The U.S. Food and Drug Administration (FDA) and Bristol-Myers Squibb have warned healthcare professionals via letter against the use of efavirenz (Sustiva) during pregnancy due to the potential risk of fetal harm, especially during the first trimester, according to an alert sent last Friday from MedWatch, the FDA’s safety information and adverse event reporting system.
The change in pregnancy category from C to D was based on four retrospective reports of neural tube defects in infants born to women with first trimester exposure to efavirenz, including three cases of meningomyelocele and one of Dandy Walker Syndrome.
The FDA recommends that women of childbearing potential undergo pregnancy testing prior to initiation of efavirenz therapy and that pregnancy be avoided during treatment through use of barrier contraception in combination with other contraceptive methods.
In animal studies of efavirenz, malformations were observed in 3 (15%) of 20 fetuses/infants (vs 0 in placebo controls) born to cynomolgus monkeys treated throughout pregnancy with a daily dose of efavirenz that yielded plasma concentrations similar to that of human adults receiving the recommended dosage of 600 mg per day.
In these monkeys, efavirenz crossed the placenta to produce fetal blood concentrations similar to that of the mother. The fetuses showed anencephaly plus unilateral anophthalmia, microophthalmia, and a cleft palate, respectively.
An increase in fetal resorptions was observed in rats administered efavirenz doses that produced peak plasma concentrations and area under the curve (AUC) values equivalent to or lower than those achieved in humans receiving a 600-mg dose per day. No reproductive toxicities were observed in pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans receiving 600 mg of efavirenz per day.
According to the FDA, limited data are available regarding birth defects occurring after intrauterine exposure to efavirenz. Of pregnancy outcomes in 206 women (207 fetuses) exposed to efavirenz-containing regimens (mostly in the first trimester), birth defects occurred in 5 (5.68%) of 188 live births with first-trimester exposure, and in 0 of 13 live births with second- or third-trimester exposure.
Although none of the defects in the prospective study were neural tube defects, four such cases have been reported retrospectively in women exposed to efavirenz-containing regimens during the first trimester. While a causal role for efavirenz has not been established, the FDA regards the combined findings as a reason for concern and cautions against the use of efavirenz during pregnancy.
Efavirenz should be used during the first trimester of pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women lacking other therapeutic options. Patients receiving efavirenz during the first trimester or who become pregnant during treatment should be apprised of the potential harm to the fetus.