Leukotriene Receptor Antagonists - Index

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • July 21, 2023
    • July 23, 2021
    • May 2019
    • March 2016
    • June 2014
    • Oct. 2012
    • Nov. 2010
    • Oct. 2010
    • Sept. 2007
    • June 2007
    • March 2007
  • Initially developed
    • Feb. 2007

1. Dosage

Leukotrienes are inflammatory molecules released by mast cells in response to inhaled allergens. Cysteinyl leukotrienes bind to receptors on airway smooth muscle and macrophages and activate a number of airway effects, ultimately resulting in bronchoconstriction and inflammation associated with asthma, as well as the pathophysiologic effects associated with allergic rhinitis. Leukotriene receptor antagonists (LTRAs) prevent binding of cysteinyl leukotrienes to active receptors. Currently available LTRAs include montelukast and zafirlukast, with montelukast FDA-approved for prevention and chronic management of asthma in adults and children 12 months of age and older, seasonal allergic rhinitis in adults and children 2 years of age and older, perennial allergic rhinitis in adults and children 6 months of age and older, and prevention of exercise-induced bronchoconstriction in adults and children 6 years of age and older. Zafirlukast is only FDA-approved for use in preventing and managing chronic asthma in adults and children 5 years of age and older.

The Expert Panel created by the National Heart, Lung and Blood Institute considers LTRAs to be alternative, not preferred, treatment options. The GINA guidelines consider LTRAs to be an option for children greater than 5 years of age, adolescents, and adults at all levels of severity, although clinical benefit is not as significant as that seen with low-dose inhaled corticosteroids. In adult patients, LTRAs may be used as an alternative therapy for mild persistent asthma; however, when used as monotherapy, LTRAs are less effective than low-dose inhaled corticosteroids and may contribute to loss of asthma control if substituted in patients already maintained on inhaled corticosteroid therapy. LTRAs may also be utilized as add-on treatment in patients not adequately controlled on low-dose inhaled corticosteroids and may contribute to inhaled corticosteroid dosage reductions in adults with moderate persistent or severe asthma. However, most studies have shown that long-acting inhaled beta2-agonists are more effective than LTRAs as add-on therapy. In pediatric asthma patients, GINA guidelines state that LTRAs provide partial protection against exercise-induced bronchoconstriction and provide moderate clinical improvement with reduced exacerbations when used as adjunctive therapy in patients inadequately controlled with low-dose inhaled corticosteroids. In moderate persistent asthma, however, increasing inhaled corticosteroid doses is more effective than adding LTRAs to existing therapy, and in moderate-to-severe persistent asthma, the addition of montelukast has not been shown to decrease the use of inhaled corticosteroids.

1.1. Adults

Adult dosage recommendations for LTRAs are summarized in Table 1. Patient profiles containing dosages not conforming to these recommendations will be reviewed.

Table 1. LTRA Adult Dosage Recommendations1-4
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
montelukast (Singulair®, generics) 10 mg tablets, 4 mg, 5 mg chewable tablets, 4 mg oral granule packets asthma 10 mg once daily in the evening 
    prophylaxis, exercise-induced bronchoconstriction 10 mg as a single dose, at least 2 hours before exercise; dose should not be repeated within 24 hours of previous dose
    perennial and/or seasonal allergic rhinitis 10 mg daily
zafirlukast (Accolate®, generics) 10 mg, 20 mg tablets asthma 20 mg twice daily

1.2. Pediatrics

Pediatric dosage recommendations for LTRAs are summarized in Table 2. Patient profiles containing dosages not conforming to these recommendations will be reviewed.

Table 2. LTRA Pediatric Dosage Recommendations1-4
Drug Nam Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
montelukast (Singulair®, generics) 10 mg tablets, 4 mg, 5 mg chewable tablets, 4 mg oral granule packets asthma
  • adolescents greater than or equal to 15 years of age:
    • 10 mg once daily in the evening (as tablet)
  • children 6-14 years of age:
    • 5 mg once daily in the evening (as chewable tablet)
  • children 2-5 years of age:
    • 4 mg once daily in the evening (as chewable tablet or oral granules)
  • children 12–23 months of age:
    • 4 mg once daily in the evening (as oral granules)
    prophylaxis, exercise-induced bronchoconstriction

adolescents greater than or equal to 15 years of age:

  • 10 mg as a single dose, at least 2 hours before exercise; dose should not be repeated within 24 hours of previous dose

children 6 to 14 years of age:

