DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

This article, originally published on 17 March 2023, has been updated with the latest regulatory action endorsed on 12 October 2023.

 

Overview

Topiramate is an antiepileptic drug indicated as monotherapy or adjunctive therapy for adults and children aged two (2) years and above.¹ It is also approved for the prophylaxis of migraine headaches in adults. In Malaysia, there are currently nine (9) topiramate-containing products registered with the Drug Control Authority (DCA).²

Topiramate is known to cause foetal harm when administered to a pregnant woman.¹ It crosses the placenta, and similar concentrations have been reported in the umbilical cord and maternal blood in humans. The use of topiramate during pregnancy has been associated with increased risks of congenital malformations (including craniofacial defects and anomalies involving various body systems), as well as preterm labour and premature delivery. For this reason, its use during pregnancy should be considered only if the potential benefits outweigh the potential risks.

 

Background of the Safety Issue

In December 2022, the National Pharmaceutical Regulatory Agency (NPRA) became aware that the European Medicines Agency (EMA) had initiated a new safety review to evaluate the risk of neurodevelopmental disorders in children exposed prenatally to topiramate.³ This review was prompted following the recent publication of findings from a large epidemiological study using Nordic registries (Denmark, Finland, Iceland, Norway, and Sweden), which suggest a possible increased risk of autism spectrum disorders (ASD) and intellectual disability (ID) in children whose mothers took topiramate during pregnancy.^3-4

The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study that examined 4.5 million mother-child pairs between 1996 and 2017.⁴ Among the 24,825 children prenatally exposed to at least one antiepileptic drug (e.g., valproate, topiramate, lamotrigine, carbamazepine, gabapentin, and others), 471 children were exposed to topiramate alone, with 246 children delivered to mothers who had epilepsy.

In unexposed children of mothers with epilepsy, the 8-year cumulative incidence of ASD and ID was 1.5% and 0.8%, respectively.⁴ In contrast, in children of mothers with epilepsy exposed to topiramate, 4.3% had ASD and 3.1% had ID, with adjusted hazard ratios (aHRs) of 2.8 (95% CI, 1.4−5.7) and 3.5 (95% CI, 1.4−8.6), respectively. Besides, the study also found a dose-dependent effect for topiramate. Compared with children from the general population, the aHRs in children exposed to topiramate were 1.7 (95% CI, 1.0−2.8) for doses and 2.9 (95% CI, 1.3−6.7) for doses ≥100mg per day. Additionally, the duotherapy of lamotrigine with topiramate was associated with an increased risk of neurodevelopmental disorders in children of women with epilepsy, with aHR of 2.4 (95%CI, 1.1−4.9).

The study did not suggest that topiramate is a safe alternative to valproate, which is contraindicated in pregnancy due to known risks for serious developmental disorders and congenital malformations (see also the previous NPRA safety alert on valproate).^4-6 The prenatal use of antiepileptic drug duotherapies, except for lamotrigine and levetiracetam, was similarly associated with increased risks of neurodevelopmental disorders.⁴

  

Adverse Drug Reaction Reports⁷

The NPRA had received a total of 43 reports with 76 adverse events suspected to be related to topiramate-containing products. The most frequently reported adverse events were weight decreased (5), drug ineffective (4), dizziness (3), and stutter (3). No cases of autism spectrum disorder, intellectual disability, or neurodevelopmental disorder in children following the use of topiramate during pregnancy reported to the NPRA. However, there were three (3) reports of speech disorders. Of these, two (2) reports involved paediatric patients with unknown prenatal exposure.

 

Regulatory Actions

The NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (29) Jld.1] has been issued for all registration holders of products containing topiramate to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

On 8^th August 2023, the NPRA approved a Direct Healthcare Professional Communication (DHPC) letter issued by Johnson & Johnson Sdn. Bhd. to highlight this safety issue, informing healthcare professionals about the prescribing information of TOPAMAX^® (topiramate) has been updated information and reminder on Contraindications, Warnings and Precautions, Usage of topiramate in Pregnancy and Breast Feeding sections. For further information, please contact your local sales person for a copy of the DHPC.⁸

 

Advice for Healthcare Professionals

• Be reminded of the risk of congenital malformations associated with topiramate and be aware of recent epidemiological study indicating an increased risk of neurodevelopmental disorders (autism spectrum disorder and intellectual disability) in children exposed to topiramate in utero.
• For migraine prophylaxis, topiramate is contraindicated in pregnancy and in women of childbearing potential if a highly effective method of contraception is not used. 
• Perform a pregnancy test before initiating treatment with topiramate, and only use it during pregnancy if the potential benefit outweigh the potential risk to foetus. Weigh the benefits of therapy against the risks and consider alternative therapeutic options.
• Counsel patients about the importance of avoiding pregnancy while using topiramate due to the established risks of foetal harm.
• Ensure that patients of childbearing potential know the importance of using highly effective contraception throughout treatment with topiramate as topiramate may reduce the effectiveness of steroidal contraceptives, including oral contraceptives; therefore, consider alternative or concomitant methods.
• Advise patients not to stop taking topiramate without first discussing it with their doctor, and to consult their doctor if they plan to become pregnant or immediately if they become pregnant so that their treatment can be reviewed.
• Report all suspected adverse events associated with topiramate-containing products to the NPRA, especially cases involving pregnancy exposure. For pregnancy exposure case, please follow up accordingly to provide a more complete report.

  

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). Topamax Tablet 25mg, 50mg, 100mg package insert [Internet]. 2022 Oct 11 [cited 2023 Jan 18]. Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST 3+ system [Internet]. 2023 [cited 2023 Jan 19]. Available from: https://www.npra.gov.my/index.php/my/consumers-2/maklumat/carian-produk-berdaftar-bernotifikasi.html.
3. European Medicines Agency. Pharmacovigilance Risk Assessment Committee (PRAC) starts review of topiramate use in pregnancy and women of childbearing potential [Internet]. 2022 Sep 2 [cited 2023 Jan 18]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/topiramate
4. Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, Gilhus NE, Gissler M, Hálfdánarson Ó, Igland J, Sun Y, Tomson T, Alvestad S, Christensen J. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA 2022;79(7):672-681. Available from: https://doi.org/10.1001/jamaneurol.2022.1269 
5. Medicines and Healthcare products Regulatory Agency (MHRA). Topiramate (Topamax): start of safety review triggered by a study reporting an increased risk of neurodevelopmental disabilities in children with prenatal exposure [Internet]. 2022 Jul 21 [Cited 2023 Jan 18]. Available from: 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
6. National Pharmaceutical Regulatory Agency (NPRA). New safety measure for sodium valproate [Internet]. Safety Alerts. 2020 Jan 21 [cited 2023 Jan 19]. Available from: https://www.npra.gov.my/index.php/en/component/content/article/419-english/safety-alerts-main/safety-alerts-2020/1527061-new-safety-measure-for-sodium-valproate-i-risk-of-congenital-malformation-in-neonates-and-neurodevelopmental-problems-in-children-exposed-to-sodium-valproate-during-pregnancy-ii-additional-educational-material-for-healthcare-professionals-and-patients-caretakers.html?Itemid=1391
7. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2023 [cited 2023 Jan 19]. Available from: https://www.npra.gov.my (access restricted)
8. Direct Healthcare Professional Communication (DHPC). TOPAMAX® (topiramate): Updated information and reminder on Contraindications, Warnings and Precautions, Usage of topiramate in Pregnancy and Breast Feeding. Johnson & Johnson Sdn. Bhd.; 2023 Aug 8.

  

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali