Levatol

UCB, Inc.
Actient Pharmaceuticals, LLC

levatol® tablets(penbutolol sulfate)20mg

FULL PRESCRIBING INFORMATION: CONTENTS*

• LEVATOL DESCRIPTION
• CLINICAL PHARMACOLOGY
• LEVATOL INDICATIONS AND USAGE
• LEVATOL CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• LEVATOL ADVERSE REACTIONS
• OVERDOSAGE
• LEVATOL DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

Rx Only

LEVATOL DESCRIPTION

levatol® (penbutolol sulfate) is a synthetic ß-receptor antagonist for oral administration. The chemical name of penbutolol sulfate is (S)-1-tert-butylamino-3-(o-cyclopentylphenoxy)-2-propanol sulfate. It is provided as the levorotatory isomer. The empirical formula for penbutolol sulfate is C₃₆H₆₀N₂O₈S. Its molecular weight is 680.94. A dose of 20 mg is equivalent to 29.4 µmol. The structural formula is as follows:

Penbutolol is a white, odorless, crystalline powder. levatol® is available as tablets for oral administration. Each tablet contains 20 mg of penbutolol sulfate. It also contains corn starch, D&C Yellow No. 10, lactose, magnesium stearate, povidone, silicon dioxide, talc, titanium dioxide, synthetic black iron oxide, hypromellose, simethicone and other inactive ingredients.

CLINICAL PHARMACOLOGY

Penbutolol is a ß-1, ß-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 ß-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 ß-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 ß-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 ß-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.

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 ß-adrenergic receptor responses in isolated guinea-pig trachea and is 1/8 to 1 times as potent in anesthetized dogs.

LEVATOL INDICATIONS AND USAGE

levatol® is indicated in the treatment of mild to moderate arterial hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

LEVATOL CONTRAINDICATIONS

levatol® is contraindicated in patients with cardiogenic shock, sinus bradycardia, second and third degree atrioventricular conduction block, bronchial asthma, and those with known hypersensitivity to this product (see WARNINGS).

WARNINGS

Cardiac Failure: Sympathetic stimulation may be essential for supporting circulatory function in patients with heart failure, and its inhibition by ß-adrenergic receptor blockade may precipitate more severe failure. Although ß-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 ß-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 of Ischemic Heart Disease Following Abrupt Withdrawal: Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with ß-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 ß-blockers. levatol® should be administered with caution because it may block bronchodilation produced by endogenous catecholamine stimulation of ß-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 ß-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 ß-adrenergic receptor blockers that might precipitate a thyroid storm.

PRECAUTIONS

Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of levatol® without the physician’s advice. Although cardiac failure rarely occurs in properly selected patients, those being treated with ß-adrenergic receptor antagonists should be advised of the symptoms of heart failure and to report such symptoms immediately, should they develop.

levatol® has been used in combination with hydrochlorothiazide in at least 100 patients without unexpected adverse reactions.

In one study, the combination of penbutolol and alcohol increased the number of errors in the eye-hand psychomotor function test.

Penbutolol increases the volume of distribution of lidocaine in normal subjects. This could result in a requirement for higher loading doses of lidocaine.

Cimetidine has no effect on the clearance of penbutolol. The major metabolite of penbutolol is a glucuronide, and it has been shown that cimetidine does not inhibit glucuronidation.

Synergistic hypotensive effects, bradycardia, and arrhythmias have been reported in some patients receiving ß-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen.

Generally, levatol® should not be used in patients receiving catecholamine-depleting drugs.

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

Care should be taken when using anesthetic agents that depress the myocardium, such as ether, cyclopropane, and trichloroethylene, and it is prudent to use the lowest possible dose of levatol®. levatol®, like other ß-blockers, is a competitive inhibitor of ß-receptor agonists, and its effect on the heart can be reversed by cautious administration of such agents (eg, dobutamine or isoproterenol — see OVERDOSAGE). Manifestations of excessive vagal tone (eg, profound bradycardia, hypotension) may be corrected with atropine 1 to 3 mg IV in divided doses.

While taking ß-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.

There was no evidence of carcinogenicity observed in a 21-month study in mice or a 2-year study in rats. Mice were given penbutolol in the diet for 18 months at doses up to 395 mg/kg/day (about 500 times the Maximum Recommended Human Dose (MRHD) of 40 mg in a 50 kg person). Rats were given 141 mg/kg/day for the same length of time. Mice were observed for 3 months and rats for 5.5 to 7 months after termination of treatment before necropsy was performed.

No evidence of mutagenic activity of penbutolol was seen in the Salmonella mutagenicity test (Ames test), the point mutation induction test (Saccharomyces), and the micronucleus test.

Penbutolol had no adverse effects on fertility or general reproductive performance in mice and rats at oral doses up to 172 mg/kg/day.

