- Risk of abnormal pregnancy outcomes
- Treatment during pregnancy
- Further information
- Usage during pregnancy in the UK
- Future action
- Call for reporting
- Further materials
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 ↩
Healthcare professionals are today being urged by MHRA to give women better information on the risks associated with valproate medicines.
Healthcare professionals are today being urged by the Medicines and Healthcare products Regulatory Agency (MHRA) to give women better information on the risks associated with valproate medicines, (used to treat epilepsy and bipolar disorder) following the strengthening of product information.
Information booklets for healthcare professionals and patients are being made available as educational tools. The leaflet inside medicines packaging is also being updated with stronger warnings about the risk of developmental disorders in children exposed to valproate during pregnancy.
This follows the outcome of a European review last year which found that up to 40% of children born to women who take valproate during pregnancy may have developmental disorders.
Dr June Raine, director of MHRA’s vigilance and risk management of medicines division said:
The warnings on the risks of valproate in pregnancy have been further strengthened because we want to ensure that medical professionals inform women and girls of the latest information about the risks of developmental disorders in children exposed to valproate during pregnancy, in addition to the already well-known risks of birth defects.
If valproate is the only option, women of childbearing age should be given effective contraception. Women taking valproate must have regular reviews of their treatment.
However, it is important that no-one should stop taking valproate without discussing it first with their doctor.
The risk of birth defects in children whose mothers take valproate during pregnancy has been included in the information for patients and prescribers for several years. Of 35,000 women prescribed valproate, 375 become pregnant per year whilst taking it. The main outcome of the European review has been to better quantify and describe the risk of developmental disorders.
If you have experienced any side effects to this medicine you can report these to us using the Yellow Card Scheme
42 years later and an estimated 20,000 babies affected by the Prescription Drug Sodium Valroate (Epilim) manufacturers Sanofi have FINALLY admitted that their drug DOES harm babies when taken during pregnancy. When 1st marketed back in 1972, it was originally only prescribed for Grand Mal and Petite Mal Epilepsy , as the years have passed it in now also prescribed for
- Bipolar disorder
- Pain relief
Following the recommendations of the EMA, Sanofi has sent a letter to healthcare professionals to warn of the dangers of Sodium Valproate during pregnancy.
- Children exposed to valproate in utero have an increased risk of developmental disorders (30 to 40% of births) and / or birth defects (in approximately 10% of cases)
- Valproate should not be prescribed to female children, adolescents, women of childbearing age, women who may be pregnant unless other treatments are ineffective or not tolerated.
- Treatment with valproate should be initiated and supervised by a physician experienced in the management of epilepsy and bipolar disorder.
- We must carefully measure the benefit / risk of valproate treatment before prescribing valproate for the first time, when renewing, when a girl reaches puberty and when a woman wishes to become pregnant or become pregnant.
You must ensure that all patients are informed and understand:
- The risks associated with valproate during pregnancy;
- They must use effective contraception;
- The need for a regular review of the treatment;
- The need to quickly check if planning pregnancy or become pregnant.
Any child that has been exposed to Sodium Valproate may suffer symptoms such as:
- Premature Birth
- Small fingernail
- Spina Bifida / Cerebral Palsy
- Limb defects
- Joint Laxity
- Characteristical facial features
- Delay in reaching milestones
- Gross and fine motor skills
- Autistic Spectrum Disorders
- Speech and Language Delay
- Attention and memory difficulty
- Vision problems
- Inguinal Hernia
and officially go on to obtain a medical diagnosis of FACS (Fetal Anti Convulsant Syndrome) What is FACS? http://facsa.org.uk/vital-knowledge/
In August 2013 we (INFACT) had our first meeting with the Pharmacovigilence Director June Raines following our Panorama programme in July 2013, where we asked for an investigation into the reasons why Valproate had been allowed to harm so many in pregnancy.
Since the drug came onto the market in 1973, it has touched 20,000 with 40% of those suffering neurodevelopmental disorders (8000). 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)
These figures were agreed at that meeting as both INFACT & MHRA had used the same research papers in calculation.
After being turned down for a public enquiry, We were so pleased that our innitiation of an investigation into Valproate in pregnancy was accepted. In October 2013 a European Review began through the European Medicines Agency (EMA) and some of their conclusions were released on the 10th October 2014 (see link) http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Valproate/human_referral_000187.jsp
Approximately 500 babies are affected by Sodium Valproate each year and with it being prescribed for so many illness, it is appalling that so many children have been affected and disabled due to this medicine. What’s even more appalling is that UK Government KNEW about the effects of the medicine and allowed it to be prescribed for all of the above.
