BCFI | Folia | Valproic acid: inform men about the risks of

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The use of valproate is contraindicated in pregnant women due to an increased risk of congenital abnormalities (including neural tube defects) and neurodevelopmental disorders. In girls and women of childbearing age, valproic acid should only be used if strict precautions as part of a pregnancy prevention program are met. [zie Folia juni 2018 en het symbool  t.h.v. de specialiteiten]. Following the EMA’s 2018 risk mitigation measures on valproate use in women, manufacturers of valproate-based medicines were asked to investigate the risks of valproate exposure in men wishing to have children. The results of that study suggest a possible increased risk of neurodevelopmental disorders in children whose fathers were treated with valproate 3 months before conception1. The study was not large enough and had several limitations, which means that a causal relationship cannot be confirmed between valproate use in fertile men and the development of neurological disorders in their children.
Following these study data, the European Pharmacovigilance Committee PRAC assessed the risks of valproate exposure in men of childbearing potential and formulated risk mitigation measures.

Briefly about the study

This is a retrospective observational study based on 3 Scandinavian registers. This research has not yet been published.
The aim of the study was to examine neurodevelopmental disorders in children of fathers treated with valproate around conception, compared to the risk in children of fathers who had received lamotrigine or levetiracetam (all in monotherapy).
The hazard ratio for neurodevelopmental disorders in children whose fathers were treated with valproate compared to children whose fathers were treated with lamotrigine or levetiracetam was 1.5 (95% CI: 1.09-2.07).
The risk of developing neurodevelopmental disorders varied between 4.0% and 5.6% in the valproate group and between 2.3% and 3.2% in the lamotrigine/levetiracetam group.

Main conclusions of the PRAC

The PRAC1 concludes that there may be an increased risk of neurodevelopmental disorders (5% versus 3%) in children (aged 0 to 11 years) born to fathers who were treated with valproate monotherapy 3 months prior to conception compared to men who were treated with lamotrigine or levetiracetam. However, the limitations of the study are also emphasized, such as the variation in indications for valproate use and the limited size of the population studied.

Risk-reducing measures for fertile men

To avoid exposure to valproate in fertile men, the following risk-reducing measures1 now apply:

• Specialist guidance is recommended when starting treatment with valproate in men.

• Inform patients about the potential risk of neurodevelopmental disorders and the need for effective contraception, including for the female partner, throughout the duration of treatment and up to 3 months after discontinuation.

• Regular review of treatment to determine whether valproate remains the most appropriate treatment for the patient.

• Men who wish to have children should consult a specialist. Valproate treatment should be re-evaluated and alternative treatment options discussed.

• Inform patients that they should not donate sperm during treatment and for at least 3 months after stopping.

• Educational material on the teratogenic risk will be provided to male patients [nog niet beschikbaar op 05/03/2024].

Some comments

• The indications for valproate in the SPC are the treatment of certain forms of epilepsy as well as the treatment of manic episodes in bipolar disorder when lithium is contraindicated or not tolerated. Valproate is also used off-label in the prophylactic treatment of migraine.

• Lecrat states that based on the currently available data and pending additional information about this study, it is not justified to change or stop valproate treatment in a man who wishes to have children2.

• Lareb puts a critical note on the interpretation of the retrospective observational study on which the PRAC advice is based. In this study there was uncertainty about which type of epilepsy the men had (with a risk of confounding by indication) and the study was generally not large enough to determine for which developmental disorders the risk was higher. Lareb also emphasizes the fact that the possible risk of valproate use by the father in this study (5%) is much lower than the demonstrated risk of developmental disorders (30-40%) in children whose mothers took valproate during pregnancy. used3.

• Another study (Tomson et al.4) found that the incidence of autism and intellectual disability was slightly higher in children of fathers who used valproate than in children of fathers who did not use antiepileptic drugs. The risk increase was not statistically significant in this study.

• La Revue Préscrire states that these results provide a reason to reconsider the use of valproic acid in men who wish to have children. Especially when other options can be considered, such as lamotrigine, levetiracetam, propranolol, amitriptyline and lithium, in the treatment of epilepsy, migraine and mood disorders such as bipolar disorder, respectively5.

Specialty names:

Valproate: Depakine®, Valproate (see Repertoire)

Sources

1 EMA. https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures. A DHPC was sent to the healthcare providers: via https://geneemiddelsdatabank.be/human-use > search term: valproate > download the DHPC for each specialty via “DHPC”
2 CRAT. https://www.lecrat.fr/1778/ accessed on 03/05/2023
3 Lareb. Valproic acid use by men who wish to have children. Accessed on 03/05/2024. Lareb website
4 Tomson T, Muraca G, Razaz N. Paternal exposure to antiepileptic drugs and offspring outcomes: a nationwide population-based cohort study in Sweden. J Neurol Neurosurg Psychiatry. 2020;91(9):907-13. PMID:32651245
5 Paternal exposure to valproic acid before conception: neuropsychological developmental disorders in children? Rev Prescrire 2024; 44 (485): 190-192