MHRA's new measures aim to reduce valproate use and protect patients from harm

Other effective medicines are available for epilepsy and bipolar disorder and valproate should only be used if these don’t work or aren’t suitable for an individual patient.

Healthcare organizations are being instructed by the Medicines and Healthcare products Regulatory Agency (MHRA) 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 January 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, 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 Commission on Human Medicines 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.

Dr Alison Cave, MHRA Chief Safety Officer said:

“Valproate use in pregnancy carries significant risk of harm to the unborn child and should only be used in girls and women of child-bearing potential if a pregnancy prevention programme is in place. It also carries a risk of impaired fertility in males.

“To better protect patients from these harms, we are taking robust regulatory action to ensure greater scrutiny of valproate prescribing.  Valproate should only be used when no other treatment is effective.

“If you are a patient on valproate, we ask you to attend any appointments offered over the next year to discuss your treatment plan. Please talk to a healthcare professional if you are concerned.

“No one should stop taking valproate without advice from their specialist.”

I am pleased to see the recommendations of the independent Commission on Human Medicines being prepared to be put into practice. Valproate is a highly teratogenic medicine that also carries known risks to male fertility – it is therefore vital valproate is only used when there is no other effective or tolerated treatment option.

We have consulted with patients and healthcare professionals with experience of valproate to inform our recommendations and to ensure that they are introduced in a way that does not disrupt ongoing patient care.”

Professor Munir Pirmohamed, Chair of The Commission on Human Medicines

Health Minister Maria Caulfield said:

“We are focused on improving how the system listens to patients and healthcare professionals, and our sympathies remain with all those affected by the side effects of sodium valproate.

“These regulatory measures will help to further improve patient safety and ensure valproate is only used when the benefits outweigh the risk.

“I’d encourage anyone affected or concerned to speak with a healthcare professional, including to get further information about the other effective medicines to treat epilepsy and bipolar disorder .”

The Patient Safety Commissioner Dr Henrietta Hughes said:

“We must dramatically reduce the number of babies exposed to teratogens which can cause physical and learning disabilities in children.  To do this, all organizations must ensure they bring in new measures from January 2024.”

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. We do not know 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.