In a meeting we had recently with Norman Lamb, Minister for Care and Support he stated :
“What frustrates me is that know we all now that prescribing this to women of childbearing age, unless totally necessary is a total disaster. It is a very stupid thing to do and yet we also know that not many GPS know about this”
“Going back to the issue of those that already have this, and you have it in many cases because the message hasn’t got across, and there’s been a failure of the system really, there is a responsibility to make sure that we think through and support those people through good care given for what happened to them.”
- The UK has one of the highest childhood asthma rates in the world
- The condition affects 1.1 million UK children – or one in 11
- The urine test measures levels of inflammation that warns of attack
- Research was carried out by Queen Mary Hospital London
- It is due to be presented to the British Thoracic Society
A simple test could help ensure asthmatic children get the right amount of medication to help prevent future asthma attacks.
The test can accurately measure levels of inflammation within the urine that give warning signs of an imminent attack.
Research led by Queen Mary University of London could result in a ‘transformational’ step to preventing worsening symptoms, hospital admissions and deaths.
The research led by Queen Mary University could help prevent worsening symptoms, hospital admissions and deaths. (file picture)
The UK has one of the highest rates of childhood asthma symptoms in the world, affecting 1.1 million children.
One in 11 British children in the UK has asthma, the most common long term condition in childhood.
Researchers reviewed 73 children aged 7-15 years to investigate the most efficient and non-invasive way of finding the optimum level of anti-inflammatory treatment for asthma.
They analysed levels of prostaglandin metabolites – chemicals released by immune cells that are activated in asthma – in the urine.
One of the ‘protective’ prostaglandins was greatly reduced in those children who went on to have an asthma attack within three months, giving an early warning of a worsening condition.
Testing was carried out among children with asthma on days when they had no symptoms, and the researchers counted the number of days when they received medical attention or missed school due to asthma symptoms.
These urine samples were compared with those of children who did not have asthma.
The findings by the QML researchers, in partnership with Jagiellonian University Medical School in Krakow, Poland, are being presented today (thurs) at The British Thoracic Society Winter Meeting (must credit) in London.
Dr Rossa Brugha, co-author of the report and Clinical Research Fellow at Queen Mary University of London hospital, said ‘The key factor in treating children with asthma is to tailor their medicine accurately, ensuring the right amount of anti-inflammatory medication is being prescribed.
‘This simple urine test provides an accurate way to assess chemical markers in the child’s urine, which show the level of inflammation caused by the asthma.
‘When children see their GP for their annual review, we hope that this test can help indicate the level of steroid medication they actually need.
Dr Samantha Walker from Asthma UK said the research was ‘promising’
‘If implemented it will help the child to manage their asthma more effectively and hopefully reduce the number of asthma attacks.’
Dr Bernard Higgins, Chairman of the British Thoracic Society Executive Committee, and consultant lung specialist at the Freeman Hospital in Newcastle said ‘GPs manage a large number of children with asthma throughout the UK – and this simple test could help them to prescribe tailored treatment.
‘Most of all this is good news for the well-being of our children with asthma, but attacks of asthma are expensive to treat and if this helps us prevent them it could also save vital NHS resources.’
Asthma is a condition that affects the airways – the small tubes that carry air in and out of the lungs.
When a person with asthma comes into contact with something that irritates their airways, the muscles around the walls of the airways tighten and become narrower, and the lining of the airways becomes inflamed and starts to swell, causing difficulty in breathing and other symptoms..
Dr Samantha Walker, Director of Research and Policy at Asthma UK, said ‘Asthma is a complex condition that affects 1 in 11 children in the UK, yet years of research underfunding means it still remains a relative mystery.
‘The development of a simple test that can be used to accurately identify children at risk of an asthma attack and then to get them on the right dose of the right treatment could be transformational in preventing attacks; this research is a promising step in that direction.
‘Parents of children with asthma now need to see more investment in asthma research like this so that life-changing breakthroughs become a reality. We need to keep children with asthma healthy and out of hospital.’
- Nicola Lynch was diagnosed with the condition hypermobility syndrome
- It means the 18-year-old’s joints dislocate, which is incredibly painful
- She’s dislocated her shoulder 80 times in six years, since being diagnosed
- Regularly dislocates hips, ankles, her jaw and her thumbs too
- The last time she enjoyed a burger for dinner she ended up in hospital
- She is left in agony as dislocations cause traumatic injuries
- Needs help with basic tasks like eating and says she cannot work
- She has even been accidentally injured by her fiance, Stephan Filmer, 22
- As she gets older she will need to have operations to replace joints
- Teenager says she lives in constant fear of ‘what will dislocate next’
For teenager Nicola Lynch the simple pleasure of enjoying dinner can leave her writhing in agony.
