Children exposed to valproate in utero are at a high risk of serious developmental disorders (30–40% risk) and congenital malformations (10% risk). Valproate is now contraindicated in pregnancy for all indications, except for the treatment of epilepsy in the absence of a suitable alternative
. In April 2018, the Medicines and Healthcare products Regulatory Agency (MHRA) advised that medicines containing valproate are now contraindicated in women and girls of childbearing potential unless the patient is on the pregnancy prevention programme (PPP) and other treatments have been judged ineffective or are not tolerated. Healthcare professionals across the system are now addressing the impact of this change on their clinical practice and commissioning arrangements.
Valproate is prescribed for the management of epilepsy and bipolar disorder, and for off-label use in the prophylaxis of migraine. Epilepsy is more prevalent in people with a learning disability, so prescribing rates for sodium valproate in this group may be higher compared with the general population. The drug has also been used in the management of behaviour that challenges in people with a learning disability and autism, but who do not have a diagnosis of epilepsy or bipolar disorder. Therefore, valproate is an important consideration in the ‘Stopping the overprescribing of medication in people with a learning disability or autism or both programme’ (STOMP) — the NHS England-backed deprescribing programme which aims to reduce the inappropriate use of psychotropic medicines in people without a mental health diagnosis
Frequently, patients with a learning disability receive several psychotropic medicines for the management of behaviour that challenges, in the absence of a documented mental health diagnosis
. Off-label prescribing of valproate may be confusing because Depakote (divalproex sodium; Sanofi) is licensed only for bipolar disorder, Epilim (sodium valproate; Sanofi) is licensed only for epilepsy, and Episenta (sodium valproate; Desitin Pharma Ltd) is licensed for both
Given that there are no valproate formulations with a marketing authorisation for the management of behaviour that challenges and in light of the new guidance, valproate deprescribing must be prioritised in the STOMP agenda
. In cases of polypharmacy of psychotropic medicines, it is good practice to reduce one medication at a time. For women prescribed both valproate and an antipsychotic, it is imperative to review the valproate first. However, if valproate is prescribed for epilepsy or bipolar disorder in a woman of childbearing potential and the neurology or psychiatry team decide to continue the medicine, it must be considered that reducing an antipsychotic, such as risperidone or amisulpride, may reduce prolactin levels; this may increase fertility and the risk of pregnancy if the woman is not taking effective contraception and is sexually active.
Educating women with a learning disability and/or autism about valproate and the PPP may be complex. The MHRA has sent repeated alerts to healthcare professionals since 2016; the most recent in May 2018 comprised a set of resources for the safer use of valproate for all indications, plus off-label use
. Guidance for healthcare professionals, a patient guide and an alert card were included. Healthcare professionals must be sure that information they give patients complies with the accessible information standard
. But the development of easy-to-read material may pose a risk; consideration must be given to the risk of over-simplifying content, which could result in incomplete communication.
In the absence of capacity to consent to treatment, the valproate risk acknowledgement form can be signed by a relative or a carer. However, if a woman with a learning disability or literacy impairment has the capacity to consent to treatment, it may not be appropriate for another individual to act on her behalf if she has not given permission. Her consent will not be valid if she has not fully understood all material risks and what is meant by effective contraception. In addition, further consent must be given when prescribing any valproate formulation off-label.
This aspect of the STOMP programme should be addressed by all stakeholders to ensure that women of childbearing potential with a learning disability or autism, or both, are appropriately advised. Pharmacists should be vigilant when deprescribing is considered, especially when doses of antipsychotics, known to cause hyperprolactinemia, are reduced in women who have been coprescribed sodium valproate.
The first step in the implementation of the MHRA’s advice is to identify female patients of childbearing potential who are currently prescribed valproate. This may be carried out at various stages of the patient journey, which provides opportunities for pharmacists.
For some women, valproate may continue to be prescribed as an appropriate treatment subject to a completed risk acknowledgement form, effective contraception and an annual review by a specialist. Pharmacy consultations must be bespoke and appropriate, backed by evidence, and make use of the MHRA resources.
The risks of taking valproate should be imparted with care and should not raise undue alarm or panic, which could lead to sudden unplanned discontinuation of valproate and, perhaps, other anti-epileptic medicines in the absence of advice from the responsible clinician. Patients who stop taking their prescribed valproate are at increased risk of relapse and, subsequently, morbidity and mortality.
The accessibility of pharmacists in primary care, both in the community and at GP practices, provides opportunities to discuss contraceptive choices that are considered effective as part of the PPP. When switching from valproate to alternative anti-epileptic drugs, or lithium, the pharmacist should review the risks of adverse effects, the monitoring required, and potential drug interactions with prescribed and non-prescribed medicines.
It is imperative that patients are informed of the risks associated with alternative prescribed medicines and not led to believe that they are safe for use in pregnancy. In cases in which valproate is being switched to carbamazepine, consideration should be given to current prescriptions of combined oral contraception to ensure that the correct strength of oestrogen is prescribed and to avoid inadvertent reduced efficacy of contraception.
Implementation of the new MHRA regulations requires a collaborative approach between healthcare professionals, commissioners and provider organisations in primary, secondary and, in some circumstances, tertiary care. The implications of these regulations provide pharmacists with a pivotal role in highlighting medicines-related issues to the healthcare team at both a strategic and individual patient level.
Danielle Adams, principal clinical pharmacist, Hertfordshire Partnership University NHS Foundation Trust
Indermeet Sawhney, consultant psychiatrist and medical lead, Learning Disability Services North Essex, Hertfordshire Partnership University NHS Foundation Trust
 NHS England. Stopping over medication of people with a learning disability, autism or both (STOMP). 2018. Available at: http://www.england.nhs.uk/learning-disabilities/improving-health/stomp (accessed October 2018)
 NHS England. The use of medicines in people with learning disabilities. Letter to healthcare professionals from Dominic Slowie and Keith Ridge. 14 July 2015. Available at: https://www.england.nhs.uk/wp-content/uploads/2015/07/med-advice-ld-letter.pdf (accessed October 2018)
 Medicines and Healthcare products Regulatory Agency. Drug safety update: Valproate medicines (Epilim, Depakote): Pregnancy Prevention Programme materials online. 2018. Available at: www.gov.uk/drug-safety-update/valproate-medicines-epilim-depakote-pregnancy-prevention-programme-materials-online (accessed October 2018)
 NHS England. Accessible Information Standard. 2017. Available at: https://www.england.nhs.uk/ourwork/accessibleinfo/ (accessed October 2018)