Outdated medication warning risks lives

Packaging warnings on antiepileptic meds are inaccurate and are scaring patients and prescribers off.

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The warning of increased suicide risk from use of antiseizure medications is outdated and based on flawed research, and almost certainly costs more lives than it saves, new research finds.

This was the conclusion of a large meta-analysis into five common anti-epileptic medications (eslicarbazepine, perampanel, brivaracetam, cannabidiol and cenobamate), involving almost 6,000 patients.

Despite all these drugs carrying a warning about an increased risk of suicidality associated with their use, this meta-analysis found no evidence of any such increased risk.

“No difference in suicidality was observed for either the group as a whole or for any individual medication,” the study authors wrote in JAMA Neurology.

Not only was the suicidality class warning not warranted, it was also likely to be doing harm, they concluded.

“Some patients may refuse to take the medication because of the warning, forgoing the medications’ potential benefits, which may include seizure freedom or amelioration with reduction in risk of mortality, including sudden unexpected death in epilepsy,” they said.

The warning was first instigated back in 2008 by the US Food and Drug Administration, following a meta-analysis involving 11 drugs, which found patients treated for epilepsy had a 1.8-fold increase in suicidality risk compared to placebo.

Since then, this original meta-analysis and its findings have been repeatedly criticised by researchers and specialists. According to the authors of this latest study the old analysis had methodological limitations – including inconsistent definitions of suicidal ideation and behaviour, inclusion of different disease indications with differing suicidality risks and not accounting for baseline suicidality. 

Despite the criticisms all antiseizure medications, including those approved since 2008, have been required to feature a prominent warning of increased suicidality risk – which the JAMA Neurology authors say has “greatly influenced” prescribing habits and acted as deterrent to patients achieving optimal control of their seizures, which in itself can be fatal for some patients.

“Although we are not aware of any studies documenting this, all six clinician authors have seen such patients. Notably, the risk of death from sudden unexpected death in epilepsy, status epilepticus, and drowning due to a seizure (>4/1000 per year) exceeds the 2.1/1000 per year suicide risk in the 2008 FDA meta-analysis.”

In Australia, eslicarbazepine, perampanel and brivaracetam are included in the Black Triangle Scheme.

The PIs include warnings ranging from a “small increased risk” through to citing the 2008 study’s 1.8-fold increase and stating that “antiepileptic drugs, including Briviact, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication.”

Deputy director of research at Alfred Health Professor Terry O’Brien told TMR the JAMA Neurology study was well-designed and the findings reassuring.

“That 2008 analysis and the warning have been very heavily criticised, and there’s been a lot of publications since that have reanalysed the data and contradicted its findings,” said Professor O’Brien, a neurologist with a particular interest in epilepsy.

He said that most experts in the field did not believe either old or new antiseizure medications increased the risk of suicidality.

“We know that people with epilepsy have an increased incidence of psychiatric comorbidities, and we don’t really believe that antiepileptic drugs, as a class, increase that … Most of the experts in the field believe that it’s a false signal, confounded by the fact that the condition has an increased risk of suicidality.”

He said the original FDA alert was “very harmful” and the understanding of the issue would vary among health professionals.

“Some would see the black box warning and that’s all, some would have a more nuanced understanding of it. There’s so much noise out there and people, including patients, are confused.”

He encouraged clinicians to reassure patients who were prescribed antiseizure medications.

“Because they were labelled that way, some patients don’t take the medication and can have uncontrolled seizures, which they can die from.

“The risk of not taking medications, in terms of increased risk of injury and death and other problems, is much more important.”

JAMA Neurology 2021, 2 August