Acebutolol Hydrochloride (Page 2 of 3)

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 challenged, 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 ar tery 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.

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: 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 wellcontrolled 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.

Nonteratogenic 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.

LABOR AND DELIVERY: The effect of acebutolol on labor and delivery in pregnant women is unknown. Studies in animals have not shown any effect of acebutolol on the usual course of labor and delivery.

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.

PEDIATRIC USE: Safety and effectiveness in pediatric patients have not been established.

GERIATRIC USE: Clinical studies of acebutolol and other reported clinical experience is inadequate to determine whether there are differences in safety or effectiveness between patients above or below age 65. Elderly subjects evidence greater bioavailability of acebutolol (see Clinical Pharmacology — PHARMACOKINETICS AND METABOLISM), presumably because of age related reduction in first-pass metabolism and renal function. Therefore, it may be appropriate to start elderly patients at the low end of the dosing range (see Dosage and Administration — USE IN OLDER PATIENTS).

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.

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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.)

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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 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.

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