Acebutolol Hydrochloride

INDICATIONS AND USAGE Hypertension Acebutolol Hydrochloride Capsules USP are indicated for the management of hypertension in adults. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. Ventricular Arrhythmias Acebutolol Hydrochloride Capsules USP 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.

DOSAGE AND ADMINISTRATION Hypertension The initial dosage of acebutolol 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 mg to 800 mg per day, although some patients have been maintained on as little as 200 mg per 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 dose of acebutolol 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 mg to 1200 mg per day. If treatment is to be discontinued, the dosage should be reduced gradually over a period of about two 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.

WARNINGS Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by β-adrenergic receptor blockade may precipitate more severe failure. Although β-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 If cardiac failure persists, therapy with acebutolol should be withdrawn.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 β-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 β-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 two weeks. (If therapy with an alternative β-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of β-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 β-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 β-BLOCKER. Because of its relative β1-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 β1-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 theophylline or a β2-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 β-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 β-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. Abrupt withdrawal of β-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom acebutolol therapy is to be withdrawn should be monitored closely.

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 .)

Drug Interactions Catecholamine-depleting drugs, such as reserpine, may have an additive effect when given with β-blocking 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 β-adrenergic antagonists and α-adrenergic stimulants, including those contained in proprietary cold remedies and vasoconstrictive nasal drops. Patients receiving β-blockers should be warned of this potential hazard. Blunting of the antihypertensive effect of beta-adrenoreceptor blocking agents by nonsteroidal anti-inflammatory 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.

Pregnancy Teratogenic Effects Reproduction studies have been performed with acebutolol in rats (up to 630 mg/kg/day) and rabbits (up to 135 mg/kg/day). These doses are equivalent to approximately 31.5 and 6.8 times the maximum recommended therapeutic dose in a 60-kg human, respectively. The compound was not teratogenic in either species. In the rabbit, however, doses of 135 mg/kg/day caused slight fetal growth retardation; this effect was considered to be a result of maternal toxicity, as evidenced by reduced food intake, a lowered rate of body weight gain, and mortality. Studies have also been performed in these species with diacetolol (at doses of up to 450 mg/kg/day in rabbits and up to 1800 mg/kg/day in rats). Other than a significant elevation in post-implantation loss with 450 mg/kg/day diacetolol, a level at which food consumption and body weight gain were reduced in rabbit dams and a nonstatistically significant increase in incidence of bilateral cataract in rat fetuses from dams treated with 1800 mg/kg/day diacetolol, there was no evidence of harm to the fetus. There are no adequate and well-controlled trials in pregnant women. Because animal teratology studies are not always predictive of the human response, acebutolol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Non–Teratogenic Effects Studies in humans have shown that both acebutolol and diacetolol cross the placenta. Neonates of mothers who have received acebutolol during pregnancy have reduced birth weight, decreased blood pressure, and decreased heart rate. In the newborn the elimination half-life of acebutolol was 6 to 14 hours, while the half-life of diacetolol was 24 to 30 hours for the first 24 hours after birth, followed by a half-life of 12 to 16 hours. Adequate facilities for monitoring these infants at birth should be available.

Nursing Mothers Acebutolol and diacetolol also appear in breast milk with a milk:plasma ratio of 7.1 and 12.2, respectively. Use in nursing mothers is not recommended.

ADVERSE REACTIONS Acebutolol is well tolerated in properly selected patients. Most adverse reactions have been mild, not required discontinuation of therapy, and tended to decrease as duration of treatment increases. The following table shows the frequency of treatment-related side effects derived from controlled clinical trials in patients with hypertension, angina pectoris, and arrhythmia. These patients received acebutolol, propranolol, or hydrochlorothiazide as monotherapy, or placebo. TOTAL VOLUNTEERED AND ELICITED (U.S. STUDIES) Body System/ Adverse Reaction Acebutolol (N=1002) % Propranolol (N=424) % Hydrochlorothiazide (N=178) % Placebo (N=314) % Cardiovascular Chest Pain 2 4 4 1 Edema 2 2 4 1 Central Nervous System Depression 2 1 3 1 Dizziness 6 7 12 2 Fatigue 11 17 10 4 Headache 6 9 13 4 Insomnia 3 6 5 1 Abnormal dreams 2 3 0 1 Dermatologic Rash 2 2 4 1 Gastrointestinal Constipation 4 2 7 0 Diarrhea 4 5 5 1 Dyspepsia 4 6 3 1 Flatulence 3 4 7 1 Nausea 4 6 3 0 Genitourinary Micturition (frequency) 3 1 9 <1 Musculoskeletal Arthralgia 2 1 3 2 Myalgia 2 1 4 0 Respiratory Cough 1 1 2 0 Dyspnea 4 6 4 2 Rhinitis 2 1 4 <1 Special Senses Abnormal Vision 2 2 3 0 The following selected (potentially important) side effects were seen in up to 2% of acebutolol patients: Cardiovascular: hypotension, bradycardia, heart failure. Central Nervous System: anxiety, hyper/hypoesthesia, impotence. Dermatological: pruritus. Gastrointestinal: vomiting, abdominal pain. Genitourinary: dysuria, nocturia. Liver and Biliary System: A small number of cases of liver abnormalities (increased SGOT, SGPT, LDH) have been reported in association with acebutolol therapy. In some cases increased bilirubin or alkaline phosphatase, fever, malaise, dark urine, anorexia, nausea, headache, and/or other symptoms have been reported. In some of the reported cases, the symptoms and signs were confirmed by rechallenge with acebutolol. The abnormalities were reversible upon cessation of acebutolol therapy. Musculoskeletal: back pain, joint pain. Respiratory: pharyngitis, wheezing. Special Senses: conjunctivitis, dry eye, eye pain. Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported. The incidence of drug-related adverse effects (volunteered and solicited) according to acebutolol dose is shown below. (Data from 266 hypertensive patients treated for 3 months on a constant dose.) Body System 400 mg/day (N=132) 800 mg/day (N=63) 1200 mg/day (N=71) Cardiovascular 5% 2% 1% Gastrointestinal 3% 3% 1% Musculoskeletal 2% 3% 4% Central Nervous System 9% 13% 17% Respiratory 1% 5% 6% Skin 1% 2% 1% Special Senses 2% 2% 6% Genitourinary 2% 3% 1% Potential Adverse Events 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 acebutolol. 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 acebutolol during investigational use and extensive foreign clinical experience. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.