The measures being recommended by the EMA’s Safety Committee (PRAC), for the treatment of male patients with valproate are intended to address a potential increased risk of neurodevelopmental disorders in children born to male patients treated with valproate during three months before conception.

PRAC reviewed data from a retrospective observational study carried out by companies that market valproate as an obligation following a previous review of valproate use during pregnancy. The Committee also considered data from other sources, including non-clinical (laboratory) studies and scientific literature, and consulted patients and clinical experts.

The results of the study suggest there may be an increased risk of neurodevelopmental disorders in children born to male patients taking valproate in the three months before conception. Neurodevelopmental disorders are problems with development that begin in early childhood, such as autism spectrum disorders, intellectual disability, communication disorders, attention deficit/hyperactivity disorders and movement disorders.

The data showed that around five out of 100 children had a neurodevelopmental disorder when born to fathers treated with valproate, compared with around three out of 100 when born to fathers treated with lamotrigine or levetiracetam. The study did not investigate the risk in children born to men who stopped using valproate more than three months before conception.

The possible risk in children born to men treated with valproate in the three months before conception is lower than the previously confirmed risk in children born to women treated with valproate during pregnancy. It is estimated that up to 30 to 40 out of 100 preschool children whose mothers took valproate during pregnancy may have problems with early childhood development.

The study data on male patients had limitations and PRAC could therefore not establish whether the increased occurrence of these disorders suggested by the study was due to valproate use. Nonetheless, the Committee considered precautionary measures were warranted to inform patients and healthcare professionals.

There will be updates to the patient guide, patient cards and SPCs in due course.

Practice points for pharmacists:

• Valproate treatment in male patients must be initiated and supervised by a specialist;
• Check that male patients have been informed of the potential risk of neurodevelopmental disorders;
• Check if their therapy has been reviewed by their doctor to consider whether valproate remains the most appropriate treatment. This is particularly important if the male patient is planning to conceive;
• Discuss with male patients the need to consider effective contraception, including for their female partner, while using valproate and for at least three months after stopping treatment;
• Advise male patients not to donate sperm during treatment and for at least three months after treatment discontinuation;
• Check that male patients have received the new patient guide for male patients once these become available;
• Check that male patients have been provided also with a patient card once these become available;
• Remember that Valproate products are subject to additional monitoring (black triangle) and pharmacists are asked to report any suspected adverse reactions to the HPRA to allow continued monitoring; and

Previous contraindications, recommendations and risk-minimisation measures to avoid exposure to valproate medicines in women during pregnancy due to the risk of congenital malformations and neurodevelopmental disorders remain in place.

• These can all be reviewed on the HPRA website at Use in women of childbearing potential and during pregnancy (hpra.ie) (available at hpra.ie Medicines > Special Topics > Valproate (Epilim)).