The European Medicines Agency (EMA) has recommended a series of precautions for the treatment of male patients with valproate due to concerns about an increased risk of neurological developmental disorders in children whose fathers were treated with the medication in the three months before conception.
Valproates are used to treat epilepsy and bipolar disorder. Some European Union (EU) member states also approve its use for the treatment of migraines.
The Pharmacovigilance Risk Assessment Committee (PRAC) of the EMA recommended on January 12 that the treatment of male patients with valproate should be initiated and monitored by a specialist in the treatment of epilepsy, bipolar disorder, or migraines. Doctors should also explain the potential risks to patients and discuss the need for effective contraception for the patient and their partner, the committee said.
The recommendations also call for the regular review of valproate treatment in men to ensure it remains the most suitable drug, especially if the patient is planning a pregnancy.
A Nordic study on neurodevelopmental disorders was taken into account in the committee’s conclusions. This study investigated the relationship between paternal valproate treatment and neurodevelopmental disorders, including autism spectrum disorder and congenital malformations, in offspring in Denmark, Norway, and Sweden.
The data showed that about 5 out of 100 children born to fathers treated with valproate in the three months before conception had a neurodevelopmental disorder, compared to about 3 out of 100 children born to fathers treated with the alternative drugs lamotrigine or levetiracetam. No difference in the risk of congenital malformations was found between the two groups.
The study did not investigate the risk in children of men who stopped taking valproate more than 3 months before conception.
The EMA cautioned that the increased risk of neurological developmental disorders caused by valproate could not be confirmed due to the observational nature of the study. The committee also considered other evidence, including non-clinical studies, as well as the views of patients and clinical experts in developing its recommendations.
The recent EMA measures were issued in addition to the existing restrictions to protect pregnant women being treated with valproate drugs, as their babies have a high risk of malformations and developmental problems. According to EMA estimates, up to 30-40 out of 100 pre-school children whose mothers took valproate during pregnancy could have early childhood developmental problems. Typical issues include delays in walking and speaking, lower intellectual ability than other children, and speech and memory difficulties.
It is worth noting that the British Medicines and Healthcare Products Regulatory Agency has directed that starting from January 2024, new female or male patients under 55 should no longer be initiated on valproate unless two specialists “consider and independently document” that there is no other effective or tolerable treatment, or unless there are compelling reasons that the reproductive risks do not exist.
Valproate drugs are marketed in Europe under several brand names, including Absenor, Convival Chrono, Convulex, Delepsine, Depakin, Depakine, Depakote, Depamide, Deprakine, Diplexil, Epilim, Episenta, Epival CR, Ergenyl, Hexaquin, Kentlim, Micropakine LP, Orfiril, Valpam, Valpros, and ValproLEK.