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Background

Valproate (as sodium valproate, valproate semisodium, or valproic acid) is authorised for use in epilepsy and bipolar disorder.

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders.

Valproate should not be prescribed to female children or women of childbearing potential unless other treatments are ineffective or not tolerated. Valproate is contraindicated in women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled see Conditions of the valproate Pregnancy Prevention Programme below.

Clinicians prescribing in epilepsy should continue to consult the findings of the epilepsy medicines in pregnancy review, 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.

Valproate administration may also impair fertility in men. Fertility dysfunctions are in some cases reversible at least 3 months after treatment discontinuation, however in some cases the reversibility of male infertility was unknown. In addition, pre-clinical studies have reported adverse effects to the male reproductive system in juvenile and adult animals receiving valproate.

Re-analysis of study examining risk in children of men taking valproate

The MHRA has kept under close review the possibility of risks to children associated with paternal exposure to valproate (in other words, whether a child could be affected if a father was taking valproate). Two studies were conducted by researchers in 2013 that did not find evidence of an increased risk to children with paternal use of epilepsy medicines, but the studies had limitations. ^{[footnote 1] [footnote 2]} As part of the outcome of the 2018 European review of valproate, a new retrospective study was requested from the marketing authorisation holders to examine this risk. ^{[footnote 3]}

The study report submitted to the MHRA and to other regulatory authorities suggested an increased risk of neurodevelopmental disorders in children whose fathers took valproate during the 3-month period before they were conceived compared to children whose fathers had taken the antiseizure medicines lamotrigine or levetiracetam. However, we were subsequently informed of errors in the study that may impact on the results.A full re-analysis is required before conclusions can be drawn. As soon as the revised study analysis is available, it will be re-assessed by the MHRA.

No action is currently needed from patients. No one should stop taking valproate without advice from their specialist.

Reminder of the conditions of the valproate Pregnancy Prevention Programme

The prescriber must ensure that:

• individual circumstances are evaluated in each case, involving the patient in the discussion, to guarantee her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks
• the potential for pregnancy is assessed for all female patients
• the patient has understood and acknowledged the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero
• the patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed
• the patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception, without interruption during the entire duration of treatment with valproate
• the patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy.
• the patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued
• the patient understands the need to urgently consult her physician in case of pregnancy
• the patient has received the patient guide
• the patient has acknowledged that she has understood the hazards and necessary precautions associated with valproate use (Annual Risk Acknowledgement Form).

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

Pharmacists should continue to ensure patients receive the patient card, a copy of the Patient Information Leaflet and packaging bearing pregnancy warnings.

Article citation: Drug Safety Update volume 17, issue 1: August 2023: 3.