Teratology studies in rats and rabbits revealed no teratogenic effects related to treatment with penbutolol at oral doses up to 200 mg/kg/day (250 times the MRHD). In rabbits, a slight increase in the intrauterine fetal mortality and a reduced 24-hour offspring survival rate were observed in the groups treated with 125 mg/kg/day (156 times the MRHD) but not in the groups treated with 0.2 and 5 mg (0.25 to 6 times the MRHD).

There are no adequate and well-controlled studies in pregnant women. levatol® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a perinatal and postnatal study in rats, the pup body weight and pup survival rate were reduced at the highest dose level of 160 mg/kg/day (200 times the MRHD).

It is not known whether levatol® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when levatol® is administered to a nursing woman.

Safety and effectiveness of levatol® in pediatric patients have not been established.

Clinical studies of levatol® 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.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

LEVATOL ADVERSE REACTIONS

levatol® is usually well tolerated in properly selected patients. Most adverse effects observed during clinical trials have been mild and reversible.

Table 1 lists the adverse reactions reported from 4 controlled studies conducted in the United States involving once-a-day administration of levatol® (at doses ranging from 10 to 120 mg) as monotherapy or in combination with hydrochlorothiazide. levatol® doses above 40 mg/day are not, however, recommended. The table includes only those events where the prevalence rate in the levatol® group was at least 1.5%, or where the reaction is of particular interest.

Over a dose range from 10 to 40 mg, once a day, fatigue, nausea, and sexual impotence occurred at a greater frequency as the dose was increased.

In a double-blind clinical trial comparing levatol® (40 mg and greater once a day) and propranolol (40 mg or more twice a day), heart rates of less than 60 beats/min. were recorded at least once in 25% of the patients in the group receiving levatol® and in 37% of the patients in the propranolol group. Corresponding figures for heart rates of less than 50 beats/min. were 1.2% and 6% respectively. No symptoms associated with bradycardia were reported.

Discontinuations of levatol® because of adverse reactions have ranged between 2.4% and 6.9% of patients in double-blind, parallel, controlled clinical trials, as compared to 1.8% to 4.1% in the corresponding control groups that were given placebo. The frequency and severity of adverse reactions have not increased during long-term administration of levatol®. The prevalence of adverse reactions reported from 4 controlled clinical trials (referred to in Table 1) as reasons for discontinuation of therapy by >0.5% of the levatol® group is listed in Table 2.

Potential Adverse Effects: In addition, certain adverse effects not listed above have been reported with other ß-blocking agents and should also be considered as potential adverse effects of levatol®.

Central Nervous System: Reversible mental depression progressing to catatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics).

Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).

Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.

Hematologic: Agranulocytosis, nonthrombocytopenic and thrombocytopenic purpura.

Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis.

Miscellaneous: Reversible alopecia and Peyronie’s disease. The oculomucocutaneous syndrome associated with the ß-blocker practolol has not been reported with levatol® during investigational use and extensive foreign clinical experience.

OVERDOSAGE

There is no actual experience with levatol® overdose. The signs and symptoms that would be expected with overdosage of ß-adrenergic receptor antagonists are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. In addition to discontinuation of levatol®, gastric emptying, and close observation of the patient, the following measures might be considered as appropriate:

Excessive Bradycardia: Administer atropine sulfate to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride may be administered cautiously; larger than usual doses may be needed. In refractory cases, the use of a transvenous cardiac pacemaker may be necessary.

Hypotension: Sympathomimetic drug therapy, such as dopamine, dobutamine, or levarterenol, may be considered if hypotension persists despite correction of bradycardia. In refractory cases, administration of glucagon hydrochloride has been reported to be useful.

Bronchospasm: A ß-2-agonist or isoproterenol hydrochloride may be administered. Additional therapy with aminophylline may be considered.

Acute Cardiac Failure: Institute conventional therapy immediately. Intravenous administration of dobutamine and glucagon hydrochloride has been reported to be useful.

Heart Block (Second or Third Degree): Isoproterenol hydrochloride or a transvenous cardiac pacemaker may be used.

LEVATOL DOSAGE AND ADMINISTRATION

The usual starting and maintenance dose of levatol®, used alone or in combination with other antihypertensive agents, such as thiazide-type diuretics, is 20 mg given once daily.

Doses of 40 mg and 80 mg have been well-tolerated but have not been shown to give a greater antihypertensive effect. The full effect of a 20- or 40-mg dose is seen by the end of 2 weeks. A dose of 10 mg also lowers blood pressure, but the full effect is not seen for 4 to 6 weeks.

HOW SUPPLIED

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.

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.

SCHWARZ PHARMA, LLC
a subsidiary of UCB, Inc.
Smyrna, GA 30080

levatol® is a registered trademark of SRZ Properties, Inc.

Rev. 3E 5/2011

PRINCIPAL DISPLAY PANEL

NDC 0091-4500-15

levatol^® tablets

(penbutolol sulfate)

20 mg

Rx only

100 tablets