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This is to inform you of important new information and strengthened warnings related to safety of medicines related to valproate (sodium valproate, valproic acid [brand leader: Epilim] and valproate semisodium [brand leader: Depakote]), following completion of a Europe-wide review:
- children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases)
- valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated
- valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder
- carefully balance the benefits of valproate treatment against the risks when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant
- you must ensure that all female patients are informed of and understand:
- risks associated with valproate during pregnancy
- need to use effective contraception
- need for regular review of treatment
- the need to rapidly consult if she is planning a pregnancy or becomes pregnant
Risk of abnormal pregnancy outcomes
Valproate is associated with a dose-dependent risk of abnormal pregnancy outcomes, whether taken alone or in combination with other medicines. Data suggest that when valproate is taken for epilepsy with other medicines, the risk of abnormal pregnancy outcomes is greater than when valproate is taken alone.
The risk of congenital malformations is approximately 10 % while studies in preschool children exposed in utero to valproate show that up to 30-40% experience delays in their early development such as talking, and/or walking, have low intellectual abilities, poor language skills and memory problems.12345
Intelligence quotient (IQ) measured in a study of 6 years old children with a history of valproate exposure in utero was on average 7-10 points lower than those children exposed to other antiepileptics.6
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).789
Given these risks, valproate for the treatment of epilepsy or bipolar disorder should not be used during pregnancy and in women of child-bearing potential unless clearly necessary ie in situations where other treatments are ineffective or not tolerated.
Carefully balance the benefits of valproate treatment against the risks when prescribing valproate for the first time, at routine treatment reviews, when a female child reaches puberty and when a woman plans a pregnancy or becomes pregnant.
If you decide to prescribe valproate to a woman of child-bearing potential, she must use effective contraception during treatment and be fully informed of the risks for the unborn child if she becomes pregnant during treatment with valproate.
Treatment during pregnancy
If a woman with epilepsy or bipolar disorder who is treated with valproate plans a pregnancy or becomes pregnant, consideration should be given to alternative treatments.
If valproate treatment is continued during the pregnancy:
- the lowest effective dose should be used and the daily dose should be divided into several small doses to be taken throughout the day – the use of a prolonged release formulation may be preferable to other treatment forms
- initiate specialised prenatal monitoring in order to monitor the development of the unborn, including the possible occurrence of neural tube defects and other malformations
- folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies; however the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure
The Cochrane review10 published in November 2014 assessed 22 prospective cohort studies and 6 registry studies. The review supported findings from the European review that children exposed to valproate in utero were at an increased risk of poorer neurodevelopmental scores compared to the general study population both in infancy and when school aged.
A dose-related risk of developmental disorders was reported for valproate in 6 of the 28 studies included in the Cochrane review. However, based on the available data, it is not possible to establish a threshold dose below which no risk of developmental disorders exists.
Usage during pregnancy in the UK
Data from the Clinical Practice Research Datalink suggest that approximately 35,000 women aged 14 to 45 per year had a prescription for sodium valproate between 2010 and 2012, the majority for epilepsy. Of these, at least 375 per year had a prescription for sodium valproate while pregnant.
Pharmaceutical companies holding licences for valproate containing medicines must monitor the usage of these medicines to assess the effectiveness of these new measures on reducing the number of pregnant women taking valproate. We will continue to monitor valproate usage using the Clinical Practice Research Datalink. We will also work with stakeholders such as clinical guideline bodies to develop tools to aid decision-making for healthcare professionals and patients. We have already developed information booklets for healthcare professionals and patients (see further information below).
The product information will now be updated to reflect our current understanding of the available evidence and to make information as clear as possible.
Educational materials are available to healthcare professionals and patients in order to inform about the risks associated with valproate in female children, female adolescents, women of childbearing potential and pregnant women (see further materials below).
