Zafirlukast is used in the management of asthma. Zafirlukast also has been evaluated for the management of allergic rhinitis and for the prevention of exercise-induced bronchospasm.
Zafirlukast is used for the prevention and long-term symptomatic management of asthma.
Zafirlukast is not a bronchodilator and should not be used to relieve symptoms of acute asthma, including status asthmaticus; however, therapy with the drug generally should be continued during acute asthmatic attacks. All patients receiving zafirlukast should be provided with a short-acting, orally inhaled sympathomimetic agent (e.g., albuterol) to use as supplemental therapy for acute symptoms that may occur despite zafirlukast therapy. Patients receiving zafirlukast should be cautioned not to decrease the dose of, or discontinue therapy with, other antiasthma drugs unless instructed to do so by a clinician.
Mild Persistent Asthma
Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma). When control of symptoms deteriorates in patients with intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), current asthma management guidelines and most clinicians recommend initiation of an anti-inflammatory agent, preferably with a low-dose orally inhaled corticosteroid (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma, supplemented by as-needed use of a short-acting, inhaled β2-agonist. Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include certain leukotriene modifiers (i.e., zafirlukast, montelukast), extended-release theophylline (in adults and children older than 5 years of age), or mast-cell stabilizers (e.g., cromolyn, nedocromil [preparation for oral inhalation no longer commercially available in the US]), but these agents are less effective and generally not preferred as initial therapy. Limited evidence suggests that zafirlukast may be considered for maintenance therapy in young children with mild persistent asthma when inhaled corticosteroid delivery is suboptimal as a result of poor technique or adherence.
Moderate Persistent Asthma
According to current asthma management guidelines, therapy with a long-acting inhaled β2-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β2-agonist treatment. However, the National Asthma Education and Prevention Program recommends that the beneficial effects of long-acting inhaled β2-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.
Current asthma management guidelines also that that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents). Alternative, but less effective therapies that may be added to a low dosage of inhaled corticosteroid include oral extended-release theophylline or certain leukotriene modifiers (i.e., zafirlukast, montelukast). Considerations favoring these leukotriene modifiers in 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. Limited data are available in infants and children 11 years of age or younger with moderate persistent asthma, and recommendations of care are based on expert opinion and extrapolation from studies in adults. According to current asthma management guidelines, a long-acting inhaled β2-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., zafirlukast, montelukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy in children 5-11 years of age. Because comparative data establishing relative efficacy of these agents in this age group are lacking, there is no clearly preferred agent for use as adjunctive therapy with a low-dose inhaled corticosteroid for treatment of asthma in these children.
Severe Persistent Asthma
Maintenance therapy with an inhaled corticosteroid at medium dosages (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate in adults and adolescents or 176 but not more than 352 mcg of the drug [or its equivalent] in children 5-11 years of age daily via a metered-dose inhaler) or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug [or its equivalent] in children 5-11 years of age daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β2-agonist is the preferred treatment according to current asthma management guidelines in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week). Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in older children and adults. Alternatives to a long-acting inhaled β2-agonist for severe persistent asthma in patients 5 years of age or older receiving medium-dose inhaled corticosteroids include certain leukotriene modifiers (i.e., zafirlukast, montelukast) or extended-release theophylline, but these therapies are generally not preferred. Omalizumab may be considered in adults and adolescents with severe persistent asthma with an allergic component who are inadequately controlled with high-dose inhaled corticosteroids and a long-acting β2-agonist. In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β2-agonist or montelukast is the only preferred treatment according to current asthma management guidelines. Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in adolescents and adults. For additional details on the stepped-care approach to drug therapy in asthma, and .
Clinical Experience with Zafirlukast
Current data indicate that leukotriene modifiers such as zafirlukast generally produce modest improvements in pulmonary function, diminish asthma symptoms, and decrease the need for supplemental, short-acting β2-adrenergic agonist therapy in patients with mild to moderate persistent asthma. Efficacy of zafirlukast has been established in a limited number of clinical trials in patients 12 years of age or older with mild to moderate persistent asthma (i.e., a baseline forced expiratory volume in 1 second [FEV1] averaging 75% of the predicted normal value and an inhaled, short-acting β2-adrenergic agonist [e.g., albuterol] requirement averaging 4-5 puffs daily) who generally received zafirlukast for 13 weeks. Patients enrolled in these studies had an FEV1 of at least 55% of the predicted value, demonstrated bronchial hyperresponsiveness, and were symptomatic. In these trials, zafirlukast was more effective than placebo in alleviating respiratory symptoms (i.e., daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms), improving pulmonary function (as measured by FEV1 and morning peak expiratory flow rate [PEFR]), and reducing the need for supplemental therapy with orally inhaled sympathomimetic agents (e.g., albuterol). Limited data from clinical trials indicate that patients who respond to zafirlukast generally experience improvement in asthma symptoms within the first week (range: 3-14 days) of therapy.
