Warning about Pregnancy Risks
When FDA approved Accutane, the drug was known to be teratogenic--able to cause birth defects. It was designated as Category X, meaning that it must be avoided under all circumstances during pregnancy. Nursing mothers also should not use Accutane.Though not every fetus exposed to Accutane becomes deformed, the risk of birth defects among pregnant women is extremely high. These defects include hydrocephaly (enlargement of the fluid-filled spaces of the brain) and microcephaly (small head), heart defects, facial deformities such as cleft lip and missing ears, and mental retardation.
Reports in the literature suggest that about 25 to 35 percent of babies will suffer a malformation after exposure, and that doesn't account for other defects, such as learning disabilities, that aren't detectable at birth. Miscarriages and premature births have also been reported.
Though FDA approved labeling in 1982 that warned Accutane should not be used in pregnant women, reports of severe birth defects associated with the drug began to arrive in June 1983. Over the following years, a series of labeling changes and letters to pharmacists and prescribers of the drug stressed pregnancy warnings and sought to increase awareness about reported malformations.
Then, after an FDA review of pregnancy exposures to Accutane, Roche launched the Pregnancy Prevention Program (PPP) in late 1988 to further educate women using Accutane and their physicians about the dangers. The goal was to ensure that prescriptions would only be given to women with severe recalcitrant nodular acne who could comply with contraceptive requirements.
Roche sent PPP kits to physicians and encouraged them to review pregnancy prevention materials with patients before starting the drug. Materials included a contraceptive booklet, checklists to help assess whether patients could adhere to the drug's requirements, and consent forms that patients sign to acknowledge their understanding of the risk of birth defects. Roche also set up a toll-free line, made contraceptive information available in 13 languages, and offered to pay for contraceptive counseling and pregnancy testing by a specialist.
To further reinforce pregnancy prevention, Roche began packaging Accutane in blister packs that include red and black warnings, along with a drawing of a malformed baby and the "Avoid Pregnancy" symbol.
Even though Accutane's labeling recommended use of two reliable forms of contraception, there have been reports of pregnancies occurring in patients who used hormonal contraception, including pills, injectables, and implantables, while taking Accutane. Accutane's labeling was updated in the summer of 2000. One change emphasized the need for two reliable forms of contraception for at least one month before taking Accutane, during treatment, and for one month after discontinuing Accutane, even when one of the forms of contraception is hormonal.
Evaluating Compliance
Yolonda Lawrence of Santa Monica, Calif., says there was no way she could miss the point about pregnancy prevention before she used Accutane for severe adult-onset acne in 1998. "I got a pamphlet, I signed papers, the doctor told me over and over, and the pictures of what can happen were very clear--babies with no ears" and other deformities, she says.But reports of Accutane-exposed pregnancies continue, and that's enough to make FDA concerned, says Peter Honig, MD, director of FDA's office of postmarketing drug risk assessment (OPDRA) in CDER.
Shortly after the Pregnancy Prevention Program began, Roche sponsored a survey of women taking Accutane to assess compliance with the program, and the company encouraged doctors to enroll patients. Run by the Slone Epidemiology Unit at Boston University's School of Public Health, the survey set out to track pregnancy rates and outcomes, patients' awareness of risks, and patient and physician behavior.
Of the 500,000 women enrolled in the Slone survey from 1989 to 1998, there have been 958 pregnancies, 834 of which were terminations (either elective, spontaneous or due to ectopic pregnancies), 110 that resulted in live births, and 14 patients that had unknown outcomes. Of the 60 infants with available medical records, eight had congenital abnormalities. Since Accutane's approval, Roche has received close to 2,000 reports of Accutane-exposed pregnancies, 70 percent of which occurred after the PPP began.
According to FDA, exactly how well the PPP has worked is unclear. Experts say the PPP is a significant program that has prevented many pregnancies and is the first of its kind initiated by a pharmaceutical company. Roche has made extraordinary efforts to educate patients that they must not become pregnant while taking Accutane, says a Roche spokesperson.
