The Therapeutic Goods Administration (TGA) announces that a retrospective observational study in Europe has suggested there may be an increased risk of neurodevelopmental disorders in children born to men who had been taking sodium valproate in the 3 months before conception compared to children born to men treated with lamotrigine or levetiracetam.
Sodium valproate belongs to a group of medicines called anticonvulsants. It is used to treat epilepsy and mania. Neurodevelopmental disorders studied included autism spectrum disorder, intellectual disability, communication disorder and attention deficit/hyperactivity disorder, and movement disorders.
Due to methodological limitations, the findings of this study should be interpreted with caution. As a precaution, Sanofi-Aventis, the sponsor of Epilim, which is the original brand of sodium valproate, have added new warnings about paternal exposure to the Product Information (PI) and Consumer Medicine Information (CMI). Sponsors of generic sodium valproate products will be required to align their safety information with Epilim.
The TGA reviewed the evidence provided by the sponsor and approved the sponsor’s application to add warnings to the PI in April 2024. After reviewing further evidence, including careful consideration of the limitations of the European study, the TGA made the decision to retain the new warnings in the PI out of an abundance of caution, and to align with other regulators. No Australian adverse events relating to paternal exposure to sodium valproate have been reported to the TGA. For details of the additions of warnings to the PI, please refer to the website in TGA.
Sodium valproate is a known teratogen with a long-documented history of congenital malformations (including spina bifida) and neurodevelopmental disorders following maternal sodium valproate exposure. There are already recommendations in the Australian PI to avoid this medicine in pregnancy and advice about its use in people with childbearing potential.
Prescribing restrictions for sodium valproate for all patients under 55 years have been recently introduced in the UK. In response to this change, we conducted a review and requested expert advice from the Advisory Committee on Medicines (ACM) on whether Australia should follow the UK in imposing similar restrictions.
The ACM advised there has been no real change in the risk profile to children following maternal exposure since they last reviewed this issue in 2018, and that there was insufficient evidence to amend the indication or implement restrictions for sodium valproate to exclude particular patient groups. The TGA will continue to monitor this signal as part of its routine safety monitoring of medicines.
What health professionals should do:
- The new warnings instruct health professionals to inform their male patients about the potential risks of sodium valproate and discuss the need for effective contraception, for both the patient and their female partner.
- Male patients taking sodium valproate should be specifically advised to consult their doctor to discuss alternative treatment options if they are planning to father a child, and before discontinuing contraception; to consult their doctor to discuss alternative treatment options if they are planning to father a child, and before discontinuing contraception; to consult their doctor to discuss alternative treatment options if they are planning to father a child, and before discontinuing contraception.
- Men taking sodium valproate should be reviewed regularly (at least annually) by a specialist experienced in the management of epilepsy or bipolar disorder to consider whether valproate-containing medicine remains the most suitable option, particularly when the patient is planning to conceive a child.
- Existing recommendations in the PI about maternal exposure to sodium valproate remain unchanged as we continue routine safety monitoring and surveillance of this medicine. Patients with childbearing potential and taking sodium valproate are encouraged to discuss any concerns with a health professional.
Please refer to the following website in TGA for details:
http://www.tga.gov.au/news/safety-updates/potential-risk-neurodevelopmental-disorders-children-born-men-taking-sodium-valproate
In Hong Kong, there are 10 registered pharmaceutical products containing valproate. All products are prescription-only medicines. So far, the Department of Health (DH) has received 17 cases of adverse drug reaction with regard to valproate, of which 2 cases were reported as congenital malformations following maternal exposure to valproate during pregnancy, and these cases were not related to neurodevelopmental disorders in children after paternal exposure to valproate. Related news was previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 2 Jul 2011, with the latest update posted on 14 Feb 2025. Letters to inform local healthcare professionals were issued by the DH on 4 Jul 2011, 7 May 2013, 13 Oct 2014, 12 Feb 2018, 13 Dec 2022 and 22 Mar 2023.
The Registration Committee of the Pharmacy and Poisons Board discussed the matter related to the risks in pregnancy associated with the use of valproate in Sep 2011, Dec 2014, Dec 2018 and Jun 2019. Currently, the package insert or sales pack label of locally registered valproate-containing products should include safety information on the risk of malformations and impaired cognitive development in children exposed to valproate during pregnancy, and contraindications, e.g. in women of childbearing potential unless pregnancy preventive measures have been implemented, etc. The certificate holders of locally registered valproate-containing products are also required to implement risk minimisation measures, e.g. patient information leaflet should be provided, etc.
As previously reported, the matter will be further discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Friday, Mar 7, 2025
Issued at HKT 19:00
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