In a randomized, placebo-controlled study in 762 patients with mild to moderate asthma who were allowed to receive an orally inhaled β-adrenergic agonist (albuterol) on an as-needed basis, therapy with zafirlukast (20 mg twice daily) reportedly was associated with greater improvement than placebo in daytime asthma symptom scores, fewer nighttime awakenings per week, and fewer mornings per week with asthma symptoms. Approximately 60% of patients in this study responded to therapy with zafirlukast; response was defined as a reduction of at least 50% in asthma symptom score, nighttime awakenings, or mornings with asthma, without a 50% increase in inhaled β-agonist use; a 30% improvement in morning or evening PEFR without a 50% increase in inhaled β-agonist use; or a 50% reduction in inhaled β-agonist use. Compared with baseline values, reductions in asthma symptom scores (on a scale of 0 to 3) averaged 0.44 or 0.25 for zafirlukast or placebo, respectively, nighttime awakenings per week were reduced by 1.27 or 0.43, respectively, and mornings per week with asthma symptoms were reduced by 1.32 or 0.75, respectively. Zafirlukast produced modest improvements in pulmonary function compared with baseline values in this study, with increases in FEV1 and morning PEFR averaging 0.15 L or 22 L/minute, respectively. Zafirlukast therapy also enabled a reduction averaging about 1.2 puffs/day in the use of supplemental orally inhaled albuterol. In an analysis involving a subset of 146 patients from this study, therapy with zafirlukast (20 mg twice daily) and intermittent use of orally inhaled albuterol was associated with 89% more days without symptoms (7 versus 3.7 days per month), 89% more days without β2-adrenergic agonist use (11.3 versus 6 days per month), and 98% more days without episodes of asthma (10.1 versus 5.1 days per month) than intermittent use of orally inhaled albuterol alone. In addition, zafirlukast therapy was associated with 55% fewer health-care contacts (e.g., clinician's office visits) and 55% fewer days of asthma-related absenteeism from work or school.
In a placebo-controlled, dose-ranging study in patients with mild to moderate asthma who received zafirlukast 10, 20, or 40 mg daily in 2 divided doses, therapy with zafirlukast 40 mg daily was consistently more effective than placebo or lower dosages of zafirlukast in improving daytime asthma symptom scores and reducing nighttime awakenings and morning asthma symptoms. Zafirlukast 40 mg daily also produced improvements in FEV1 and evening PEFR averaging 11 and 4%, respectively, and enabled a reduction of about 1 puff/day in the use of supplemental orally inhaled albuterol. Treatment failure, defined as the requirement of additional therapy or hospitalization to improve pulmonary function or control asthma symptoms, occurred in less than 10% of patients in the study and was less common with zafirlukast therapy than with placebo; no treatment failures occurred in patients receiving zafirlukast 40 mg daily.
Limited data from a few comparative studies suggest that zafirlukast (20 mg twice daily) and orally inhaled cromolyn sodium (1600 mcg 4 times daily) are comparable in efficacy and safety in patients with mild to moderate persistent asthma. The efficacy of zafirlukast in the long-term treatment of asthma has not been compared directly with that of orally inhaled corticosteroids; however, improvements in FEV1 reported with inhaled corticosteroids generally have been greater than those reported with zafirlukast therapy. In addition, whether zafirlukast therapy reduces the requirements for long-term inhaled corticosteroids has not been established in controlled studies. Limited data suggest that the efficacy of zafirlukast is maintained during long-term therapy (e.g., 1 year or longer) with the drug, and some patients have received therapy for up to 4 years. Additional study and experience are needed to clarify long-term benefits and risks of the drug in patients with asthma.
Zafirlukast has been used in a limited number of patients with seasonal allergic rhinitis. In a placebo-controlled, dose-finding study, patients with a history of allergic rhinitis who received single 20- or 40-mg oral doses of zafirlukast prior to environmental exposure to ragweed pollen experienced reduced nasal congestion, sneezing, and rhinorrhea compared with the placebo group.
Limited data suggest that zafirlukast may attenuate decreases in FEV1 associated with exercise-induced bronchospasm in patients with asthma when administered orally or by oral inhalation.