Call for reporting
Article citation: Drug Safety Update volume 8 issue 6 January 2015: 1
- Meador K, Reynolds MW, Crean S et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81(1):1-13. ↩
- Meador KJ, Penovich P, Baker GA, Pennell PB, Bromfield E, Pack A, Liporace JD, Sam M, Kalayjian LA, Thurman DJ, Moore E, Loring DW; NEAD Study Group. Antiepileptic drug use in women of childbearing age. Epilepsy Behav. 2009;15(3):339-43. ↩
- Bromley RL, Mawer G, Clayton-Smith J, Baker GA; Liverpool and Manchester Neurodevelopment Group. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology. 2008;71(23):1923-4. ↩
- Thomas SV, Sukumaran S, Lukose N, George A, Sarma PS. Intellectual and language functions in children of mothers with epilepsy. Epilepsia. 2007 Dec;48(12):2234-40. ↩
- Cummings C, Stewart M, Stevenson M, Morrow J, Nelson J. Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child 2011 July;96(7):643-7. ↩
- Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12(3):244-52. ↩
- Christensen J, Grønborg TK, Sørensen MJ et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013; 309(16):1696-703. ↩
- Cohen MJ, Meador KJ, Browning N, May R, Baker GA, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; NEAD study group. Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6years. Epilepsy Behav. 2013;29(2):308-15. ↩
- Cohen M.J et al. Fetal Antiepileptic Drug Exposure: Motor, Adaptive and Emotional/Behavioural Functioning at age 3 years. Epilepsy Behav. 2011; 22(2):240-246 ↩
- Bromley R, Weston J, Adab N et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev. 2014, Issue 10 ↩
Official Press Release : Defective Drug Sodium Valproate NOT to be prescribed to women or girls of Childbearing Age
CMDh agrees to strengthen warnings on the use of valproate medicines in women and girls
Women to be better informed of risks of valproate use in pregnancy and need for contraception
The CMDh, a regulatory body representing EU Member States, has agreed to strengthen warnings on the use of valproate medicines in women and girls due to the risk of malformations and developmental problems in babies who are exposed to valproate in the womb. The warnings aim to ensure that patients are aware of the risks and that they take valproate only when clearly necessary.
Doctors in the EU are now advised not to prescribe valproate for epilepsy or bipolar disorder in pregnant women, in women who can become pregnant or in girls unless other treatments are ineffective or not tolerated. Those for whom valproate is the only option for epilepsy or bipolar disorder should be advised on the use of effective contraception and treatment should be started and supervised by a doctor experienced in treating these conditions.
Women and girls who have been prescribed valproate should not stop taking their medicines without consulting their doctor as doing so could result in harm to themselves or to an unborn child.
In countries where valproate medicines are also authorised for the prevention of migraine, valproate must not be used for this purpose in pregnant women, and doctors should exclude pregnancy before starting preventive treatment for migraine. Doctors must not prescribe valproate for migraine prevention for women who are not on effective contraception.
These recommendations follow a review of recent studies showing developmental problems in up to 30 to 40% of pre-school children exposed to valproate in the womb, including delayed walking and talking, memory problems, difficulty with speech and language and lower intellectual ability.1,2,3,4,5
Previous data have shown that children exposed to valproate in the womb are also at increased risk of autistic spectrum disorder (around 3 times higher than in the general population) and childhood autism (5 times higher than in the general population). There are also limited data suggesting that children exposed to valproate in the womb may be more likely to develop symptoms of attention deficit hyperactivity disorder (ADHD).6,7,8
In addition, children exposed to valproate in the womb are at an approximately 11% risk of malformations at birth (such as neural tube defects and cleft palate)9 compared with a 2 to 3% risk for children in the general population.
Doctors should ensure that their patients are adequately informed of the risks of taking valproate during pregnancy, and should regularly review the need for treatment in female patients who can have children. Doctors should also re-assess the balance of the benefits and risks of valproate medicines for any female patient who becomes or plans to become pregnant and for girls reaching puberty.
The review of valproate was conducted by the EMA’s Pharmacovigilance and Risks Assessment Committee (PRAC), following which the CMDh endorsed the PRAC’s recommendations.
The recommendations on the use of valproate in women and girls will be implemented by EU Member States according to an agreed timetable.
Information to patients
- Do not stop taking your valproate medicine without consulting your doctor as doing so could cause harm to you or an unborn child.
- Valproate medicines can cause malformations and problems with early development of children if they are exposed to these medicines in the womb.
