Brand name: Accolate
Drug class: Leukotriene Modifiers
- Leukotriene-receptor Antagonists
ATC class: R03DC01
VA class: RE109
Chemical name: [3-[[2-Methoxy-4-[[[(2-methylphenyl)-sulfonyl]amino]carbonyl]phenyl]methyl]-1H-indol-5-yl-carbamic acid cyclopentyl ester
Molecular formula: C₃₁H₃₃N₃O₆S
CAS number: 107753-78-6

Medically reviewed by Drugs.com on Apr 14, 2025. Written by ASHP.

Introduction

Antiasthmatic agent; leukotriene-receptor antagonist.

Uses for Zafirlukast

Asthma

Prevention and long-term symptomatic management of asthma.

In patients with mild persistent asthma, low-dose orally inhaled corticosteroids considered first-line agents for long-term control. Alternative agents, including certain leukotriene modifiers (i.e., zafirlukast, montelukast), may be used but are less effective than inhaled corticosteroids and are not preferred as initial therapy.

In patients with moderate persistent asthma, low-dose inhaled corticosteroids with a long-acting inhaled β₂-agonist bronchodilator (e.g., salmeterol, formoterol) or monotherapy with medium-dose inhaled corticosteroids preferred. However, the National Asthma Education and Prevention Program (NAEPP) recommends that beneficial effects of long-acting inhaled β₂-agonists be weighed carefully against increased risk of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.

Alternative agents, including certain leukotriene modifiers (i.e., zafirlukast, montelukast), can be added to a low dosage of inhaled corticosteroid for treatment of moderate persistent asthma, but these options are less effective. Considerations favoring combination with orally inhaled corticosteroids include intolerance to long-acting β₂-adrenergic agonists, marked preference for oral therapy, and demonstration of superior responsiveness to these leukotriene modifiers.

In adults and children ≥5 years of age with severe persistent asthma, NAEPP and the Global Initiative for Asthma (GINA) state that maintenance therapy with inhaled corticosteroids at medium to high dosages and adjunctive therapy with a long-acting inhaled β₂-agonist is preferred. Alternatives to a long-acting inhaled β₂-agonist in such patients receiving medium-dose inhaled corticosteroids include certain leukotriene modifiers (i.e., zafirlukast, montelukast), but these agents are generally not preferred.

Therapy with zafirlukast may be especially useful in patients who are unable or unwilling to comply with therapy using inhaled drugs (e.g., children).

Not recommended for relief of acute bronchospasm; however, may continue therapy during acute asthma exacerbations. (See Acute Asthma under Cautions.)

Allergic Rhinitis

Has been used for symptomatic management of seasonal allergic rhinitis^{† [off-label]}.

Exercise-induced Bronchospasm

Has been used for prevention of exercise-induced bronchospasm^{† [off-label]}.

Leukotriene modifiers not included as first-line agents or as alternative agents to orally inhaled β₂-adrenergic agonists in current guidelines.

Zafirlukast Dosage and Administration

Administration

Oral Administration

Administer twice daily on an empty stomach (i.e., at least 1 hour before or two hours after meals).

Dosage

Pediatric Patients

Asthma

Oral

Children 5–11 years of age: 10 mg twice daily.

Children ≥12 years of age: 20 mg twice daily.

Adults

Asthma

Oral

20 mg twice daily.

Special Populations

Hepatic Impairment

Clearance may be decreased. Dosage reduction may be necessary; however, the manufacturer currently makes no specific recommendations for dosage adjustment. Not evaluated in patients with hepatitis or in long-term studies in patients with cirrhosis. (See Special Populations under Absorption and under Elimination in Pharmacokinetics and see Hepatic Impairment.)

Renal Impairment

Dosage adjustment not required.

Geriatric Patients

Dosage adjustment not required. (See Special Populations under Absorption and under Elimination in Pharmacokinetics.)

Cautions for Zafirlukast

Contraindications

Known hypersensitivity to zafirlukast or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hepatic Effects

Hepatic dysfunction, including increases in liver enzyme concentrations, hepatitis, and/or hyperbilirubinemia, reported. Zafirlukast-induced hepatotoxicity usually is reversible following discontinuance of the drug.

Serious and potentially fatal hepatotoxicity, including fulminant hepatitis and liver failure, reported rarely.

Monitor closely for signs and symptoms of hepatic impairment; consider performing liver function tests (e.g., serum AST and ALT) periodically. Advise patients to immediately contact their clinician if they notice signs and symptoms of liver dysfunction.

Discontinue therapy if signs and/or symptoms suggestive of liver dysfunction occur; immediately perform liver function tests (i.e., serum ALT) and manage patient accordingly.

Do not reinitiate therapy if results of liver function tests are consistent with hepatic dysfunction or if zafirlukast was discontinued because of hepatic dysfunction when no other attributable cause could be identified.

Acute Asthma

Do not use for relief of acute bronchospasm (including status asthmaticus); zafirlukast can be continued during acute exacerbations of asthma, but it will not provide immediate symptomatic relief. Patients who experience exacerbations of asthma should continue their usual regimen of inhaled β₂–adrenergic agonists for prophylaxis and have a short-acting orally inhaled β₂-adrenergic agonist available for rescue.

Interactions

Concomitant use with warfarin results in a clinically important increase in PT. (See Specific Drugs under Interactions.)

Sensitivity Reactions

Eosinophilia and Churg-Strauss Syndrome

Systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome reported rarely in patients receiving leukotriene modifiers; these events usually associated with reduction (tapered dosage) or withdrawal of oral or high-dose inhaled corticosteroid therapy.

Be alert to the development of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy; causal relationship not established.

