This page includes: Actions for specialist prescribers; Actions for GPs; Pregnancy Prevention Programme; Contraception; Safety materials; Supporting clinical guidance

National Patient Safety Alert (November 2023) and MHRA Drug Safety Update (January 2024)

New safety measures were introduced from January 2024. Accompanying educational and safety materials are highlighted below.

Refer to the electronic medicines compendium, for the SmPCs for valproate-containing medicines (including valproic acid)

The new measures apply to the following patient groups:

New patients (male or female younger than 55 years)*

Valproate must not be started in new patients (male or female) younger than 55 years, unless two specialists independently consider and document that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply.

Thereafter, annual specialist review and Annual Risk Acknowledgement Form completion with a single signature is required for women only.

Female patients under 55 years of age currently on valproate*

At their next annual specialist review, women of childbearing potential and girls receiving valproate should be reviewed using the revised valproate Risk Acknowledgement Form, which will include the need for a second specialist signature if the patient is to continue on valproate, and subsequent annual reviews with one specialist unless the patient’s situation changes.

* Prescribers should consider these measures to be applicable to any patient of child-bearing potential (including trans men and non-binary people with female reproductive organs).

Male patients under 55 years of age currently on valproate

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 (MHRA Drug Safety Update, January 2024)

Additional recommendations are expected later in 2024 in relation to review of men under 55 years of age on valproate.

Actions for specialist prescribers

Extracted from the valproate Guide for Healthcare Professionals

Female patients under 55 years

Female patients not planning to become pregnant.

• For new female patients aged under 55 years, only start treatment with valproate if:
  • You and another specialist (countersigning specialist) independently consider and document that there is no other effective or tolerated treatment.
  • Pregnancy is excluded by means of a negative pregnancy test.
• Assess the potential for pregnancy in all female patients and if necessary, discuss the need for the patient to fulfil the conditions of the ‘prevent’ (Pregnancy Prevention Programme) if they are to take valproate.
• Where possible, existing patients should be switched to another treatment and for those continuing to receive valproate the benefits and risks of valproate should be carefully reconsidered at regular treatment reviews, at least annually.
• Ensure the patient understands the risks to an unborn baby exposed to valproate in utero and provide them the Patient Guide.
• Ensure the patient understands the need to comply with effective contraception throughout treatment and undergo pregnancy testing when required – e.g., if there is any reason to suggest lack of compliance or lack of effectiveness of contraception.
• Ensure that you invite all female patients on valproate for an annual review. Continue treatment with valproate only if there is no other effective or tolerated treatment.
• Two specialists (specialist prescriber and countersigning specialist) must complete and sign the Annual Risk Acknowledgment Form:
  • for new patients at initiation of valproate treatment.
  • for existing patients, only at their next annual review, unless their circumstances change.
• For subsequent annual reviews, only the prescribing specialist must complete and sign the Annual Risk Acknowledgement Form.
• The completed form should be stored in the patient’s medical notes and shared with the patient and any healthcare professionals named on the form.
• Refer for contraception advice as needed.
• For female children receiving valproate, the importance of risks relating to pregnancy exposure to valproate should be discussed well before menarche and patients should be switched to another treatment unless two specialists independently consider and document that there is no other effective or tolerated treatment or the risk associated with exposure during pregnancy is not applicable.

See here for guidance on whether ‘prevent’ (valproate Pregnancy Prevention Programme) applies to a patient, including BPNA/RCPH guidance for females under 18 years of age

Female patients planning to become pregnant

• Ensure the patient understands the risks of taking valproate during pregnancy.
• Switch valproate to another therapeutic option. The conditions of ‘prevent’ (Pregnancy Prevention Programme) continue to apply until the switch from valproate is complete.
• Remind the female patient not to stop contraception until the switch is achieved and they are no longer taking valproate.
• If switching is not possible, refer the patient for counselling about the risks of valproate to an unborn baby during pregnancy.

Female patients who are pregnant

• Female patients who are pregnant should have their treatment switched to another treatment whenever possible.
• Female patients with epilepsy who have to continue treatment in pregnancy (i.e., if two specialists independently consider and agree that switching to another treatment is not possible) should be referred to a specialist experienced in prenatal medicine for appropriate monitoring.

Male patients under 55 years

• No new male patients aged under 55 years should be initiated on valproate, unless two specialists independently consider and document that there is no other effective or tolerated treatment or the risk of infertility or potential risk of testicular toxicity are not applicable.
• If a new male patient has a permanent reason that these risks do not apply (e.g., vasectomy or infertility due to other causes), the countersigning specialist is not required, and the specialist prescriber should record the reason in the relevant section of Risk Acknowledgement Form for male patients and in their medical notes.
• Ensure male patients on valproate have the Patient Guide or know they can access it online using the QR code on the package leaflet.
• A Risk Acknowledgement Form for Males needs to be discussed and completed with the patient at time of treatment initiation. The completed form should be stored in the patient’s medical notes and shared with the patient and any healthcare professionals named on the form.
• Ensure the patient is made aware of the risk of male infertility and testicular toxicity in animals associated with valproate therapy.
• As a precaution, male patients currently receiving valproate who are planning a family within the next year should speak to a healthcare professional about their treatment options (MHRA Drug Safety Update, January 2024).
• For male children receiving valproate, their responsible person should be made aware of the data available showing testicular toxicity in animals exposed to valproate and the uncertain clinical relevance.

