Modafinil and increased risk of congenital malformations if used during pregnancy

Modafinil (Provigil): increased risk of congenital malformations if used during pregnancy

Modafinil potentially increases the risk of congenital malformations when used in pregnancy. Modafinil should not be used during pregnancy and women of childbearing potential must use effective contraception during treatment and for 2 months after stopping modafinil.

Advice for healthcare professionals:

• modafinil potentially increases the risk of congenital malformations (including congenital heart defects, hypospadias, and orofacial clefts); modafinil should not be used in pregnancy and alternative treatment options for narcolepsy should be considered

• women of childbearing potential must use effective contraception during treatment and for 2 months after stopping modafinil

• modafinil may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, therefore alternative or concomitant methods of contraception are required – see Advice on contraception use

• ensure all female patients of childbearing potential taking modafinil are informed and fully understand that:
  • modafinil should not be used during pregnancy due to the increased risk to the fetus
  • effective contraception is needed during treatment with modafinil and for 2 months after stopping modafinil treatment
  • they should discuss plans for pregnancy early with their doctor and continue contraception for 2 months after stopping modafinil

• report any suspected adverse reactions experienced by a woman or child associated with medicines taken during pregnancy via the Yellow Card Scheme

Data for risk of congenital malformations

The Nuvigil and Provigil registry, a prospective, observational study in the USA, was established in 2010 to characterise the pregnancy and foetal outcomes associated with exposure to modafinil and related drug armodafinil from 6 weeks before conception and/or during pregnancy.

• data ascertained from the 2018 Annual Registry report (considered by the review that led to the most recent changes to product information) estimated that the prevalence of major congenital malformations was approximately 14.75% (95% CI 5.85–23.65), compared with 3% in the general population
  • estimated prevalence of cardiac anomalies of 4.92% (0–10.34) was also higher than reported in the general population (1%). These rates are based on prospective data from 78 pregnancy cases; 61 of these reported a live birth outcome, of which 9 presented with major congenital anomalies (including 3 cardiac congenital anomalies)

Advice on contraception use

• before starting modafinil, women of childbearing potential must be informed of the risk of teratogenicity. Patients must use effective contraception during treatment with modafinil and for 2 months after stopping

• modafinil may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, through the induction of CYP3A4/5. (2) Alternative or concomitant methods of contraception are required

• guidance is available on interactions with contraception from the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit (January 2017, last reviewed 2019). For enzyme-inducing medicines such as modafinil, the guidance recommends avoiding combined hormonal contraception (CHC) pills, rings, and patches; progestogen-only pill; progestogen-only implants; and ulipristal acetate emergency contraception
  • suitable long-term methods are copper intrauterine device (copper IUD), levonorgestrel-releasing intrauterine system (LNG-IUS), and depot progestogen-only injections. For emergency contraception, if a copper IUD is not suitable, a double dose of oral levonorgestrel emergency contraception is advised – see the product information for levonorgestrel
  • the guidance recommends that if use of modafinil is only anticipated for a short time (2 months), barrier methods in conjunction with existing contraceptives may be advised

• when using any medicine with teratogenic potential, a woman should be advised of the risks and encouraged to use the most effective contraceptive method taking into account her personal circumstances. See Drug Safety Update March 2019 for guidance on contraceptive methods and frequency of pregnancy testing to reduce inadvertent exposures during pregnancy in a woman taking a medicine of teratogenic potential

• women of childbearing potential planning a pregnancy should be advised on the need to discuss other narcolepsy treatment options with their doctor before stopping contraception.

Reference:

• Damkier P and others. ‘First-Trimester Pregnancy Exposure to Modafinil and Risk of Congenital Malformations’. JAMA 2020; volume 323: pages 374–76.

• Robertson P Jr and others. ‘Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers’. Clin Pharmacol Ther 2002; volume 71: pages 46–56.

• Drug Safety Update volume 14, issue 4: November 2020: 1.