The Spanish Agency for Medicines and Health Products (AEMPS), under the Ministry of Health, has reported the preliminary results of a study suggesting an increased risk of neurodevelopmental disorders in children whose fathers were treated with valproate, compared with parents treated with other antiepileptics (lamotrigine or levetiracetam) in the 3 months prior to conception.
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) is evaluating the results of the retrospective observational study EUPAS34201 conducted in several registries in the Scandinavian countries (Denmark, Norway and Sweden).
According to the AEMPS, the study has certain limitations whose impact on the validity of the results is still unknown.. In this sense, he clarifies that the PRAC has requested additional information from pharmaceutical companies to assess the robustness of the data.
Pending the final conclusions, as a precautionary measure, the AEMPS recommends that healthcare professionals inform their male patients who are undergoing treatment with valproate of the existence of a study that is still ongoing whose data suggest that the use of these medications in the three months prior to conception, could expose the child to a possible risk of neurodevelopmental disorders. In this sense, it indicates to health professionals to assess the need to implement adequate contraceptive measures.
The AEMPS, in a statement, also reminds men or male adolescents who are undergoing treatment with valproate that “they should not interrupt treatment without first talking to their doctor, since the symptoms of their disease could reappear”. In the same way, it also recommends that patients assess with their doctor the need to implement effective contraceptive measures, as well as advises patients treated with the medication to notify their doctor if they intend to have a child soon.
Medications containing valproate and its derivatives are indicated for the treatment of epilepsy and as a second option in manic episodes of bipolar disorder.. They are marketed both in generic format and under the brand name Depakine (Sanofi Aventis).
Teratogenic effects in case of maternal exposure are widely known and there are preventive measures to avoid maternal exposure during pregnancy.. In 2022, Sanofi, the laboratory responsible for Depakine, was sentenced in the first instance in Spain to pay compensation of around one million euros to three families, after finding a relationship between the neuronal damage of three children and the consumption of this antiepileptic by of their mothers.
In 2014, a review of the benefit-risk balance of medicines containing valproate was carried out, motivated by the results of published studies that showed a risk of long-term neurodevelopmental disorders in children born to women treated with the medicine. (in up to 40% of cases), as well as its known risk of congenital malformations (in approximately 10% of cases). Following this review, its use was restricted and recommendations were established for girls, adolescents, and women with pregnancy capacity. However, in 2018 the conditions for its clinical use were further restricted.
Valproate belongs to a group of drugs used for the treatment of partial or generalized epilepsy; primary generalized epilepsy: convulsive (clonic, tonic, tonic-clonic, myoclonic) and non-convulsive or absence seizures; partial epilepsy: simple and complex seizures; secondary generalized seizures, and for the treatment of idiopathic generalized and mixed seizures and/or symptomatic generalized epilepsy (West and Lennox-Gastaut). In addition, it is a medication used in the treatment of mania in adults, one of the phases of bipolar disorder.
The EUPAS34201 study was registered in April 2020 in the European registry of post-authorization studies, the registry that includes the analyzes that are carried out after a certain drug receives authorization to market.
According to the data presented, this is an observational and retrospective study that is being carried out using data from the national registries of Norway, Denmark and Sweden.. Its objective is to examine a possible association between paternal exposure to valproate in the moments before conception with the risk of offspring developing neurodevelopmental disorders, including autism spectrum disorders (ASDs) and congenital malformations.. The study evaluates the effects of the drug in comparison with other antiepileptics, such as lamotrigine or levetiracetam.