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PAR PHARM.
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zafirlukast 10 mg tablet (generic accolate)

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Uses

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.

Asthma

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.

Allergic Rhinitis

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.

Exercise-Induced Bronchospasm

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.

Dosage and Administration

Administration

Zafirlukast is administered orally, usually in 2 equally divided doses daily. Because food generally decreases oral bioavailability of the drug, the manufacturer recommends that zafirlukast be taken on an empty stomach (i.e., at least 1 hour before or 2 hours after meals).

Dosage

For the prevention and long-term symptomatic control of asthma, the usual dosage of zafirlukast for adults and children 12 years of age or older is 20 mg twice daily.

For the prevention and long-term symptomatic control of asthma, the usual dosage of zafirlukast for children 5-11 years of age is 10 mg twice daily.

Patients should be advised that zafirlukast must be taken at regular intervals to be therapeutically effective. In addition, patients should be advised that the drug will not provide immediate symptomatic relief and should not be used for the relief of acute bronchospasm; however, zafirlukast therapy generally should be continued during acute exacerbations of asthma. Patients should not discontinue or reduce the dosage of other antiasthmatic agents, even if they feel better as a result of initiation of zafirlukast therapy, unless instructed to do so by their clinician.

Although clearance of zafirlukast is reduced in geriatric patients 65 years of age or older (See Pharmacokinetics: Elimination), the overall incidence of adverse effects or study withdrawal because of adverse effects in clinical trials was comparable in geriatric or younger patients receiving zafirlukast 20 mg twice daily, and the manufacturer makes no specific recommendations regarding alteration of zafirlukast dosage solely on the basis of age.

Dosage in Renal and Hepatic Impairment

Limited evidence in patients with stable alcoholic cirrhosis indicates that the peak plasma concentration and area under the plasma concentration-time curve (AUC) of zafirlukast are 50-60% higher in these patients relative to these pharmacokinetic values in patients with normal hepatic function. While the manufacturer currently makes no specific recommendations for adjustment of zafirlukast dosage in patients with hepatic impairment, the possibility that dosage reduction may be necessary should be considered. Zafirlukast has not been evaluated systematically in patients with hepatitis or in long-term studies in patients with cirrhosis.

Limited data suggest that renal impairment does not affect the pharmacokinetics of zafirlukast, and the manufacturer currently states that dosage adjustment in patients with renal impairment (e.g., creatinine clearance 10-30 mL/minute) is not necessary.

Cautions

Zafirlukast generally is well tolerated. Information on the safety of zafirlukast has been obtained from clinical trials principally in healthy adults 18 years of age or older and in adults with asthma; information also is available from trials in a limited number of patients 12-18 years of age. While most patients 12 years of age or older with asthma received zafirlukast in clinical trials of 6 or 13 weeks' duration, safety data also have been collected from long-term, open-label studies lasting up to 4 years. For many adverse reactions reported with zafirlukast, a causal relationship to the drug has not been established.

The incidence of serious adverse events reported with zafirlukast or placebo in controlled trials was approximately 1%. Exacerbation of asthma was the most common reason for drug discontinuance in clinical trials, necessitating withdrawal of drug therapy in about 1.6% of patients receiving zafirlukast and about 2.7% of those receiving placebo.

In general, adverse effects reported with zafirlukast therapy in controlled trials were similar in type and frequency to those reported with placebo. Headache was the most frequently reported adverse effect with zafirlukast therapy, occurring in 12.9% of adults and children 12 years of age or older and in 4.5% of children 5-11 years of age.

Infection

Infection was reported in 3.5% of patients receiving the drug in clinical trials. While the clinical importance has not been established, infection was reported more frequently with zafirlukast therapy than with placebo in patients older than 55 years of age; similar differences in the incidence of infection between zafirlukast and placebo were not observed in younger patients. In more than 8000 patients exposed to zafirlukast in North American and European short-term, placebo-controlled trials, infection in geriatric patients (65 years of age or older) was reported in 7 or 2.9% of zafirlukast- or placebo-treated patients, respectively. These infections generally involved the respiratory tract (e.g., pharyngitis, rhinitis) and were mild to moderate in intensity. The infections occurred with similar frequency in men and women and at a frequency proportional to the total drug dosage administered, and were associated with concomitant administration of orally inhaled corticosteroids.

