The Medicines and Healthcare products Regulatory Agency (MHRA) has introduced new measures to reduce the known harms of valproate, a drug used to treat epilepsy and bipolar disorder.
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.
Evidence suggests that use in pregnancy leads to physical birth defects in 10% of children born compared with a background rate of 2% to 3% and there is also increased risk of developmental delays and this includes delays in walking, talking, poor language skills, memory problems, and low intellectual ability in approximately 30 to 40% children born to mothers taking valproate.
Furthermore, developing foetuses, if exposed to valproate in-utero, are at increased risk of autistic spectrum disorder (approximately three-fold), and also more likely to develop symptoms of attention-deficit/hyperactivity disorder.
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.
Patients with a learning disability might need help from specialist intellectual disability epilepsy nurses to meet these new regulations.
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.”
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.
Professor Munir Pirmohamed, Chair of The Commission on Human Medicines added: “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.”
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.
