LEVATOL Tablet Ref.[51203] Active ingredients: Penbutolol

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 If cardiac failure continues despite adequate intervention with appropriate drugs, levatol should be withdrawn (gradually, if possible).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 of Ischemic 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Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with β-blocking agents; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such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.

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.

Table 1. ADVERSE REACTIONS DURING CONTROLLED US STUDIES:

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.

Table 2. DISCONTINUATIONS DURING CONTROLLED US STUDIES:

Potential Adverse Effects: In addition, certain adverse effects not listed above have been reported with other β-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 β-blocker practolol has not been reported with levatol during investigational use and extensive foreign clinical experience.

Digoxin

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

Anesthesia

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 β-blockers, is a competitive inhibitor of β-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.

Risk of Anaphylactic Reaction

While taking β-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.

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 β-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 β-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.

Teratogenic Effects

Pregnancy Category C: 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.

Nonteratogenic Effects

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.