GI Effects

Adverse GI effects such as nausea, diarrhea, abdominal pain, vomiting, or dyspepsia/gastritis were reported in 3.1, 2.8, 1.8, 1.5, or 1.3%, respectively, of patients receiving zafirlukast in controlled clinical trials.

Hepatic Effects

Elevations in the results of one or more liver enzyme tests have occurred in patients receiving zafirlukast in controlled clinical trials. Increases in ALT (SGPT) occurred in 1.5% of patients receiving zafirlukast 20 mg twice daily in clinical trials and in 1.1% of patients receiving placebo. Most cases of elevated liver enzyme test results have occurred in asymptomatic patients who were receiving zafirlukast in dosages 4 times higher than the currently recommended dosage; these results returned to normal after a variable period of time following discontinuance of zafirlukast therapy. In postmarketing experience in patients (predominantly females) receiving the recommended dosage of zafirlukast (40 mg daily), cases of liver injury (e.g., symptomatic hepatitis with or without hyperbilirubinemia that could not be attributed to other causes, and hyperbilirubinemia in the absence of other elevated liver function tests), have been reported. In most, but not all patients, liver enzyme test results returned to normal or near-normal and symptoms abated following discontinuance of zafirlukast therapy. However, in rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation, and death. Zafirlukast should be discontinued in patients with suspected hepatic dysfunction and not resumed in such patients if hepatic dysfunction is confirmed.(See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions, including urticaria, angioedema, pruritus, and rash, with or without blistering, have been reported in patients receiving zafirlukast.

Eosinophilia, vasculitic rash, eosinophilic pneumonia, worsening pulmonary symptoms, cardiac complications, and/or neuropathy consistent with Churg-Strauss syndrome have been reported rarely in patients receiving leukotriene modifiers (e.g., montelukast, pranlukast, zafirlukast); these events usually, but not always, have been associated with a reduction in the dosage of concomitantly administered oral or high-dose inhaled corticosteroid therapy. For additional details on Churg-Strauss syndrome, . Although a causal relationship to zafirlukast has not been established, clinicians should be aware of the possibility of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy occurring in patients receiving zafirlukast therapy.

Other Adverse Effects

Generalized pain or asthenia have been reported in 1.9 or 1.8%, respectively, of patients receiving zafirlukast in controlled trials. Other adverse events occurring with zafirlukast therapy include accidental injury, dizziness, myalgia, or fever in 1.6%, and back pain in 1.5% of patients. Agranulocytosis, bleeding, bruising, edema, or arthralgia also has been reported in patients receiving zafirlukast. Depression, insomnia, and malaise also have been reported in patients receiving zafirlukast. (See Cautions: Precautions and Contraindications.)

In clinical trials, zafirlukast reportedly had no appreciable effect on heart rate, blood pressure, respiration, or other vital signs compared with placebo. In addition, zafirlukast therapy was not associated with increased alterations in hematology or chemistry test results, nor was the incidence of clinically important abnormal ECG results affected.

Precautions and Contraindications

Patients should be advised that zafirlukast must be taken at regular intervals to be therapeutically effective. In addition, patients should be advised that the drug will not provide immediate symptomatic relief and should not be used for the relief of acute bronchospasm; however, zafirlukast therapy can be continued during acute exacerbations of asthma. Patients receiving zafirlukast should be provided with and instructed in the use of a short-acting, inhaled β2-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms. Patients should not discontinue or reduce the dosage of other antiasthmatic agents, even if they feel better as a result of initiation of zafirlukast therapy, unless instructed to do so by their clinician.

Although a causal relationship has not been established, clinicians should be aware of the possibility of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy occurring in patients receiving zafirlukast.(See Cautions: Dermatologic and Sensitivity Reactions.)

Elevations in the results of one or more liver enzyme tests, including cases of symptomatic hepatitis and hyperbilirubinemia without other attributable cause, have been reported with zafirlukast therapy.(See Cautions: Hepatic Effects.) Clinicians may consider the value of liver function testing. The manufacturer states that while periodic tests of liver function have not been proven to prevent serious liver injury, early detection of drug-induced hepatic injury along with immediate cessation of therapy with the suspected drug enhances the likelihood for recovery. Patients should be advised that liver dysfunction is a rare adverse effect of zafirlukast. The manufacturer states that if liver dysfunction is suspected based on clinical signs and/or symptoms (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, enlarged liver), zafirlukast should be discontinued. Patients should be alert for signs and symptoms of liver dysfunction and should contact their clinician immediately if such symptoms occur. In addition, the results of standard liver function tests should be obtained immediately and the patient managed accordingly. Ongoing clinical assessment of patients should govern clinician interventions, including diagnostic evaluations and treatment. If results of liver function tests are consistent with hepatic dysfunction, therapy with zafirlukast should not be resumed. In addition, zafirlukast should not be administered again in patients in whom the drug was discontinued because of hepatic dysfunction when no other attributable cause could be identified.

