Valproate and related substances

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Summary

 

PRAC recommends new measures to avoid valproate exposure in pregnancy

New restrictions on 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.

What are the 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.
  • 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.

 

What are the main points of the 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.


Medicines containing valproate have been approved nationally in the EU to treat epilepsy, bipolar disorder and in some countries for prevention of migraine. They are known to pose a considerable risk of malformations and developmental problems in babies who are exposed to valproate in the womb. An earlier review had recommended measures aimed at better informing women about these risks in order to reduce use of the medicine during pregnancy, and not starting treatment unless other options were ineffective or could not be used because of side effects. The current review was launched because of concerns that these measures had not been sufficiently effective.

The PRAC examined the available evidence and consulted widely with healthcare professionals and with patients, including women and their children who have been affected by valproate use during pregnancy, through written submissions, expert meetings, meetings with stakeholders including healthcare professionals, patients organisations, patients and their families, and via a public hearing. The PRAC noted that women were still not always receiving the right information in a timely manner and that further measures were needed to help avoid use during pregnancy. However, it was also clear that for some women, such as those with particular forms of epilepsy, valproate is the only appropriate treatment and might be life-saving.

The PRAC therefore considered that the way the products are used should be changed. It recommended strengthening restrictions on their use and introducing new measures to require appropriate counselling and information for affected women.

The PRAC also recommended that the companies marketing these medicines carry out additional studies to further characterise the nature and extent of the risks posed by valproate and to monitor ongoing valproate use and the long-term effects from affected pregnancies.

Because valproate medicines are all licensed at national level, the PRAC recommendations will now be sent to Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human[1] (CMDh), which will adopt a position.

In the meantime, women who have any concerns should consult their doctor. Women and girls who have been prescribed valproate should not stop taking their medicines without consulting their doctor as doing so could result in harm to themselves or to an unborn child.


[1] The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

More about the medicine

Valproate medicines are used to treat epilepsy and bipolar disorder. In some EU Member States they are also authorised to prevent migraine headaches.

The active ingredient in these medicines may be valproic acid, magnesium valproate, sodium valproate, valproate semisodium or valpromide.

Valproate medicines have been authorised via national procedures in all EU Member States and in Norway and Iceland. They are marketed under several brand names including: Absenor, Convival Chrono, Convulex, Delepsine, Depakin, Depakine, Depakote, Depamag, Depamide, Deprakine, Diplexil, Dipromal, Epilim, Episenta, Epival, Ergenyl, Espa-Valept, Hexaquin, Kentlim, Leptilan, Micropakine L.P., Orfiril, Petilin, Valepil, Valhel PR, Valpal, Valpro and Valprolek.

More about the procedure

The review of valproate medicines was initiated on 9 March 2017 at the request of the French medicines regulator ANSM, under Article 31 of Directive 2001/83/EC.

The review has been carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations. The PRAC recommendations will now be sent to Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position. The CMDh is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

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Name Language First published Last updated
Valproate Article-31 referral - PRAC recommends new measures to avoid valproate exposure in pregnancy (English only) 2018-02-09  

Key facts

About this medicine

Approved nameValproate and related substances
International non-proprietary name (INN) or common name

sodium valproate, valproate magnesium, valproate semisodium, valproic acid, valpromide

Associated namesAbsenor, Convival Chrono, Convulex, Delepsine, Depakin, Depakine, Depakote, Depamag, Depamide, Deprakine, Diplexil, Dipromal, Epilim, Episenta, Epival, Ergenyl, Espa-Valept, Hexaquin, Kentlim, Leptilan, Micropakine L.P., Orfiril, Petilin, Valepil, Valhel PR, Valpal, Valpro and Valprolek
Class

About this procedure

Current statusRecommendation provided by Pharmacovigilance Risk Assessment Committee
Reference numberEMEA/H/A-31/1454
TypeArticle 31 referrals

This type of referral is triggered when the interest of the Community is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Decision making modelPRAC-CMDh
Authorisation modelNationally authorised product(s)

Key dates and outcomes

Procedure start date09/03/2017
PRAC recommendation date08/02/2018
OutcomeRisk minimisation measures

Public hearing

EMA's Pharmacovigilance Risk Assessment Committee (PRAC) held a public hearing on this topic on 26 September 2017 at the Agency's premises in London:

The hearing was broadcast live on 26 September from 12:45-18:00 UK time. 

The video recording is now available. 

At the public hearing, the PRAC sought input on a list of specific questions. These are set out in the document below, together with a summary of the safety concerns with this medicine:

The application deadline to take part in the public hearing was 25 August 2017.

For more information on the PRAC meeting where the public hearing took place, see: PRAC: 25-29 September 2017

For more information about public hearings at EMA, see Public hearings.

All documents

Procedure started

Name Language First published Last updated
Valproate Article-31 referral - PRAC list of questions EN = English 2017-03-10  
Valproate Article-31 referral - Annex I EN = English 2017-03-10 2017-04-11
Valproate Article-31 referral - Review started EN = English 2017-03-10  
Valproate Article-31 referral - Notification EN = English 2017-03-10  

Under evaluation

Name Language First published Last updated
Valproate Article-31 referral - Timetable EN = English 2017-03-10 2017-12-07

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Name Language First published Last updated
Valproate Article-31 referral - PRAC recommends new measures to avoid valproate exposure in pregnancy EN = English 2018-02-09  

More documents

Name Language First published Last updated
Agenda - Public hearing: Valproate (English only) 2017-09-22 2017-09-25
Public hearing on valproate - Written interventions (English only) 2017-10-02  
Summary of safety concerns and list of questions for the public hearing on Valproate (English only) 2017-07-11  

Document description:

  • Annex I - List of the medicines affected by the referral
  • Annex II - Scientific conclusions of the Committee for Medicinal Products for Human Use (CHMP) or Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh)
  • Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
  • Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
  • Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
  • Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
  • PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
  • PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
  • PRAC / CHMP / CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated

Current status:
Recommendation provided by Pharmacovigilance Risk Assessment Committee

Video recording of public hearing

The PRAC held a public hearing on this topic on 26 September 2017, at its meeting of 25-29 September. For more information, click on the 'Public hearing' tab on this page.

small format video Icon To watch the video recording, click on the 'Public hearing' tab on this page.