The last time the 18-year-old indulged in a burger she had to be rushed to hospital after her jaw dislocated and was left hanging out of place.
It was the latest in a 250-long list of agonising joint dislocations, Miss Lynch has suffered.
She suffers a medical condition known as hypermobility syndrome, which causes her joints to pop out of place without any warning.
In the last six years, since doctors diagnosed the condition, she has dislocated her shoulders 80 times.
Her thumbs have popped out of place 25 times each, and her hips and ankles regularly slip out of their sockets.
Nicola Lynch, 18, has dislocated her joints more than 250 times. She suffers from hypermobility syndrome, which means her joints dislocate more often than usual, leaving her in agony as most dislocations result in a traumatic injury
Hypermobility syndrome means Miss Lynch’s joints have an unusually large range of movement. Some people with the joint condition have no pain, but unfortunately Miss Lynch has a severe form which means it does hurt each time she dislocates a joint. She is pictured showing her stretchy joints (left and right)
Miss Lynch (right) is unable to work due to her condition, and struggles with every day tasks like brushing her hair and the ironing. Her fiance Stephan Filmer, 22, (left) assists her, although he has to be careful as he has accidentally injured her in the past when they were ‘mucking around’
Every time she dislocates a joint, Miss Lynch is left in agony because unlike in double-jointed people, her condition causes traumatic injuries.
She is left unable to work due to her condition, and said she lives in fear, constantly worrying about which part of her body will dislocate next.
She said: ‘I first dislocated my thumb when I was about 12. I was mucking about with a friend, and I grabbed her coat and it just popped out of place. The pain was horrendous.
‘The doctors put it in a cast and sent me home, but a couple of days later, I dislocated my other thumb, and that was put in a cast too.
‘It started off just in my hands, but then my shoulders started going, and now it’s moved on to my hips, ankles and jaw. It’s terrible – I feel like a human jigsaw.’
The fragile teenager was diagnosed with hypermobility syndrome, which means although she has an unusually large range of movement, her joints dislocate themselves regularly.
Hypermobility syndrome is thought to be caused by lack of collagen in skin and tissues, which leaves tissue fragile and joints particularly loose and stretchy.
Miss Lynch’s latest dislocation was just two weeks ago when her ankle gave way and she fell, dislocating that and also her shoulder.
In the past she has dislocated her hips about 50 times, and now her ankles pop out of their socket around three times a week.
WHAT IS JOINT HYPERMOBILITY?
Joint hypermobility means some or all of a person’s joints have an unusually large range of movement.
People with hypermobility are particularly supple and able to move their limbs into positions others find impossible.
Many people with hypermobile joints do not have any problems or need treatment.
However, joint hypermobility can sometimes cause unpleasant symptoms, such as:
- joint pain
- back pain
- dislocated joints – when the joint comes out if its correct position
- soft tissue injuries, such as tenosynovitis (inflammation of the protective sheath around a tendon)
It can cause extreme tiredness and long-term pain. The condition is often hereditary, and is linked to changes in a protein called collagen.
Collagen is found throughout the body – for example, in skin and ligaments.
If collagen is weaker than it should be, tissues in the body will be fragile. This can make ligaments and joints particularly loose and stretchy.
There are estimates that up to three in 10 people may be affected to some degree.
Source: NHS Choices
Miss Lynch, who is unable to work as a result of her condition, lives with her retired nurse mum Rosemary Walker, 51, and postman stepfather Martin Walker, 51, in Rainham, Kent.
She tries to not let her condition get in the way of her life – despite being hospitalised the last time she ate a burger.
She said: ‘I was in a restaurant with my fiance and family when I ordered a burger.
‘It was quite big, and when I opened my mouth to take a bite my jaw just clicked out of place.
‘I had to go to the hospital because it was just hanging loose and absolutely killing.
‘Since then my jaw has popped out twice more, so I’ve got be really careful not to eat anything too chewy or hard. It’s tough, but my fiance and family are really supportive.’
She met her fiance Stephan Filmer through friends and started dating about 15 months ago.
Mr Filmer, a greenkeeper, got down on one knee on their one-year anniversary.
Miss Lynch said: ‘I wasn’t expecting it at all, but it was wonderful.
‘I can’t really get down on one knee in case something pops out, but he did and it was lovely.
‘He’s so supportive of me and really understands that there are certain things I can’t do because of my condition.’
But he also has to be careful around her because her fragile joints mean he’s accidentally caused several dislocations while ‘mucking around’.
Miss Lynch said: ‘The look on his face whenever it’s happened is terrifying. Of course he never means to hurt me, but sometimes it happens anyway.
‘I try to put on a brave face and not let on how much pain I’m in, but it’s tough.
