Acebutolol Hydrochloride 400 mg Capsule, 100-count — NDC 51407-667-01 (Billing 51407-0667-01)

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If cardiac failure persists, therapy with acebutolol should be withdrawn.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If cardiac failure continues despite adequate digitalization and/or diuretic, acebutolol therapy should be withdrawn.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be carefully observed, and should be advised to limit physical activity to a minimum while acebutolol is gradually withdrawn over a period of about two weeks.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.

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.

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.

PRECAUTIONS Risk of Anaphylactic Reaction While taking beta-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. Impaired Renal or Hepatic Function Studies on the effect of acebutolol in patients with renal insufficiency have not been performed in the U.S.

Foreign published experience shows that acebutolol has been used successfully in chronic renal insufficiency. Acebutolol is excreted through the GI tract, but the active metabolite, diacetolol, is eliminated predominantly by the kidney. There is a linear relationship between renal clearance of diacetolol and creatinine clearance.

Therefore, the daily dose of acebutolol should be reduced by 50% when the creatinine clearance is less than 50 mL/min and by 75% when it is less than 25 mL/min. acebutolol should be used cautiously in patients with impaired hepatic function. Acebutolol has been used successfully and without problems in elderly patients in the U.S. clinical trials without specific adjustment of dosage. However, elderly patients may require lower maintenance doses because the bioavailability of both acebutolol and its metabolite are approximately doubled in this age group.

Information for Patients Patients, especially those with evidence of coronary artery disease, should be warned against interruption or discontinuation of acebutolol therapy without a physician’s supervision. Although cardiac failure rarely occurs in properly selected patients, those being treated with β-adrenergic blocking agents should be advised to consult a physician if they develop signs or symptoms suggestive of impending CHF, or unexplained respiratory symptoms. Patients should also be warned of possible severe hypertensive reactions from concomitant use of α-adrenergic stimulants, such as the nasal decongestants commonly used in OTC cold preparations and nasal drops.

Clinical Laboratory Findings Acebutolol, like other β-blockers, has been associated with the development of antinuclear antibodies (ANA). In prospective clinical trials, patients receiving acebutolol had a dose-dependent increase in the development of positive ANA titers, and the overall incidence was higher than that observed with propranolol. Symptoms (generally persistent arthralgias and myalgias) related to this laboratory abnormality were infrequent (less than 1% with both drugs).

Symptoms and ANA titers were reversible upon discontinuation of treatment. 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.

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