Review of the Asthma Drugs Montelukast (SINGULAIR) and Zafirlukast (ACCOLATE)

Asthma is a chronic respiratory disease in which the airways in the lungs become inflamed and narrow, resulting in difficulty breathing. The disease is very common in the U.S., afflicting 26.5 million adults and 6 million children.[1] The Food and Drug Administration (FDA) approved the oral prescription drugs montelukast (SINGULAIR) and zafirlukast (ACCOLATE) for the long-term treatment of asthma in patients aged one year and older and five years and older, respectively.[2],[3]

Montelukast, which has been one of the best-selling drugs in the U.S. of all time,[4] 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 perennial allergic rhinitis (a year-round allergic condition commonly caused by indoor allergens such as mold and pet dander) in patients six months and older.[5] It is additionally approved for the prevention of exercise-induced bronchoconstriction (narrowing of the airways) in patients 15 years of age and older.

Montelukast and zafirlukast are members of the selective leukotriene inhibitor family of asthma drugs. Because montelukast and zafirlukast have only limited benefits, none of which are unique, but pose some unique risks, such as psychiatric adverse reactions, Public Citizen’s Health Research Group has designated these drugs as Do Not Use since their approval.

Less effective than other drugs

Leukotrienes are chemicals produced by the immune system that can lead to bronchoconstriction, increased mucus production and inflammation. Anti-leukotrienes work by blocking the function or preventing the production of these chemicals, which are thought to play a role in asthma.[6] However, clinical trials have shown that these drugs are less effective than other asthma drugs.[7]

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 the inhaled corticosteroid beclomethasone (QVAR REDIHALER).[8] These trials, which together enrolled a few thousand subjects, overall showed that montelukast was better than 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.[9] These trials were double-blinded, randomized, placebo-controlled and lasted 13 weeks. These trials showed that zafirlukast improved asthma symptoms and measures of lung function compared with 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.[10]

The evidence on the effectiveness of anti-leukotrienes also was 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 anti-leukotrienes with those of inhaled corticosteroids for four weeks or longer in patients with asthma aged two years or older.[11] The review found that inhaled corticosteroids were superior to anti-leukotrienes in improving lung function. It also found that compared with the use of inhaled corticosteroids, the use of anti-leukotrienes 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.

This review bolsters FDA's initial evaluation of a preapproval clinical trial that investigated supplementing asthma treatment with the inhaled corticosteroid beclomethasone with montelukast treatment.[12] The combination of the two drugs did not significantly improve lung function as compared with beclomethasone alone. Furthermore, the agency's reviewers noted that the trial results demonstrated that it was better to leave patients with mild-to-moderate asthma on beclomethasone than to switch them to montelukast.

Dangerous adverse effects

In addition to their limited effectiveness, both montelukast and zafirlukast can cause serious adverse events.

Particularly concerning, these drugs have been associated with a wide range of adverse neuropsychiatric effects. These reactions include aggression, agitation, anxiety, depression, nightmares, hallucinations, insomnia, and suicidal thinking or behavior, among many other behavioral abnormalities.[13],[14] Children seem to be particularly susceptible to these psychiatric reactions. Post-approval reports of these neuropsychiatric effects eventually prompted the manufacturer of montelukast to add a precaution about these adverse effects to the drug's label in August 2009.[15]

These drugs also have been linked to liver injury. Cases of life-threatening liver failure have been reported with zafirlukast use,[16] and the labeling for this drug includes a liver toxicity warning. Likewise, the labeling for montelukast indicates that postmarketing cases of hepatitis (inflammation of the liver) and other types of liver injury have been reported in patients using the drug.[17] 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,[18],[19] which is characterized by a marked increase in a type of white blood cells called eosinophils in the blood and 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.[20],[21]

Montelukast may cause severe hypersensitivity allergic reactions, including life-threatening anaphylaxis — a type of allergic reaction characterized by throat tightness, drop in blood pressure, swelling of the upper airways that impairs breathing, and hives.[22]

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.[23]

What You Can Do

Although montelukast and zafirlukast have been categorized as Do Not Use by Public Citizen’s Health Research Group, you should not stop any asthma medication without first consulting your physician. Abruptly stopping a medication may result in the acute deterioration of asthma control.

