Yael Waknine

April 28, 2010

April 28, 2010 — The US Food and Drug Administration (FDA) approved in March safety labeling revisions for a fixed-dose combination capsule containing the dihydropyridine calcium channel blocker amlodipine besylate and the angiotensin-converting enzyme (ACE) inhibitor benazepril HCl (Lotrel; Novartis Pharmaceuticals Corp).

The revisions address benazepril-related fetal and neonatal risks; drug interactions; and the potential for renal impairment and angioedema, as well as the risk for amlodipine-associated peripheral edema.

Amlodipine plus benazepril capsules are indicated for the treatment of hypertension in patients not adequately controlled with monotherapy with either agent.

Benazepril Component Linked to Fetal and Neonatal Risks

The FDA has advised of risks associated with use of the benazepril component of amlodipine plus benazepril capsules in pregnancy.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when used in pregnant women. Such drugs include angiotensin II receptor antagonists, renin inhibitors, and ACE inhibitors such as benazepril.

Use of ACE inhibitors during the second and third trimesters has been associated with several dozen published cases of fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, and associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Although not conclusively linked to ACE inhibitor exposure, cases of prematurity, intrauterine growth retardation, and patent ductus arteriosus also have occurred.

Citing data from a published retrospective epidemiologic study, the FDA also warned that first-trimester exposure to ACE inhibitors may be linked to an increased risk for major congenital malformations. According to the agency, the number of cases was small, and the study findings have not yet been repeated.

Women of childbearing age should be warned of the consequences associated with gestational exposure to benazepril, and alternative therapies should be explored for those planning on becoming pregnant.

Clinicians are advised to make every effort to discontinue treatment immediately on detection of pregnancy. In rare instances (< 0.1% of pregnancies) in which no other therapy is possible, serial ultrasound examinations are required to assess the intraamniotic environment.

If oligohydramnios is observed, amlodipine/benazepril therapy should be discontinued unless considered life-saving for the mother. Contraction stress testing, a nonstress test, or biophysical profiling may be appropriate, depending on the week of pregnancy. Patients and clinicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to benazepril should be closely observed for hypotension, oliguria, and hyperkalemia. Blood pressure and renal perfusion support may be required, and exchange transfusion or dialysis may be needed to reverse hypotension and/or support decreased renal function. Although experience is limited, benazepril, which crosses the placenta, may be removed from neonatal circulation by these measures.

Benazepril Component Linked to Risk for Renal Impairment

Renal function should be monitored periodically in patients receiving benazepril. Use of benazepril is contraindicated in patients with severe renal disease (creatinine clearance < 30 mL/minute).

In patients with severe heart failure, whose renal function may depend on activity of the renin-angiotensin-aldosterone system, benazepril therapy may be associated with oliguria or progressive azotemia. Rare cases of acute renal failure and/or death have been reported.

In a small study of patients with hypertension with unilateral or bilateral renal artery stenosis, treatment with benazepril was linked to increases in levels of serum urea nitrogen and serum creatinine that were reversible on discontinuation of benazepril, concomitant diuretic therapy, or both. Renal function should be monitored for the first few weeks of amlodipine/benazepril therapy for such patients.

Some benazepril-treated patients with hypertension but with no apparent preexisting renal vascular disease have experienced increases in serum urea nitrogen and serum creatinine levels that were usually minor and transient, especially when benazepril has been given concomitantly with a diuretic. Dosage reduction of benazepril may be required for such cases.

Additional Warnings and Precautions

The FDA warns of the risk for dose-dependent peripheral edema associated with use of amlodipine and notes that the addition of benazepril to the regimen substantially reduces this risk (amlodipine, 5.1% vs amlodipine/benazepril, 2.1% and placebo, 2.2%). However, this addition should not be expected to provide additional antihypertensive effect in African Americans.

Although benazepril is effective for attenuating potassium loss caused by thiazide diuretics, use with potassium-sparing diuretics (eg, spironolactone, amiloride, and triamterene) or potassium supplements can increase the risk for hyperkalemia and necessitate monitoring of serum potassium levels.

The agency also warned of the risk for head/neck and intestinal angioedema that can occur at any time during treatment with ACE inhibitors such as benazepril and has been reported at an increased rate in black vs nonblack patients.

Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis, or larynx has been observed in approximately 0.5% of patients treated with benazepril in clinical studies and can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, immediate discontinuation of therapy and initiation of epinephrine therapy are warranted.

Intestinal angioedema has also been reported in patients receiving ACE inhibitors. Patients usually presented with abdominal pain with or without nausea or vomiting; in some cases, no history of facial angioedema was noted, and C-1 esterase levels were within the normal range. The condition was diagnosed on abdominal computed tomography, ultrasound, or during surgery, and symptoms resolved on discontinuation of ACE inhibitor therapy.

The FDA recommends that intestinal angioedema be included in the differential diagnosis of patients receiving ACE inhibitors and presenting with abdominal pain.





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