FDA Downgrades the Antiviral Efavirenz to Pregnancy Category D

The Food and Drug Administration has downgraded efavirenz to pregnancy category D, “Positive Evidence of Fetal Risk,” and is urging women to avoid becoming pregnant while taking the antiretroviral drug.

The new package label stems from four retrospective reports of women who gave birth to infants with neural tube defects after first-trimester exposure to efavirenz (Sustiva). Three infants were diagnosed with meningomyelocele and one with Dandy Walker syndrome.

Physicians are being asked to report pregnant patients who have been exposed to efavirenz to the Antiretroviral Pregnancy Registry (800–258–4263), which was established to monitor fetal outcomes. The drug had previously been labeled category C: “Risk of Fetal Harm Cannot Be Ruled Out.”

Bristol-Myers Squibb Co., Princeton, N.J., alerted health care providers to the label change in a letter dated March 2005 and made public in June. Signed by Freda C. Lewis-Hall, M.D., senior vice president for medical affairs, the letter urged pregnancy testing before women start on efavirenz.

“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,” Dr. Lewis-Hall advised. “Barrier contraception should always be used in combination with other contraceptive methods.”

Dr. Lewis-Hall described a prospective review of pregnancy outcomes for 206 women who carried 207 fetuses, while exposed to efavirenz. Five of 188 infants born after first-trimester exposure had birth defects; none were observed in 13 live births after second- or third-trimester exposures. Dr. Lewis-Hall did not describe the birth defects, except to say they were not neural tube defects, which, so far, have only been seen in retrospective reports.

“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,” she wrote. Her letter cited a preclinical animal study that reported malformations in 3 of 20 fetuses from cynomolgus monkeys treated with efavirenz throughout pregnancy.

Gerald G. Briggs, B.Pharm., told this newspaper that data from pregnancy registries and retrospective reports should be viewed as identifying possible signals and raising hypotheses.

“Follow-up controlled studies are needed to determine if the association is causative,” said Mr. Briggs, a pharmacist clinical specialist at Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., and coauthor of the reference book “Drugs in Pregnancy and Lactation” (Philadelphia: Lippincott Williams & Wilkins, 2005).

He did not rule out prescribing efavirenz for a pregnant woman who is positive for HIV. If she cannot take an alternative nonnucleoside reverse transcriptase inhibitor and has done well on efavirenz, he recommended continuing her on the drug.

“Taken in sum, the data suggest that there may be a small risk of neural tube defects and other defects, but no neural tube defects were observed in 188 prospective cases, so the risk must be low,” he said.

As in all potential pregnancies, he added, the woman should be taking folic acid before conception.

“It may not be preventive,” Mr. Briggs said, “but based on the potential signal, I would recommend the same folic acid dose used for anticonvulsants known to cause neural tube defects and for women with a history of giving birth to an infant with a neural tube defect: 4 or 5 mg per day.”

The Food and Drug Administration has downgraded efavirenz to pregnancy category D, “Positive Evidence of Fetal Risk,” and is urging women to avoid becoming pregnant while taking the antiretroviral drug.

The new package label stems from four retrospective reports of women who gave birth to infants with neural tube defects after first-trimester exposure to efavirenz (Sustiva). Three infants were diagnosed with meningomyelocele and one with Dandy Walker syndrome.

Physicians are being asked to report pregnant patients who have been exposed to efavirenz to the Antiretroviral Pregnancy Registry (800–258–4263), which was established to monitor fetal outcomes. The drug had previously been labeled category C: “Risk of Fetal Harm Cannot Be Ruled Out.”

Bristol-Myers Squibb Co., Princeton, N.J., alerted health care providers to the label change in a letter dated March 2005 and made public in June. Signed by Freda C. Lewis-Hall, M.D., senior vice president for medical affairs, the letter urged pregnancy testing before women start on efavirenz.

“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,” Dr. Lewis-Hall advised. “Barrier contraception should always be used in combination with other contraceptive methods.”

Dr. Lewis-Hall described a prospective review of pregnancy outcomes for 206 women who carried 207 fetuses, while exposed to efavirenz. Five of 188 infants born after first-trimester exposure had birth defects; none were observed in 13 live births after second- or third-trimester exposures. Dr. Lewis-Hall did not describe the birth defects, except to say they were not neural tube defects, which, so far, have only been seen in retrospective reports.

