Effects: Though usually of short duration, these may require symptomatic treatment.

Abnormalities in BUN and/or Serum Electrolytes: Monitor serum electrolyte levels and renal function; institute supportive measures as required individually to maintain hydration, electrolyte balance, respiration, and cardiovascular-renal function.

The dosage must be determined by individual titration.

Hydrochlorothiazide can be given at doses of 12.5 to 50 mg per day when used alone. The initial dose of propranolol is 80 mg daily, and it may be increased gradually until optimal blood pressure control is achieved. The usual effective dose when used alone is 160 to 480 mg per day.

One propranolol hydrochloride and hydrochlorothiazide tablet twice daily can be used to administer up to 160 mg of propranolol and 50 mg of hydrochlorothiazide. For doses of propranolol greater than 160 mg the combination products are not appropriate, because their use would lead to an excessive dose of the thiazide component.

When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.

Propranolol hydrochloride and hydrochlorothiazide tablets, USP are available in the following combinations:

40 mg/25 mg - contains 40 mg of propranolol hydrochloride, USP and 25 mg of hydrochlorothiazide, USP. Each round, white, scored tablet is debossed with MYLAN over 731 on the unscored side. They are available as follows:

    NDC 0378-0731-01
    bottles of 100 tablets

80 mg/25 mg - contains 80 mg of propranolol hydrochloride, USP and 25 mg of hydrochlorothiazide, USP. Each round, white, scored tablet is debossed with MYLAN over 347 on the unscored side. They are available as follows:

    NDC 0378-0347-01
    bottles of 100 tablets