Females And Males Of Reproductive Potential: Fertility: CellCept is contraindicated in women of childbearing potential not using highly effective contraceptive methods. (see Contraindications). Malformations (including anophthalmia, agnathia, and hydrocephaly) occurred in the first generation offspring of female rats treated with oral doses of mycophenolate mofetil in the absence of maternal toxicity (see Pharmacology: Toxicology: Preclinical Safety: Impairment of Fertility under Actions). No effect was seen on the fertility of male rats treated with mycophenolate mofetil.
Pregnancy Testing: Prior to starting therapy with CellCept, female patients of childbearing potential must have two negative serum or urine pregnancy tests with a sensitivity of at least 25mIU/mL. A second test should be performed 8-10 days later. If it is not possible to perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), a pregnancy test must be performed immediately before starting treatment and a second test performed 8-10 days later.
Contraception: Females: Cellcept is contraindicated in women of childbearing potential not using highly effective contraceptive methods (see Contraindications).
Before the start of treatment, female and male patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention, and planning.
Women of child bearing potential should use two reliable forms of contraception simultaneously, including at least one of which must be highly effective before beginning CellCept therapy, during therapy and for six weeks following discontinuation of therapy, unless abstinence is the chosen method of contraception.
Males: Limited clinical evidence is currently available on paternal exposure to CellCept. This evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate.
Non-clinical evidence shows that the dose of mycophenolate that could be transferred via the seminal fluid to a potentially pregnant partner is 30-fold lower than the concentration without teratogenic effects in animals, and 200-fold lower than the lowest teratogenic concentration in animals. Therefore, the risk of harm mediated via seminal fluid is considered negligible. However, genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5-times. Thus, the risk of genotoxic effects on sperm cells cannot completely be excluded.
In absence of sufficient data to exclude a risk of harm to the fetus conceived during or directly after the treatment of the father, the following precautionary measure is recommended: sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment.
Pregnancy: CellCept is contraindicated during pregnancy due to its mutagenic and teratogenic potential (see Contraindications). CellCept is a human teratogen, with an increased risk of spontaneous abortions (mainly in the first trimester) and congenital malformations in case of maternal exposure during pregnancy (see Post Marketing under Adverse Reactions). In the medical literature, the risk of spontaneous abortions has been reported as 45 to 49% following mycophenolate mofetil exposure, compared to a reported rate between 12 and 33% in solid organ transplant patients treated with other immunosuppressants.
Congenital malformations (including multiple malformations in individual newborns) have been reported in 23 to 27% of live births in mycophenolate mofetil exposed pregnancies in published literature. For comparison the risk of malformations is estimated at approximately 2% of live births in the overall population and at approximately 4 to 5 % in solid organ transplant patients treated with immunosupressants other than mycophenolate mofetil.
The following malformations were most frequently reported post-marketing, in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy: Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits; Abnormalities of the ear (e.g. abnormally formed or absent external/middle ear) and eye (e.g. coloboma, microphthalmos); Malformations of the fingers (e.g. polydactyly, syndactyly, brachydactyly); Cardiac abnormalities such as atrial and ventricular septal defects; Oesophageal malformations (e.g. oesophageal atresia); Nervous system malformations (such as spina bifida).
These findings were consistent with teratology studies performed in rats and rabbits where fetal resorptions and malformations occurred in absence of maternal toxicity (see Pharmacology: Toxicology: Preclinical Safety: Teratogenicity under Actios).
Labor and delivery: The safe use of CellCept during labor and delivery has not been established.
Lactation: It is not known whether the drug is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants, CellCept is contraindicated during breastfeeding (see Contraindication).
Although the relevance to humans is unknown, tudies in rats have shown mycophenolate mofetil to be excreted in milk.