is available to support the Valproate Pregnancy Prevention Programme.
Compliance by healthcare professionals with the new valproate measures for pregnancy prevention appears currently patchy
Women are not always receiving Patient Information Leaflets with their medicines, as is required
Some women using valproate for off-label indications are not being reviewed in line with the new pregnancy prevention measures
Guidance is available for psychiatrists on the withdrawal of, and alternatives to, valproate in women of childbearing potential
Advice and information for healthcare professionals:
- valproate should not be used in women and girls of childbearing potential unless there is no suitable alternative and the conditions of the Pregnancy Prevention Programme are met
- although use in female patients in the UK continues to slowly decline, data shows a wide geographical variation in the prescribing of valproate medicines — you can check your region here
- women continue to report instances when pharmacists have not provided a Patient Information Leaflet or a Patient Card when dispensing valproate
- ensure you are complying with the responsibilities of healthcare professionals involved in the care of female patients on valproate – including when valproate is used outside the licensed indications (see advice on off-label use below)
- an audit function is available on all GP software systems – use this now 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
Reminder for pharmacists:
- 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 – situations can change and a one-time conversation is not sufficient
- check whether women are enrolled in the Pregnancy Prevention Programme and have signed a Risk Acknowledgement Form (updated March 2019) – if not, dispense the prescription and advise the patient to speak to her GP as soon as possible (including by contacting the GP directly if necessary) for a specialist referral
- GPhC inspectors will be systematically checking compliance with the Pregnancy Prevention Programme during inspections of registered pharmacies (see GPhC statement)
- ensure materials are placed in a defined area in the pharmacy and that all staff, including locums, know where they are located and aware of the local policies
- if you require more copies, contact the Sanofi medical information department without delay on 0845 372 7101 or email UK-Medicalinformation@sanofi.com
Valproate Pregnancy Prevention requirements, including when used off-label
Valproate should not be used in girls (of any age) and women of childbearing potential unless there is no suitable alternative, as judged by a specialist experienced in the management of epilepsy or bipolar disorder. If valproate is the only effective or tolerated medicine, women and girls of childbearing potential should be enrolled in the Pregnancy Prevention Programme and a Risk Acknowledgement Form should be completed by the prescriber and patient every year at an annual specialist review (see Drug Safety Update April 2018 and Drug Safety Update May 2018).
We are aware of off-label use of valproate for pain, migraine, and other conditions. Prescribers are reminded that off-label use of valproate carries all the accompanying responsibilities for the pregnancy prevention measures to be followed (see guidance from MHRA and the General Medical Council on prescribing unlicensed medicines).
Irrespective of condition being treated, valproate medicines should not be used in women of childbearing potential unless the patient is fully aware of the serious risks in pregnancy and the conditions of the Pregnancy Prevention Programme are fulfilled. Valproate should only be initiated in girls (of any age) and women of childbearing potential by specialists experienced in the management of their treated condition. The Risk Acknowledgement Form should be completed by the specialist prescriber at initiation. If valproate treatment is to be issued by repeat prescription in general practice, the GP and specialist should ensure the patient has an annual review with a specialist prescriber to discuss the need for treatment and any change in her situation. If valproate treatment is continued, the risks and pregnancy prevention measures must be fully discussed with the patient, and the Risk Acknowledgement Form completed by both prescriber and patient annually.
For patients with a first language that is not English, the conclusions of the EU review and a summary of the new measures are available on the website of the European Medicines Agency in 22 European languages, including Polish.
New guidance for prescribers
A Position Statement from the Royal College of Psychiatrists is now available to provide guidance for prescribers on the withdrawal of, and alternatives to, valproate-containing medicines in girls and women of childbearing potential who have a psychiatric illness. The guidance summarises evidence for alternatives to valproate, provides advice on how women who are currently undergoing treatment with valproate medicines can be switched to alternative treatments, and provides a link to the annual Risk Acknowledgment Form to facilitate discussions with patients about hazards associated with valproate medicines.
