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From the World of Pharmacovigilance: Strengthening of risk minimisation measures for topiramate demonstrates dynamic nature of risk minimisation activities

The MHRA has recently introduced restrictions on the use of topiramate, accompanied by enhanced risk minimisation activities. In this blog we explain the background to this decision and use this case as a reminder that risk minimisation measures are dynamic and can either be enhanced or reduced depending on their effectiveness.

Background

In the UK, topiramate is approved as monotherapy for partial seizures in adults, adolescents and children aged 6 or over, and as adjunctive therapy for partial onset seizures and seizures due to Lennox-Gastaut syndrome in adults, adolescents and children aged 2 or over. Topiramate is also indicated for the prevention of migraine in adults after other options have been discounted, but is not intended for acute treatment of migraine.1

New safety concerns

The MHRA undertook a comprehensive review of the safety of antiseizure medicines during pregnancy which led to publication of new safety recommendations in January 2021.2 A new study and further data subsequently suggested that children exposed to topiramate during gestation were at increased risk of autism spectrum disorder and learning difficulties, and that more women of child-bearing age were using topiramate. In 2022 a review of the safety of topiramate was conducted by the MHRA, which found that use of topiramate is linked to significant harm to the unborn child, including congenital malformations, low birth weight and neurodevelopmental disorders.3

MHRA’s new requirements

In light of the new findings, in June 2024 MHRA introduced further restrictions on the use of topiramate in women of childbearing potential. Topiramate was already contraindicated in women of childbearing potential for prophylaxis of migraine (since 2010) but is now also contraindicated for all indications for women of childbearing potential unless conditions of the Pregnancy Prevention Programme are met, and for pregnant women with epilepsy unless no suitable alternative treatment is available.4

The new Pregnancy Prevention Programme requires that women of child-bearing potential use highly effective contraception, exclude the possibility of pregnancy by providing a negative pregnancy test and understand the risks of topiramate use. Women of childbearing potential are also required to sign a Risk Awareness Form. Further risk minimisation materials include a patient guide, a guide for healthcare professionals and a patient card to inform female patients of the risks associated with topiramate.4

Risk minimisation measures are dynamic

The new restrictions introduced by the MHRA are additional Risk Minimisation Measures (aRMMs), which are typically required where routine risk minimisation measures are not adequate to ensure that the benefits of a medicinal product exceed the risks by the greatest possible margin. After aRMMs are introduced, their effectiveness is monitored, both in terms of the process and the outcomes. Risk minimisation activities are dynamic, not static, so that in cases such as topiramate where existing risk minimisation measures are not adequate and new data suggests the risks are greater than previously thought, measures are enhanced. 

New data also suggested that more women of child-bearing potential are now using topiramate. In light of recent safety reviews on antiseizure medicines and the widely publicised robust risk minimisation measures on the use of sodium valproate in women of childbearing potential, it would be logical for epileptic women to seek alternative treatments.5 If this is the case, it demonstrates the importance of considering the safety of alternative treatments available to patients when a key treatment is withdrawn or restricted.

References

  1. Topiramate Summary of Medical Characteristics https://www.medicines.org.uk/emc/product/9923/smpc Accessed 9th July 2024
  2. Antiepileptic drugs in pregnancy: updated advice following comprehensive safety review https://www.gov.uk/drug-safety-update/antiepileptic-drugs-in-pregnancy-updated-advice-following-comprehensive-safety-review  Accessed 9th July 2024
  3. Topiramate (Topamax): start of safety review triggered by a study reporting an increased risk of neurodevelopmental disabilities in children with prenatal exposure https://www.gov.uk/drug-safety-update/topiramate-topamax-start-of-safety-review-triggered-by-a-study-reporting-an-increased-risk-of-neurodevelopmental-disabilities-in-children-with-prenatal-exposure  Accessed 9th July 2024
  4. Topiramate (Topamax): introduction of new safety measures, including a Pregnancy Prevention Programme https://www.gov.uk/drug-safety-update/topiramate-topamax-introduction-of-new-safety-measures-including-a-pregnancy-prevention-programme#fn:1 Accessed 9th July 2024
  5. MHRA Guidance on Valproate Use by Women and Girls: https://www.gov.uk/guidance/valproate-use-by-women-and-girls  Accessed 9th July 2024