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Safety Information

Trans-Tasman Early Warning System - Alert Communication

Use of sodium valproate (Epilim) in pregnancy

28 September 2015

Products Affected
Information for consumers and caregivers
Information for healthcare professionals
Review Summary
What actions are Medsafe taking?
How to report adverse events
Further information

The use of Sodium valproate (Epilim) is contraindicated in pregnancy due to the risk to the unborn baby (fetus). 

Congenital malformations have been estimated to affect between 6.7%1 and 12.4%2 of children exposed to Epilim in the womb.  The rate of malformations in the general population is 2-3%.  The most common types of malformations in children exposed to Epilim are:

Developmental delay is also common (30-40%) in children exposed to Epilim in the womb2. The IQ of Epilim exposed children is 7-10 points lower than the IQ of children exposed to other anti-epileptics 2. The risk of autism in children exposed to Epilim has been estimated at 2.5%. This is about five times higher than the rate in the general population.2

Epilim should not be used in female children or in women of child-bearing age, unless other treatments are ineffective or not tolerated.

It is important that girls (and their caregivers) and women of child-bearing age taking Epilim are aware of these risks.

Products Affected

This alert applies only to Epilim which contains sodium valproate


 

Information for consumers and caregivers

Female children and their caregivers

  • Make sure you understand the risks to an unborn child when taking Epilim (sodium valproate) and the need for effective contraception, when this becomes appropriate.

Women of childbearing age

  • Make sure you understand the risks to an unborn child when taking Epilim
  • Ensure you are using effective contraception (if required).
  • If you decide to try for a baby, discuss this with your doctor first
  • Tell your doctor as soon as you are pregnant, or think you may be pregnant.
  • It is important to keep taking your medicine.  There is a risk to your baby if you have a seizure during pregnancy.
  • Make sure you take any recommended supplements like folic acid and attend all your pregnancy screening and monitoring visits.
  • If you have any questions speak to your doctor.

More information is also available from consumer support groups (see below).  There is also a leaflet explaining this risk in more detail (additional information).

 

Information for healthcare professionals

  • Ensure that all other treatments have been tried and failed before using Epilim (sodium valproate) in female children or women of childbearing age.
  • Discuss the risks to the fetus of exposure to Epilim in pregnancy before use with all female patients and regularly during use with women of childbearing age.
  • Discuss the need to use effective contraception with women of childbearing age taking Epilim.
  • Ensure that your patient and her caregivers (if appropriate) have understood the potential consequences of pregnancy whilst taking Epilim.
  • Advise women considering trying for a baby that they should discuss this with you.
  • Consider referring women thinking of becoming pregnant for specialist pre-conception advice.
  • Advise women trying for a baby to take recommended supplements such as folic acid prior to becoming pregnant.
  • Advise women that if they think they might be pregnant they should contact you immediately.
  • Ensure that any pregnant women taking sodium valproate receive appropriate pregnancy monitoring and tests to detect neural tube defects and other malformations.

Review Summary

Sodium valproate was first introduced as an antiepileptic in 1964.3  The first report of teratogenic effects was published in 1980.  The term fetal valproate syndrome (FVS) was suggested in 19842. A number of different anomalies have been associated with in utero sodium valproate exposure. The most commonly associated anomalies affect the neural tube, heart, limb, genitourinary system, skin and facial features2.

The frequency of malformations has been estimated from pregnancy registries.  Reported estimates vary from 6.7% 1 to 12.4%2. A meta-analysis estimated that 10.7% of children exposed to Epilim in utero were born with a malformation2.

There is some evidence that a dose of sodium valproate greater than 1000mg per day may carry a higher risk than doses below 1000mg per day.  Use of more than one anti-epileptic also increases the risk of malformations in an exposed fetus2.

It is estimated that 30-40% of preschool children whose mothers took valproate in pregnancy may have development problems.  Affected children can be slow to walk and talk2. Autistic spectrum disorders and autism are more frequent in children exposed to valproate. The risk of autism has been estimated at 2.5% in valproate exposed children compared to 0.5% in the general population2.

High dose folic acid has not been shown to reduce the risk of malformations.  However some sources report a trend to a decrease in neural tube defects (but not other malformations) in woman taking folic acid and Epilim.  There is some evidence that children born to women who take folic acid and Epilim whilst pregnant have higher IQ than those whose mothers did not take folic acid.5,8

Further information was published in Prescriber Update 2014 35(4):46-48. ‘Use of sodium valproate in pregnancy’, (see below).

What actions are Medsafe taking?

Medsafe continues to monitor the safety of sodium valproate.  The data sheet has been updated to provide more information on the risks of using Epilim in pregnancy.

How to report adverse events

Phone + 64 3 479 7247 to speak to a Medical Assessor at the Centre for Adverse Reactions Monitoring (CARM)
Online Submit a report to CARM
Prescribers can submit using the online reporting tool available in patient management software
Yellow Card A completed Yellow card can be submitted to CARM via email, fax or mail (address is on the card)
Email carmnz@otago.ac.nz
Fax +64 3 479 7150


Medsafe cannot give advice about an individual’s medical condition.  If you have any concerns about a medicine you are taking Medsafe encourages you to talk to your healthcare professional.

Further information

Advice on how to take this medicine and possible side effects can be found in the consumer medicine information (CMI) and data sheet

Consumer medicine information for Epilim  

Data sheet for Epilim

Sanofi provided additional guidance

Prescriber Update

Consumer support group 1

Consumer support group 2

Consumer support group 3

References

  1. Campbell E, Kennedy F, Russell A et al (2014) ‘Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers’ J Neurol  Neurosurg Psychiatry 85: 1029-1034.
  2. Vajda FJ, O’Brien TJ, Graham JE (2013) ‘Dose dependence of fetal malformations associated with valproate’ Neurology 81: 999-1003.
  3. Kini U (2006) ‘Fetal valproate syndrome: a review’ Paediatric and Perinatal Drug Therapy 7: 123-130.
  4. Bromley RL, Mawer G, Love J et al (2010) ‘Early cognitive development in children born to women with epilepsy: A prospective report’ Epilepsia 51: 2058-2065.
  5. Meador KJ, Baker GA, Browning N et al (2013) ‘Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study’ Lancet Neurol 12: 244-52
  6. Christensen J, Grønborg TK, Sørensen MJ et al (2013) ‘Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism’ JAMA 309: 1696-1703.
  7. Meador K, Reynolds MW, Crean S et al (2008) ‘Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts’ Epilepsy Research 81: 1-13.
  8. Cohen MJ, Meador KJ, Browning N et al (2013) ‘Fetal antiepileptic drug exposure: adaptive and emotional/behavioural functioning at age 6 years’ Epilepsy & behaviour 29: 308-315.
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