Amlodipine Besylate and Benazepril Hydrochloride (Page 2 of 7)

5.5 Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the RAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue amlodipine and benazepril hydrochloride as soon as possible [see USE IN SPECIFIC POPULATIONS (8.1)].

5.6 Hepatitis and Hepatic Failure

There have been rare reports of predominantly cholestatic hepatitis and isolated cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The mechanism is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevation of hepatic enzymes should discontinue the ACE inhibitor and be kept under medical surveillance.

5.7 Impaired Renal Function

Monitor renal function periodically in patients treated with amlodipine and benazepril hydrochloride. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAS. Patients whose renal function may depend in part on the activity of the RAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on NSAIDS or ARBs may be at particular risk of developing acute renal failure on amlodipine and benazepril hydrochloride. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine and benazepril hydrochloride.

5.8 Hyperkalemia

Monitor serum potassium periodically in patients receiving amlodipine and benazepril hydrochloride. Drugs that affect the RAS can cause hyperkalemia. 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. In U.S. placebo-controlled trials of amlodipine and benazepril hydrochloride, hyperkalemia [serum potassium at least 0.5 mEq/L greater than the upper limit of normal (ULN)] not present at baseline occurred in approximately 1.5% of hypertensive patients receiving amlodipine and benazepril hydrochloride. Increases in serum potassium were generally reversible.

5.9 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.

5.10 Surgery/Anesthesia

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 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 and benazepril hydrochloride capsules doses up to 5 mg/20 mg, 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 and benazepril hydrochloride capsules and in 3% of patients treated with placebo.

The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride capsules 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 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 and benazepril hydrochloride capsules (3.3%) than on placebo (0.2%).

Percent Incidence in U. S. Placebo-controlled Trials
*
Edema refers to all edema, such as dependent edema, angioedema, facial edema.
Benazepril/Amlodipine N=760 Benazepril N=554 Amlodipine N=475 Placebo 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

The incidence of edema was greater in patients treated with amlodipine monotherapy (5.1%) than in patients treated with amlodipine and benazepril hydrochloride capsules (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 and benazepril hydrochloride capsules 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 and benazepril hydrochloride.

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