FDA ALERT [5/16/2008] - Inosine Monophosphate Dehydrogenase Inhibitors (IMPDH) Immunosuppressants
FDA is aware of reports of infants born with serious congenital anomalies, including microtia and cleft lip and palate, following exposure to mycophenolate mofetil (MMF) during pregnancy. MMF, the active drug substance in CellCept, is an ester of the active metabolite mycophenolic acid (MPA), the active drug substance in Myfortic. In most cases, the mothers were taking MMF following an organ transplant to prevent organ rejection. However, some mothers taking MMF were being treated for immune-mediated conditions such as systemic lupus erythematosus (SLE) and erythema multiforme. Treatment began before their pregnancies and continued into the first trimester or until the pregnancy was detected. MMF is approved in the US for use in the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants and MPA is approved in the US for use in the prophylaxis of organ rejection in patients receiving allogeneic renal transplants. In patients who are transplant recipients, these drugs are almost always used in combination with other immunosuppressant drugs.
MMF and MPA increase the risk of spontaneous abortion in the first trimester and can cause congenital malformations in the offspring of women who are treated during pregnancy. The labeling for both MMF and MPA was revised in November 2007 to change the Pregnancy Category to "D" (positive evidence of human fetal risk, but potential benefits may warrant use of the drug in pregnant women despite the potential risk) and to add these findings about the risk of early pregnancy loss and congenital malformations to the boxed warning.
FDA is continuing to work with the manufacturers of these drug products to develop and implement means to mitigate the risks of fetal exposure.
This information reflects FDA's current analysis of data available to FDA concerning this drug. FDA intends to update this when additional information or analyses become available.
To report any unexpected adverse or serious events associated with the use of these drugs, please contact the FDA MedWatch program and complete a form on line at http://www.fda.gov/medwatch/report/hcp.htm or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.
Health care professionals who prescribe MMF or MPA to women of childbearing potential (including pubertal girls and peri-menopausal women) should be aware of the increased risk of fetal harm from exposure to these drugs during pregnancy and ways to mitigate this risk. Prior to prescribing MMF or MPA, clinicians should:
- Provide information on the fetal risks: Women of childbearing potential should be made aware of the risk of fetal harm from exposure to MMF or MPA during pregnancy.
- Provide counseling about contraception options: Women of childbearing potential should be made aware of the different contraceptive options while being treated with MMF or MPA. Women may choose to commit to abstinence as their only form of birth control. Women who choose an oral contraceptive pill as one of their methods should be told that MMF and MPA reduce blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness.
- Provide instruction on the appropriate use of contraceptive methods: To prevent pregnancy, women of childbearing potential must use two effective forms of birth control. Women should begin using the two forms of contraception four weeks prior to starting treatment and continue use for six weeks after the last treatment dose of MMF or MPA. If abstinence is the chosen method, the same start and stop times as for birth control should be observed.
- Confirm that the woman is not pregnant: Before initiating therapy, women of childbearing potential should have a negative serum or urine pregnancy test (sensitivity at least 25 mIU/mL) within one week prior to starting treatment with MMF or MPA. Do not initiate treatment before obtaining the results of the pregnancy test.
If women begin treatment with MMF or MPA in the hospital setting immediately following organ transplantation, appropriate contraception should be started at that time. Continuing the use of two forms of contraception or the need to choose alternative pregnancy prevention methods should be discussed at each clinical visit with women of childbearing potential who are using MMF or MPA.
If therapy must be 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.
Information for female patients of childbearing potential:
- Taking MMF or MPA early in your pregnancy can increase your chance of miscarriage and increase the chance that your baby will have serious birth defects.
- Tell your doctor if you are planning a pregnancy and are using MMF (CellCept®) or MPA (Myfortic®). Based on your health, your doctor will decide which medicines are best for you during pregnancy and while you are trying to get pregnant.
- You must use two forms effective birth control if you are taking MMF or MPA, unless you choose abstinence as your only form of birth control.
- You must start using two forms of birth control four weeks before you begin taking MMF or MPA and continue until six weeks after you stop taking the medicine.
In November 2007, FDA revised the prescribing information (labeling) for MMF (CellCept®) and MPA (Myfortic®) based on published and unpublished reports of use during pregnancy that identified an increased risk of spontaneous abortion (miscarriage) and congenital malformations. These malformations included bilateral microtia or anotia, sometimes accompanied by atresia of the external auditory canals, oral clefts, and/or other major structural malformations.
As a result of these findings, FDA changed the pregnancy category to "D" (positive evidence of human fetal risk based on adverse reaction data, but potential benefits may warrant use of the drug in pregnant women despite the potential risk) from "C" (drug has been shown to be teratogenic or have embryocidal effects in animals; no human data). Information on these findings was also added to the Boxed Warning and Warnings sections of the labeling. Subsequent to the labeling changes, Dear Healthcare Professional (DHCP) letters were sent to alert prescribers to these changes in the MMF and MPA labeling. The data reviewed by FDA that supported these labeling changes are summarized below.
In the National Transplantation Pregnancy Registry (NTPR) there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4-5% among babies born to organ transplant patients using other immunosuppressive drugs.
In postmarketing data (collected worldwide, 1995-2007) on 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Overall, six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. The malformations seen in offspring were similar to findings in animal reproductive toxicology studies.
FDA is aware that MMF is used by healthcare practitioners to treat immune-mediated conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis or erythema multiforme; these are not approved uses in the U.S. FDA is aware of infants with microtia or anotia with or without other congenital malformations whose mothers used MMF during the first trimester of pregnancy for the treatment of SLE or erythema multiforme. Malformations in these infants share common features with the malformations seen in infants born to mothers using MMF for prevention of solid organ transplant rejection.
FDA is working with the manufacturers of MMF and MPA to develop a program to mitigate the risks of fetal exposure.