GOV.UK Drug Safety Update
Sources: GOV.UK Department of Health
Medicines and Healthcare Products Regulatory Agency, 22 January 2015
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.
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.
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).
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 review 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).