FDA Panel Rejects OTC Use of Montelukast (Singulair Allergy)

Larry Hand

May 02, 2014

The Nonprescription Drugs Advisory Committee of the US Food and Drug Administration (FDA) has voted against recommending that montelukast (Singulair Allergy, Merck) be approved as an over-the-counter (OTC) drug for the treatment of allergic rhinitis (AR).

Montelukast has been a prescription medicine for the treatment of asthma for children and adults since 1998, for seasonal AR since 2002, for perennial AR since 2005, and for exercise-induced bronchoconstriction since 2007.

Merck has asked for FDA approval on a partial addition to OTC for adults 18 years old and older only, and only for the treatment of allergy symptoms, with specific wording that it not be used OTC for asthma treatment and specific warning that it not be used for children younger than 18 years. The dosage requested for OTC is 10 mg/day, which is the current approved dosage for individuals 15 years old and older.

On a question before the committee regarding whether "the safety of OTC use for relief of allergy symptoms, considering off-label use, been adequately demonstrated," 11 panel members voted no and 4 voted yes.

On the other question before the committee, regarding whether "the risk/benefit profile of montelukast sodium supportive of OTC use in adults for the nasal indication 'temporary relieves these symptoms due to hay fever and other respiratory allergies,' " the vote count came out the same, but with 2 panel members changing their votes on the second question.

Merck has asked the FDA to add ocular symptoms of allergies in the indication, along with currently approved language on daytime nasal symptom relief, to the OTC labeling, but FDA staff members took that option off the table for the advisory committee vote.

Montelukast has been approved for prescription use in more than 100 countries worldwide and has about 66 million patient-years of exposure with about 24 million dose units being prescribed, according to Merck officials. But no countries have approved it for OTC use.

Still Do Not Know

But it is what is still unknown that led to committee members' decisions, particularly with regard to potential off-label use for asthma patients and for pediatric patients, as well as potential neuropsychiatric adverse effects, including suicide.

Although clinical trials assessed for approval of prescription of montelukast did not turn up neuropsychiatric adverse effects as a safety factor, adverse event reports in postmarketing databases have, primarily for depression, aggression, irritability, nightmares, and insomnia, FDA officials said at the committee hearing.

The FDA initiated a safety review of drugs that act through the leukotriene pathway, including montelukast, and potential association with neuropsychiatric events, including suicidality. The suicide of a 15-year-old boy taking montelukast in 2007 was 1 event prompting the review, according to FDA documents. The FDA review found 43 completed potentially related suicides between March 2008 and October 2013.

Merck amended its product labels to include a precaution against neuropsychiatric events, which the FDA approved in 2009 and has planned to continue the labeling for OTC use.

But committee members were not satisfied with labeling as a solution to uncertainties.

As to potential neuropsychiatric adverse effects, "We really just don't know much about them," said committee member Tobias Gerhard, PhD, RPh, assistant professor of pharmacy at Rutgers University, New Brunswick, New Jersey. He questioned whether the association would become a bigger problem if OTC use was approved.

He also questioned what effect OTC use for allergies might have on patients with asthma, many of whom have concomitant allergies and are already taking montelukast as a prescription.

Merck's proposed labeling information advises patients who are taking asthma medications to continue their treatments. However, panel members questioned whether some patients, to save money, might drop their asthma medications because montelukast in prescription form is approved for asthma and allergies.

"If only 0.1% of [asthma] patients stopped taking their medications, it has a potentially significant risk," said Dr. Gerhard.

"Conflicting Testimonials"

Panel members were also struck by "conflicting testimonials" during the hearing as to montelukast's benefits and risks, said committee member Kenneth Towbin, MD, chief of the Clinical Child and Adolescent Psychiatry Unit at the National Institutes of Health in Bethesda, Maryland. Among the witnesses at the public hearing portion of the hearing were 2 parents who described their children's neuropsychiatric adverse reactions to montelukast.

"Conflicting testimonials are difficult to be used in making scientific decisions, especially with no scientific data to assist us in understanding neuropsychiatric events," Dr. Towbin said.

Committee members in favor of adding the drug to OTC use and Merck officials expressed concern that the safety issues were overblown, considering that the drug has been used so much already and that the safety profile is considered positive overall.

Committee chair Ruth M. Parker, MD, professor of medicine at Emory University School of Medicine in Atlanta, Georgia, summed up the reasons for resistance to adding OTC use as the risk of being used off-label and the complexity of the labeling being too difficult for the average adult to understand.

The advisory committee members have disclosed no relevant financial interests.

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