FDA Safety Changes: Lotensin, Sustiva, Zevalin

April 4, 2007 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the risk for fetal harm associated with use of benazepril HCl during the first trimester of pregnancy; drug interactions with efavirenz; and the risk for myelodysplastic syndrome and/or acute myelogenous leukemia associated secondary to ibritumomab tiuxetan therapy.

First-Trimester Exposure to Benazepril HCl (Lotensin) Linked to Birth Defects
On February 2, the FDA approved safety labeling revisions for the angiotensin-converting enzyme (ACE) inhibitor benazepril HCl (Lotensin tablets; Novartis Pharmaceuticals Inc) to warn of the potential risks for fetal injury and death with this class of drugs in pregnancy. When pregnancy is detected, benazepril use should be discontinued as soon as possible.

Prescribing information previously advised that ACE inhibitor use be discontinued as soon as possible in pregnant patients — benazepril is classified as a pregnancy category D drug during the second and third trimesters and as a category C agent during the first trimester.

Although the first-trimester pregnancy category has not been altered at this time, the FDA advises that consideration be given to recently published data.

Findings from an observational study published in The New England Journal of Medicine in June 2006 revealed that infants exposed to ACE inhibitors during the first trimester of the gestational period had an increased overall relative risk (RR) for congenital malformations compared with those not exposed (RR, 2.71; 95% confidence interval [CI], 1.72 - 4.27).

Half of these defects were various cardiac septal defects, and the remainder included some defects of the central nervous, urologic, or other systems. Women receiving ACE inhibitor therapy were generally older and more likely to have other chronic conditions compared with those not receiving therapy.

Although the FDA notes that the number of cases reported is small and that the study findings have not been reproduced, use of benazepril is not recommended in women planning to conceive and should only be used in women of childbearing age after careful counseling and consideration of individual risks and benefits.

Use of ACE inhibitors during the second and third trimester has already been linked to risks for fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure, and death. In addition, oligohydramnios has been reported in association 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.

Benazepril is indicated for use alone or in combination with thiazide diuretics for the treatment of hypertension.

Efavirenz (Sustiva) Linked to Drug Interactions With Bepridil, Pimozide, and Voriconazole
On January 24, the FDA approved revisions to the safety labeling for efavirenz (Sustiva tablets and capsules; Bristol-Myers Squibb) to warn of new drug interactions associated with its use.

Studies suggest that efavirenz is primarily metabolized by the cytochrome P450 3A4 and 2B6 isoenzymes (CYP3A4 and CYP2B6, respectively). As with astemizole, cisapride (which has been discontinued), midazolam, triazolam, and ergot derivatives, concomitant use of the CYP3A4-metabolized calcium channel blocker bepridil (Vascor; discontinued by Johnson & Johnson) or the neuroleptic pimozide (Orap; Teva Pharmaceuticals Inc) is contraindicated because of the potential for their decreased metabolism. Increased serum levels of these drugs can lead to serious and life-threatening adverse events such as cardiac arrhythmias, prolonged sedation, or respiratory depression.

Also, standard doses of the antifungal drug voriconazole (Vfend; Pfizer Inc) are contraindicated with efavirenz because efavirenz significantly decreases voriconazole plasma concentrations while voriconazole significantly increases efavirenz plasma concentrations.

The warning was based on data from a pharmacokinetic study of healthy subjects, showing that systemic exposure of voriconazole (400 mg given orally every 12 hours for 1 day followed by 200 mg every 12 hours for 8 days) was significantly decreased (mean area under the curve, 61%; Cmax, 77%) when given concurrently with efavirenz (400 mg every 12 hours for 9 days). The area under the curve and Cmax for efavirenz increased by an average of 38% and 44%, respectively.

Concomitant therapy therefore requires dosage adjustments for both agents. Voriconazole maintenance dosing should be increased from 200 to 400 mg and given every 12 hours. The once-daily dose of efavirenz should be decreased from 600 to 300 mg using the capsule formulation.

Efavirenz is a nonnucleoside reverse transcriptase inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Ibritumomab Tiuxetan (Zevalin) Linked to Risk for Secondary MDS and/or AML
In January, the FDA approved safety labeling revisions for the radiopharmaceutical ibritumomab tiuxetan (Zevalin injection; Idec Pharmaceuticals Corp) to warn of the potential risk for myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML).

The warning was based on data showing that secondary MDS and/or AML were diagnosed in 19 (2.6%) of 846 patients enrolled in clinical studies and expanded-access programs.

The incidence rate among those enrolled in clinical studies was 5.2% (11/211) at a median follow-up of 6.5 years. The median time to development of MDS/AML in this population was 2.9 years, but cumulative data show a continued increase in risk (2.2% at 2 years, 5.9% at 5 years).

Of the patients registered in the expanded-access programs, 8 (1.5%) of 535 developed MDS/AML at a median of 1.5 years.

The FDA notes that multiple cytogenetic abnormalities were described, most commonly involving chromosomes 5 and/or 7. The risk for MDS/AML was not related to the number of prior treatments (0 or 1 vs 2 - 10).

Ibritumomab tiuxetan is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, including rituximab-refractory follicular disease. The intravenously administered regimen consists of rituximab followed by indium-111 and yitrium-90 ibritumomab tiuxetan.

http://www.fda.gov/medwatch/SAFETY/2007/Feb_PI/Lotensin_PI.pdf

http://www.fda.gov/medwatch/SAFETY/2007/Jan_PI/Sustiva_PI.pdf

http://www.fda.gov/medwatch/SAFETY/2007/Jan_PI/Zevalin_PI.pdf

Source: http://www.medscape.com/viewarticle/554655?src=mp