Drug Profile

The Food and Drug Administration (FDA) approved montelukast (SINGULAIR) and zafirlukast (ACCOLATE) for the prevention and long-term treatment of asthma in patients aged one year and older and five years and older, respectively.[1],[2] These drugs are taken orally.

Montelukast also is approved for the treatment of seasonal allergic rhinitis (hay fever) — a collection of symptoms affecting the nose that are typically caused by inhaled allergens such as tree pollen — in adults and children two years of age and older and for the treatment of perennial allergic rhinitis (a year-round allergic condition commonly caused by indoor allergens such as mold and pet dander) in patients six months of age and older.[1] It is additionally approved for the prevention of exercise-induced bronchoconstriction (narrowing of the airways) in patients 15 years of age and older.[3]

Montelukast and zafirlukast are members of the leukotriene inhibitor family of asthma drugs. Leukotrienes are chemicals produced by the immune system that can lead to bronchoconstriction, increased mucus production and inflammation. Leukotriene inhibitors work by blocking the function, or preventing the production, of these chemicals, which are thought to play a role in asthma and allergic rhinitis. However, clinical trials have shown that these drugs are less effective than other asthma drugs.[4]

Because montelukast and zafirlukast have only limited benefits — none of which are unique — but pose some unique risks, such as psychiatric adverse reactions, we have designated these drugs as Do Not Use since their approval.

The effectiveness of montelukast for treatment of asthma was assessed in several large preapproval randomized, double-blind clinical trials that compared this oral drug to use of a placebo or to the inhaled corticosteroid beclomethasone (QVAR REDIHALER).[5] These trials, which together enrolled a few thousand subjects, showed that, overall, montelukast was better than a placebo for improving measures of lung function and asthma symptoms. However, the trials also demonstrated that inhaled corticosteroids were superior to montelukast for treating asthma.

Similarly, approval of zafirlukast for treating asthma was based primarily on three trials that enrolled nearly 1,400 subjects.[2] These trials were randomized, double-blind, placebo-controlled and lasted 13 weeks. These trials showed that zafirlukast improved asthma symptoms and measures of lung function compared with a placebo. However, a fourth trial that compared zafirlukast with inhaled cromolyn (generic only), another type of asthma drug, found that zafirlukast was no better than cromolyn in reducing rescue asthma inhaler use.

The evidence on the effectiveness of leukotriene inhibitors was also reviewed by the Cochrane Collaboration, an independent organization that examines published studies. The review looked at 65 randomized clinical trials that compared the safety and effectiveness of leukotriene inhibitors with those of inhaled corticosteroids for four weeks or longer in patients with asthma who were aged two years or older.[4]

The review found that inhaled corticosteroids were superior to leukotriene inhibitors in improving lung function. It also found that, compared with the use of inhaled corticosteroids, the use of leukotriene inhibitors was associated with an enhanced risk of exacerbations (worsening of asthma symptoms) that required systemic (oral or injectable) corticosteroids, more frequent hospital admissions for asthma exacerbations and an increased risk of withdrawal from the trials due to poor asthma control. The review concluded that inhaled corticosteroids should remain the first-choice drug in adults and children with persistent asthma.

Overall, montelukast is an unremarkable treatment for hay fever. Clinical trials of the leukotriene inhibitors have shown that, when used alone, these drugs are inferior to inhaled steroids in preventing and treating asthma, and their use to help reduce exposure to steroids is questionable. Thus, the lack of a documented therapeutic advantage over current treatment and the chance of some serious adverse effects should rule out the use of these drugs.

Adverse effects

Particularly concerning, both montelukast and zafirlukast have been associated with a wide range of adverse neuropsychiatric effects. These reactions include aggression, agitation, anxiety, depression, nightmares, hallucinations, insomnia, attention or memory disturbances, and suicidal thinking or behavior, among many other behavioral abnormalities.[6],[1],[2],[7] Because of these adverse neuropsychiatric effects, the FDA in March 2020 required the addition of a boxed warning — the strongest warning that the agency can require — about these effects to the product labeling for montelukast.[8] The new warning advises that, for allergic rhinitis, the drug should be used only by patients who are not treated effectively with, or cannot tolerate, other allergy medicines.

These drugs also have been linked to liver injury. Cases of life-threatening liver failure have been reported with zafirlukast use,[2] and the labeling for this drug includes a liver toxicity warning. Likewise, the labeling for montelukast indicates that post-marketing cases of hepatitis (inflammation of the liver) and other types of liver injury have been reported in patients using the drug.[1] Most of these cases occurred in patients who had underlying liver disease or risk factors for liver injury, such as alcohol use.

Both drugs also rarely can cause a condition known as systemic eosinophilia, which is characterized by a marked increase in a type of white blood cells called eosinophils as well as inflammation in organs such as the lungs or liver. Sometimes this condition can develop into Churg-Strauss syndrome, a serious disorder in which blood vessels become inflamed, leading to restricted blood flow to vital organs and tissues.[9],[10]

Montelukast may cause severe hypersensitivity allergic reactions, including life-threatening anaphylaxis — a type of allergic reaction characterized by throat tightness, a drop in blood pressure, swelling of the upper airways that impairs breathing, and hives.[10]

In addition to the aforementioned adverse events, zafirlukast can have a dangerous interaction with the blood thinner warfarin (COUMADIN, JANTOVEN). Studies have shown that concomitant use of zafirlukast with warfarin can increase blood levels of warfarin and, thus, increase the risk of bleeding.

Montelukast contains aspartame, which is a source of the amino acid phenylalanine. Too much intake of phenylalanine can be harmful to patients with a medical condition known as phenylketonuria.[11]

In 2023 The Journal of Allergy and Clinical Immunology Practice published an article showing that montelukast was associated with adverse neuropsychiatric effects.[3279]

In 2023 Iranian Journal of Allergy, Asthma and Immunology published an article showing that children hospitalized for an asthma attack did not benefit from adding montelukast to standard asthma treatment.[12]

In 2024 Journal of Affective Disorders published an article showing that the use of montelukast and zafirlukast for a long time is associated with an increased risk of depression.[13]