UK: United Kingdom's MHRA Bans Valproate Medicines Without The Pregnancy Prevention Programme

On April 24, 2018, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) announced that 'to protect public health, the Medicines and Healthcare products Regulatory Agency (MHRA) has changed the license for valproate medicines (Epilim, Depakote and generic brands). Valproate must no longer be prescribed to women or girls of childbearing potential unless they are on the pregnancy prevention programme (PPP)'24.

The MHRA regulates medicines, medical devices and blood components for transfusion in the UK. MHRA is an executive agency, sponsored by the Department of Health and Social Care, United Kingdom25.

Background

Valproate (Epilim, Depakote and other generic brands) is associated with a significant risk of birth defects and developmental disorders in children born to women who take valproate 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. In March 2018, the European Union's Coordination Group for Mutual Recognition and Decentralized Procedures - Human (CMDh) endorsed a strengthened regulatory position on valproate medicines26. Valproate must no longer be used in any woman or girl able to have children unless she has a pregnancy prevention programme in place. This is designed to make sure patients are fully aware of the risks and the need to avoid becoming pregnant.

MHRA Updates – April 2018

The agency has recommended that healthcare professionals who seek to prescribe valproate to their female patients must make sure they are enrolled in the PPP. This includes the completion of a signed risk acknowledgement form when their treatment is reviewed by a specialist, at least annually. The agency has also advised that all women and girls who are prescribed valproate should contact their General Practitioner (GP) and arrange to have their treatment reviewed. No woman or girl should stop taking valproate without medical advice.

These regulatory changes will be further supported in the upcoming months by:

  • smaller pack sizes to encourage monthly prescribing
  • a pictogram/warning image on valproate labelling

These new regulatory measures are being supported across the National Health Service (NHS) with other authorities also making changes – such as new General Practitioner (GP) system computer alerts – to make sure changes in prescribing behaviour take place promptly. NHS Digital has worked with GP systems suppliers to provide a search and audit function to identify women and girls on valproate as well as updating valproate prescribing alerts. A letter will be sent to all relevant healthcare professionals in the coming weeks outlining the new requirements and providing updated educational materials.

Parallelly, the National Institute for Health and Care Excellence (NICE) is amending its guidelines where valproate is mentioned, to reflect the new regulatory position. NICE has also begun work on a full update of its guideline on epilepsy. This will specifically focus on areas where valproate is currently regarded as the drug of choice and where this conflicts with the new position.

Working together, across the health sector, these measures will help reduce the number of pregnancies exposed to valproate medicines to an absolute minimum and will make sure all women and girls of childbearing potential are aware of the risks.

Since it was introduced in 1974, the information provided with valproate included a warning about the possible risk of birth defects. As with all medicines, the safety of valproate has been kept under constant review and as new data have become available, and the magnitude and the nature of the risks were better understood, warnings were updated – resulting in this most recent regulatory change.

As part of the pregnancy prevention programme (PPP) the prescriber must:

  • ensure the patient understands the risks to the unborn child from using valproate during pregnancy and provide patient guide;
  • ensure the patient understands the need to comply with contraception throughout the treatment and undergo pregnancy testing when required e.g. if there is any reason to suggest lack of compliance or effectiveness of contraception;
  • complete and sign the acknowledgement of risk form (at every annual visit), give a copy to the patient and send one to the GP;
  • refer for contraception services as needed.

Advice for healthcare professionals

New contraindication unless Pregnancy Prevention Programme in place

  • Valproate medicines must not be used in women and girls of childbearing potential unless the conditions of the Pregnancy Prevention Programme are met and only if other treatments are ineffective or not tolerated, as judged by an experienced specialist.
  • HCPs will receive materials by post in the coming weeks to use in the implementation of the Pregnancy Prevention Programme (Patient Guide, Healthcare Professional Guide, Risk Acknowledgement Form and, for pharmacists, Patient Cards and stickers to attach a warning label to the pack)
  • GPs must identify and recall all women and girls who may be of childbearing potential, provide them Patient Guide and check they have been reviewed by a specialist in the last year and are on highly effective contraception (see later for information on contraception)
  • Specialists must book review appointments at least annually with women and girls under the Pregnancy Prevention Programme and re-evaluate treatment as necessary; explain clearly the conditions as outlined in the supporting materials; and complete and sign the Risk Acknowledgement Form—copies of the form must be given to the patient or patient/caregiver/responsible person and sent to their GP.

