Health Sciences Authority - Suicidality associated with antiepileptic drugs

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25 Mar 2008: Suicidality associated with antiepileptic drugs

HSA would like to inform healthcare professionals about the recent findings of the US Food and Drug Administration (FDA) on the increased risk of suicidal thoughts and behaviour associated with antiepileptic drugs (AEDs) from the analysis of 199 placebo-controlled clinical trials. This analysis was triggered by a preliminary finding in March 2005 that several drugs in this class were associated with an increased risk of suicidality.

Findings from FDA’s review of clinical trials

The US FDA's analysis of involved 11 AEDs (see table 1) which examined the effectiveness of the drugs in epilepsy, psychiatric disorders (e.g. bipolar disorder, depression and anxiety) and other conditions (e.g. migraine and neuropathic pain syndrome). The analysis included a total of 43,892 patients (5 years old and above) with 27,863 patients in the drug treatment groups and 16,029 in the placebo groups.

Table 1: AEDs included in US FDA analysis and AEDs available in Singapore

AEDs studied by the US FDA

AEDs available in Singapore

Carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide

Carbamazepine, gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate, valproate, *phenytoin, *vigabatrin

* AEDs not included in the US FDA's review.

The findings revealed four completed suicides among patients in the drug treatment groups and none among the patients in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behaviour or ideation (0.43%) as compared to patients receiving placebo (0.22%), corresponding to an estimated 2.1 per 1,000 (95% CI 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behaviour or ideation than in the placebo groups.

This increased risk of suicidal behaviour and ideation was observed between one to 24 weeks after taking the drugs and could not be reliably assessed beyond 24 weeks. The results were found to be consistent among the drugs and were reflected in all demographic subgroups. There was no clear pattern of risk across age groups observed. It was also noted that the relative risk for suicidal thoughts or behaviour was higher for patients with epilepsy compared to those with psychiatric or other disorders (see table 2 below).

Table 2: Relative risk and risk difference for suicidality

Indication	Placebo patients with events per 1,000 patients	Drug patients with events per 1,000 patients	Relative risk: Incidence of events in drug patients/incidence in placebo patients	Risk difference: Additional drug patients with events per 1,000 patients
Epilepsy	1.0	3.5	3.6	2.5
Psychiatric	5.2	8.3	1.6	3.1
Other	0.8	2.0	2.3	1.1
Total	2.2	4.3	2.0	2.1

The local situation and HSA’s advisory

To date, HSA has not received any local ADR reports of suicidality associated with AEDs. Nevertheless, healthcare professionals are advised to monitor patients treated with AEDs for suicidality and other unusual changes in behaviour, and to consider symptoms such as anxiety, agitation, hostility, mania and hypomania to be precursors to emerging suicidality. Healthcare professionals are also encouraged to report adverse events of suicidality suspected to be associated with AEDs to HSA.

In the meanwhile, HSA will be working with drug companies to update the labelling of the local package inserts of the class of AEDs.

Last updated on 02 Jul 2010 16:58:06