Benazepril Hydrochloride (Page 3 of 4)

8.2 Lactation

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.

8.3 Pediatric Use

The antihypertensive effects of benazepril have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age [see Clinical Pharmacology (12.3)]. The pharmacokinetics of benazepril have been evaluated in pediatric patients 6 to 16 years of age [see Clinical Pharmacology (12.3)]. Infants below the age of 1 year should not be given benazepril because of the risk of effects on kidney development.

Safety and effectiveness of benazepril have not been established in pediatric patients less than 6 years of age or in children with glomerular filtration rate < 30 mL/min/1.73m² [see Dosage and Administration (2.1) and Clinical Pharmacology 12.3)].

8.4 Geriatric Use

Of the total number of patients who received benazepril in U.S. clinical studies of benazepril, 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 [see Dosage and Administration (2.2)].

8.5 Race

ACE inhibitors, including benazepril, as monotherapy, have an effect on blood pressure that is less in Black patients than in non-Blacks.

8.6 Renal Impairment

Dose adjustment of benazepril is required in patients undergoing hemodialysis or whose creatinine clearance is ≤ 30 mL/min. No dose adjustment of benazepril is required in patients with creatinine clearance > 30 mL/min [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 6 g/kg. Reduced activity was seen at 1 g/kg in mice and at 5 g/kg in rats. Human overdoses of benazepril have not been reported, but the most common manifestation of human benazepril overdosage is likely to be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Hypotension can be associated with electrolyte disturbances and renal failure.

Benazepril is only slightly dialyzable, but consider dialysis to support patients with severely impaired renal function [see Warnings and Precautions (5.3)].

If ingestion is recent, consider activated charcoal. Consider gastric decontamination (e.g., vomiting, gastric lavage) in the early period after ingestion.

Monitor for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.

In the case of marked hypotension, infuse physiological saline solution; as needed, consider vasopressors (e.g., catecholamines i.v.).

11 DESCRIPTION

Benazepril hydrochloride, USP is a white to off-white crystalline powder, soluble (> 100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is benazepril 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl] amino]-2,3,4,5-tetrahydro-2-oxo-1H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is

Chemical Structure
(click image for full-size original)

Its molecular formula is C24 H28 N2 O5 •HCl and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor.
Benazepril hydrochloride is supplied as tablets containing 10 mg, 20 mg and 40 mg of benazepril hydrochloride USP for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, polysorbate 80, pregelatinized starch (maize) and titanium dioxide. In addition, the 10 mg contains iron oxide yellow and 20 mg and 40 mg contains iron oxide red.
Meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. Benazeprilat has much greater ACE inhibitory activity than does benazepril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of benazepril remains to be elucidated. While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

12.2 Pharmacodynamics

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60% to 90% (up to 4 hours post-dose) at the 10 mg dose.

Drug Interactions

Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. Benazepril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.

12.3 Pharmacokinetics

The pharmacokinetics of benazepril are approximately dose-proportional within the dosage range of 10 to 80 mg.

Following oral administration of benazepril, peak plasma concentrations of benazepril, and its active metabolite benazeprilat are reached within 0.5 to 1 hours and 1 to 2 hours, respectively. While the bioavailability of benazepril is not affected by food, time to peak plasma concentrations of benazeprilat is delayed to 2 to 4 hours.

The serum protein binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24 to 23.6 μmol/L).

Benazepril is almost completely metabolized to benazeprilat by cleavage of the ester group (primarily in liver). Both benazepril and benazeprilat undergo glucuronidation.

Benazepril and benazeprilat are cleared predominantly by renal excretion. About 37% of an orally administered dose was recovered in urine as benazeprilat (20%), benazeprilat glucuronide (8%), benazepril glucuronide (4%) and as trace amounts of benazepril. Nonrenal (i.e., biliary) excretion accounts for approximately 11% to 12% of benazeprilat excretion. The effective half-life of benazeprilat following once daily repeat oral administration of benazepril hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily.

Accumulation ratio based on AUC of benazeprilat was 1.19 following once daily administration.

Specific Populations

Renal impairment

The pharmacokinetics of systemic exposure to benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance > 30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance ≤ 30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady-state may be delayed [see Dosage and Administration (2)].

When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not detected in the dialysate.

Hepatic impairment

In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are essentially unaltered.

Drug Interactions

The pharmacokinetics of benazepril are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).

Pediatrics

The pharmacokinetics of benazeprilat, evaluated in pediatric patients with hypertension following oral administration of a single dose is presented in table below.

Age group Cmax (ng/mL) Tmax * (h) AUC0-inf (ng/mL*h) CL/F/wt (L/h/Kg) T1/2 (h)
> 1 to ≤ 24 months n=5 277(192, 391) 1(0.6, 2) 1328(773, 2117) 0.26 (0.18, 0.4) 5 (4, 5.8)
> 2 to ≤ 6 years n=7 200 (168, 244) 2(1.4, 2.4) 978(842, 1152) 0.36(0.31, 0.42) 5.5(4.7, 6.5)
> 6 to ≤ 12 years n=7 221(194, 258) 2(1.2, 2.2) 1041(855, 1313) 0.25(0.21, 0.31) 5.5(4.7, 6.5)
> 12 to ≤ 17 years n=8 287(217, 420) 2(1.3, 2.3) 1794(1478, 2340) 0.16(0.13, 0.21) 5.1(4.2, 5.7)

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