Conditions and guidance for the Pregnancy Prevention Programme

The agency has put forward strong conditions for all women and girls of childbearing potential being treated with valproate medicines, to be supported by a Pregnancy Prevention Programme. These conditions are also applicable to female patients who are not sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy27.

The Pregnancy Prevention Programme is a system of ensuring all female patients taking valproate medicines:

  • have been told and understand the risks of use in pregnancy and have signed a Risk Acknowledgement Form;
  • are on highly effective contraception if necessary;
  • see their specialist at least every year.

The conditions of the Pregnancy Prevention Programme for valproate are consistent with other similar programmes available for other highly teratogenic drugs such as thalidomide and isotretinoin.

The Pregnancy Prevention Programme is supported by the following requirements, which have been revised to be consistent with the new requirements:

  • A Patient Guide – to be provided to girls (of any age) and women of childbearing potential (or their parent/caregiver/responsible person) who are started on or are continuing to use valproate medicines;
  • A Guide for Healthcare Professionals – for guidance to all prescribers, pharmacists, and other healthcare providers involved in the care of women and girls of childbearing potential using valproate medicines;
  • A Risk Acknowledgement Form – for the specialist and patient (or their parent/caregiver/responsible person) to sign at initiation and at treatment reviews at least every year. The patient should receive a copy of the form; one copy should be filed in the specialist notes, and one copy sent to the patient's GP;
  • A Patient Card – to be given by pharmacists to all female patients who are dispensed valproate medicines to inform them of the risks;
  • Stickers with warning symbols – for pharmacists to add to the packaging of valproate medicines.

Warnings added to the packaging of valproate medicines

The agency has further recommended a visual warning symbol will be added to the carton of valproate medicines by September 2018. This symbol will show a pregnant woman in a red circle with a line through it, with warning text about the risks and information about the new measures.

Pharmacists should therefore, dispense in whole packs whenever possible. This will ensure that patients always see the warning symbol and receive the statutory information. If a pharmacist must split a pack, or if the carton does not have a symbol on it, warning labels should be added to the box – stickers will be available with the educational materials to be sent to pharmacists by post.

Pharmacists should give the patient card to female patients when dispensing valproate. Packs of valproate medicines will start to be available with a detachable patient card from December 2018.

If a woman or girl of childbearing potential reports that she is not taking effective contraception, pharmacists should advise her to contact her GP for an urgent follow-up.

Audit functions and prescribing alerts in GP software

United Kingdom's National Health Service (NHS) Digital has asked GP systems suppliers to provide a search and audit function to allow GPs to identify women on valproate medicines. Prescribing alerts for valproate medicines will also be updated with reminders of the responsibilities of prescribing GPs in line with the regulatory position. NHS Digital has also worked with community pharmacy dispensing system suppliers so that alerts are shown when prescriptions are dispensed.

New contraindication in pregnancy

The strengthened regulatory position includes a new absolute contraindication for use of valproate medicines in pregnancy for the bipolar disorder indication. In the epilepsy indication, the contraindication for use in pregnancy applies unless there are no suitable alternatives, recognising that in some patients who are already pregnant switching antiepileptic medicines may not be feasible. In this case, access to counselling about the risks should be provided and the Risk Acknowledgement Form signed by both specialist and patient.

Conclusion:

The MHRA's ban on usage of Valproate medicines without the pregnancy prevention programme is a step towards enhancing patient safety. The agency is ensuring that women and girls are aware of the real risks of taking valproate during pregnancy. Usage of information technology, communication and alert system is a good example of how IT systems can effectively support important issues affecting public health.

Footnotes

24. https://www.gov.uk/government/news/valproate-banned-without-the-pregnancy-prevention-programme

25. https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency

26. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/03/news_detail_002929.jsp&mid=WC0b01ac058004d5c1

27. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/701831/DSU-April-2018-PDF.pdf

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