ACEBUTOLOL HYDROCHLORIDE- acebutolol hydrochloride capsule
CLINICAL PHARMACOLOGY Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. Pharmacodynamics ? -cardioselectivity has been demonstrated in experimental animal studies. In anesthetized dogs and cats, acebutolol is more potent in antagonizing isoproterenol-induced tachycardia (? ) than in antagonizing isoproterenol-induced vasodilatation (? ). In guinea pigs and cats, it is more potent in antagonizing this tachycardia than in antagonizing isoproterenol-induced bronchodilatation (? ). ISA of acebutolol has been demonstrated in catecholamine-depleted rats by tachycardia induced by intravenous administration of this agent. A membrane-stabilizing effect has been detected in animals, but only with high concentrations of acebutolol. Clinical studies have demonstrated ? -blocking activity at the recommended doses by: a) reduction in the resting heart rate and decrease in exercise-induced tachycardia; b) reduction in cardiac output at rest and after exercise; c) reduction of systolic and diastolic blood pressures at rest and postexercise; d) inhibition of isoproterenol-induced tachycardia. The ? -selectivity of acebutolol has also been demonstrated on the basis of the following vascular and bronchial effects: Vascular Effects
Acebutolol has less antagonistic effects on peripheral vascular ? -receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Bronchial Effects In single-dose studies in asthmatics examining effects of various beta-blockers on pulmonary function, low doses of acebutolol produce less evidence of bronchoconstriction and less reduction of ? agonist, bronchodilating effects, than nonselective agents like propranolol but more than atenolol. ISA has been observed with acebutolol in man, as shown by a slightly smaller (about three beats per minute) decrease in resting heart rate when compared to equivalent beta-blocking doses of propranolol, metoprolol or atenolol. Chronic therapy with acebutolol induced no significant alteration in the blood lipid profile. Acebutolol has been shown to delay AV conduction time and to increase the refractoriness of the AV node without significantly affecting sinus node recovery time, atrial refractory period, or the HV conduction time. The membrane-stabilizing effect of acebutolol is not manifest at the doses used clinically. Significant reductions in resting and exercise heart rates and systolic blood pressures have been observed 1.5 hours after acebutolol administration with maximal effects occurring between 3 and 8 hours postdosing in normal volunteers. Acebutolol has demonstrated a significant effect on exerciseinduced tachycardia 24 to 30 hours after drug administration. There are significant correlations between plasma levels of acebutolol and both the reduction in resting heart rate and the percent of beta-blockade of exercise-induced tachycardia. The antihypertensive effect of acebutolol has been shown in double-blind controlled studies to be superior to placebo and similar to propranolol and hydrochlorothiazide. In addition, patients responding to acebutolol administered twice daily had a similar response whether the dosage regimen was changed to once daily administration or continued on a b.i.d. regimen. Most patients responded to 400 to 800 mg/day in divided doses. The antiarrhythmic effect of acebutolol was compared with placebo, propranolol, and quinidine. Compared with placebo, acebutolol significantly reduced mean total ventricular ectopic beats (VEB), paired VEB, multiform VEB, R-on-T beats, and ventricular tachycardia (VT). Both acebutolol and propranolol significantly reduced mean total and paired VEB and VT. Acebutolol and quinidine significantly reduced resting total and complex VEB; the antiarrhythmic efficacy of acebutolol was also observed during exercise.
INDICATIONS AND USAGE Hypertension Acebutolol hydrochloride capsules are indicated for the management of hypertension in adults. They may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. Ventricular Arrhythmias Acebutolol hydrochloride capsules are indicated in the management of ventricular premature beats; it reduces the total number of premature beats, as well as the number of paired and multiform ventricular ectopic beats, and R-on-T beats.
CONTRAINDICATIONS Acebutolol hydrochloride capsules are contraindicated in: 1) persistently severe bradycardia; 2) second- and third-degree heart block; 3) overt cardiac failure; and 4) cardiogenic shock (see WARNINGS).
