2018 measures to avoid valproate exposure in pregnancy recommended by the European Medicines Agency

PRAC new restrictions on valproate use; pregnancy prevention programme to be put in place

The European Medicines Agency’s experts in medicines safety, the Pharmacovigilance Risk Assessment Committee (PRAC) are recommending new measures to avoid exposure of babies to valproate medicines in the womb. Babies exposed are at risk of malformations and developmental problems.

Main measures recommended by the PRAC

Where licensed for migraine or bipolar disorder

  • In pregnancy – valproate must not be used.
  • In female patients from the time they become able to have children – valproate must not be used unless the conditions of a new pregnancy prevention programme (see below) are met.

For epilepsy

  • In pregnancy – valproate must not be used. However it is recognised that for some women with epilepsy it may not be possible to stop valproate and they may have to continue treatment (with appropriate specialist care) in pregnancy.
  • In female patients from the time they become able to have children – valproate must not be used unless the conditions of the new pregnancy prevention programme are met.

Drugs Packaging

  • The PRAC has also recommended that the outer packaging of all valproate medicines must include a visual warning about the risks in pregnancy. In addition to boxed text, this may include a symbol/pictogram, with the details to be adapted at national level.
  • A patient reminder card will also be attached to the outer package for pharmacists to discuss with the patient each time the medicine is dispensed.
  • Companies that market valproate should also provide updated educational materials in the form of guides for healthcare professionals and patients.

New valproate pregnancy prevention programme

Assessing patients for the potential of becoming pregnant, and involving the patient in evaluating her individual circumstances and supporting informed decision making, pregnancy tests before starting and during treatment as needed, counselling patients about the risks of valproate treatment, explaining the need for effective contraception throughout treatment, carrying out reviews of treatment by a specialist at least annually, introduction of a new risk acknowledgement form that patients and prescribers will go through at each such review to confirm that appropriate advice has been given and understood.

Read the full press release.

Mise en garde, boîtes de Dépakote®

L’ansm agit au nom de l’Etat “pour des produits de santé sûrs, efficaces et innovants”

Récents pictogramme et mise en garde sur les boîtes dépakote®.

Image via l’ansm (agence nationale de sécurité du médicament et des produits de santé) sur Twitter.

Valproate : le formulaire d’accord de soins utilisé seulement une fois sur deux

Médicaments contenant du valproate : le niveau d’application des conditions de prescription et de délivrance est insuffisant

Plusieurs mesures ont été mises en place par l’ANSM depuis 2015 afin de réduire les risques liés à l’utilisation pendant la grossesse des médicaments contenant du valproate ou un dérivé (Depakine, Depakine Chrono 500, Micropakine, et génériques, Depakote, Depamide) et en particulier une démarche sécurisée de prescription et de délivrance. Cette démarche repose sur la présentation en pharmacie pour les patientes d’un formulaire d’accord de soin co-signé avec le médecin spécialiste associé à une ordonnance de ce spécialiste datant de moins d’un an. L’ANSM, en collaboration avec l’Ordre des pharmaciens, a demandé à Sanofi de réaliser une étude pour s’assurer de la bonne application de ces conditions de prescription et de délivrance (CPD).

” … le respect des conditions de prescription et délivrance était de l’ordre de 31% en 2016. Il n’atteint que 47% en 2017. … Le formulaire d’accord de soins n’était présenté que pour 50% des dispensations en 2017 (33% en 2016)… ”

Les résultats de l’étude montrent que les CPD ne sont pas suffisamment respectées.

“Actuellement, tout n’est pas fait pour éviter le valproate chez la femme enceinte. Il faut que l’information soit la plus répandue possible”

Dominique Martin, directeur général de l’ANSM.

L’utilisation des médicaments contenant du valproate ou un dérivé nécessite une attention particulière de l’ensemble des professionnels de santé et une information complète des patientes. En effet, ces médicaments présentent des risques importants de malformation et de troubles neuro-développementaux pour les enfants s’ils sont utilisés pendant la grossesse.

Communiqués ANSM
  • Médicaments contenant du valproate : le niveau d’application des conditions de prescription et de délivrance est insuffisant – Communiqué, ansm, 20/10/2017.
  • Dossier Valproate et dérivés de l’ANSM.
Articles de Presse:

Valproate Drug Harms : EMA Public Hearing in London

Many pregnant women are still unaware of epilepsy drug risks

The public hearing was part of a review of the safety of using valproate-containing medicines in women and girls who are pregnant or of childbearing age by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). There is a risk of malformations and neurodevelopmental problems in babies who are exposed to valproate in the womb, and the review follows concerns that European Union (EU)-wide risk minimisation measures currently in place do not seem to be sufficiently effective.

Warnings to young women who might become pregnant that the epilepsy drug sodium valproate could cause birth defects and developmental problems in their babies could have been made public more than 40 years ago, according to campaigners.

EMA Public Hearing about Drug Valproate Use in Pregnancy

Pregnant women still unaware of epilepsy drug risks

Was there a deliberate decision not to publish Valproate’s risks ?

The public hearing was part of a review of the safety of using valproate-containing medicines in women and girls who are pregnant or of childbearing age by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). There is a risk of malformations and neurodevelopmental problems in babies who are exposed to valproate in the womb, and the review follows concerns that European Union (EU)-wide risk minimisation measures currently in place do not seem to be sufficiently effective.

Warnings to young women who might become pregnant that the epilepsy drug sodium valproate could cause birth defects and developmental problems in their babies could have been made public more than 40 years ago, according to campaigners.