Because of postmarketing reports of neuropsychiatric events (e.g., depression, anxiety, agitation, aggressive behavior, irritability, suicidal ideation and behavior [suicidality]) in adults, adolescents, and pediatric patients, the US Food and Drug Administration (FDA) reviewed the safety of zafirlukast and other leukotriene modifiers to evaluate a possible link between the use of these agents and such behavior or mood changes. Data from placebo-controlled trials with zafirlukast, montelukast, and zileuton submitted to FDA indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of the patients treated with other leukotriene modifiers. In these studies, no completed suicide occurred during therapy with any leukotriene modifier. Following review of the postmarketing reports and analysis of available clinical data, FDA has concluded that some of the neuropsychiatric events reported during postmarketing surveillance with zafirlukast (e.g., depression, insomnia) appear consistent with a drug-induced effect. The manufacturer of zafirlukast states that patients receiving the drug and their clinicians should be alert to the potential for neuropsychiatric events. Patients should be instructed to contact their clinician if behavior or mood changes occur during therapy with zafirlukast. Clinicians should carefully evaluate the risks and benefits of continuing zafirlukast therapy in patients who develop neuropsychiatric symptoms.

Concomitant administration of zafirlukast and warfarin may result in clinically important increases in prothrombin time.(See Drug Interactions: Warfarin.) Patients receiving concurrent therapy with these drugs should have close monitoring of prothrombin times and adjustment of their anticoagulant dosage if indicated.

Zafirlukast is contraindicated in patients who have shown hypersensitivity to the drug or any other ingredient in the formulation.

Pediatric Precautions

Safety of zafirlukast has been evaluated in a number of children 5-11 years of age; some of these children received zafirlukast dosages of 10 mg twice daily in clinical trials of 6 weeks' duration, and others received the drug in an open-label extension lasting up to 1 year. The safety profile of zafirlukast in children 5 years of age and older receiving the drug in a dosage of 10 mg twice daily in clinical studies was similar to that in adults receiving zafirlukast 20 mg twice daily in clinical studies. The types of adverse effects reported in long-term studies were comparable to those reported in the short-term, controlled clinical trials. Data from postmarketing experience have not revealed differences in the safety of the drug between pediatric patients 5-11 years of age and adult patients, including the occurrence of liver dysfunction or failure. Use of zafirlukast for the management of asthma in children 5-11 years of age is supported by evidence from studies in adults and adolescents; the likelihood that the disease course, pathophysiology, and the drug's efficacy are essentially the same in the 2 populations; pharmacokinetic data in children; and the safety profile in children. Safety and efficacy of zafirlukast in children younger than 5 years of age have not been established. The effect of zafirlukast on growth of children has not been determined.

Geriatric Precautions

Clearance of zafirlukast is reduced in geriatric patients 65 years of age or older. In clinical trials, peak plasma concentration and area under the plasma concentration-time curve (AUC) were approximately 2- to 3-fold higher in these patients compared with younger patients. In geriatric patients 65 years of age or older who received zafirlukast at the usual dosage of 20 mg twice daily in clinical trials, the overall incidence of adverse effects (except for an increase in the frequency of infection) or study withdrawal because of adverse effects was comparable to that in younger patients. In an open-label study that evaluated safety and efficacy of zafirlukast 20 mg twice daily in adolescents (12-17 years of age), adults (18-65 years of age), and geriatric patients (older than 65 years of age), the overall incidence of adverse effects in geriatric individuals was higher than that in the other patient age groups; these geriatric patients also showed less improvement in efficacy measures. While infection was reported more frequently with zafirlukast therapy than with placebo in patients older than 55 years of age in overall clinical trials (see Cautions: Adverse Effects), the incidence of infection in geriatric patients in this open-label study was lower than that in the other patient age groups. The manufacturer makes no recommendations for alteration of zafirlukast dosage in geriatric patients solely on the basis of age.(See Dosage and Administration: Dosage.)

