Valproate (Epilim▼, Depakote▼) indicated for the treatment of epilepsy or bipolar disorder and also to prevent pain, migraine headaches as an unlicensed indication. Valproate is highly teratogenic with risk of physical birth defects (10%) and neurodevelopmental disorders (30-40%) in children born to mothers taking valproate.
Valproate medicines must not be used in women and girls of childbearing potential unless the conditions of the Pregnancy Prevention Programme (PPP) are met and only if other treatments are ineffective or not tolerated. Treatment should be reviewed by a specialist at least once a year and both the patient and prescriber should complete a risk-acknowledgment form at the same time, which confirms they understand the dangers to an unborn child associated with the drug. Also prescribers are reminded that off-label use of valproate carries all the accompanying responsibilities for the pregnancy prevention measures to be followed. The agency advises that healthcare professionals who seek to prescribe valproate to their female patients must make sure women are enrolled in the PPP. This includes the completion of a signed risk acknowledgement form when their treatment is reviewed by a specialist annually. Prescribers will be expected to do the following:
- valproate should not be used in women and girls of childbearing potential unless other treatments are ineffective or not tolerated and the conditions of the Pregnancy Prevention Programme are met
- ensure all the responsibilities of healthcare professionals involved in the care of female patients on valproate – including when valproate is used outside the licensed indications fulfilled
- an audit function is available on all GP software systems – use this to identify and recall all women and girls on valproate who may be of childbearing potential and refer to an appropriate specialist for a review.
Advice to pharmacist:
- always provide the statutory Patient Information Leaflet to female patients with a valproate medicine, even when dispensed in a pharmacy ‘white dispensing box’ (plain carton)
- remind women of the risks and provide with a Patient Card every time they are dispensed a valproate medicine
- check whether women are enrolled in the Pregnancy Prevention Programme and have signed a Risk Acknowledgment Form – if not, dispense the prescription and advise the patient to speak to her GP as soon as possible for a specialist referral
- GPhC inspectors will be systematically checking compliance with the Pregnancy Prevention Programme during inspections of registered pharmacies
The MHRA worked with stakeholders, including charities and patient support networks, to implement and monitor compliance with the 2018 strengthened regulatory measures to protect female patients taking valproate. Support networks have raised concerns that patients are not being properly informed of the risks and that they have not been given the patient information materials with every dispensed medicine. Survey of 78 patients on the INFACT website between June and September 2018, revealed that 88% respondents had not signed the Risk Acknowledgment Form to agree they had been informed of the risks of valproate in pregnancy. Many respondents to the survey had also received their valproate medicines in a white dispensing boxes (plain cartons) without the statutory Patient Information Leaflet (58% of respondents stated that they never receive a leaflet if their medicines are repackaged in a white dispensing box). Only 8% of respondents had ever received the new Patient Card from their pharmacist with their valproate medicine.
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.
According to the analysis of primary care prescribing data for valproate medicines from the Clinical Practice Research Datalink (CPRD) up to the end of June 2018, there is a steady decline in the initiations of valproate medicines in female patients, particularly in adolescent girls. Overall rates of prescribing of valproate in female patients in primary care are also slowly declining throughout the UK. However, there were an estimated 3.3 per 10,000 pregnancies in the UK exposed to the harm of valproate in 2017 – around 250 live births. Data from the NHS in England shows clear variation in the prescribing of valproate in women of childbearing age across England.
As part of their responsibility for the safety of medicines, the MHRA monitors data on the impact of regulatory action. The MHRA uses a variety of data sources for this. CPRD collects de-identified patient data from a network of GP practices across the UK. The data used here includes over 2.2 million currently registered patients.