Valproate Safety: Regulatory Measures and Support Resources
National Medication Safety Improvement Programme (MedSIP)
Improving care for people with epilepsy, bipolar and conditions for which Valproate is prescribed is one of the four priorities in the National MedSIP. The Valproate Integrated Quality Improvement national programme launched in November 2023, to support Integrated Care Boards to make the use of Valproate as safe as possible. The programme strives to eliminate the harm Valproate causes to babies in the womb, while providing the best possible personalised care for patients and preventing deaths from epilepsy and/or bipolar disorders. The programme has so far seen a 35% reduction in number of women of childbearing age prescribed Valproate.
Risks of Valproate
No one should stop taking valproate without advice from a specialist. This is because epilepsy or bipolar disorder may become worse without treatment, which can be harmful.
All women and girls of childbearing potential being treated with valproate medicines must be supported on a Pregnancy Prevention Programme (PPP).
Valproate is highly teratogenic causing foetal valproate syndrome. Exposure in utero leads to physical birth defects in 11% of babies and neurodevelopmental disorders in up to 30-40% of children, which may lead to permanent disability.
As a precaution, male patients on valproate who are planning a family within the next year should speak to a healthcare professional about their treatment options. January 2024 Drug Safety Update
Valproate may cause infertility in men. Some toxic effects on the testes (testicles) have been observed in animals; it is unclear what it means for humans. Data currently being analysed by MHRA may suggest an increased risk of neurodevelopmental disorders in children whose fathers took valproate in the 3 months before conception. Around 5% children born to fathers treated with valproate around conception were diagnosed with a neurodevelopmental disorder compared to 3% in children whose fathers were taking lamotrigine or levetiracetam around conception (two other anti-seizure medicines).
For comprehensive information view the November 2023 MHRA Public assessment report.
MHRA Regulatory Measures: required when prescribing valproate
All women and girls of childbearing potential being treated with valproate medicines must be supported on a Pregnancy Prevention Programme (PPP) unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy. Valproate is contraindicated in women of childbearing potential unless PPP is in place.
The PPP is designed to make sure patients are fully aware of the risks and the need to avoid becoming pregnant. Healthcare professionals prescribing or dispensing valproate to their female patients must ensure this is within the terms of the PPP.
The PPP includes a set of conditions to ensure all female patients taking valproate:
- See their specialist at least every year
- Have been informed and understand the risks of use in pregnancy and have signed an Annual Risk Acknowledgement Form (ARAF)
- Are prescribed highly effective contraception as appropriate
Conditions of the PPP for valproate are consistent with programmes available for other highly teratogenic drugs.
For more info, see MHRA Valproate Pregnancy Prevention Programme
Aim to reduce prescribing of valproate only to patients (female or male) where no other therapeutic options are suitable, and ensure patients are informed and understand the risk and this is documented via a formal signed risk acknowledgement form. There are two forms: the Annual Risk Acknowledgment form for female patients and the Risk Acknowledgement form for male patients (links below).
New regulatory measures were introduced in January 2024 because the MHRA are concerned that the regulatory requirements for safe use of valproate are not being followed. Nationally pregnancies continue to be exposed to valproate (53 in the last year) and there is new data which suggests there may be potential reproductive risks in males.
Phase One Measures from January 2024:
- Valproate must not be started in new patients (male or female) younger than 55 years, unless two specialists independently consider and document (using the formal Risk Acknowledgement Form) that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply.
- At their next annual specialist review, women of childbearing potential and girls should be reviewed using a revised valproate Risk Acknowledgement Form, which will include the need for a second specialist signature if the patient is to continue with valproate and subsequent annual reviews with one specialist unless the patient’s situation changes
A Male Risk Acknowledgement Form for any new initiations of valproate in males was produced and the Annual Risk Acknowledgement Form for females updated. Phase Two Measures (to cover existing male patients) are expected later in 2024.
Risk materials to explain the measures include a Healthcare Professionals Guide and a Patient Guide.
Further information:
- Smaller pack sizes to encourage monthly prescribing
- A pictogram/warning image on valproate labelling
- Rules introduced in 2023 to ensure all patients receive the whole pack of valproate with the warnings on the box
Hear the stories from women with children who have foetal valproate syndrome https://www.youtube.com/watch?v=JJygXxObLlI & https://youtu.be/GQM26zTID7k
Hope talks about her experience of the Pregnancy Prevention Programme:
Women and girls of childbearing potential should preferably use a highly effective user independent form of contraception without interruption during the entire duration of treatment with valproate (see guidance from Faculty of Sexual and Reproductive Health (FSRH)). They should be provided with information and counselling on the need for highly effective contraception to prevent pregnancy.
At initiation and at regular review at least every year, specialists should discuss the risks of valproate in pregnancy and complete and sign the Annual Risk Acknowledgement Form with the patient to document that they have discussed and understood the risks and have been fully informed on the need to use highly effective contraception. General practice should reinforce this message and ensure ongoing use of highly effective contraception.
Highly effective methods have typical-use failure rates of less than 1% and in this context include the long-acting reversible contraceptives (LARC):
- copper intrauterine device (Cu-IUD),
- levonorgestrel intrauterine system (LNG-IUS),
- progestogen-only implant (IMP), and
- male and female sterilisation,
all of which have a failure rate of less than 1% with typical use. If a user-independent form is not used, two complementary forms of contraception including a barrier method should be used and regular pregnancy testing considered.
