According to FDA, Bristol-Myers Squibb (BMS) sent a letter to Health Care Providers, who are caring for HIV-1-infected patients, to make clinicians aware of important new information in the Sustiva (Efavirenz) Package Insert regarding pregnancy.
The pregnancy category for Sustiva has been changed from Category C (risk of fetal harm cannot be ruled out) to Category D (positive evidence of fetal risk).
This change is a result of four retrospective reports of neural tube defects in infants born to women with first trimester exposure to Sustiva including three cases of meningomyelocele and one Dandy Walker Syndrome.
As Sustiva may cause fetal harm when administered during the first trimester to a pregnant woman, pregnancy should be avoided in women receiving Sustiva.
Women of childbearing potential should undergo pregnancy testing before initiation of Sustiva.
If Sustiva is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
Though there are no adequate,well-controlled studies in pregnant women, Sustiva 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 without other therapeutic options.
Barrier contraception should always be used in combination with other contraceptive methods.
During the development of Sustiva, animal studies were performed to assess the potential for birth defects.
Malformations were observed in 3 of 20 fetuses/infants from Efavirenz-treated cynomolgus monkeys ( versus 0 of 20 concomitant controls ) in a developmental toxicity study.
The pregnant monkeys were dosed throughout pregnancy ( postcoital days 20-150 ) with Efavirenz 60 mg/kg daily, a dose resulting in plasma drug concentrations similar to those in humans given 600 mg/day of Sustiva.
Anencephaly and unilateral anophthalmia were observed in one monkey fetus, microophthalmia was observed in another fetus, and cleft palate was observed in a third fetus.
Efavirenz crosses the placenta in cynomolgus monkeys and produces fetal blood concentrations similar to maternal blood concentrations.
An increase in fetal resorptions was observed in rats given Efavirenz doses that produced peak plasma concentrations and area under the curve ( AUC ) values in female rats equivalent to or lower than those achieved in humans given 600 mg once daily of Sustiva.
Efavirenz produced no reproductive toxicities when given to pregnant rabbits at doses that produced peak plasma concentrations similar to and AUC values approximately half of those achieved in humans given 600 mg once daily of Sustiva.
Limited data are available regarding birth defects occurring after intrauterine exposure to Sustiva.
The outcomes of pregnancy have been reviewed for 206 women ( 207 fetuses ) after being exposed to Efavirenz-containing regimens, most of which were first-trimester exposures.
Birth defects occurred in 5 of 188 live births with first-trimester exposure and in 0 of 13 live births with second-or third-trimester exposure.
None of these prospectively reported defects were neural tube def ects. However, there have been 4 retrospective reports ( i.e.,after the results of the pregnancy were known ) of findings consistent with neural tube defects, including 3 cases of meningomyelocele.
All 4 mothers were exposed to Efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Sustiva has not been established, similar defects have been observed in preclinical studies of Efavirenz.