Reports of instances of non-adherence to new regulatory measures and reminder to pharmacists
The MHRA has worked closely 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.
Concerns have been raised by support networks that patients are not being properly informed of the risks and that they have not been given the patient information materials including with every dispensed medicine. In a survey of 78 patients on the INFACT website between June and September 2018, 88% respondents had not signed the Risk Acknowledgment Form (updated March 2019) 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.
Given the serious risk of harm with valproate being used in pregnancy, with up to 40% of exposed children having a birth defect or persistently impaired mental development, the Patient Information Leaflet should always be provided with this medicine, even when dispensed in a white dispensing box. Warning stickers should also be applied to white dispensing boxes to ensure all patients are visually reminded of the risk.
If pharmacists or pharmacies require additional Patient Information Leaflets, they may photocopy the leaflet from the bulk product or download them from the following sites, together with the risk materials:
For hard copies of all the information contact Sanofi medical information department on 0845 372 7101 or email UK-Medicalinformation@sanofi.com.
The MHRA is working with the wider healthcare system, including professional regulators, to ensure compliance with the new regulatory measures. When inspecting registered pharmacies, inspectors from the General Pharmaceutical Council are looking to see whether the standards are being met, and will systematically check compliance with the requirements of the Pregnancy Prevention Programme (see statement from GPhC).
See also the joint resource for pharmacists on Valproate Safety from the Community Pharmacy Patient Safety Group and Royal Pharmaceutical Society to support pharmacy teams in helping women and girls who have been prescribed valproate medicines. The resource includes a decision pathway and key points for consideration to prompt conversations between the pharmacy team and their patients.
Analysis of prescribing data and trends, including for CCGs
We have recently completed analysis of primary care prescribing data for valproate medicines from the Clinical Practice Research Datalink (CPRD) up to the end of June 2018. For the detailed data, see .
There continues to be a slow, sustained 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. You can review the data from your CCG from the NHS Business Services Authority, including how prescribing has changed over time and how it compares to neighbouring CCGs.
We will continue to monitor these and other data sources, including clinical audits and patient surveys. We will communicate updates via Drug Safety Update and the Valproate Guidance page. If data show women continue to be exposed to valproate during pregnancy and therefore measures may have not been sufficient to inform and protect women and their children, MHRA will consider the need for strengthened action.
About the data used to assess prescribing
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. Primary care data are linked to a range of other health related data to provide a longitudinal, representative UK population health dataset. The data used here includes over 2.2 million currently registered patients.
Data for CCGs in England is from the NHS Business Services Authority (NHSBSA). Quarterly data for based on the number of female patients of childbearing age who have received prescriptions for sodium valproate (including valproic acid and semisodium valproate). At the time of publication, data are available up to September 2018.
Valproate medicines are licensed for the treatment of epilepsy and bipolar disorder. Epilim▼ and Depakote▼ are the most commonly dispensed valproate medicines in the UK. Other brands available are Convulex▼, Episenta▼, Epival▼, Kentlim▼, Orlept▼, Syonell▼, and Valpal▼.
Valproate is highly teratogenic and use in pregnancy leads to physical birth defects in 10 in every 100 babies (compared with a background rate of 2 to 3 in 100) and persistent neurodevelopmental disorders in approximately 30 to 40 in every 100 children born to mothers taking valproate.
You can read more about the risk, and the actions taken to prevent exposure in pregnancy, in Drug Safety Update July 2018 and Drug Safety Update November 2018.
Ensure you are subscribed to receive Drug Safety Update or download the Yellow Card App to access the latest safety information from the MHRA about medicines and medical devices on the Newsfeed. Download the app via iTunes Yellow Card for iOS devices or via PlayStore Yellow Card for Android devices.
In April 2019, links to the original Annual Risk Acknowledgement Form (dated May 2018) were edited to direct to a revised form (dated March 2019).
Article citation: Drug Safety Update volume 12, issue 5: December 2018: 2.