Penbutolol sulfate

levatol® (penbutolol sulfate) 20 mg tablets are capsule-shaped, film-coated, yellow tablets scored on both sides and imprinted in black with "SP 22" on one side. They are supplied as follows:

Bottles of 100 NDC 0091 -4500-15

Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Keep tightly closed and protect from light.

Schwarz Pharma, LLC a subsidiary of UCB, Inc. Smyrna, GA 30080. Revised 12/2010

Cardiac Failure

Sympathetic stimulation may be essential for supporting circulatory function in patients with heart failure, and its inhibition by β-adrenergic receptor blockade may precipitate more severe failure. Although β-blockers should be avoided in overt congestive heart failure, levatol® can, if necessary, be used with caution in patients with a history of cardiac failure who are well compensated, on treatment with vasodilators, digitalis and/or diuretics. Both digitalis and penbutolol slow AV conduction. Beta-adrenergic receptor antagonists do not inhibit the inotropic action of digitalis on heart muscle. If cardiac failure persists, treatment with levatol® should be discontinued.

Patients Without History of Cardiac Failure

Continued depression of the myocardium with β-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first evidence of heart failure, patients receiving levatol® should be given appropriate treatment, and the response should be closely observed. If cardiac failure continues despite adequate intervention with appropriate drugs, levatol® should be withdrawn (gradually, if possible).

Exacerbation oflschemic Heart Disease Following Abrupt Withdrawal

Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with β-blocking agents; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing levatol®, particularly in patients with ischemic heart disease, the dosage should be reduced gradually over a period of 1 to 2 weeks and the patient should be monitored carefully. If angina becomes more pronounced or acute coronary insufficiency develops, administration of levatol® should be reinstated promptly, at least on a temporary basis, and appropriate measures should be taken for the management of unstable angina. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may not be recognized, it may not be prudent to discontinue levatol® abruptly, even in patients who are being treated only for hypertension.

Nonallergic Bronchospasm (eg, chronic bronchitis,emphysema)

levatol® is contraindicated in bronchial asthma. In general, patients with bronchospastic diseases should not receive β-blockers. levatol® should be administered with caution because it may block bronchodilation produced by endogenous catecholamine stimulation of β-2 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 Mellitus and Hypoglycemia

Beta-adrenergic receptor blockade may prevent the appearance of signs and symptoms of acute hypoglycemia, such as tachycardia and blood pressure changes. This is especially important in patients with labile diabetes. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of hypoglycemic drugs. Beta-adrenergic blockade may also impair the homeostatic response to hypoglycemia; in that event, the spontaneous recovery from hypoglycemia may be delayed during treatment with β-adrenergic receptor antagonists.

Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of β-adrenergic receptor blockers that might precipitate a thyroid storm.

Penbutolol is a β-1,β-2 (nonselective) adrenergic receptor antagonist. Experimental studies showed a dose-dependent increase in heart rate in reserpinized (norepinephrine-depleted) rats given penbutolol intravenously at doses of 0.25 to 1.0 mg/kg, suggesting that penbutolol has some intrinsic sympathomimetic activity. In human studies, however, heart rate decreases have been similar to those seen with propranolol.

Penbutolol antagonizes the heart rate effects of exercise and infused isoproterenol. The β-blocking potency of penbutolol is approximately 4 times that of propranolol. An oral dose of less than 10 mg will reduce exercise-induced tachycardia to one-half its usual level; maximum antagonism follows doses of 10 to 20 mg. The peak effect is between 1.5 and 3 hours after oral administration. The duration of effect exceeds 20 hours during a once-daily dosing regimen. During chronic administration of penbutolol, the duration of antihypertensive effects permits a once-daily dosage schedule.

Acute hemodynamic effects of penbutolol have been studied following single intravenous doses between 0.1 and 4 mg. The cardiovascular responses included significant reductions in heart rate, left ventricular maximum dP/dt, cardiac output, stroke volume index, stroke work, and stroke work index. Systolic pressure and mean arterial pressure were reduced, and total peripheral resistance was increased.

Chronic administration of penbutolol to hypertensive patients results in the hemodynamic pattern typical of β-adrenergic blocking drugs: a reduction in cardiac index, heart rate, systolic and diastolic blood pressures, and the product of heart rate and mean arterial pressure both at rest and with all levels of exercise, without significant change in total peripheral resistance. Penbutolol causes a reduction in left ventricular contractility. Penbutolol decreases glomerular filtration rate, but not significantly.

