"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
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 If cardiac failure continues despite adequate intervention with appropriate drugs, levatol® should be withdrawn (gradually, if possible).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Hypersensitivity to catecholamines has been observed in patients who were withdrawn from therapy with β-blocking agents; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such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.
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.
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.
Included as part of the PATIENT INFORMATION section.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
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.
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.
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/10/2011
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