Epilepsy drug warnings DO NOT reach enough women, 2017 survey finds

Almost 70% of women surveyed about a powerful epilepsy drug have not received new safety warnings about the dangers of taking it during pregnancy

Two thirds of women who take the antiepileptic drug sodium valproate said they had not received new safety warnings about the dangers of taking it during pregnancy, a survey carried out by epilepsy charities has found. A similar survey last year found that half of women taking the drug were unaware it could harm their fetus.

The new results are to be presented at a public hearing on the safety of valproate drugs organised by the European Medicines Agency on 26 September in London. …

… continue reading Women still not being told about pregnancy risks of valproate on The BMJ doi.org/10.1136/bmj.j4426, published 22 September 2017.
Featured image credit @bmj_latest.

Depakine : un silence coupable

Envoyé Spécial 16 mars 2017 : Enquête sur le Scandale de la Dépakine

Cet anti-épileptique est accusé d’avoir provoqué de graves malformations sur les enfants exposés in utero. Retour sur un scandale sanitaire et sur l’inertie des autorités de santé.

En savoir plus
  • Envoyé Spécial, émission du 16/03/2017 – Dépakine, le silence des médecins – Enquête sur le scandale de la Dépakine, un anti-épileptique pointé du doigt pour ses effets secondaires : chez la femme enceinte, il peut entraîner des malformations et des troubles neurologiques chez le nouveau-né. Vidéo publiée le 17 mars 2017 par la chaine APESAC.
  • Regardez cette liste de vidéos sur les médias et médicaments sur notre chaine YouTube.

Valproate Medicines in Female Patients: MHRA Toolkit on the Risks

Being better informed about the risks of taking valproate medicines during pregnancy

Valproate is a treatment for epilepsy and bipolar disorder and is prescribed to thousands of women. Since its introduction in 1974, the product information for doctors has included a warning about the possible risk of birth defects. As the risks to unborn children have been increasingly understood, the warnings have been strengthened.

The risk of developmental disorders is up to 4 in 10 and the risk of birth defects is approximately 1 in 10. The risk for autism, ASD and ADHD is higher for children exposed in-utero.

MHRA has worked with industry, healthcare professionals and patient groups on a toolkit to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy.

In women who take valproate while pregnant, around 1 in 10 babies will have a birth defect.

Birth defects seen when mothers take valproate during pregnancy include:

  • spina bifida (where the bones of the spine do not develop properly)
  • facial and skull malformations (including cleft lip and palate, where the upper lip or facial bones are split)
  • malformations of the limbs, heart, kidney, urinary tract and sexual organs.

In women who take valproate while pregnant, about 3–4 children in every 10 may have developmental problems. The long-term effects are not known.

The effects on development can include:

  • being late in learning to walk and talk
  • lower intelligence than other children of the same age
    poor speech and language skills
  • memory problems.

Children exposed to valproate in the womb are more likely to have autism or autistic spectrum disorders (ASD). There is also some evidence children may be more likely to be at risk of developing symptoms of attention deficit hyperactivity disorder (ADHD).

MHRA February 2016 advice

Valproate should not be used in female children, in female adolescents, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential must use effective contraception during treatment.

No-one should stop taking valproate without discussing it first with their doctor and the benefits of valproate treatment must be carefully balanced against the risks.

If valproate is the only option, women of childbearing age should be given effective contraception. Women taking valproate must have regular reviews of their treatment.

MHRA Toolkit

For Patients

For Healthcare Professionals

Toolkit on the risks of valproate medicines in female patients, Medicines and Healthcare products Regulatory Agency, 8 February 2016.

Better understanding of the risks of valproate medicines and pregnancy

New toolkit by The Medicines and Healthcare products Regulatory Agency (MHRA)

A toolkit to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy has been launched.

The Medicines and Healthcare products Regulatory Agency (MHRA) today welcomed the launch of a new toolkit to ensure female patients are better informed about the risks of taking valproate medicines during pregnancy.

Valproate (Epilim, Depakote and other generic brands) is a treatment for epilepsy and bipolar disorder and is prescribed to thousands of women. It is associated with a risk of birth defects and developmental disorders in children born to women who take valproate during pregnancy.

MHRA strengthened warnings on the risks of valproate in pregnancy last year, as understanding of the extent of these risks had increased. Up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects, if valproate is taken during pregnancy. The new toolkit addresses concerns that the risks of valproate are not being adequately explained to female patients.

Developed in consultation with stakeholders including healthcare professional and patient groups, the toolkit includes a credit card sized patient card to be issued by pharmacists, booklets for healthcare professionals and for patients together with a checklist of important questions and discussion points to be kept with the patient’s file. Warnings will appear on the medicine’s packaging later this year.

The MHRA is asking GPs, pharmacists, neurologists, psychiatrists, and other relevant healthcare and mental health professionals to use the toolkit to help facilitate discussion of the risks with their patients.

Sources and more information
  • New toolkit supports better understanding of the risks of valproate and pregnancy, GOV.UK Press release, 8 February 2016.
  • Toolkit on the risks of valproate medicines in female patients, GOV.UK Guidance, 8 February 2016.

Cognitive and behavioral outcomes following fetal exposure to valproate and antiepileptic drugs

Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years

image of staring-child
The NEAD study is the largest prospective investigation of cognitive and behavioral outcomes following fetal exposure to valproate, carbamazepine, lamotrigine, and phenytoin. Children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. the look.

2015 Study Abstract

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate).

In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6 years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales.

Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD.

The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.

Sources and more information

Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years, Epilepsy Behav. NIHMSID: NIHMS 539674, PMCID: PMC3902100, 2014 Nov 1.