Mutagenicity and Carcinogenicity

Zafirlukast was not mutagenic in bacterial reverse mutation assays using Salmonella typhimurium or Escherichia coli, or in forward point mutation (i.e., CHO/HGPRT or mouse lymphoma) assays. In addition, no chromosome aberrations were detected in the human peripheral blood lymphocyte clastogenic assay or the rat bone marrow micronucleus assay.

Although the relevance to long-term use in humans is not known, long-term (i.e., 2 years) studies in rodents have revealed some carcinogenic potential associated with high dosages/plasma concentrations of zafirlukast. In mice receiving oral zafirlukast doses of 10, 100, or 300 mg/kg daily for 2 years, an increased incidence of hepatocellular adenomas compared with controls was found in male mice receiving the highest dosage, and an increased incidence of whole body histiocytic sarcomas compared with controls was found in female mice receiving the highest dosage. In rats receiving oral zafirlukast doses of 40, 400, or 2000 mg/kg daily for 2 years, an increased incidence of urinary bladder transitional cell papillomas compared with controls was found in male and female rats receiving the highest dosage. Zafirlukast was not tumorigenic at dietary doses up to 100 or 400 mg/kg (approximately 40 or 550 times the maximum recommended daily oral dose in adults and children based on area under the plasma concentration-time curve [AUC]) in mice or rats, respectively.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies of zafirlukast in pregnant women. No evidence of teratogenicity was seen in reproductive studies in mice using oral dosages up to 1600 mg/kg daily (about 160 times the maximum recommended adult daily dosage on a mg/m basis), in rats using oral dosages up to 2000 mg/kg daily (about 410 times the maximum recommended adult daily dosage on a mg/m basis), and in cynomolgus monkeys using oral dosages up to 2000 mg/kg daily (about 20 times the maximum recommended adult daily dose based on AUC). In rats, administration of oral zafirlukast dosages of 2000 mg/kg daily resulted in maternal toxicity and deaths and an increased incidence of early fetal resorption. In cynomolgus monkeys, zafirlukast dosages of 2000 mg/kg daily resulted in maternal toxicity and spontaneous abortions.

The manufacturer states that zafirlukast should be used during pregnancy only when clearly needed. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI) state that while leukotriene modifiers generally would not be used during pregnancy, use of zafirlukast or montelukast could be considered in patients with recalcitrant asthma who have shown a uniquely favorable response to the drugs prior to pregnancy.

Fertility

Reproductive studies in rats indicate that fertility was not adversely affected by oral zafirlukast dosages up to 2000 mg/kg daily (approximately 410 times the maximum recommended human oral daily dose on a mg/m basis).

Lactation

Zafirlukast is distributed into milk. Following multiple-dose administration of zafirlukast 40 mg every 12 hours in healthy women, concurrent steady-state drug concentrations in breast milk or plasma averaged 50 or 255 ng/mL, respectively. Because of the potential for tumorigenicity associated with administration of zafirlukast in rodent studies and enhanced sensitivity of neonatal rats and dogs to adverse effects of the drug, zafirlukast should not be administered to women who are breast feeding.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Zafirlukast inhibits hepatic microsomal P-450 isoenzymes CYP3A4 and CYP2C9, and concomitant administration of drugs metabolized by these enzymes may potentially result in increased plasma concentrations of such drugs.

Warfarin

Concomitant administration of zafirlukast and warfarin may result in substantially increased plasma concentrations of s-warfarin (the pharmacologically more active enantiomer) because of inhibition of the P-450 CYP2C9 isoenzyme by zafirlukast. Administration of a single 25-mg dose of warfarin following achievement of steady-state plasma zafirlukast concentrations in healthy men receiving zafirlukast 160 mg daily (4 times the recommended daily dose) increased the mean area under the plasma concentration-time curve (AUC) and mean elimination half-life of s-warfarin by 63 and 36%, respectively, and increased the mean prothrombin time (PT) by 35%. Because warfarin has a narrow therapeutic margin, prothrombin time (preferably using the INR) should be determined frequently and appropriate adjustment of warfarin dosage made in patients receiving concomitant zafirlukast therapy.