Actions for general practitioners

Valproate guide for Healthcare Professionals: actions for general practitioners extracted from guide

Female patients under 55 years

• Refer any new patient to a specialist prescriber for diagnosis and initiation of treatment.
• Arrange to see each female patient after specialist review and, if on valproate, ensure the patient is complying with ‘prevent’ (where applicable) i.e., ensure that:
  • The patient has the Patient Guide and a copy of the signed Annual Risk Acknowledgment Form is filed in the patient’s medical records.
  • The patient is using effective contraception and understands the need to comply with effective contraception throughout treatment with valproate and undergo pregnancy testing when required e.g., if there is any reason to suggest lack of compliance or lack of effectiveness of contraception.
  • Remind the patient to contact you immediately if they suspect there has been a problem with their contraception or if they may be pregnant.
  • In case of female children using valproate, remind the patient’s responsible person to contact their GP once the patient using valproate experiences their first period (menarche). Their GP will refer the patient back to the specialist.
• Remind all female patients that they will need to see their specialist prescriber at least annually whilst taking valproate and arrange the referral annually as required.
  • In Devon, specialists will be reviewing all patients on their review registers at least annually without the need for the GP to arrange separate referral.
  • To ensure that all female patients of childbearing age are included on secondary care review registers, GPs are asked to follow the recommendations in Actions for general practice in Devon (18 March 2024).

See here for guidance on whether ‘prevent’ (valproate Pregnancy Prevention Programme) applies to a patient, including BPNA/RCPH guidance for females under 18 years of age

Female patients who are planning to become pregnant.

• Inform the patient not to stop contraception or valproate until told to by their specialist prescriber.
• Refer the patient to their specialist prescriber who is managing their condition.

Female patients who are pregnant

• Inform the patient not to stop valproate and explain the reasons (e.g., their condition may become worse).
• Refer the patient to their specialist prescriber and ask for them to be seen urgently (within days).

Male patients under 55 years

• For any new male patient aged under 55 years commenced on treatment with valproate, two specialists are required to independently consider and document that there is no other effective or tolerated treatment. No new action is required by GPs.
• As a precaution, male patients currently receiving valproate who are planning a family within the next year should speak to a healthcare professional about their treatment options (MHRA Drug Safety Update, January 2024)
• Additional recommendations are expected later in 2024 in relation to review of men under 55 years of age on valproate.
• Refer any new patient to a specialist prescriber for diagnosis and to initiate treatment if appropriate.

Does the valproate Pregnancy Prevention Programme (‘prevent’) apply to my patient?

The ‘prevent’ Pregnancy Prevention Programme is described in section 4.4 of the SmPCs for valproate-containing medicines.

For females under 18 years of age, refer to British Paediatric Neurology Association (BPNA) and the Royal College of Paediatrics and Child Health (RCPCH) – Joint guidance to provide recommendations about the use of valproate in female patients under 18 years of age.

• See page 5 for a visual summary

Extracted from the valproate Guide for Healthcare Professionals:

Women of childbearing potential (from menarche to menopause) who are taking any medicine containing valproate, regardless of the indication, should fulfil all the requirements of ‘prevent’.

The only exception to ‘prevent’ is when the specialist prescriber considers that there are reasons to indicate that there is no risk of pregnancy:

• The absence of risk of pregnancy is permanent (e.g., post-menopausal patients or those after hysterectomy).
• The absence of risk may change (e.g., the patient is pre-menarche). Although ‘prevent’ does not apply to these patients, their treatment with valproate must be reviewed regularly and at least annually.

Female children receiving valproate who have not yet reached menarche DO NOT need to fulfil the conditions of ‘prevent’, but they and their responsible person (parent/caregivers) need to be aware of the importance of the risks relating to exposure to valproate during pregnancy. The patient or responsible person must be asked to contact their General Practitioner (GP) once the patient using valproate experiences their first period (menarche). Their GP will refer the patient back to the specialist.

The reasons why ‘prevent’ does not apply to the patient should be documented on the Annual Risk Acknowledgment Form. The patient or responsible person should sign the Annual Risk Acknowledgment Form to confirm that ‘prevent’ does not currently apply to this patient and that risks have been discussed.

Contraception

Extracted from the valproate Guide for Healthcare Professionals

Female patients of childbearing potential who are prescribed valproate must use effective contraception without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception.