- If you can become pregnant, you should use an effective method of contraception. Speak to your doctor if you have any questions about which contraceptive method is appropriate for you.
- Tell your doctor at once if you become pregnant, think you might be pregnant or are planning to become pregnant. Your doctor will urgently review your treatment.
- If you have any questions about your treatment or contraception, speak to your doctor or pharmacist.
Information to healthcare professionals
Following an evaluation of the data on the risks of valproate use during pregnancy, the recommendations for the use of valproate in women and girls have been updated:
- For treatment of epilepsy and bipolar disorder in female patients who can have children
- Only prescribe valproate medicines for epilepsy and bipolar disorder if other treatments are ineffective or not tolerated.
- Advise patients taking valproate medicines about effective contraception during their treatment.
- Ensure that the treatment of epilepsy or bipolar disorder is supervised by a doctor experienced in treating these conditions.
- Consider alternative treatments if a female patient becomes or plans to become pregnant during valproate treatment. Regularly review the need for treatment and re-assess the balance of the benefits and risks for female patients taking valproate and for girls reaching puberty.
- Inform patients of the risks of taking valproate during pregnancy.
- For migraine prevention (in countries where this use is authorised)
- Do not prescribe valproate for female patients who can have children if they are not using effective methods of contraception or if they are already pregnant – such use is now contraindicated.
- Exclude pregnancy before starting a female patient on valproate treatment for migraine.
- Stop valproate treatment in the event of pregnancy or if pregnancy is planned.
- Ensure that female patients who can become pregnant are aware that they must keep to their contraception throughout treatment.
- Inform patients of the risks of taking valproate during pregnancy.
Healthcare professionals in the EU will be sent a dear healthcare professional letter plus additional educational material concerning these recommendations.
- Meador K, Reynolds MW, Crean S, et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 2008;81(1):1-13.
- Meador KJ, Penovich P, Baker GA, et al. Antiepileptic drug use in women of childbearing age. Epilepsy Behav 2009;15(3):339-43
- Bromley RL, Mawer G, Clayton-Smith J, et al. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008;71(23):1923-4.
- Cummings C, Stewart M, Stevenson M, et al. Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child 2011 July;96(7):643-7.
- Thomas SV, Ajaykumar B, Sindhu K, et al. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy Behav 2008 Jul;13(1):229-36.
- Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013 Apr 24;309(16):1696-1703.
- Cohen MJ, Meador KJ, Browning N, et al. Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6years. Epilepsy Behav 2013;29(2):308-15
- Cohen MJ, Meador KJ, Browning N, et al. Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years. Epilepsy Behav 2011 Oct;22(2):240-6.
- Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013;12(3):244-52.
More about the medicine
Valproate medicines are used to treat epilepsy and bipolar disorder. In some EU Member States they are also authorised to prevent migraine headaches.
The active ingredients are listed on the packages as valproic acid, sodium valproate, valproate semisodium or valpromide.
Valproate medicines have been authorised via national procedures in all EU Member States and in Norway and Iceland. They are marketed under several brand names including: Absenor, Convival Chrono, Convulex, Convulsofin Tabletten, Delepsine, Depakine, Deprakine, Diplexil, Dipromal, Epilim, Episenta, Epival, Ergenyl, Espa-Valept, Hexaquin, Leptilan, Micropakine L.P., Orfiril, Orlept, Petilin, Valberg, Valepil and Valhel.
More about the procedure
The review of valproate medicines started in October 2013 at the request of the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) under Article 31 of Directive 2001/83/EC, following the publication of new data on the risks of malformations and developmental problems in babies exposed to valproate in the womb.
The review was first conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), the EMA’s Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. As valproate medicines in the EU are all authorised nationally, the PRAC recommendations were forwarded to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for a position. The CMDh, a body representing EU Member States, is responsible for ensuring harmonised safety standards across the EU for medicines authorised via national procedures.
The CMDh position was agreed by consensus, and the recommendations on the use of valproate in women and girls will be implemented by EU Member States according to an agreed timetable.
 The Coordination Group for Mutual Recognition and Decentralised Procedures – Human