Benazepril Hydrochloride (Page 4 of 6)

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was found when benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells or in a nucleus anomaly test. In doses of 50 mg/kg/day to 500 mg/kg/day (6 to 60 times the maximum recommended human dose based on mg/m2 comparison and 37 to 375 times the maximum recommended human dose based on a mg/kg comparison), benazepril hydrochloride had no adverse effect on the reproductive performance of male and female rats.

Pregnancy Category D

See WARNINGS , Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.

Geriatric Use

Of the total number of patients who received benazepril in U.S. clinical studies of benazepril hydrochloride, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Benazepril and benazeprilat are substantially excreted by the kidney. 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.

Pediatric Use

The antihypertensive effects of benazepril hydrochloride have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Hypertension). The pharmacokinetics of benazepril hydrochloride have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). Benazepril hydrochloride was generally well tolerated and adverse effects were similar to those described in adults. (See ADVERSE REACTIONS, Pediatric Patients).

Treatment with benazepril hydrochloride is not recommended in pediatric patients less than 6 years of age (see ADVERSE REACTIONS), and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism , In Pediatric Patients and DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS

Benazepril hydrochloride has been evaluated for safety in over 6,000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in benazepril hydrochloride and placebo patients.

The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 mg to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with benazepril hydrochloride and in 3% of patients treated with placebo.

The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) (see PRECAUTIONS , Cough ).

The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with benazepril hydrochloride are shown below.

PATIENTS IN U.S. PLACEBO-CONTROLLED STUDIES
BENAZEPRIL HCl PLACEBO
(N=964) (N=496)
N % N %
Headache 60 6.2 21 4.2
Dizziness 35 3.6 12 2.4
Fatigue 23 2.4 11 2.2
Somnolence 15 1.6 2 0.4
Postural Dizziness 14 1.5 1 0.2
Nausea 13 1.3 5 1.0
Cough 12 1.2 5 1.0

Other adverse experiences reported in controlled clinical trials (in less than 1% of benazepril patients), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain):

Cardiovascular

Symptomatic hypotension was seen in 0.3% of patients, postural hypotension in 0.4% and syncope in 0.1%; these reactions led to discontinuation of therapy in 4 patients who had received benazepril monotherapy and in 9 patients who had received benazepril with hydrochlorothiazide (see PRECAUTIONS and WARNINGS). Other reports included angina pectoris, palpitations and peripheral edema.

Renal

Of hypertensive patients with no apparent preexisting renal disease, about 2% have sustained increases in serum creatinine to at least 150% of their baseline values while receiving benazepril hydrochloride, but most of these increases have disappeared despite continuing treatment. A much smaller fraction of these patients (less than 0.1%) developed simultaneous (usually transient) increases in blood urea nitrogen and serum creatinine.

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