WARNINGS Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt cardiac failure, acebutolol can be used with caution in patients with a history of heart failure who are controlled with digitalis and/or diuretics. Both digitalis and acebutolol impair AV conduction. If cardiac failure persists, therapy with acebutolol should be withdrawn. In Patients Without a History of Cardiac Failure In patients with aortic or mitral valve disease or compromised left ventricular function, continued depression of the myocardium with beta-blocking agents over a period of time may lead to cardiac failure. At the first signs of failure, patients should be digitalized and/or be given a diuretic and the
response observed closely. If cardiac failure continues despite adequate digitalization and/or diuretic, acebutolol therapy should be withdrawn. Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal Following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbation of angina pectoris and, in some cases, myocardial infarction and death have been reported. Therefore, such patients should be cautioned against interruption of therapy without a physician's advice. Even in the absence of overt ischemic heart disease, when discontinuation of acebutolol is planned, the patient should be carefully observed, and should be advised to limit physical activity to a minimum while acebutolol is gradually withdrawn over a period of about 2 weeks. (If therapy with an alternative beta-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of beta-blocking therapy.) If an exacerbation of angina pectoris occurs, antianginal therapy should be restarted immediately in full doses and the patient hospitalized until his condition stabilizes. Peripheral Vascular Disease Treatment with beta-antagonists reduces cardiac output and can precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease. Caution should be exercised with such patients, and they should be observed closely for evidence of progression of arterial obstruction. Bronchospastic Disease PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE A BETA-BLOCKER. Because of its relative ? -selectivity, however, low doses of acebutolol may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. Since ? -selectivity is not absolute and is dose dependent, the lowest possible dose of acebutolol should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose-interval. A bronchodilator, such as a theophylline or a ? stimulant, should be made available in advance with instructions concerning its use. 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 and Hypoglycemia Beta-blockers may potentiate insulin-induced hypoglycemia and mask some of its manifestations such as tachycardia; however, dizziness and sweating are usually not significantly affected. Diabetic patients should be warned of the possibility of masked hypoglycemia. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom acebutolol therapy is to be withdrawn should be monitored closel
Drug Interactions Catecholamine-depleting drugs, such as reserpine, may have an additive effect when given with betablocking agents. Patients treated with acebutolol plus catecholamine depletors should, therefore, be observed closely for evidence of marked bradycardia or hypotension which may present as vertigo, syncope/presyncope, or orthostatic changes in blood pressure without compensatory tachycardia. Exaggerated hypertensive responses have been reported from the combined use of beta-adrenergic antagonists and alpha-adrenergic stimulants, including those contained in proprietary cold remedies and vasoconstrictive nasal drops. Patients receiving beta-blockers should be warned of this potential hazard. Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal antiinflammatory drugs has been reported. No significant interactions with digoxin, hydrochlorothiazide, hydralazine, sulfinpyrazone, oral contraceptives, tolbutamide, or warfarin have been observed. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Carcinogenesis, Mutagenesis, Impairment of Fertility Chronic oral toxicity studies in rats and mice, employing dose levels as high as 300 mg/kg/day, which
is equivalent to 15 times the maximum recommended (60 kg) human dose, did not indicate a carcinogenic potential for acebutolol. Diacetolol, the major metabolite of acebutolol in man, was without carcinogenic potential in rats when tested at doses as high as 1800 mg/kg/day. Acebutolol and diacetolol were also shown to be devoid of mutagenic potential in the Ames Test. Acebutolol, administered orally to two generations of male and female rats at doses of up to 240 mg/kg/day (equivalent to 12 times the maximum recommended therapeutic dose in a 60-kg human) and diacetolol, administered to two generations of male and female rats at doses of up to 1000 mg/kg/day, had no significant impact on reproductive performance or fertility. Pregnancy Teratogenic Effects Pregnancy Category B
DOSAGE AND ADMINISTRATION Hypertension The initial dosage of acebutolol hydrochloride capsules in uncomplicated mild-to-moderate hypertension is 400 mg. This can be given as a single daily dose, but in occasional patients twice daily dosing may be required for adequate 24-hour blood-pressure control. An optimal response is usually achieved with dosages of 400 to 800 mg/day, although some patients have been maintained on as little as 200 mg/day. Patients with more severe hypertension or who have demonstrated inadequate control may respond to a total of 1200 mg daily (administered b.i.d.), or to the addition of a second antihypertensive agent. Beta-1 selectivity diminishes as dosage is increased. Ventricular Arrhythmia The usual initial dosage of acebutolol hydrochloride capsules is 400 mg daily given as 200 mg b.i.d. Dosage should be increased gradually until an optimal clinical response is obtained, generally at 600 to 1200 mg/day. If treatment is to be discontinued, the dosage should be reduced gradually over a period of about 2 weeks. Use in Older Patients Older patients have an approximately 2-fold increase in bioavailability and may require lower maintenance doses. Doses above 800 mg/day should be avoided in the elderly