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.

From:
Medicines and Healthcare products Regulatory Agency
Published
16 November 2020
Last updated
16 November 2020 — See all updates
Therapeutic area:
Neurology and Pregnancy

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

Review of safety in pregnancy

Modafinil (Provigil, generics) is indicated in adults for the treatment of excessive sleepiness associated with narcolepsy with or without cataplexy (see full indication in summary of product characteristics). Narcolepsy is a rare long-term brain condition that causes excessive daytime sleepiness, cataplexy (loss of muscle tone), and sleep disturbance. Recommended supportive measures for narcolepsy symptoms include behaviour modifying measures, sleep hygiene, and scheduled daytime naps.

A European review concluded that there was a possible increased risk of congenital malformations in the children of women treated with modafinil during pregnancy. The product information, including the patient information leaflet, has been updated and a letter sent to prescribers of modafinil in January 2020.

The review considered data from a prospective US registry and spontaneous reports of major congenital malformations including congenital heart defects, hypospadias, and orofacial clefts, for which causal relationship with modafinil was considered possible. The MHRA has considered the European review and other safety data,[footnote 1] which support the suggestion of an increased risk of major congenital malformations with use of modafinil in pregnancy.

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.

Interim 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. The 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). While the target sample size for the registry has not yet been reached, this interim analysis has shown that the prevalence of major congenital malformations is above the background rate in the general population. In addition to the registry findings, studies in animals have shown reproductive toxicity.

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.[footnote 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.

The guidance states that 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.

Report on a Yellow Card

Please continue to report any suspected adverse drug reactions (ADRs) associated with modafinil or any other medicines via the Yellow Card scheme.

Please report any suspected ADRs associated medicines taken during pregnancy or breastfeeding experienced by the woman and any suspected effects on the baby or child.

All patients, caregivers, and healthcare professionals can report a Yellow Card when they suspect a medication used during pregnancy has caused an adverse reaction or adverse pregnancy outcome.

When reporting ADRs related to medicines used in pregnancy, the following information is particularly valuable for our assessment of the report:

  • Timings of when the medicine was taken during the pregnancy

  • The outcome of the pregnancy (when known)

  • Details of any relevant family history, including any obstetric history

  • For reports concerning congenital malformations, a detailed clinical description of any congenital anomaly and the results of any imaging (for example, scans), or laboratory tests

Please include any other relevant information; including other medications or substances taken during the pregnancy, as well as folic acid intake.

Report Yellow Cards using:

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

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

  2. 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. ↩

Updates to this page

Published 16 November 2020
Last updated 16 November 2020 + show all updates

  1. Added to DSU November

  2. Article part of DSU November

  3. First published.

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