Amlodipine Besylate and Benazepril Hydrochloride (Page 2 of 7)

5.5 Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and, sometimes, death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered.

However, since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t_1/2 ) is 56 hours in patients with impaired hepatic function, titrate amlodipine besylate and benazepril hydrochloride slowly in patients with severe hepatic impairment.

5.6 Impaired Renal Function

Amlodipine Besylate and Benazepril Hydrochloride Capsules should not be used in patients with severe renal disease (Clearance creatinine < 30 mL/min) [see Dosage and Administration (2)]

In patients with severe heart failure, whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with benazepril may be associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death.

In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis, treatment with benazepril was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of benazepril therapy, concomitant diuretic therapy, or both. When such patients are treated with Amlodipine Besylate and Benazepril Hydrochloride Capsules, monitor renal function during the first few weeks of therapy.

Some benazepril-treated hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when benazepril has been given concomitantly with a diuretic. Dosage reduction of Amlodipine Besylate and Benazepril Hydrochloride Capsules may be required.

Renal function should be monitored periodically in patients receiving benazepril.

5.7 Hyperkalemia

In U.S. placebo-controlled trials of Amlodipine Besylate and Benazepril Hydrochloride Capsules, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) not present at baseline occurred in approximately 1.5% of hypertensive patients receiving Amlodipine Besylate and Benazepril Hydrochloride Capsules. Increases in serum potassium were generally reversible. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Serum potassium should be monitored periodically in patients receiving benazepril.

5. 8 Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

5. 9 Surgery/Ane s thesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Amlodipine besylate and benazepril hydrochloride has been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year.

In a pooled analysis of 5 placebo-controlled trials involving amlodipine besylate and benazepril hydrochloride doses up to 5/20, 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 4% of patients treated with amlodipine besylate and benazepril hydrochloride and in 3% of patients treated with placebo.

The most common reasons for discontinuation of therapy with amlodipine besylate and benazepril hydrochloride in these studies were cough and edema (including angioedema).

The peripheral edema associated with amlodipine use is dose-dependent. When benazepril is added to a regimen of amlodipine, the incidence of edema is substantially reduced.

The addition of benazepril to a regimen of amlodipine should not be expected to provide additional antihypertensive effect in African-Americans. However, all patient groups benefit from the reduction in amlodipine-induced edema.

The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with amlodipine besylate and benazepril hydrochloride are shown in the table below. Cough was the only adverse event with at least possible relationship to treatment that was more common on amlodipine besylate and benazepril hydrochloride (3.3%) than on placebo (0.2%).

PERCENT INCIDENCE IN U.S. PLACEBO-CONTROLLED TRIALS

	Benazepril/Amlodipine	Benazepril	Amlodipine	Placebo
	N=760	N=554	N=475	N=408
Cough	3.3	1.8	0.4	0.2
Headache	2.2	3.8	2.9	5.6
Dizziness	1.3	1.6	2.3	1.5
Edema*	2.1	0.9	5.1	2.2

*Edema refers to all edema, such as dependent edema, angioedema, facial edema.

The incidence of edema was greater in patients treated with amlodipine monotherapy (5.1%) than in patients treated with amlodipine besylate and benazepril hydrochloride (2.1%) or placebo (2.2%).

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

Body as a Whole: Asthenia and fatigue.

CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido.

Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis.

Digestive: Dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, and esophagitis.

Hematologic:Neutropenia

Metabolic and Nutritional: Hypokalemia.

Musculoskeletal: Back pain, musculoskeletal pain, cramps, and muscle cramps.

Respiratory: Pharyngitis.

Urogenital: Sexual problems such as impotence, and polyuria.

Monotherapies of benazepril and amlodipine have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of amlodipine besylate and benazepril hydrochloride.