Criteria for Outpatient Use Guidelines

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[Developed, February 2007; Revised, March 2007; June 2007; September 2007; October 2010; November 2010]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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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, and perennial allergic rhinitis in adults and children 6 months 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 for mild to moderate persistent asthma, and alternative, not preferred, adjunctive therapy with inhaled corticosteroids for mild to moderate persistent asthma. The GINA guidelines consider LTRAs to be an option for children > 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-to-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.

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

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

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 eveloping 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.

Drug-drug interactions considered clinically relevant for zafirlukast are summarized in Table 3.  Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

References

1. Drug Facts and Comparisons.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2010.  Available at:  http://clineguide.com.  Accessed October 7th, 2010.
2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2010. Available at: http://www.clinicalpharmacology.com. Accessed October 7th, 2010.
3. DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.   Accessed October 7th, 2010.
4. Montelukast (Singulair®) package insert.  Merck & Co., July 2010.
5. Zafirlukast (Accolate®) package insert.  AstraZeneca Pharmaceuticals, July 2010.
6. 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.  Available at:  http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.  Accessed October 7th, 2010. 
7. National Asthma Education and Prevention Program Expert Panel Report: guidelines for the diagnosis and management of asthma update on selected topics-2002. J Allergy Clin Immunol. 2002;110(5 pt 2):S141-219.
8. Currie GP, McLaughlin K.  The expanding role of leukotriene receptor antagonists in chronic asthma.  Ann Allergy Asthma Immunol. 2006;97:731-42.
9. Global Initiative for Asthma®. Global strategy for asthma management and prevention.  Updated 2009.  Available at:   http://www.ginasthma.org/Guidelineitem.asp??l1=2&l2=1&intId=1561.  Accessed October 7th, 2010.
10. Ducharme FM, Lasserson TJ, Cates CJ. Long-acting beta2-agonists versus anti-leukotrienes as add-on  therapy to inhaled corticosteroids for chronic asthma. Cochrane Database of Systematic Reviews.2006; Issue 4. Art. No.: CD003137. DOI:10.1002/14651858.CD003137.pub3.
11. Li JT, Oppenheimer J, Bernstein IL, et al, and the Joint Task Force on Practice Parameters for the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology.  Attaining optimal asthma control: a practice parameter.  J Allergy Clin Immunol. 2005;116(5 Suppl):S3-S11.
12. Nassef M, Shapiro G, Casale TB, on behalf of the Respiratory & Allergic Disease Foundation. Identifying and managing rhinitis and its subtypes: allergic and nonallergic components – a consensus report and materials from the Respiratory & Allergic Disease Foundation.  Curr Med Res Opin. 2006;22:2541-            48.
13. Jiang RS. Efficacy of a leukotriene receptor antagonist in the treatment of perennial allergic rhinitis.  J Otolaryngol. 2006;35:117-21.
14. Mucha SM, deTineo M, Naclerio RM, Baroody FM.  Comparison of montelukast and pseudoephedrine in the treatment of allergic rhinitis.  Arch Otolaryngol Head Neck Surg. 2006;132:164-72.
15. Di Lorenzo G, Pacor ML, Pellitteri ME, et al.  Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in monotherapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis.  Clin Exp Allergy.  2004;34:259-67.
16. Nayak A, Langdon RB.  Montelukast in the treatment of allergic rhinitis: an evidence-based review.  Drugs. 2007;67:887-901.
17. DRUG-REAX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.  Accessed October 7th, 2010.
18. Strunk RC, Bacharier LB, Phillips BR, et al.  Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study.  J Allergy Clin Immunol. 2008;122(6):1138-44.
19. Lofdahl CG, Reiss TF, Leff JA, et al.  Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients.  BMJ. 1999;319 (7202):87-90.

Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.