Valproate and related substances - referral

Current status

European Commission final decision

Overview

New measures to avoid valproate exposure in pregnancy endorsed

Member State representatives agree new restrictions and pregnancy prevention programme

On 21 March 2018 the CMDh¹ endorsed new measures to avoid exposure of babies to valproate medicines in the womb, because exposed babies are at high risk of malformations and developmental problems.

Valproate-containing medicines have been approved nationally in the EU to treat epilepsy and bipolar disorder and in some countries for prevention of migraine. The new measures include a ban on the use of such medicines for migraine or bipolar disorder during pregnancy, and a ban on treating epilepsy during pregnancy unless there is no other effective treatment available.

Further, the medicines must not be used in any woman or girl able to have children unless the conditions of a new pregnancy prevention programme are met. The programme is designed to ensure that patients are made fully aware of the risks and the need to avoid becoming pregnant.

A visual warning of the pregnancy risks (in the form of boxed text with other possible elements such as a warning symbol) must also be placed on the packaging of the medicines and warnings be included on patient cards attached to the box and supplied with the medicine each time it is dispensed.

The CMDh agreed with EMA's Pharmacovigilance Risk Assessment Committee (PRAC), which carried out a review and recommended the new measures, that despite previous recommendations aimed at better informing patients of the risks with these medicines, women were still not always receiving the right information in a timely manner. The new measures endorsed by CMDh therefore strengthen previous restrictions on valproate use and requirements to inform women of the risk.

Companies marketing these medicines are also required to carry out additional studies on the nature and extent of the risks and to monitor valproate use and the long-term effects from affected pregnancies.

Because the CMDh position was agreed by majority vote it was sent to the European Commission, which issued a final legally binding decision valid across the EU.

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

 

Information for patients and healthcare professionals

• Medicines containing valproate have been available in EU countries for many years to treat epilepsy, bipolar disorder and in some countries migraine. It is known that if taken in pregnancy they can cause malformations in the baby and developmental disorders after birth.
• Although steps had been taken previously to better inform women about these risks and discourage use of valproate in girls and women unless there was no alternative, the evidence shows that this information is still not getting to patients.
• Valproate medicines are now therefore contraindicated, i.e. must not be used, in girls and women able to have children unless the terms of a special pregnancy prevention programme are followed. These include:
  • an assessment of each patient's potential for becoming pregnant,
  • pregnancy tests before starting and during treatment as needed,
  • counsellingabout the risks of valproate treatment and the need for effective contraception throughout treatment,
  • a review of ongoing treatment by a specialist at least annually,
  • introduction of a new risk acknowledgement formthat patients and prescribers will go through at each such annual review to confirm that appropriate advice has been given and understood.
• As before, valproate treatment should never be started unless alternative treatments are not suitable, including in young girls below the age of puberty.
• In pregnancy, valproate is contraindicated and an alternative treatment should be decided on, with appropriate specialist consultation, for women planning pregnancy; however, there may be a small number of women with epilepsy for whom there is no suitable alternative treatment to valproate and who should be appropriately supported and counselled.
• There will be changes to the product information (package leaflet for patients and SmPC for healthcare professionals) to reflect these new conditions and also to the packaging of the medicine, including a visual warning in the form of boxed text which may be accompanied by other elements such as a symbol. The medicines authorities in the individual countries will approve appropriate details of the visual warning for their national situation.
• Educational materials in the form of guides for patients and doctors will also be updated to reflect the current situation and provide age-appropriate advice. In addition, there will be a patient alert card attached to the packaging so that pharmacists can go through it with the patient when the medicine is dispensed.
• It is important that patients discuss any concerns about their medication with an appropriate healthcare professional. Women and girls who have been prescribed valproate should not stop taking their medicine without consulting their doctor as doing so could result in harm to themselves or to an unborn child.
• Healthcare professionals will receive further information at national level in due course as the recommendations are implemented.

The companies that market valproate must carry out further studies to characterise the nature and extent of the risks posed by valproate and monitor ongoing valproate use and the long-term effects from affected pregnancies. This will include surveys of healthcare professionals and patients to assess the reach and effectiveness of the new measures, and use of data from existing registries to further characterise the malformations known as foetal anticonvulsant syndrome in children whose mothers took valproate in pregnancy and how this compares to other anti-epileptic medicines. It also includes a retrospective observational study to look at any association between exposure to valproate in men and the risk of malformations and developmental disorders including autism in offspring, and an observational study to evaluate and identify the best practice for stopping and switching of valproate treatment.

In addition, all companies marketing such medicines will need to have in place a risk management plan which details the measures taken to ensure that a medicine is used as safely as possible.

Basis for the recommendations

The measures are based on a review of available scientific evidence, including drug utilisation studies and clinical and laboratory evidence of the effects of the medicine. During the review, the PRAC also consulted very 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 Summary of the EMA public hearing on valproate in pregnancy.

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 was first carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. The PRAC recommendations were sent to Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a position. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.

As the CMDh position was adopted by majority vote, it was sent to the European Commission, which issued an EU-wide legally binding decision on 31/05/2018.

Valproate Article-31 referral - New measures to avoid valproate exposure in pregnancy endorsed

AdoptedReference Number: EMA/375438/2018

Key facts

About this medicine

• Approved name:
  Valproate and related substances
• International non-proprietary name (INN) or common name:
  • sodium valproate
  • valproate magnesium
  • valproate semisodium
  • valproic acid
  • valpromide
• Associated names:
  • 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

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1454
• Type:
  Article 31 referrals

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

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  09/03/2017
• PRAC recommendation date:
  08/02/2018
• CMDh position date:
  21/03/2018
• EC decision date:
  31/05/2018
• Outcome:
  Risk 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:

• Agenda - Public hearing: Valproate
• Public hearing on valproate - Written interventions
• Summary of the EMA public hearing on valproate in pregnancy

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

A video recording is available below.

 

 

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:

• Public hearing on Valproate - Summary of safety concerns and list of questions for the public hearing on Valproate

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

Valproate Article-31 referral - Notification

Reference Number: EMEA/H/A-31/1454

Valproate Article-31 referral - Review started

Reference Number: EMA/144306/2017

Valproate Article-31 referral - Annex I

Reference Number: EMEA/H/A-31/1454

Valproate Article-31 referral - PRAC list of questions

Reference Number: EMA/PRAC/154222/2017

Under evaluation

Valproate Article-31 referral - Timetable

Reference Number: EMA/PRAC/154221/2017 Rev. 3

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Valproate Article-31 referral - PRAC recommends new measures to avoid valproate exposure in pregnancy

Reference Number: EMA/67672/2018

Position provided by CMDh

Valproate Article-31 referral - PRAC assessment report

AdoptedReference Number: EMA/198940/2018

Valproate Article-31 referral - Annex II

Valproate Article-31 referral - Annex IV

Valproate Article-31 referral - Annex I

Valproate Article-31 referral - New measures to avoid valproate exposure in pregnancy endorsed

Reference Number: EMA/145600/2018

Valproate Article-31 referral - Annex III

European Commission final decision

Valproate Article-31 referral - Divergent position

Valproate Article-31 referral - New measures to avoid valproate exposure in pregnancy endorsed

AdoptedReference Number: EMA/375438/2018

Valproate Article-31 referral - New measures to avoid valproate exposure in pregnancy endorsed

AdoptedReference Number: EMA/375438/2018

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.