ADR that result in revision of patient information

The United Kingdom: MHRA instructs health organisations to prepare now for new measures to reduce ongoing serious harms of valproate

Medicines and Healthcare products Regulatory Agency (MHRA) announces that healthcare organisations are being instructed now to put in place a plan to implement the first phase of new regulatory measures to reduce the known harms of valproate, including the significant risk of serious harm to the baby if taken during pregnancy and the risk of impaired fertility in males.

From Jan 2024, valproate must not be started in new patients (male or female) younger than 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment, or unless there are compelling reasons that the reproductive risks do not apply. For the majority of patients, other effective treatment options are available.

All women who could become pregnant and girls who are currently taking valproate will be reviewed at their next annual specialist review, using a revised valproate Annual Risk Acknowledgement Form, which will include the need for a second opinion’s signature if the patient is to continue with valproate.

A similar system will be introduced later in 2024 for male patients currently taking valproate. This follows advice from an independent expert group of the Commission on Human Medicines (CHM), with representation from across the healthcare system, that the measures should be introduced in a phased manner to ensure ongoing patient care is not disrupted.

These are important regulatory changes recommended by the CHM to increase scrutiny of valproate prescribing and ensure that valproate is only used when the benefits outweigh the risk.

The MHRA urges patients to attend any offered appointments to discuss their treatment plan and to talk to a healthcare professional if they are concerned. Clinicians should discuss the current warnings and upcoming measures relating to valproate with their patients and consider together how it affects the patient’s individual circumstances.

These changes are being introduced following concerns that the existing regulatory requirements are not being consistently followed. In light of these concerns, the MHRA conducted a review of the available data and asked for advice from the independent CHM, which listened to the views of patients and healthcare professionals. The review also considered risks of valproate in males including the risk of male infertility.

The CHM recommended that their safety measures apply to people under the age of 55 because this is the age-group evidence suggests is most likely to be affected by the risks of valproate when taken during pregnancy and the possible risk of impaired fertility in males, which is thought to be reversible upon dose reduction or discontinuation. The possible risk of impaired fertility in males has been in the product information since 2011 and should be discussed between patient and doctor as part of the informed consent process.

As stated in the product information, there are some animal studies that show adverse effects of valproate on the testes of juvenile animals as well as transgenerational effects. It is unknown what this means for human patients as it’s not always possible to be sure that an effect seen in animals will be the same in a person taking a medicine. Further work on this is being undertaken.

No one should stop taking valproate without advice from a specialist. This is because epilepsy or bipolar disorder may become worse without treatment, which can be harmful.

Please refer to the following website in MHRA for details: http://www.gov.uk/government/news/mhra-instructs-health-organisations-to-prepare-now-for-new-measures-to-reduce-ongoing-serious-harms-of-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 15 cases of adverse drug reaction related to valproate, but these cases were not related to the risks in pregnancy or impaired fertility in males.

Related news on the risks in pregnancy and impaired fertility in males associated with the use of valproate 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 13 Dec 2022. Letters to inform local healthcare professionals were issued by the DH on 4 Jul 2011, 7 May 2013, 13 Oct 2014, 12 Feb 2018 and 13 Dec 2022.

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/Thursday, Nov 30, 2023
Issued at HKT 14:30

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