The alert, including information for patients, is on the FDA Web site at www.fda.gov/cder/drug/infopage/mycophenolate/default.htm
Rheumatologists who have been using mycophenolate mofetil off label to treat lupus and rheumatoid arthritis in women of reproductive age should be aware that the Food and Drug Administration has issued an alert about cases of birth defects and spontaneous abortions associated with its use in the first-trimester.
Mycophenolate mofetil—CellCept—is also used off label in women with erythema multiforme. The FDA's report concerns a second drug: Myfortic (mycophenolic acid). Mycophenolate mofetil (MMF) is an ester of the metabolite mycophenolic acid (MPA), which is the active drug substance in Myfortic. Both agents are approved to prevent organ rejection after transplantation.
The information about early pregnancy loss and congenital malformations was described in a letter to health care professionals and added to the black box warning in the labels of the two drugs in November 2007, when they were reclassified as pregnancy category D drugs. A classification of category D means there is positive evidence of human fetal risk, but potential benefits might warrant the use of the drug during pregnancy anyway. The drugs previously were classified as category C, meaning they were shown to be teratogenic or to have embryocidal effects in animals, but that there are no human data.
Now, published and unpublished reports associate the drugs with an increased risk of spontaneous abortions and serious congenital malformations in humans, including bilateral microtia or anotia, sometimes with atresia of the external auditory canals; oral clefts; and other major structural malformations, according to the FDA. In most cases, the mothers were taking MMF after an organ transplant, but in some cases, the women were taking MMF for systemic lupus erythematosus, erythema multiforme, or other immune-mediated conditions.
The data include 33 pregnancies exposed to MMF in 24 transplant patients in the National Transplantation Pregnancy Registry. There were 15 spontaneous abortions (45%). Of the 18 live-born infants, four (22%) had a major structural malformation. This is compared with the 3% background rate of congenital anomalies in the United States, and a rate of 4%–5% among babies born to women in the registry who took other immunosuppressive drugs. The FDA cited postmarketing data in 77 women exposed to MMF during pregnancy between 1995 and 2007: 25 had a spontaneous abortion and 14 had a malformed infant or fetus (including ear abnormalities in six cases).
The FDA is advising health care professionals to counsel women of childbearing potential about the fetal risks associated with taking the medications, and about contraceptive options. Health care professionals should not start treatment until they confirm patients are not pregnant, using a serum or urine pregnancy test that has a sensitivity of at least 25 mIU/mL, within 1 week of starting treatment.
“If therapy is initiated in a patient who is already pregnant or the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the developing fetus,” according to the FDA. “Women taking CellCept and Myfortic and who are planning to become pregnant should also talk with their doctors about the risks involved and whether alternative immunosuppressive agents can be considered,” according to the release.