At least one effective method of contraception, preferably a highly effective user independent form such as an intra-uterine device or implant or two complementary forms of contraception including a barrier method should be used.

• Refer to the FSRH position statement below for advice on specific methods of contraception

Individual circumstances should be evaluated in each case when choosing the contraception method with the patient, involving the patient in the discussion to support her engagement and compliance with the chosen measures. Even if she has amenorrhea, she must follow all the advice on effective contraception.

FSRH position statement: Contraception for women using a teratogenic drug or drugs with a known teratogenic effect

Women should be made aware that no method of contraception is 100% effective.

Always advise the use of ‘highly effective’ contraceptive methods. These have a failure rate of less than 1% with typical use and include:

• Copper intrauterine device (Cu-IUD)
• Levonorgestrel intrauterine device (LNG-IUD)
• Progestogen-only implant (IMP)
  • Women using IMP must not take any interacting drugs that could reduce contraceptive effectiveness. See below for advice on drug interactions.
• Male and female sterilisation

The typical use failure rate of combined hormonal contraception (CHC) and the progestogen-only pill (POP) is 9%; for progestogen-only injectables including depot medroxyprogesterone acetate (DMPA) it is 6%:

• Advise women using the CHC (pills, vaginal ring or patch), POP or DMPA to use additional contraceptive precautions (e.g. condoms)
• Women using CHC (pills, vaginal ring or patch) or POP must not take any interacting drugs that could reduce contraceptive effectiveness. See below for advice on drug interactions.

For formulary guidance on contraception, see here

For formulary options, see: CHC; Cu-IUD; Progestogen-only contraceptives (DPMA; IMP; LNG-IUD; POP)

Drug interactions with hormonal contraceptives

Sodium valproate is not an enzyme-inducer but many anti-epileptic drugs (AEDs) are enzyme inducers and special precautions apply to lamotrigine.

Refer to Formulary guidance on contraception, see ‘Drug Interactions with Hormonal Contraceptives'. This section covers AEDs and other interacting drugs and provides advice on contraceptive methods, including emergency contraception, based on FSRH guidance and local specialist advice.

Emergency contraception

Refer to formulary guidance on contraception and FSRH guidance. See above for patients taking a drug which interacts with hormonal contraceptives.

Contact details for local services

• Devon Sexual Health (Barnstaple, Exeter, and Torbay). Telephone: 0300 303 3989
• SHiP (Sexual Health in Plymouth). Telephone: 01752 431124

Resources

• For guidance on specific contraceptive methods and specific patient populations, refer to the Faculty of Sexual & Reproductive Healthcare Website.
• Devon Formulary: Contraception guidance; Contraceptives
• Detailed information on teratogenic drugs available on the UKTIS website
• Pregnancy testing and contraception for pregnancy prevention during treatment with medicines of teratogenic potential (MHRA Drug Safety Update, March 2019) (see table here)

Safety materials

Available at MHRA Valproate safety measures

• Guide for Healthcare Professionals

• Actions for healthcare professionals
• Females: includes information on the following: congenital malformations and on neurodevelopmental disorders; contraception; does ‘Prevent’ (the valproate Pregnancy Prevention Programme) apply to my patient
• Males: includes information on male infertility and testicular toxicity in male animals
• Switching or discontinuation of valproate in epilepsy and bipolar disorder, and prescribing of valproate during pregnancy in patients with epilepsy

• Patient guide
• Annual Risk Acknowledgement Form for female patients
• Risk Acknowledgement Form for male patients starting valproate
• Patient card to be provided to female patients by pharmacists when dispensing

NHS England

Decision support tools have been developed for women, girls and anyone who could become pregnant, aged between 12 – 55, considering or taking valproate for epilepsy or bipolar disorder:

• Epilepsy: Is valproate the right epilepsy treatment for me?
• Bipolar disorder - Is valproate the right treatment for me?

Supporting clinical guidance

Available at MHRA Valproate use by women and girls

• Association of British Neurologists – ABN Guidelines for Valproate prescribing in Adult (16 or over) Neurology
  • Implementation of the new measures including obtaining two specialist agreement and documentation
• British Paediatric Neurology Association (BPNA) and the Royal College of Paediatrics and Child Health (RCPCH) – Joint guidance to provide recommendations about the use of valproate in female patients under 18 years of age

• See page 5 for a visual summary
• Developed to provide greater clarity on the approach to prescribing valproate in female patients under 18-years of age and when the requirement to fulfil ‘prevent’ (valproate Pregnancy Prevention Programme) applies. The guidance covers all age ranges starting from below 10 years to transition to adult services at between 16 and 18 years and includes patients with a learning disability.

• BPNA, OPEN UK, RCPCH prescribing guidance document

• Provides guidance on obtaining and documenting two specialist agreement for treatment with valproate. Includes examples in paediatric epilepsies where two specialists are likely to agree that valproate could be used as the first line medication.