Medicines Healthcare Products Regulatory Agency
Summary
In view of data showing ongoing exposure to valproate in pregnancy, this article reminds healthcare professionals of the risks in pregnancy and the current Pregnancy Prevention Programme requirements, and provides information about the potential risks of valproate in other patients following a review of the latest safety data. Following advice from the Commission on Human Medicines (CHM), new safety measures for valproate-containing medicines are to be put in place in the coming months.
The CHM has established an implementation group with a cross-health sector membership to support the safe introduction of the new measures into clinical practice. This will be via a phased programme currently under development according to patient safety priorities, and developed in collaboration with the healthcare bodies, to ensure ongoing patient care is not disrupted. No action is currently needed from patients.
Patients currently taking valproate must be advised not to stop taking it unless they are advised by a specialist to do so. Any patient who thinks they are pregnant while on valproate should be advised to talk to a specialist urgently.
Before initiating valproate in patients younger than 55 years, healthcare professionals should consider all other suitable therapeutic options and consult the findings of the epilepsy medicines in pregnancy review.
Advice for healthcare professionals:
- continue to follow the existing strict precautions, including that valproate should not be prescribed to female children or women of childbearing potential unless other treatments are ineffective or not tolerated and that any use of valproate in women of childbearing potential who cannot be treated with other medicines is in accordance with the Pregnancy Prevention Programme
- following a new safety review conducted in light of concerns that the current regulatory requirements for safe use are not being consistently followed, the Commission on Human Medicines (CHM) has advised that there should be greater scrutiny of the way valproate is prescribed and that further risk minimisation measures are required in particular that 2 specialists should independently consider and document that there is no other effective or tolerated treatment for patients aged under 55 years
- consider all other suitable therapeutic options before newly prescribing valproate in patients younger than 55 years
- these new measures will be implemented over the coming months. In the meantime, GPs and pharmacists should continue to provide repeat prescriptions for valproate and dispensers should continue to ensure patients receive the patient card, a copy of the Patient Information Leaflet and packaging bearing pregnancy warnings
- patients currently taking valproate must be advised not to stop taking it unless they are advised by a specialist to do so
Current safety measures for valproate due to risks with pregnancy exposure
Valproate (as sodium valproate or valproic acid) is authorised for use in epilepsy and bipolar disorder. It is also used outside of the licence (off label) to treat other conditions.
Valproate has a high teratogenic potential. Exposure of an unborn child to valproate in utero is associated with a high risk of congenital malformations (11%) and neurodevelopmental disorders (3040%), which may lead to permanent disability. The available evidence does not support a specific at-risk gestational period and the possibility of a risk of valproate throughout pregnancy cannot be excluded.
Due to the serious harms to an unborn baby associated with use of valproate in pregnancy, the existing advice is that valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated. As a further strengthening of this position in April 2018, we introduced the Valproate Pregnancy Prevention Programme (PPP) as a requirement of any valproate use in patients of childbearing potential. We continue to closely monitor the impact of these requirements.
Safety review of data relating to valproate
In 2022, the Commission on Human Medicines (CHM) considered a review of safety data relating to valproate. This review included prescribing data showing continued use of valproate in female patients and also some use during pregnancy, as well as evolving information about potential risks in male patients. The CHM also considered the views of patients and other stakeholders on the current use of valproate and on how the risks of valproate are currently managed.
Although rates of valproate usage in female patients have declined since the introduction of the Pregnancy Prevention Programme in 2018, recently there has been a plateauing of this decline and there is no room for complacency (shown in the March 2022 report of the Medicines and Pregnancy Registry - Antiepileptic use in females aged 0 to 54 in England). Furthermore, although the number of pregnant women prescribed valproate in a 6-month period has fallen since 2018, the latest report of the registry, published September 2022, noted that 17 female patients prescribed valproate in a month in which they were pregnant were identified as new additions to the registry between October 2021 and March 2022.
The review also considered data for other potential risks, including that, as indicated in the current product information, valproate may impair male fertility, and there is some evidence that this is reversible upon discontinuation. In addition, data were considered from studies in juvenile rats and adult rats and dogs reporting adverse effects to the male reproductive system in animals receiving valproate, as well as non-clinical studies on the potential for epigenetic effects of valproate and transgenerational risks. There are currently limited data available on these risks in humans and further studies are planned. There is also an ongoing retrospective study on the outcomes of babies exposed to valproate via paternal use.
CHM advice and recommended new measures
On the basis of the evidence, the CHM has recommended a number of regulatory actions to further strengthen safety measures for valproate. These measures will be introduced over the coming months according to patient priorities so they can be introduced safely. Advice on the timing of introduction will be provided once the CHMs implementation group has finalised plans and after full engagement with stakeholders. No action is needed at present except for women of childbearing potential not on the Pregnancy Prevention Programme.
The CHM recommends that no patients (male or female) under the age of 55 years should be initiated on valproate unless 2 specialists independently consider and document that there is no other effective or tolerated treatment. For patients under 55 years currently receiving valproate, 2 specialists should independently consider and document that there is no other effective or tolerated treatment or the risks do not apply. The CHM has advised that these measures should apply to people under the age of 55 because this is the age group most likely to be affected by the risks of valproate when taken during pregnancy and the possible risk of impaired fertility in males.
Other measures recommended by CHM included further warnings in the product information, improved educational materials, and better monitoring of healthcare professionals compliance with the new measures.
Clinicians should continue to?consult the findings of the epilepsy medicines in pregnancy review?when considering prescribing of epilepsy medicines in female patients, particularly that lamotrigine (Lamictal) and levetiracetam (Keppra) were not associated with an increased risk of birth defects compared with the rate in the general population. We also note that the risks associated with topiramate use in pregnancy are under review.
Adherence to Pregnancy Prevention Programme requirements must continue
Full adherence to the