Antihistamines

Concomitant administration of terfenadine (no longer commercially available in the US) (60 mg twice daily), which is metabolized by P-450 isoenzyme CYP3A4, and high doses of zafirlukast (320 mg daily) resulted in average reductions of 66 and 54% in zafirlukast steady-state peak plasma concentration and AUC, respectively; terfenadine plasma concentrations were not affected and ECG parameters (i.e., QTc interval) were unaltered. However, specific pharmacokinetic drug interaction studies examining potential interactions between zafirlukast and other drugs metabolized by P-450 isoenzyme CYP3A4 (e.g., astemizole [no longer commercially available in the US], cisapride, cyclosporine, dihydropyridine calcium-channel blocking agents) are not available, and patients receiving such concomitant therapy should be monitored appropriately for potential adverse effects and/or alterations in therapeutic response.

Erythromycin

Concomitant administration of zafirlukast and erythromycin may reduce the bioavailability of zafirlukast; the mechanism for and the clinical importance of this finding are unknown, and data on possible interactions with other macrolides currently are not available. Administration of a single 40-mg dose of zafirlukast in a limited number of asthmatic patients receiving erythromycin 500 mg 3 times daily for 5 days resulted in a 40% decrease in mean plasma concentrations of zafirlukast.

Other Drugs

Although specific pharmacokinetic drug interaction studies are not available, patients receiving zafirlukast with other drugs metabolized by P-450 isoenzyme CYP2C9 (e.g., carbamazepine, phenytoin, tolbutamide) should be monitored for potential adverse effects associated with such concomitant therapy.

Antiasthmatic Agents

Administration of a single dose of theophylline 6 mg/kg (as liquid) in asthmatic patients (18-44 years of age) with steady-state plasma zafirlukast concentrations while receiving zafirlukast 80 mg daily resulted in a 30% decrease in mean plasma concentrations of zafirlukast, but did not affect plasma theophylline concentrations. Administration of a single 16-mg/kg dose of sustained-release theophylline in healthy children (6-11 years of age) receiving zafirlukast 20 mg daily (at steady state) did not affect the pharmacokinetic parameters of theophylline. Substantial increases in serum theophylline concentrations, sometimes accompanied by clinical signs or symptoms of theophylline toxicity, have been reported rarely in patients receiving long-term theophylline therapy following addition of zafirlukast to the regimen. The mechanism of this drug interaction is unknown.

No evidence of clinically important drug interactions between zafirlukast and inhaled or oral corticosteroids, inhaled or oral β-adrenergic agonist bronchodilators, or antihistamines has been observed in clinical studies.

Aspirin

Concomitant administration of zafirlukast (40 mg daily) and aspirin (650 mg 4 times daily) for 3 days was associated with an average increase of 45% in zafirlukast plasma concentrations. While the mechanism and clinical importance of this interaction remain to be determined, the increase in plasma zafirlukast concentration appears to be related to the duration of aspirin therapy.

Oral Contraceptives

In a 3-week study in healthy women receiving an ethinyl estradiol-containing oral contraceptive agent (fixed-dose, estrogen-progestin combination), administration of zafirlukast (40 mg twice daily) was not associated with clinically important changes in plasma ethinyl estradiol concentrations. In addition, administration of zafirlukast did not appear to affect contraceptive efficacy in these women.

Pharmacokinetics

The pharmacokinetics of zafirlukast have been studied in healthy adults, adults with asthma, and children 7-11 years of age. Available data suggest that the pharmacokinetics of the drug are similar in healthy individuals and patients with asthma. In addition, the pharmacokinetics of zafirlukast are not affected by gender, race, or renal function. Limited data indicate that the pharmacokinetics of the drug are affected by advanced age and hepatic function.

Absorption

Zafirlukast is rapidly absorbed from the GI tract, with peak plasma drug concentrations generally occurring within 3 hours (range: 1.5-6 hours) following single oral doses of 5-80 mg. The absolute bioavailability of zafirlukast has not been determined. Peak plasma concentrations reportedly are proportional to dose in individuals receiving single oral zafirlukast dosages of 5-50 mg. Following oral administration of a single 20-mg dose of zafirlukast in healthy men, peak plasma concentrations of the drug averaged 326 ng/mL and were achieved at 2 hours (range: 0.5-5 hours). Following administration of a single 40-mg dose of zafirlukast in patients with asthma, peak plasma drug concentrations reportedly averaged 568 ng/mL and were achieved at 2.5 hours (range: 2-5 hours). In asthmatic patients receiving zafirlukast 40 mg twice daily (twice the currently recommended daily dosage) for 14 days, peak plasma zafirlukast concentrations averaged 655 ng/mL at 2 hours (range: 1-2 hours). Steady-state plasma zafirlukast concentrations average about 1.2-1.4 times those achieved with single doses and are reached within 3 days when the drug is given twice daily. Accumulation of zafirlukast in plasma following administration twice daily is about 45%.

