ROCKVILLE, Maryland, and NUTLEY, New Jersey—The US Food and Drug Administration (FDA) and Roche Laboratories, Inc, today issued a warning that mycophenolate mofetil (MMF, CellCept®, Roche) has been positively linked to first-trimester miscarriages and birth defects in the children of women who have taken it.¹

MMF is approved and widely used for prevention of organ rejection in kidney, heart, or liver transplant recipients, but is also used off-label with corticosteroid for treating lupus nephritis. At the 8th International Congress on SLE held in Shanghai last May, Tak Mao Chan, MD, professor of medicine at the University of Hong Kong's Queen Mary Hospital in China, said, "The favorable efficacy and tolerability profile, and the ease of treatment without hospitalization or intravenous drug administration has resulted in [MMF and corticosteroid] being increasingly adopted as standard therapy, often before regulatory approval."

Roche and Aspreva Pharmaceuticals Corp announced in September that they would not be seeking approval of MMF as induction therapy for lupus nephritis because phase III data did not show it to be better than intravenous cyclophosphamide.

The letter to physicians from Roche vice president for medical affairs Lars E. Birgerson, MD, PhD, stated, "The pregnancy category for CellCept 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 postmarketing data from the United States National Transplantation Pregnancy Registry (NTPR), and additional postmarketing data collected in women exposed by systemic MMF during pregnancy."

The Roche letter advises that

• women of childbearing potential have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 1 week prior to beginning MMF
• MMF not be initiated until a negative pregnancy test is obtained
• women of childbearing potential (including pubertal girls and perimenopausal women) taking MMF receive contraceptive counseling and use two effective methods of contraception, beginning 4 weeks prior to starting MMF "unless abstinence is the chosen method"
• use of contraception should continue for 6 weeks after stopping MMF
• women planning pregnancy should not use MMF unless they cannot be successfully treated with other immunosuppressant drugs

Dr. Birgerson's letter continued, "Based on postmarketing data from the NTPR and Roche worldwide adverse event reporting system, use of CellCept during pregnancy is associated with an increased risk of first-trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney."

"In December 2006, the NTPR published data from prospective cases where 24 female transplant patients reported 33 pregnancies exposed to MMF-containing regimens. There were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected from 1995 to 2007) on 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions, and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities...Similar structural malformations have been observed in preclinical animal reproductive toxicology studies."

"Patients should be aware that CellCept reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness."

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