  • 5 mg (as chewable tablet) as a single dose, at least 2 hours before exercise; dose should not be repeated within 24 hours of previous dose
    seasonal allergic rhinitis
  • adolescents greater than or equal to 15 years of age:
    • 10 mg daily (as tablet)
  • children 6-14 years of age:
    • 5 mg daily (as chewable tablet)
  • children 2-5 years of age:
    • 4 mg daily (as chewable tablet or oral granules)
    perennial allergic rhinitis
  • adolescents greater than or equal to 15 years of age:
    • 10 mg daily (as tablet)
  • children 6-14 years of age:
    • 5 mg daily (as chewable tablet)
  • children 2-5 years of age:
    • 4 mg daily (as chewable tablet or oral granules)
  • children 6-23 months of age:
    • 4 mg daily (as oral granules)
zafirlukast (Accolate®, generics) 10 mg, 20 mg tablets asthma
  • adolescents greater than or equal to 12 years of age:
  • 20 mg twice daily
  • children 5-11 years of age:
    • 10 mg twice daily

2. Duration of Therapy

LTRAs are indicated for the management of chronic asthma and seasonal allergic rhinitis and may be continued indefinitely, as both allergic rhinitis and asthma are chronic, lifelong processes.

3. Duplicative Therapy

Zileuton (Zyflo®), a 5-lipoxygenase inhibitor, inhibits formation of cysteinyl leukotrienes. Concurrent administration of LTRAs with zileuton does not provide additional clinical benefit and may increase risk of developing adverse events. Concurrent administration of LTRAs with zileuton is not recommended and will be reviewed.

Adjunctive administration of montelukast and zafirlukast does not provide additional clinical benefit and may result in additive adverse effects. Combined administration of montelukast and zafirlukast is not recommended and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

No dosage adjustments are necessary when montelukast is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, digoxin, warfarin, thyroid hormones, sedative hypnotics, nonsteroidal anti-inflammatory agents, benzodiazepines, decongestants, and cytochrome P450 enzyme inducers. Continuous monitoring for montelukast efficacy is recommended when concurrently taking cytochrome P450 enzyme inducers.

Drug-drug interactions considered clinically relevant for zafirlukast are summarized in Table 3. Only those drug-drug interactions identified as severe or those considered life-threatening which have not yet been classified will be reviewed.

Table 3. Zafirlukast Drug-Drug Interactions2,4
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
zafirlukast erythromycin, clarithromycin decreased zafirlukast concentrations; mechanism unknown monitor patient for lack of response to zafirlukast therapy; may consider azithromycin or montelukast as alternatives moderate (CP)
zafirlukast drugs metabolized by CYP2C9 (e.g., warfarin, phenytoin) increased concentrations of drugs metabolized by CYP2C9 due to zafirlukast enzyme inhibition; prothrombin time increased by 35% with warfarin-zafirlukast combination monitor for increased adverse events (e.g., regularly assess PT or INR with warfarin-zafirlukast combination, phenytoin levels) major (CP) 
zafirlukast other drugs metabolized by CYP3A4 (e.g., dofetilide, ergot alkaloids, aripiprazole, cilostazol) increased concentration of drugs metabolized by CYP3A4 due to CYP3A4 inhibition by zafirlukast carefully monitor patient therapy for potentially enhanced pharmacologic effects and toxicity major (CP)
zafirlukast pimozide increased pimozide concentrations resulting in QTc prolongation and ventricular arrhythmias due to CYP3A4 inhibition by zafirlukast contraindicated severe (CP)
zafirlukast saquinavir (boosted with ritonavir) saquinavir and zafirlukast are CYP3A4 inhibitors; combined use may increase saquinavir serum levels and potentially result in life-threatening arrhythmias (including torsades de pointes) contraindicated severe (CP)
zafirlukast theophylline increased theophylline concentration due to CYP 1A2 inhibition by zafirlukast and/or decreased zafirlukast serum levels monitor for theophylline toxicity and/or reduced zafirlukast efficacy moderate (CP)

Legend:

  • *CP = Clinical Pharmacology

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: June 14, 2023).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2023. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 14, 2023.
  3. Montelukast (Singulair®) package insert. Organon LLC, June 2021.
  4. Zafirlukast (Accolate®) package insert. Strides Pharma Science Limited, December 2022.
  5. U.S. Department of Health and Human Services. National Institutes of Health. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program. Expert Panel 3: guidelines for the diagnosis and management of asthma. Full report 2007. NIH Publication No. 08-4051. Accessed June 14, 2023.
  6. National Heart, Lung, and Blood Institute. 2020 focused updates to the asthma management guidelines: a report from the national asthma education and prevention program coordinating committee expert panel working group. National Institutes of Health. December 2020. Accessed June 14, 2023. 
  7. Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2022. Available at: https://ginasthma.org/gina-reports/. Accessed June 14, 2023.
  8. Zileuton extended release oral tablets package insert. Rising Pharmaceuticals, Inc., March 2023.