FDA Continues to Review Link Between Montelukast and Neuropsychiatric Effects

Laurie Barclay, MD

January 14, 2009

January 14, 2009 — The US Food and Drug Administration (FDA) is continuing to review clinical trial data regarding neuropsychiatric events associated with montelukast (Singulair, Merck), according to an alert sent yesterday from MedWatch, the FDA's safety information and adverse event reporting program.

The alert represents updated information to the FDA's Early Communication issued in March 2008.

The FDA is continuing to review data from clinical trials to evaluate adverse neuropsychiatric events affecting mood and behavior associated with drugs acting through the leukotriene pathway, namely montelukast, zafirlukast (Accolate, AstraZeneca), and zileuton (Zyflo and Zyflo CR, Cornerstone Therapeutics). The FDA has not yet reached a definitive conclusion regarding these clinical trial data on mood and behavioral adverse events associated with montelukast, zafirlukast, and zileuton.

The FDA's Adverse Event Reporting System has received postmarketing reports of neuropsychiatric events associated with montelukast, zafirlukast, and zileuton. Although most of the neuropsychiatric event reports are associated with montelukast, it is currently the most commonly prescribed drug that acts through the leukotriene pathway.

"The clinical details of some reports involving montelukast are consistent with a drug-induced effect. Because of the paucity of reports involving zafirlukast and zileuton, assessment of a drug-induced effect with these is limited," the FDA points out.

The FDA advises healthcare professionals and caregivers to monitor patients taking montelukast, zafirlukast, and zileuton for suicidality and changes in behavior and mood. Patients with questions regarding these possible effects should not stop taking the drugs before consulting their physician.

On March 27, 2008, the FDA informed healthcare professionals and patients of the FDA's investigation of the possible link between use of montelukast and behavioral and mood changes, notably suicidal thinking, suicidal behavior, and completed suicide.

At that time, the FDA requested analyses of clinical trial data from Merck, AstraZeneca, and Cornerstone Therapeutics. The companies were instructed to use the Columbia Classification Algorithm of Suicide Assessment to classify suicidal events.

Of the 9929 patients treated with montelukast, 1 patient (0.01%) had suicidal ideation, and there were no completed suicides. None of the patients treated with zafirlukast or zileuton had suicidal ideation or completed suicide.

"Although these data do not suggest that montelukast, zafirlukast, or zileuton are associated with suicide or suicidal behavior, these clinical trials were not designed specifically to examine neuropsychiatric events. As a result, some events may not have been reported," according to an FDA news release.

Montelukast is a leukotriene receptor antagonist indicated for the treatment of asthma and symptoms of allergic rhinitis (sneezing and stuffy, runny, and itchy nose) and to prevent exercise-induced asthma.

Zafirlukast is also a leukotriene receptor antagonist used to treat asthma. Zileuton is a leukotriene synthesis inhibitor also used in the treatment of asthma.

Adverse events related to the use of montelukast should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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