其 他 安 全 警 示
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| The United Kingdom: Topiramate (Topamax): Start of safety review triggered by a study reporting an increased risk of neurodevelopmental disabilities in children with prenatal exposure (English only) |
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Medicines and Healthcare products Regulatory Agency (MHRA) announces that it has initiated a new safety review into topiramate as a result of an observational study reporting an increased risk of neurodevelopmental disabilities in children whose mothers took topiramate during pregnancy. Topiramate is known to be associated with an increased risk of congenital malformations and effects on fetal growth if used during pregnancy. Healthcare professionals are advised to continue to counsel patients who can become pregnant on the known and emerging risks of topiramate for an unborn baby and on the need to use effective contraception throughout use.
A recently published study (Bjørk and colleagues) reported prenatal exposure to topiramate to be associated with an increased risk of autism and intellectual disability. The Commission on Human Medicines considered the findings of this new study and advised that it provides robust evidence to support an association between prenatal exposure to topiramate and an increased risk of autism spectrum disorder, intellectual disability and the composite outcome of any neurodevelopmental disorder. MHRA has now started a safety review to evaluate these findings in the context of the accumulating data relating to the benefits and risks of use of topiramate, with a particular focus on women of childbearing potential and during pregnancy. The review will also explore the need for additional risk minimisation measures to reduce the potential harms associated with the use of topiramate during pregnancy.
While the review is ongoing, MHRA is alerting healthcare professionals to the findings of this new study and reminding them of the important risks and precautions to take when prescribing or dispensing topiramate in women of childbearing potential.
The study by Bjørk and colleagues is a large, well-conducted study using established data sources from 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). It reports that children whose mothers use topiramate or valproate during pregnancy are at an increased risk of autism spectrum disorder, intellectual disability, and a composite outcome of any neurodevelopmental disorder. These risks are known for valproate.
Data from around 4.5 million mother-child pairs were examined and this included 24,825 children (0.6%) who were prenatally exposed to antiepileptic drugs. Of these, 16,170 were born to mothers who had epilepsy. These data were analysed to estimate the risk of autism spectrum disorder and intellectual disability after exposure to the 10 most frequently used antiepileptic drugs when used as monotherapy (one medicine) and the 5 most frequently used antiepileptic drugs when used as duotherapy (two medicines at the same time). In unexposed children of mothers with epilepsy, the 8-year cumulative incidence of autism spectrum disorder and intellectual disability were 1.5% and 0.8% respectively compared with 4.3% and 3.1% in children of mothers with epilepsy exposed to topiramate. The adjusted hazard ratios for autism spectrum disorder and intellectual disability were 2.8 (95% CI 1.4 to 5.7) and 3.5 (95% CI 1.4 to 8.6). A range of sensitivity analyses were conducted that broadly showed consistent and statistically significant effect estimates of a greater than 2-fold increase in risk of neurodevelopmental disorders across most of the analyses. The data also showed a dose-dependent effect for topiramate.
Before the initiation of topiramate in a woman of childbearing potential, pregnancy testing should be performed, and the patient should be fully informed of the risks if used during pregnancy. For epilepsy, alternative therapeutic options should be considered for women of childbearing potential. If topiramate is used, a highly effective contraception is strongly recommended, and the discussion with the patient should include information on both the risks associated with taking topiramate and of uncontrolled epilepsy during pregnancy. For migraine prophylaxis, topiramate is contraindicated in pregnancy and in women of childbearing potential if not using a highly effective method of contraception. As such, topiramate should not be prescribed for migraine prevention in a patient who is pregnant. Topiramate may reduce the effectiveness of steroidal contraceptives, including oral contraceptives. Alternative or concomitant methods of contraception should be considered.
Advice for healthcare professionals:
- MHRA has started a new safety review to assess the benefits and risks of topiramate and to consider whether further measures are required to reduce the risk of harm associated with topiramate use during pregnancy.
- The new safety review was triggered by a large observational study reporting that prenatal exposure to topiramate is associated with an increased risk of autism spectrum disorders, intellectual disability, and neurodevelopmental disorders.
- Of the antiepileptic medicines reviewed for use in pregnancy, lamotrigine and levetiracetam continue to be considered the safer for the baby since they were not associated with an increased risk of birth defects.
- It remains vital that the strict restrictions for valproate prescribing in women and girls of childbearing potential are followed given the known significant risks if valproate is used in pregnancy.
- Reminder of current advice for topiramate: do not prescribe topiramate during pregnancy for migraine prophylaxis; ensure any patients of childbearing potential know to use highly effective contraception throughout treatment with topiramate; counsel patients on the importance of avoiding pregnancy during topiramate use due to these emerging data and also the established increased risks of major congenital malformations and fetal growth restriction in babies exposed to topiramate in-utero; topiramate may reduce the effectiveness of steroidal contraceptives, including oral contraceptives, therefore consider alternative or concomitant methods; for migraine prophylaxis, topiramate can be withdrawn in pregnancy by an appropriate prescriber but alternative treatments should be considered; for epilepsy, urgently refer anyone on topiramate who is planning a pregnancy or who is pregnant for specialist advice on their antiepileptic treatment.
Please refer to the following website in MHRA for details:
http://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
In Hong Kong, there are 32 registered pharmaceutical products containing topiramate. All products are prescription-only medicines. So far, the Department of Health (DH) has received 4 cases of adverse drug reaction related to topiramate, but these cases were not related to neurodevelopmental disabilities in children with prenatal exposure. Related news was previously issued by European Medicines Agency, and was posted on the Drug Office website on 9 Jul 2022. The DH will remain vigilant on the conclusion of the review and any safety updates issued by other overseas drug regulatory authorities for consideration of any action deemed necessary.
Ends/Friday, Jul 22, 2022
Issued at HKT 15:30
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