Following oral administration of a single 20-mg dose of zafirlukast in children 5-6 or 7-11 years of age, peak plasma zafirlukast concentrations averaged 756 or 601 ng/mL, respectively, and were achieved at 2.1 or 2.5 hours, respectively. Systemic exposure as determined by mean area under the plasma concentration-time curve (AUC) is greater in children than in adults receiving the same zafirlukast dose, reflecting decreased clearance of the drug in children relative to adults. Accumulation of zafirlukast in plasma following administration of multiple doses in children is similar to that observed in adults; disposition of zafirlukast following multiple doses is similar to that following a single dose.

Limited data suggest that the therapeutic effects of zafirlukast (e.g., as determined by improvements in asthma symptoms and/or lung function test results, decreased use of β-agonist bronchodilators) are evident within 3-14 days after initiation of therapy.

In a limited number of patients with stable alcoholic cirrhosis, peak plasma concentrations and AUC of zafirlukast reportedly were increased by 50-60% compared with those values in healthy individuals receiving the drug. In addition, in patients 5-11 years of age and those older than 65 years of age, plasma clearance of zafirlukast is decreased and dose-normalized peak plasma concentrations and AUC are increased. In geriatric asthmatic men 65-78 and geriatric asthmatic women 66-75 years of age, peak plasma concentration and AUC averaged 2- to 3-fold greater than in younger patients.(See Elimination.)

The presence of food in the GI tract alters zafirlukast bioavailability. Although bioavailability of zafirlukast reportedly has been enhanced in some individuals receiving the drug with food (possibly as a result of intraindividual variability), administration with food generally reduces the rate and extent of zafirlukast absorption, and the manufacturer recommends that the drug be given on an empty stomach.(See Dosage and Administration: Administration.) Bioavailability was decreased by an average of 40% when zafirlukast was administered with a high-fat or -protein meal.

Distribution

Distribution of zafirlukast into body tissues and fluids has not been fully characterized. Zafirlukast is about 99% bound to plasma proteins, predominantly albumin, over a concentration range of 0.25-10 mcg/mL.

It is not known whether zafirlukast crosses the placenta in humans; limited placental transfer of the drug (4-18% of maternal plasma concentrations) reportedly has been demonstrated in rats and mice. Zafirlukast is distributed into human milk. Following administration of zafirlukast 40 mg every 12 hours for 5 days (total of 9 doses) in healthy women, concurrent steady-state drug concentrations in breast milk and plasma averaged 50 and 255 ng/mL, respectively.

Elimination

The elimination half-life of zafirlukast ranges from 8-16 hours. Plasma concentrations of zafirlukast appear to decline in a biphasic manner after oral administration of the drug. The apparent oral clearance of zafirlukast in adults or children 7-11 years of age is about 20 or 11.4 L/hour, respectively.

The metabolic fate of zafirlukast has not been fully determined, but the drug is extensively metabolized in the liver. One metabolic pathway identified reportedly involves hydrolysis of the ester-amide linkage at the 5-aminoindole position, followed by N-acetylation, demethylation of the indole nitrogen, and hydroxylation at one or more sites on the molecule. In vitro studies indicate that the microsomal cytochrome P-450 isoenzyme CYP2C9 is the major enzyme involved in formation of the hydroxylated metabolites of zafirlukast. The metabolites of zafirlukast found in plasma are 90 times less potent than the parent drug in vitro as leukotriene receptor antagonists.

Zafirlukast is excreted principally in feces, both as unchanged drug and metabolites. Following oral administration of radiolabeled zafirlukast, approximately 10% of administered radioactivity is recovered in urine and the remainder excreted in feces. Three hydroxylated metabolites account for about 65% of radioactivity recovered in feces. Unchanged zafirlukast is not detected in urine.

Limited data indicate that the pharmacokinetics of zafirlukast are not altered, and dosage adjustment is not required, in patients with renal impairment. In addition, although plasma concentrations and AUC are increased in some patients older than 65 years of age and some with hepatic cirrhosis (see Absorption), there are no specific recommendations for adjustment of zafirlukast dosage in geriatric patients or in patients with hepatic impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

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