If you are currently taking either montelukast or zafirlukast, talk to your doctor about switching to a more effective and less dangerous alternative for the management of your asthma symptoms, such as inhaled corticosteroids.
 

References

[1] Centers for Disease Control and Prevention. Most recent asthma data. May 2018. https://www.cdc.gov/asthma/most_recent_data.htm. Accessed April 2, 2019.

[2] Merck Sharp & Dohme. Label: montelukast (SINGULAIR). February 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8c166755-7711-4df9-d689-8836a1a70885&type=display. Accessed April 10, 2019.

[3] Par Pharmaceutical. Label: zafirlukast (ACCOLATE). November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0262e192-94f4-423d-a58e-bb374dc106fe&type=display. Accessed April 10, 2019.

[4] Williams S. The 19 best-selling prescription drugs of all time. Motley Fool LLC. March 13, 2017. https://www.fool.com/investing/2017/03/13/the-19-best-selling-prescription-drugs-of-all-time.aspx. Accessed April 9, 2019.

[5] Merck Sharp & Dohme. Label: montelukast (SINGULAIR). February 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8c166755-7711-4df9-d689-8836a1a70885&type=display. Accessed April 10, 2019.

[6] Drug profile: montelukast (SINGULAIR) and zafirlukast (ACCOLATE). August 2018. /monographs/view/240. Accessed April 2, 2019.

[7] Chauhan BF, Ducharme FM. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database of Sys Rev. 2014(5):CD002314.

[8] Food and Drug Administration. Medical reviews for application number 20-829 for montelukast (SINGULAIR). https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020829s000_Singular_Medr.pdf. Accessed April 9. 2019.

[9] Par Pharmaceutical. Label: zafirlukast (ACCOLATE). November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0262e192-94f4-423d-a58e-bb374dc106fe&type=display. Accessed April 10, 2019.

[10] Ibid.

[11] Chauhan BF, Ducharme FM. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database of Sys Rev. 2014(5):CD002314.

[12] Food and Drug Administration. Medical reviews for application number 20-829 montelukast (SINGULAIR). https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020829s000_Singular_Medr.pdf. Accessed April 9, 2019.

[13] Cereza G, Garcia Dolade N, Laporte JR. Nightmares induced by montelukast in children and adults. Eur Respir J. 2012;40(6):1574-1575.

[14] Par Pharmaceutical. Label: zafirlukast (ACCOLATE). November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0262e192-94f4-423d-a58e-bb374dc106fe&type=display. Accessed April 10, 2019.

[15] Food and Drug Administration. Letter to Merck and Co. August 19, 2009. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/020829s051,020830s052,021409s028ltr.pdf. Accessed April 10, 2019.

[16] Par Pharmaceutical. Label: zafirlukast (ACCOLATE). November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0262e192-94f4-423d-a58e-bb374dc106fe&type=display. Accessed April 10, 2019.

[17] Merck Sharp & Dohme. Label: montelukast (SINGULAIR). February 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8c166755-7711-4df9-d689-8836a1a70885&type=display. Accessed April 10, 2019.

[18] Ibid.

[19] Par Pharmaceutical. Label: zafirlukast (ACCOLATE). November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0262e192-94f4-423d-a58e-bb374dc106fe&type=display. Accessed April 10, 2019.

[20] National Institute of Health. Eosinophilic disorders. December 31, 2018. https://medlineplus.gov/eosinophilicdisorders.html. Accessed April 2, 2019.

[21] Churg-Strauss syndrome. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/churg-strauss-syndrome/symptoms-causes/syc-20353760?p=1. Accessed April 2, 2019.

[22] Ibid.

[23] Par Pharmaceutical. Label: zafirlukast (ACCOLATE). November 2017. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=0262e192-94f4-423d-a58e-bb374dc106fe&type=display. Accessed April 10, 2019.