Mycophenolate mofetil, mycophenolic acid: updated contraception advice for male patients

Mycophenolate mofetil and its active metabolite mycophenolic acid, both used to prevent transplant rejection, are teratogenic and genotoxic. The available clinical evidence does not indicate an increased risk of malformations or miscarriage in pregnancies where the father was taking mycophenolate medicines, but there is insufficient evidence to rule out any risk. As a precautionary measure for male patients, it is now recommended that either the patient or their female partner use reliable contraception during treatment with mycophenolate medicines and for at least 90 days after stopping. Female patients of childbearing potential receiving mycophenolate should always use contraception.

From:
Medicines and Healthcare products Regulatory Agency
Published
6 February 2018
Therapeutic area:
Immunosuppression and transplantation, Obstetrics, gynaecology and fertility, Rheumatology, Urology and nephrology

Advice for healthcare professionals prescribing mycophenolate to male patients:

  • available clinical evidence does not indicate an increased risk of malformations or miscarriage in pregnancies where the father was taking mycophenolate medicines, however mycophenolate mofetil and mycophenolic acid are genotoxic and a risk cannot be fully excluded.
  • it is therefore recommended that male patients or their female partner use reliable contraception during treatment and for at least 90 days after stopping mycophenolate medicines
  • discuss with male patients planning to have children the implications of both immunosuppression and the effect of prescribed medications on the pregnancy

Reminder for healthcare professionals prescribing mycophenolate to female patients:

  • mycophenolate medicines remain contraindicated in women of childbearing potential who are not using reliable contraception and in pregnant women unless there are no suitable alternatives to prevent transplant rejection
  • female patients of childbearing potential must use at least one reliable form of contraception before and during treatment and for 6 weeks after stopping mycophenolate medicines; 2 forms of contraception are preferred
  • report suspected adverse drug reactions associated with mycophenolate medicines, including adverse pregnancy outcomes, to us on a Yellow Card

Background to teratogenic and genotoxic risk

Mycophenolate (mycophenolate mofetil and mycophenolic acid), authorised to prevent transplant rejection, is a major human teratogen known to cause miscarriages and congenital malformation in pregnant women. Between 45% and 49% of cases of exposure to mycophenolate in pregnancy result in miscarriage, and between 23% and 27% result in malformations (see below for reminder of pregnancy-prevention advice for female patients).

Mycophenolate medicines are also genotoxic. Mycophenolate medicines are excreted in the semen, raising concerns regarding pregnancies exposed via the father. In December 2015, based on a review of evidence at the time, we advised that men receiving treatment and their female partners should both use contraception to prevent pregnancy.

Male patients – review of risks associated with pregnancies exposure via the father

Following an in-depth routine review in Europe of all the available non-clinical and clinical data for men fathering children while receiving mycophenolate mofetil and mycophenolic acid, recommendations to prevent pregnancy have been updated.

Although the amount of mycophenolate present in semen has not been determined precisely, calculations based on animal data show that the maximum amount of mycophenolate that could be transferred to a woman is low and is unlikely to have any teratogenic effect. However, mycophenolate has also been shown to be genotoxic in animal studies, albeit at concentrations higher than the human therapeutic exposure levels, and the risk of genotoxic effects on sperm cells cannot be completely excluded. The available clinical evidence, while reassuring, is currently insufficient to rule out any risk in humans.

It is therefore recommended that, as a precautionary measure, either male patients or their female partners use reliable contraception and that men planning to have children discuss this with their doctor. The previous recommendation for men receiving treatment, specifying both the male patient and their partner use contraception, is no longer considered necessary. The clinical situation is continually monitored and, as more data becomes available, advice may be updated.

Female patients – reminder of pregnancy-prevention advice

In female patients the risk of serious birth defects and increased spontaneous abortion remains high (see December 2015 Drug Safety Update). The 2015 review of worldwide cases of congenital malformations after exposure during pregnancy confirmed mycophenolate mofetil as a powerful human teratogen, and showed evidence of an increased rate of congenital malformations and spontaneous abortions compared with other immunosuppressants.

In the literature,[footnote 1][footnote 2][footnote 3] the risk for malformations associated with the use of mycophenolate is reported to be between 23% and 27% of livebirths, compared with 4–5% for female organ transplant recipients in the USA receiving immunosuppressants other than mycophenolate. For spontaneous abortions, the reported risk is between 45% and 49%, whereas the risk in organ transplant recipients receiving immunosuppressants other than mycophenolate varies between 12% and 33%, according to the type of immunosuppressant and type of transplanted organ.

Mycophenolate medicines remain contraindicated in women of childbearing potential who are not using reliable contraception. These medicines are also contraindicated in pregnant women unless there are no suitable alternatives to prevent transplant rejection.

Female patients of childbearing potential must use at least one reliable form of contraception before and during treatment and for 6 weeks after stopping treatment. Two forms of contraception are preferred. Mycophenolate treatment should only be initiated in women of childbearing potential when there is a negative pregnancy test result to rule out unintended use in pregnancy. Two pregnancy tests 8–10 days apart are recommended.

Physicians should ensure that female patients taking mycophenolate mofetil and mycophenolic acid understand:

  • the risk of harm to a baby
  • the need for effective contraception
  • the need to plan for pregnancy and change treatment as necessary
  • the need to immediately consult a physician if there is a possibility of pregnancy

Report suspected adverse drug reactions

Suspected adverse drug reactions associated with mycophenolate medicines, including adverse pregnancy outcomes, should be reported on a Yellow Card.

Further information

Article citation: Drug Safety Update volume 11 issue 7; February 2018: 2.

Post-publication note:

See also our 2019 guidance on contraceptive methods and frequency of pregnancy testing to reduce inadvertent exposures during pregnancy to medicines of teratogenic potential.

  1. Sifontis NM, et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82: 1698–702. ↩

  2. Coscia LA, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 2009: 103–22. ↩

  3. Hoeltzenbein M, et al. Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services. Am J Med Genet A 2012; 158A: 588–96. ↩

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Published 6 February 2018
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