US regulators are requesting that asthma therapies belonging to the leukotriene inhibitors class of drugs carry stronger precautions in their labelling regarding the possibility of neuropsychiatric side effects.

The move follows an investigation launched last year spurred by growing reports of behavioural and mood changes in patients taking Merck & Co’s Singulair (montelukast), AstraZeneca’s Accolate (zafirlukast), and Cornerstone Therapeutics’ Zyflo/Zyflo CR (zileuton).

The blockbuster Singulair – Merck’s biggest product - and the multi-million-dollar selling Accolate are leukotriene receptor antagonists that work by blocking leukotrienes, which are released by the body in response to an inflammatory stimulus. Zyflo is a leukotriene synthesis inhibitor that stops the formation of certain substances responsible for causing swelling, tightening and mucus production in the airways.

However, despite their efficacy in the treatment of asthma, it seems that patients taking this class of drugs have reported a whole host of neuropsychiatric side effects, including: agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behaviour (including suicide), and tremor.

No risk of suicide?
Earlier this year, regulators said that clinical data assessed for the safety review do not suggest that the three drugs are associated with a higher risk of suicide or suicidal behaviour, but they also stressed that as the trials were not specifically designed to examine neuropsychiatric side effects some events may not have been reported.

Specifics of the labelling updates required by the Food and Drug Administration have not yet been released, but according to the Associated Press a spokesman for Merck said the information is already contained in Singulair’s product information but will now be raised in the precautions section instead, while a spokesman for AstraZeneca reportedly said Accolate’s new labelling will only highlight risks of depression and insomnia.

Shares in Merck and Cornerstone only slipped slightly while AstraZeneca’s stock remained unharmed as news over the potential psychiatric side effects of these medicines is essentially old hat. However, analysts have suggested that any changes to their safety profiles could be used as ammunition by competitors seeking to attack the drugs’ market shares.