“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,” she wrote. Her letter cited a preclinical animal study that reported malformations in 3 of 20 fetuses from cynomolgus monkeys treated with efavirenz throughout pregnancy.

Gerald G. Briggs, B.Pharm., told this newspaper that data from pregnancy registries and retrospective reports should be viewed as identifying possible signals and raising hypotheses.

“Follow-up controlled studies are needed to determine if the association is causative,” said Mr. Briggs, a pharmacist clinical specialist at Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., and coauthor of the reference book “Drugs in Pregnancy and Lactation” (Philadelphia: Lippincott Williams & Wilkins, 2005).

He did not rule out prescribing efavirenz for a pregnant woman who is positive for HIV. If she cannot take an alternative nonnucleoside reverse transcriptase inhibitor and has done well on efavirenz, he recommended continuing her on the drug.

“Taken in sum, the data suggest that there may be a small risk of neural tube defects and other defects, but no neural tube defects were observed in 188 prospective cases, so the risk must be low,” he said.

As in all potential pregnancies, he added, the woman should be taking folic acid before conception.

“It may not be preventive,” Mr. Briggs said, “but based on the potential signal, I would recommend the same folic acid dose used for anticonvulsants known to cause neural tube defects and for women with a history of giving birth to an infant with a neural tube defect: 4 or 5 mg per day.”

The Food and Drug Administration has downgraded efavirenz to pregnancy category D, “Positive Evidence of Fetal Risk,” and is urging women to avoid becoming pregnant while taking the antiretroviral drug.

The new package label stems from four retrospective reports of women who gave birth to infants with neural tube defects after first-trimester exposure to efavirenz (Sustiva). Three infants were diagnosed with meningomyelocele and one with Dandy Walker syndrome.

Physicians are being asked to report pregnant patients who have been exposed to efavirenz to the Antiretroviral Pregnancy Registry (800–258–4263), which was established to monitor fetal outcomes. The drug had previously been labeled category C: “Risk of Fetal Harm Cannot Be Ruled Out.”

Bristol-Myers Squibb Co., Princeton, N.J., alerted health care providers to the label change in a letter dated March 2005 and made public in June. Signed by Freda C. Lewis-Hall, M.D., senior vice president for medical affairs, the letter urged pregnancy testing before women start on efavirenz.

“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,” Dr. Lewis-Hall advised. “Barrier contraception should always be used in combination with other contraceptive methods.”

Dr. Lewis-Hall described a prospective review of pregnancy outcomes for 206 women who carried 207 fetuses, while exposed to efavirenz. Five of 188 infants born after first-trimester exposure had birth defects; none were observed in 13 live births after second- or third-trimester exposures. Dr. Lewis-Hall did not describe the birth defects, except to say they were not neural tube defects, which, so far, have only been seen in retrospective reports.

“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,” she wrote. Her letter cited a preclinical animal study that reported malformations in 3 of 20 fetuses from cynomolgus monkeys treated with efavirenz throughout pregnancy.

Gerald G. Briggs, B.Pharm., told this newspaper that data from pregnancy registries and retrospective reports should be viewed as identifying possible signals and raising hypotheses.

“Follow-up controlled studies are needed to determine if the association is causative,” said Mr. Briggs, a pharmacist clinical specialist at Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., and coauthor of the reference book “Drugs in Pregnancy and Lactation” (Philadelphia: Lippincott Williams & Wilkins, 2005).

He did not rule out prescribing efavirenz for a pregnant woman who is positive for HIV. If she cannot take an alternative nonnucleoside reverse transcriptase inhibitor and has done well on efavirenz, he recommended continuing her on the drug.

“Taken in sum, the data suggest that there may be a small risk of neural tube defects and other defects, but no neural tube defects were observed in 188 prospective cases, so the risk must be low,” he said.

As in all potential pregnancies, he added, the woman should be taking folic acid before conception.

“It may not be preventive,” Mr. Briggs said, “but based on the potential signal, I would recommend the same folic acid dose used for anticonvulsants known to cause neural tube defects and for women with a history of giving birth to an infant with a neural tube defect: 4 or 5 mg per day.”