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Therapeutics Letter, issue 29, April/May 1999

LEUKOTRIENE ANTAGONISTS:

What is their role in the management of ASTHMA?


Management options for chronic asthma were reviewed in Therapeutics Letter #12 (Jan/Feb 1996). In 1998 Canada licensed two members of a new class of drugs for asthma, leukotriene antagonists, zafirlukast (Accolate®) and montelukast (Singulair®). The goal of this Letter is to assess the published randomised controlled trial evidence to determine the role of these drugs in the management of asthma.


What is the rationale for leukotriene receptor antagonists (LTRAs)?

LTRAs inhibit the effects of the cysteinyl leukotrienes, which represent 3 of a large number of chemical mediators of asthma. Leukotrienes are released by several types of cells and can cause bronchoconstriction and inflammation(1), (2).The cysteinyl leukotrienes are particularly important mediators in patients with aspirin-sensitive asthma (characterized by chronic severe asthma symptoms, nasal polyps, and aspirin-induced bronchospasm)(3). LTRAs competitively block leukotriene receptors on bronchial smooth muscle and elsewhere(1), (2).


How are LTRAs handled in the body?

Both drugs are rapidly absorbed after oral administration. Zafirlukast absorption is decreased in the presence of food. Both drugs are highly bound to plasma albumin and are eliminated by liver meta- bolism. The half-life of montelukast is 3 to 6 hours and that for zafirlukast is 10 hours.


What is the evidence for their effectiveness?

Zafirlukast administered twice daily has been compared with placebo in two published short-term trials(4), (5) of patients > age 11 (see Table). There have been no published trials comparing zafirlukast with inhaled corticosteroids.

Montelukast has been compared with placebo in 11 published RCTs. Most of these trials were designed to ascertain the dose and dose regimen, and showed that 10 mg of montelukast once daily at bedtime produces maximum effects in adults. At the recommended doses montelukast has been compared with placebo in one large trial in adults(6) and one large trial in children(7), (see Table). In one trial of 110 patients with exercise induced asthma the maximal decrease in FEV1 associated with exercise was 32.4% with placebo as compared to 22.2% with montelukast(8). A recently published trial compared montelukast to inhaled glucocorticoid and placebo in adults with chronic asthma. Montelukast was better than placebo but not as effective as low-dose inhaled beclomethasone(9) (see Table).

The average effects in the trials, though statistically significant, are small and of questionable clinical significance. The effect on home peak expiratory flow rate, increase of 20 L/min (6%), is maximal the day after the first dose.(10)


Safety

In the short-term clinical trials, adverse effects did not differ between the leukotriene antagonists, placebo or inhaled glucocorticoids. Rare cases of Churg-Strauss syndrome (allergic angiitis and granulomatosis) have been reported with both drugs(10). Some of these cases may have been unmasked by steroid withdrawal, however, not all cases have coincided with steroid withdrawal. Zafirlukast inhibits liver microsomal enzymes, P450 CYP3A4 and CYP2C9, and has been shown to increase the effects of warfarin. Other clinically important drug interactions are likely, but unknown at present. Montelukast has been shown to not interact with human P450s in vitro and not to interact with theophylline, prednisone, prednisolone, ethinyl estradiol, terfenadine, digoxin and warfarin in clinical studies.

TABLE: Evidence of effectiveness of leukotriene antagonists

Drug and dose

N

Outcomes

Trial details

D FEV1 #

â B2 agonist*

Zafirlukast (4) (20 mg BID)

Placebo

57

56

+11%

+ 1%

-31%

-15%

Chronic asthma

Age: 18-65

6 weeks

Zafirlukast (5) (20 mg BID)

Placebo

514

248

+5.6%

+1.0%

-22.3%

+ 7%

Chronic asthma

Age: > 11 years

13 weeks

Montelukast (6) (10 mg HS)

Placebo

408

273

+13%

+ 4.2%

-25%

0%

Chronic asthma

Age: > 14 years

12 weeks

Montelukast (7) (5 mg HS)

Placebo

201

135

+8.2%

+3.6%

-12%

+ 6%

Chronic asthma

Age: 6-14 years

8 weeks

Beclomethasone (9) (200 ug BID)

Montelukast (10 mg HS)

Placebo

251

387

257

+13.1%

+7.4%

+0.7%

-40%

-24%

0%

Chronic asthma

Age: 15-85

12 weeks

# Forced expiratory volume in one second

* inhalers (e.g. salbutamol)


Dose and daily cost

  Dose Daily cost
zafirlukast

20 mg tablet BID
on an empty stomach
age >11 years)
$1.50

montelukast


10 mg tablet at HS
(age >14 years)
5 mg chewable tablet at HS
(age 6 to 14 years)
$2.20

$1.50

Conclusions:

LEUKOTRIENE ANTAGONISTS IN ASTHMA

This Therapeutics Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to March 15,1999. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 110 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians.

References:

  1. Sampson A, Holgate S. Leukotriene modifiers in the treatment of asthma. Brit Med J 1998;316:1257-1258.
  2. Renzi P. Antileukotriene agents in asthma: The dart that kills the elephant? CMAJ 1999; 160: 217-23.
  3. Christie PE. Aspirin sensitive asthma. Clinical and Experimental Allergy 1992;22:171-175.
  4. Fish JE, Kemp JP, Lockey RF, et al. Zafirlukast for symptomatic mild-to-moderate asthma: A 13-week multicenter study. Clin Therap 1997;19:675-690.
  5. Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Amer J Respir Crit Care Med 1994;150:618-623.
  6. Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998; 158: 1213-20.
  7. Knorr B et al. Montelukast for chronic asthma in 6 to 14 year-old children. JAMA 1998; 279: 1181-6.
  8. Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998; 339: 147-52.
  9. Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized controlled trial. Ann Intern Med 1999; 130: 487-495.
  10. Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. J Amer Med Assoc 1998;279:455-457.

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