Antiepileptics

On the basis of the available evidence it is not possible to say whether the risk of suicidal thoughts and behaviour differs between antiepileptic medicines. Furthermore, the mechanism by which antiepileptic medicines may increase the risk of a patient having suicidal thoughts and behaviour is not known and therefore it is not possible to identify which medicines might not be associated with increased risk. The US Food and Drug Administration has also investigated the risk of suicidal thoughts and behaviour with antiepileptic medicines and their findings are consistent with those of the European review. For further information about the US review, see the FDA website (external link).
 (external link)

The key findings from the US review are:

• individuals who received antiepileptics were at a small but significantly increased risk of having suicidal thoughts and behaviour compared with those who received placebo 
• 0.43% in the antiepileptic group had suicidal thoughts or behaviour compared with 0.22% in the placebo group: approximately two additional patients per 1000 in the antiepileptic group had such events compared with the placebo group
• increased risk was generally recorded for all antiepileptics studied and was evident as early as 1 week after starting treatment
• increased risk could not be attributed to particular patient demographics. In particular, there was no clear pattern of risk across age-groups.
• product information for all antiepileptic medicines will be updated to reflect current evidence for the potential risk of suicidal thoughts and behaviour. The agreed wording for the product information below.

Key information

• Treatment with antiepileptic medicines is associated with a small risk of suicidal thoughts and behaviour; available data suggest that the increased risk applies to all antiepileptic medicines and may be seen as early as one week after starting treatment.
• There is no need to stop treatment or change your antiepileptic medicine on the basis of this new information. Anyone who is concerned about their treatment should talk to their doctor.
• Patients should be monitored for signs of depression or suicidal thoughts and behaviour throughout treatment, and should be referred for appropriate treatment if necessary.
• Patients and caregivers should be advised to be alert to any mood changes, distressing thoughts, or feelings about suicide or harming themselves at any point during treatment. Patients should be advised to seek medical advice if they develop such thoughts.
  

Product information - agreed wording
The agreed wording (July 2008) for product information is below:
Antiepileptics and suicidal behaviour - agreed wording for product information (12Kb)

Application form
The variations application form can be downloaded from the link below:
Variations application form (95Kb)

Questions and answers
What are antiepileptic medicines used to treat?
Antiepileptic medicines are used to treat epilepsy. Some of them are also used to treat disorders such as schizophrenia, bipolar disorder, anxiety, and nerve pain.

Why was there a review of their safety in relation to the risk of suicidal thoughts and behaviour?
Over the past few years, reviews of available evidence have identified an increased risk of suicidal thoughts and behaviour in people who take some antiepileptics. These medicines were topiramate, levetiracetam, vigabatrin, and zonisamide, andproduct information for doctors and patients was updated accordingly. Furthermore, information about a risk of depressed mood or depression has been included in the prescribing information for some antiepileptics—carbamazepine, gabapentin, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide.

However, the available evidence had not been assessed for all antiepileptics. Therefore, a European review took place. In the USA, the Food and Drug Administration has also investigated the potential risk of suicidal thoughts and behaviour with antiepileptics.

What kind of analysis was done and by whom?
To analyse evidence for the potential link between these medicines and the risk of having suicidal thoughts or suicidal behaviour, medicines regulatory authorities throughout the European Union gathered and analysed information from clinical trials of these medicines, information reported in the scientific literature, and from databases that recorded spontaneous reports of side-effects in people who have taken an antiepileptic medicine.

The US review looked at the findings from 199 clinical trials that compared antiepileptic medicines with that of placebo (dummy treatment). The US review included 11 antiepileptics and the trials included more than 40 000 participants.

Which medicines were assessed?
The following antiepileptics were assessed in the European review:

• carbamazepine
• divalproex sodium
• felbamate
• gabapentin
• lamotrigine
• levetiracetam
• oxcarbazepine
• pregabalin
• tiagabine
• topiramate
• vigabatrin
• zonisamide.

What are the main findings?
The findings suggest that antiepileptic treatment is associated with a small risk of suicidal thoughts and behaviour but this risk does not outweigh the benefits of these treatments in their authorised indications. They also show that the increased risk applies to all antiepileptics and can occur as early as 1 week after starting treatment. The US review identified that approximately four patients in every 1000 who received an antiepileptic had suicidal thoughts or behaviour compared with two in every 1000 who received a placebo.

What will happen as a result?
The product information for doctors and patients for all antiepileptic medicines that are authorised in the European Union will be updated. New information will reflect current evidence for the potential risk of suicidal thoughts and behaviour and advise that patients should be monitored for signs of suicidal thoughts, or suicidal behaviour throughout treatment.

How might antiepileptic medicines increase the risk of suicidal thoughts or behaviour?
At present, how antiepileptic medicines increase the risk of having suicidal thoughts or behaviour is not known. Therefore, it is not possible to identify which medicines might not be associated with increased risk. 

I currently take an antiepileptic medicine. What should I do?
There is no need to stop treatment or change antiepileptic medicine on the basis of this new information. Talk to your doctor if you have any concerns about your treatment, and attend scheduled check-ups your doctor may arrange for you.

You or, where appropriate, your carer should contact your doctor if either of you notice that you develop any mood changes, distressing thoughts, or feelings about suicide or harming yourself at any point during treatment.

Should I switch to another antiepileptic?
There is no need to change your antiepileptic medicine on the basis of this new information. The available evidence does not show clearly whether the risk of suicidal thoughts and behaviour differs between antiepileptics. Therefore it cannot be said for certain that particular antiepileptics are not associated with an increased risk of suicidal thoughts and behaviour.

It is very important that patients do not stop their antiepileptic medicine(s) unless they have first discussed this with their doctor.

Vigabatrin: risk of movement disorders and brain MRI abnormalities
A European review of clinical trial data, published literature and adverse drug reaction reports for vigabatrin has concluded that the product information should contain warnings on the risks of movement disorders and brain MRI abnormalities associated with its use. The following Public Assessment Report (published November 2009) summarises the data and conclusions of the review.

Download the Public Assessment Report (152Kb).

Read the November Drug Safety Update for further information.