‘I’ve met a couple of other people with hypermobility syndrome, and it’s good to know that they go through the same things as me.
‘I know my joints are sadly getting worse, so I’m probably going to have to have quite a few replacement operations soon.
‘I’m living in fear of what will dislocate next, really.’
Each time she dislocates her joint, which often happens carrying out basic tasks, she suffers a traumatic injury. She is pictured (left) struggling to pick up a bag, and with her arm in a sling (right) after a dislocation
Some people with hypermobility are able to stretch much further than normal. But the syndrome form of the condition, which Miss Lynch suffers, is more severe as it causes pain.
Miss Lynch has already had operations on tendons and ligaments in her hands, but she still dislocates them from time to time.
She said: ‘I was told it would get easier as I got older, but it just seems to have gotten worse.
‘It happens to my jaw now. My ankles also give way and I just fall over. I’ve fallen down the stairs before.
‘I was at college once and fainted. When I came round, my hip and both shoulders were dislocated. I couldn’t do anything. An air ambulance had to take me to hospital.
‘It’s constantly happening and it’s affected my life in every way.
‘I can’t lift anything heavy, even shopping bags. I can’t walk far, either, and have to be careful walking up the stairs.
‘I haven’t been able to hold down a job and relationships have always been tricky.
‘Thankfully Stephan is very supportive and caring – even if we have to be careful when we’re together.’
Miss Lynch has dislocated her shoulders 80 times, her hips 50 times, her thumbs 25 time, and now her ankles pop out of their socket around three times a week. Here, she is pictured struggling with brushing her hair
Back in June 2013 after the Panorama Documentry “Pills in Pregnancy” aired, very shortly after we were invited to meet with head of Pharmacovigilence Dr June Raine who also featured in Panorama.
It was a very lengthy meeting and we spoke in detail of the whole topic surrounding AEDs in Pregnancy particularly Epilim as whilst taken during pregnancy poses the worst risk to the foetus. INFACT had previously written to Ministers expressing our need for a public inquiry due to the systematic failure concerning the prescribing of Epilim, we expected it and obviously due to funding were turned down with our request. We thought about this long and hard, how and where could we get an investigation into the prescribing of Epilim during pregnancy???? We proposed to Dr Raine and her team that this was investigated at the highest level you can get to….. European Medicines Agency, and were delighted when this was sanctioned.
We were told this would be a lengthy investigation as it involved other EU states, but we needed this time to prepare all our evidence…..and we had a lot. We produced a National Survey, in which MHRA (Medicines Healthcare and Regulatory Agency) had viewed before we submitted it to the public, in which would be used as evidence, and the results of this survey were outstanding. With every question it proved system failure on all levels and have since been told it was a much needed contributing part of the investigation.
Another big part of our evidence was to hear from our families, what their experiences of taking Epilim was and how it had affected themselves and their families. Preparing these documents was heartbreaking. Hearing from other mums how their babies had been affected, the impact it had on their families and also how they felt as mums. Very tough and distressing, but looking back we are glad we submitted these case studies and yet again there were a lot.
It has been nearly a year now and the Official Results of the PRAC Assessment have come back.
EPILIM IS NOT TO BE PRESCRIBED TO ANY LADY WITH EPILEPSY OR BIPOLAR DISORDER
We were always hopeful it would come back this way, as over the years the evidence with regards to Epilim and Birth Defects has continued to get stronger and stronger. So as it stands EPILIM (Sodium Valproate) WILL NOT be prescribed to any lady of child bearing age with regards to Epilepsy / Bipolar Disorder and any other condition. A brilliant result for all those involved.
At our 1st initial meeting with DR Raine and her team we expressed our concern about the reporting system Yellow Card Scheme, how on the form there was no where to report the effects of medication to the baby. For the last year we have been working with them on this and can now say this has been changed . The Yellow Card Scheme was initiated following The Thalidomide Scandal and was made available for all Practitioners and Patients to report and adverse side affects of their medicine. On 25th November we were invited to attend 50th Anniversary of Yellow Card Scheme – an event to celebrate some of the achievements of this scheme but also a chance to discuss how to make it better. IT was a great day and we are thrilled to be involved in such a poignant initiative.
With regards to the prescribing of Epilim in UK it is now upto MHRA, Department of Health and Government to make sure ladies are fully informed of the risks of prescribing during pregnancy. INFACT are involved with this and we have had meeting after meeting with different departments and health care professionals about this and will continue to do so until the message is loud and clear.
INFACT / FACSA want to sincerely thank each and every parent that gave us their account of how taking Epilim has affected your family. They were all in great detail and we understand it must have been hard writing this, but you have helped make a difference. Your voice has been heard and helped change the prescribing of Epilim.
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