General Precautions

Concomitant Corticosteroid Therapy

Do not abruptly substitute zafirlukast for oral or inhaled corticosteroids. Orally inhaled corticosteroid requirements may be reduced during zafirlukast therapy; undertake only gradual (e.g., at 2-week intervals) reduction of corticosteroid dosage.

Neuropsychiatric Effects

Neuropsychiatric events reported with zafirlukast during postmarketing experience. Data from placebo-controlled trials with leukotriene modifiers indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of those receiving other leukotriene modifiers; no completed suicide occurred during therapy with any leukotriene modifier. FDA concluded that some neuropsychiatric events reported with zafirlukast (e.g., depression, insomnia) appear consistent with a drug-induced effect.

Be alert to the potential for neuropsychiatric events in patients receiving the drug. Instruct patients to contact their clinician if behavior or mood changes occur. Carefully evaluate the risks and benefits of continuing zafirlukast therapy in patients who develop neuropsychiatric symptoms.

Specific Populations

Pregnancy

Category B.

ACOG generally recommends use of leukotriene receptor antagonists (i.e., zafirlukast, montelukast) as alternatives to a long-acting β₂-agonist in pregnant women with moderate persistent asthma who are inadequately controlled with low to medium dosages of an inhaled corticosteroid. (See Asthma under Uses.)

Lactation

Distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety demonstrated in children 5–11 years of age; efficacy extrapolated from demonstrated efficacy in adults with asthma and the likelihood that the disease course, pathophysiology, and drug’s effect are similar between the two populations.

Safety and efficacy not established in children <5 years of age.

Increased systemic exposure and AUC, reflecting decreased clearance in children relative to adults.

Effect on growth in pediatric patients not evaluated in clinical studies to date.

Geriatric Use

Possible increased incidence of infection (e.g., pharyngitis, rhinitis) compared with younger adults.

Hepatic Impairment

Decreased clearance; dosage reduction may be necessary. (See Special Populations under Absorption and under Elimination in Pharmacokinetics.)

Common Adverse Effects

Headache, infection, nausea, diarrhea.

Drug Interactions

Metabolized by CYP2C9.

Inhibits CYP3A4 and CYP2C9.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2C9 and CYP3A4 substrates: Potential pharmacokinetic interaction (increased plasma substrate concentrations).

Specific Drugs

Zafirlukast Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained within 3 hours.

Steady-state plasma concentrations are proportional to dose.

Children 5–11 years of age: Increased peak plasma concentrations, AUC, and systemic exposure.

Onset

Improvement in asthma symptoms and/or lung function test results and decreased use of β-agonist bronchodilators are evident within 3–14 days.

Food

Food decreases rate and extent of absorption; high-fat or high-protein meal decreases mean bioavailability by approximately 40%.

Special Populations

In patients with hepatic impairment (stable alcoholic cirrhosis), peak plasma concentration and AUC increased 50–60%.

Asthmatic patients ≥65 years of age: Increased peak plasma concentration and AUC.

Distribution

Extent

Not fully characterized.

Minimally crosses the placenta and blood-brain barrier in animals (rats, mice); not known whether zafirlukast crosses the placenta in humans.

Distributed into human milk.

Plasma Protein Binding

>99% (mainly albumin).

Elimination

Metabolism

Extensively metabolized in the liver principally via CYP2C9.

Elimination Route

Excreted principally in feces (about 90%) via biliary excretion as unchanged drug and metabolites.

Half-life

Adults: 8–16 hours.

Special Populations

Clearance is reduced in children 5–11 years of age and adults >65 years of age.

Clearance is reduced in patients with hepatic impairment.

Pharmacokinetics not affected by gender, race, or renal function.

Stability

Storage

Oral

Tablets

20–25°C; protect from light and moisture.

Actions

• Selective, competitive leukotriene-receptor antagonist.

• Binds selectively and with high affinity to a group of cysteinyl leukotriene receptors (CysLT₁) in airway smooth muscle and competitively inhibits the action of LTD₄ and LTE₄ (cysteinyl leukotrienes) at these receptors.

• Modification of leukotriene activity may be used to reduce symptoms of asthma since cysteinyl leukotrienes are especially important in the pathogenesis of asthma, causing increased mucous secretion and vascular permeability, airway edema, bronchoconstriction, and altered cellular activity associated with the inflammatory process.

• Inhibits bronchoconstriction induced by exposure to known precipitating factors (e.g., allergens, environmental pollutants, cold and/or dry air, exercise); inhibits both the acute bronchoconstrictor response and the delayed inflammatory response to inhaled antigens.

• Has essentially no affinity for α- or β-adrenergic, histamine, type-2 serotonergic, muscarinic, thromboxane, prostaglandin, and calcium-channel receptors.

Advice to Patients

• Risk of hepatotoxicity; importance of patients immediately informing their clinicians if right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, or anorexia occurs.

• Importance of taking zafirlukast at regular intervals, when asymptomatic as well as during periods of worsening asthma.

• Importance of contacting clinician if asthma is not well controlled; seek medical attention if short-acting, inhaled β₂-adrenergic bronchodilators are needed more often than usual or if more than the maximum number of inhalations for a 24-hour period are needed.

• Importance of not using zafirlukast for the relief of acute bronchospasm. Patients should be provided with and instructed in the use of a short-acting, inhaled β₂-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms.

• Importance of not discontinuing or reducing the dosage of other antiasthmatic agents unless instructed to do so by the clinician.

• If patient experiences exacerbations of asthma after exercise, necessity of continuing the usual regimen of inhaled β₂-adrenergic agonist for prophylaxis and of having a short-acting, orally inhaled β₂-adrenergic agonist available for rescue.

• Importance of informing clinicians if behavior or mood changes occur.

• Importance of informing clinicians of existing or concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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