Clinical trial doses of 10 to 80 mg per day in single daily doses have reduced supine and standing systolic and diastolic blood pressures. In most studies, effects were small, generally a change in blood pressure 5 to 8/3 to 5 mm Hg greater than seen with a placebo measured 24 hours after dosing. It is not clear whether this relatively small effect reflects a characteristic of penbutolol or the particular population studied (the population had relatively mild hypertension but did not appear unusual in other respects). In a direct comparison of penbutolol with adequate doses of twice daily propranolol, no difference in blood pressure effect was seen. In a comparison of placebo and 10-, 20-, and 40-mg single daily doses of penbutolol, no significant dose-related difference was seen in response to active drug at 6 weeks, but, compared to the 10-mg dose, the two larger doses showed greater effects at 2 and 4 weeks and reached their maximum effect at 2 weeks. In several studies, dose increases from 40 to 80 mg were without additional effect on blood pressure. Response rates to penbutolol are unaffected by sex or age but are greater in Caucasians than blacks.

Penbutolol decreases plasma renin activity in normal subjects and in patients with essential and renovascular hypertension. The mechanisms of the antihypertensive actions of β-receptor antagonists have not been established. However, factors that may be involved are: (1) competitive antagonism of catecholamines at peripheral adrenergic receptor sites (especially cardiac) that leads to decreased cardiac output; (2) a central nervous system (CNS) action that results in a decrease in tonic sympathetic neural outflow to the periphery; and (3) a reduction of renin secretion through blockade of β-receptors involved in release of renin from the kidneys.

Penbutolol dose dependently increases the RR and QT intervals. There is no influence on the PR, QRS, or QT c (corrected) intervals.

Pharmacokinetics

Following oral administration, penbutolol is rapidly and completely absorbed. Peak plasma concentrations of penbutolol occur between 2 and 3 hours after oral administration and are proportional to single and multiple doses between 10 and 40 mg once a day. The average plasma elimination half-life of penbutolol is approximately 5 hours in normal subjects. There is no significant difference in the plasma half-life of penbutolol in healthy elderly persons or patients on renal dialysis. Twelve to 24 hours after oral administration of doses up to 120 mg, plasma concentrations of parent drug are 0% to 10% of the peak level. No accumulation of penbutolol is observed in hypertensive patients after 8 days of therapy at doses of 40 mg daily or 20 mg twice a day. Penbutolol is approximately 80% to 98% bound to plasma proteins.

The metabolism of penbutolol in humans involves conjugation and oxidation. The metabolites are excreted principally in the urine. When radiolabeled penbutolol was administered to humans, approximately 90% of the radioactivity was excreted in the urine. Approximately 1/6 of the dose of penbutolol was recovered as penbutolol conjugate while the remaining fraction was not identified. Conjugated penbutolol has a plasma elimination half-life of approximately 20 hours in healthy persons, 25 hours in healthy elderly persons, and 100 hours in patients on renal dialysis. Thus, accumulation of penbutolol conjugate may be expected upon multiple-dosing in renal insufficiency. An oxidative metabolite of penbutolol, 4-hydroxy penbutolol, has been identified in small quantities in plasma and urine. It is 1/8 to 1/15 times as active as the parent compound in blocking isoproterenol-induced β-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs.

Animal Toxicology

Studies in rats indicated that the combination of penbutolol, triamterene, and hydrochlorothiazide (up to 40, 50 and 25 mg/kg respectively) increased the incidence and severity of renal tubular dilation and regeneration when compared to that in rats treated only with triamterene and hydrochlorothiazide. Dogs administered the same doses of triamterene and hydrochlorothiazide alone and in combination with penbutolol had an increase in serum alkaline phosphatase and serum alanine transferase, but there were no gross or microscopic abnormalities observed. No significant toxicologic findings were observed in rats and dogs treated with a combination of penbutolol and hydrochlorothiazide.

You should not take penbutolol if you are allergic to it, or if you have:

• asthma; or
• certain serious heart conditions such as"AV block" or slow heart rhythm.

To make sure you can safely take penbutolol, tell your doctor if you have any of these other conditions:

• kidney disease;
• liver disease;
• bronchitis, emphysema, or other breathing disorder;
• congestive heart failure;
• diabetes; or
• a thyroid disorder.

FDA pregnancy category C. It is not known whether penbutolol will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether penbutolol passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.