Benazepril Hydrochloride and Hydrochlorothiazide (Page 5 of 6)

Non-Clinical Safety Data

Carcinogenesis, Mutagenicity, Fertility

No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104 weeks at doses up to 150 mg/kg/day. On a body-surface-area basis, this dose is 18 times (rats) and 9 times (mice) the maximum recommended human dose. 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. At doses of 50 to 500 mg/kg/day (6 to 61 times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse effect on the reproductive performance of male and female rats.

Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.

Fertility

There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception (see PRECAUTIONS, Non-Clinical Safety Data).

Use in Specific Populations

Nursing Mothers

Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat. Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue benazepril hydrochloride and hydrochlorothiazide, taking into account the importance of the drug to the mother.

Geriatric Use

Of the total number of patients who received benazepril hydrochloride and hydrochlorothiazide in U.S. clinical studies of benazepril hydrochloride and hydrochlorothiazide, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients.

A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

Pediatric Use

Neonates with a history of in utero exposure to benazepril hydrochloride and hydrochlorothiazide:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.

Safety and effectiveness in pediatric patients have not been established.

Renal Impairment

Safety and effectiveness of benazepril hydrochloride and hydrochlorothiazide in patients with severe renal impairment (CrCL ≤30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60 to 90 mL/min) or moderate (CrCL 30 to 60 mL/min) renal impairment.

Hepatic Impairment

No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see CLINICAL PHARMACOLOGY).

Hydrochlorothiazide

Minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

ADVERSE REACTIONS

Benazepril hydrochloride and hydrochlorothiazide has been evaluated for safety in over 2500 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 200 were treated for more than 1 year.

The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 7% of U.S. patients treated with benazepril hydrochloride and hydrochlorothiazide and in 4% of patients treated with placebo.

The most common reasons for discontinuation of therapy with benazepril hydrochloride and hydrochlorothiazide in U.S. studies were cough (1.0%; see PRECAUTIONS), “dizziness” (1.0%), headache (0.6%), and fatigue (0.6%).

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 and hydrochlorothiazide are shown in the table below.

Reactions Possibly or Probably Drug Related Patients in U.S. Placebo-Controlled Studies

Benazepril Hydrochloride and Hydrochlorothiazide

N=665

Placebo

N=235

N

%

N

%

“Dizziness”

41

6.3

8

3.4

Fatigue

34

5.2

6

2.6

Postural Dizziness

23

3.5

1

0.4

Headache

20

3.1

10

4.3

Cough

14

2.1

3

1.3

Hypertonia

10

1.5

3

1.3

Vertigo

10

1.5

2

0.9

Nausea

9

1.4

2

0.9

Impotence

8

1.2

0

0.0

Somnolence

8

1.2

1

0.4

Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in 0.3% to 1.0% of patients treated with benazepril hydrochloride and hydrochlorothiazide were the following:

Cardiovascular

Palpitations, flushing.

Gastrointestinal

Vomiting, diarrhea, dyspepsia, anorexia, and constipation.

Neurologic and Psychiatric

Insomnia, nervousness, paresthesia, libido decrease, dry mouth, taste perversion, and tinnitus.

Dermatologic

Rash and sweating.

Other

Urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and abdominal pain).

Other adverse experiences reported in 0.3% or more of benazepril hydrochloride and hydrochlorothiazide patients in U.S. controlled clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked entries occurred in more than 1% of patients (in some, a causal relationship to benazepril hydrochloride and hydrochlorothiazide is uncertain):

Cardiovascular

Syncope, peripheral vascular disorder, and tachycardia.

Body as a Whole

Infection, back pain*, flu syndrome*, fever, chills, and neck pain.

Dermatologic

Photosensitivity and pruritus.

Gastrointestinal

Gastroenteritis, flatulence, and tooth disorder.

Neurologic and Psychiatric

Hypesthesia, abnormal vision, abnormal dreams, and retinal disorder.

Respiratory

Upper respiratory infection*, epistaxis, bronchitis, rhinitis*, sinusitis*, and voice alteration.

Other

Conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency*.

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