The additional protective effect of using barrier method with oral contraception has not been quantified in the guidance and is not considered to be as effective as a user-independent method.
Even women with amenorrhea, must follow all the advice on contraception. These conditions also apply to women who are not currently sexually active unless the specialist considers that there are compelling reasons to indicate that there is no risk of pregnancy.
See MHRA Guidance ‘Medicines with teratogenic potential: what is effective contraception and how often is pregnancy testing needed?’. With a colour coded summary ‘aid-memoir’ table also available.
Individual circumstances should be, in each case, evaluated when choosing the contraception method, involving the patient in the discussion to guarantee her engagement and compliance with the chosen measures.
Concomitant use with oestrogen-containing products, may potentially result in decreased valproate efficacy. Prescribers should monitor clinical response (seizure control) when initiating or discontinuing oestrogen-containing products.
Valproate does not reduce the efficacy of hormonal contraceptives.
Resources for patients and healthcare professionals
- Patient guide: Provides those taking valproate (or their parent, caregiver, or responsible person) with information on the risks of valproate in pregnancy and the risks to male patients and what they need to do.
- Healthcare Professional Guide: Provides updated information for healthcare professionals on the risks of valproate in pregnancy and the risks for male patients, the new conditions for valproate prescribing and key points for patient discussions.
- Annual Risk Acknowledgement Form: For female patients starting valproate and at annual review. Used to support and record the discussion between the patient and specialist prescriber on the risks associated with valproate in pregnancy and to record the decision of the countersigning specialist. At subsequent annual reviews only one specialist is required.
- Risk Acknowledgement Form for male patients starting valproate: Used to support and record the discussion between the patient and specialist prescriber of the risks associated with valproate in males when starting treatment with valproate and to record the decision of the countersigning specialist. This is only to be completed at initiation of valproate.
- Patient card: Provides key information for female patients receiving valproate on contraception and pregnancy prevention.
- Pharmacy poster: Provides important actions for pharmacists dispensing valproate to female patients.
- Warning stickers: To be added to packaging of medicine in exceptional circumstances where the original pack cannot be dispensed.
See Product Information for valproate medicines, including the Patient Information Leaflet.
To be used by specialist neurology or psychiatry teams to reach shared decisions about how appropriate valproate treatment is for this as an individual. https://www.england.nhs.uk/publication/decision-support-tool-is-valproate-the-right-epilepsy-treatment-for-me/ & https://www.england.nhs.uk/publication/decision-support-tool-bipolar-disorder-is-valproate-the-right-treatment-for-me/ Information should be provided in an accessible format where necessary, for example easy read, other languages. https://www.choiceandmedication.org/awp/printable-leaflets/patient-information-leaflets/139/ALL/
For all indications and all patients, valproate products should only be prescribing in primary care following specialist initiation and stabilisation (BSW formulary traffic light status ‘Amber’). Currently, for women of childbearing potential using valproate, ongoing division of responsibility for drug and disease monitoring is formalised in a Shared Care Agreement (SCA) (BSW formulary traffic light status Amber with Shared Care)
It is anticipated that this formal shared care approach may be extended to also include male patients in future, as part of Phase two national regulatory measures.
The multiple requirements of the PPP and the number of organisations and teams involved in the valproate safety pathway mean there is a high risk of issues arising from problems with communication at transfer of care/interface, or confusion around responsibilities.
Our full BSW System Roles and Responsibilities flow chart aims to clarify the pathway and will be available soon.
Specialist Pharmacy Services have a suite of webinars and Podcasts available which are designed to support the national Valproate MedSIP.
Including:
- Safer use of Valproate Webinar
- ICB Investigation into a pregnancy while prescribed valproate
- Safe Prescribing in Mental Health and Acute Trust settings
- Considerations for an equitable approach for people with learning and intellectual disabilities and the patient voice.
BSW Valproate Safety Working Group established in January 2024, with stakeholders from partner organisation, including clinical leads in neurology, mental health, paediatrics, contraception, and sexual health, learning disability, general practice, and medication safety teams. Medical, nursing and pharmacy professionals.
The group have identified local themes for improvement:
All Partner Organisations to review internal procedures for valproate safety measures. Document internal ‘procedure’ for the new and existing valproate regulatory measures [including Pregnancy Prevention Programme (PPP), Annual Risk Acknowledgement Form (ARAF), Risk Acknowledgement Form (RAF) (new males)]. Include defined roles and responsibilities and the secondary independent signatory arrangement at both inpatients and outpatient setting.
A system Share Care Agreement and role & responsibility document. To clearly define role and responsibility for safe valproate prescribing & facilitate transfer of care.
Data validation of registers. Digital Tools to empower specialist team colleagues to hold an up-to-date register and proactively recall patients for annual review and communicate risk acknowledgement forms across pathways. Minimise administrative burden on referral arrangements.
Highly effective contraception. Focus on education and clarification of the contraception pathways/choices/approach.
Learning Disability Inequalities. Mapping exercise to establish the current pathway and resources available.
Please get in touch if you’d like to be involved in valproate safety improvement work with the ICB, by emailing: bswicb.prescribing@nhs.net
Please share learning from Medication Safety Events you identify.
Sharing learning from medication safety events and recording events on the national Learn from Patient Safety Events (LFPSE) service helps improve patient safety, by raising awareness and prompting local and national actions/alerts to mitigate the risks identified. If you’d like to share your learning from a medication safety event, get in touch via bswicb.prescribing@nhs.net and mark for the attention of the Medication Safety Team.