propranolol hydrochloride 160 mg Capsule, Extended Release, 100-count — NDC 42291-525-01 (Billing 42291-0525-01)

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-stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.

At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain. Propranolol Hydrochloride Extended-Release Capsules, USP, should not be considered a simple mg-for-mg substitute for conventional propranolol and the blood levels achieved do not match (are lower than) those of two to four times daily dosing with the same dose (see DOSAGE AND ADMINISTRATION ).

When changing to Propranolol Hydrochloride Extended-Release Capsules, USP, from conventional propranolol, a possible need for retitration upwards should be considered, especially to maintain effectiveness at the end of the dosing interval. In most clinical settings, however, such as hypertension or angina where there is little correlation between plasma levels and clinical effect, Propranolol Hydrochloride Extended-Release Capsules, USP, have been therapeutically equivalent to the same mg dose of conventional propranolol as assessed by 24-hour effects on blood pressure and on 24-hour exercise responses of heart rate, systolic pressure, and rate pressure product.

Mechanism of Action The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol.

Effects of propranolol on plasma volume appear to be minor and somewhat variable. In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period.

The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity. Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action which affects the cardiac action potential.

The significance of the membrane action in the treatment of arrhythmias is uncertain. The mechanism of the anti-migraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.

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. Propranolol Hydrochloride Extended-Release Capsules, USP, (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate.

Peak blood levels following dosing with Propranolol Hydrochloride Extended-Release Capsules, USP, occur at about 6 hours. The effect of foo… [Excerpted — this section continues on DailyMed.]

Mechanism of Action The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol.

Effects of propranolol on plasma volume appear to be minor and somewhat variable. In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period.

The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity. Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action which affects the cardiac action potential.

The significance of the membrane action in the treatment of arrhythmias is uncertain. The mechanism of the anti-migraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.

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. Propranolol Hydrochloride Extended-Release Capsules, USP, (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate.

Peak blood levels following dosing with Propranolol Hydrochloride Extended-Release Capsules, USP, occur at about 6 hours. The effect of food on Propranolol Hydrochloride Extended-Release Capsules, USP, bioavailability has not been investigated. Distribution Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha-1-acid glycoprotein).

The binding is enantiomer-selective. The S(–)-enantiomer is preferentially bound to alpha- 1-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 naphthyloxylactic acid was significantly lower in EMs than PMs.

When measured at steady state over a 24-hour period the areas under the propranolol plasma concentration-time curve (AUCs) for the Propranolol Hydrochloride Extended-Release Capsules, USP, are approximately 60% to 65% of the AUCs for a comparable divided daily dose of propranolol hydrochloride extended-release capsules. The lower AUCs for the Propranolol Hydrochloride Extended-Release Capsules, USP, are due to greater hepatic metabolism of propranolol, resulting from the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood levels are fairly constant for about twelve (12) hours, then decline exponentially.

The apparent plasma half-life is about 10 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 The pharmacokinetics of Propranolol Hydrochloride Extended-Release Capsules, USP, have not been investigated in patients over 65 years of age.

In a study of 12 elderly (… [Excerpted — this section continues on DailyMed.]

PHARMACODYNAMICS AND CLINICAL EFFECTS Hypertension In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mm Hg received propranolol 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other hypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained. Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with mild or moderately severe hypertension treated with Propranolol Hydrochloride Extended-Release Capsules, USP, 160 mg once daily or propranolol 160 mg given either once daily or in two 80 mg doses.

Three of these studies were conducted over a 4-week treatment period. One study was assessed after a 24-hour period. Propranolol Hydrochloride Extended-Release Capsules, USP, were as effective as propranolol in controlling hypertension (pulse rate, systolic and diastolic blood pressure) in each of these trials.

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. Twelve male patients with moderately severe angina pectoris were studied in a double-blind, crossover study. Patients were randomized to either Propranolol Hydrochloride Extended-Release Capsules, USP, 160 mg daily or conventional propranolol 40 mg four times a day for 2 weeks.

Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG's were recorded during serial exercise treadmill testing. Propranolol Hydrochloride Extended-Release Capsules, USP, were as effective as conventional propranolol for exercise heart rate, systolic and diastolic blood pressure, duration of anginal pain and ST-segment depression before or after exercise, exercise duration, angina attack rate and nitroglycerine consumption.

In another double-blind, randomized, crossover trial, the effectiveness of Propranolol Hydrochloride Extended-Release Capsule, USP, 160 mg daily and conventional propranolol 40 mg four times a day were evaluated in 13 patients with angina. ECG's were recorded while patients exercised until angina developed. Propranolol Hydrochloride Extended-Release Capsules, USP, were as effective as conventional propranolol for amount of exercise performed, ST-segment depression, number of anginal attacks, amount of nitroglycerine consumed, systolic and diastolic blood pressures and heart rate at rest and after exercise.

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. 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.