Information for the Patient
Accolate
Pharmacology
Absorption: Zafirlukast is rapidly absorbed following oral administration. The absolute bioavailability of zafirlukast is unknown. Peak plasma concentrations are achieved 3 hours after dosing. In 2 separate studies, one using a high fat and the other a high protein meal, administration of zafirlukast with food reduced the mean bioavailability by approximately 40%.
Plasma Kinetics and Disposition: The mean terminal elimination half-life of zafirlukast is approximately 10 hours in both normal subjects and patients with asthma. Steady-state plasma concentrations of zafirlukast are proportional to the dose and predictable from single dose pharmacokinetic data. In the concentration range of 0.25 to 10 µg/mL, zafirlukast is >99% bound to plasma proteins, predominantly albumin.
Biotransformation: Zafirlukast is extensively metabolized. Following oral administration of a radiolabeled dose, urinary excretion accounts for approximately 10% of the dose and the remainder is excreted in feces. Unmetabolized zafirlukast is not detected in urine. In vitro studies using human liver microsomes showed that the hydroxylated metabolites of zafirlukast are formed through the cytochrome P450 2C9 (CYP2C9) enzyme pathway. Additional in vitro studies utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved plasma concentrations. The metabolites of zafirlukast found in plasma are at least 90 times less potent as LTD4 receptor antagonists than zafirlukast in a standard in vitro test of activity.
Special Populations: Elderly: Cross-study comparisons in patients ranging from 7 years to greater than 65 years of age show that mean dose (mg/kg) normalized AUC and Cmax increase and plasma clearance (CL) decreases with increasing age. In patients above 65 years of age, there is an approximately 2-3 fold greater Cmax and AUC compared to young adult patients.
Hepatic Impairment: In a study of patients with hepatic impairment (biopsy-proven cirrhosis), there was a 50 to 60% greater Cmax and AUC compared to normal subjects.
Renal Impairment: Based on a cross-study comparison, there are no apparent differences in the pharmacokinetics of zafirlukast between renally impaired patients and normal subjects.
In these trials, improvement in asthma symptoms occurred within 1 week of initiating treatment with zafirlukast. The role of zafirlukast in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as-needed, inhaled β2-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.
In a second and smaller study, the effect of zafirlukast on most efficacy parameters was comparable to the active control (inhaled sodium cromoglycate 1600 µg 4 times/day) and superior to placebo at endpoint for decreasing rescue β-agonist use. See Figure 1.
Indications
For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
Zafirlukast should be considered to be an add-on therapy following initial management with an “as needed” short-acting beta-agonist, an inhaled corticosteroid, or inhaled corticosteroid together with a long-acting beta agonist in patients who continue to experience asthma symptoms.
The clinical decision to use zafirlukast must be based on assessing its risks and benefits for each individual patient.
Precautions
Zafirlukast may be administered with other therapies routinely used in the management of asthma and allergy. Examples of agents which have been coadministered with zafirlukast without adverse interaction include inhaled steroids, inhaled and oral bronchodilator therapy, antihistamines and antibiotics.
Coadministration with:
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erythromycin will result in decreased plasma levels of zafirlukast. In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg 3 times daily for 5 days) to steady-state resulted in decreased mean plasma levels of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability.
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ASA (e.g., Aspirin) may result in increased plasma levels of zafirlukast. Coadministration of zafirlukast (40 mg/day) with ASA (650 mg 4 times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%.
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theophylline may result in decreased plasma levels of zafirlukast, without effect on plasma theophylline levels. Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed. Paradoxically, postmarketing surveillance revealed rare cases of patients experiencing increased theophylline levels (with or without theophylline toxicity symptoms) when zafirlukast was coadministered. The mechanism of action for this interaction is unknown.
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terfenadine decreases zafirlukast AUC, but has no effect on plasma terfenadine levels. In a drug interaction study in 16 healthy male volunteers, coadministration of zafirlukast (320 mg/day), with terfenadine (60 mg twice daily) to steady-state resulted in a decrease in the mean Cmax (-66%) and AUC (-54%) of zafirlukast. No effect of zafirlukast on terfenadine plasma concentrations or ECG parameters (i.e., QTc interval) was seen. No formal drug-drug interaction studies between zafirlukast and other drugs known to be metabolized by the P450 3A4 (CYP 3A4) isoenzymes have been conducted (see Cytochrome P450 Enzyme Inhibition).
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warfarin increases in prothrombin time by approximately 35%. In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see Warnings).
Oral contraceptives may be administered with zafirlukast without adverse interaction. In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy.
Cytochrome P450 Enzyme Inhibition: Aside from warfarin and terfenadine, no formal zafirlukast drug-drug interaction studies have been conducted with other drugs known to be metabolized by cytochrome P450 isoenzymes. However, care should be exercised when zafirlukast is coadministered with metabolised drugs such as: tolbutamide, phenytoin, carbamazepine (isozyme 2C9); dihydropyridine calcium channel blockers, cyclosporine, cisapride, astemizole (isozyme CYP 3A4).
A total of 8094 patients were exposed to zafirlukast in North American and European short-term placebo-controlled clinical trials. Of these, 243 patients were elderly (age 65 years and older). No overall difference in adverse events was seen in the elderly patients, except for an increase in the frequency of infection among zafirlukast treated elderly patients compared to placebo treated elderly patients (7.0% vs 2.9%). The infections were not severe, occurred mostly in the lower respiratory tract, and did not necessitate withdrawal of therapy.
An open-label, uncontrolled, 4-week trial of 3759 asthma patients compared the safety and efficacy of zafirlukast 20 mg given twice daily in 3 patient age groups, adolescents (12 to 17 years), adults (18 to 65 years), and elderly (greater than 65 years). A higher percentage of elderly patients (n=384) reported adverse events when compared to adults and adolescents. These elderly patients showed less improvement in efficacy measures. In the elderly patients, adverse events occurring in greater than 1% of the population included headache (4.7%), diarrhea and nausea (1.8%) and pharyngitis (1.3%). The elderly reported the lowest percentage of infections of all three age groups in this study.
Zafirlukast is excreted in human breast milk. Following repeated 40 mg twice-a-day dosing in healthy women, average steady-state concentrations of zafirlukast in breast milk were 50 ng/mL compared to 255 ng/mL in plasma. Because of the potential for tumorigenicity shown for zafirlukast in mouse and rat studies and the enhanced sensitivity of neonatal rats and dogs to the adverse effects of zafirlukast, Accolate should not be administered to mothers who are breast-feeding.
Zafirlukast bioavailability may be altered when taken with a meal (see Pharmacology, Pharmacokinetics).
Zafirlukast should be taken regularly as prescribed, even during symptom-free periods. Zafirlukast therapy can be continued during acute exacerbations of asthma.
Zafirlukast is not a bronchodilator and should not be used to treat acute episodes of asthma.
Patients receiving zafirlukast should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician.
The safety of zafirlukast in human pregnancy has not been established. The potential risks should be weighed against the benefits of continuing therapy during pregnancy; zafirlukast should be used only if clearly needed.
No teratogenicity was observed in the following species for the given oral doses (the approximate equivalence to the maximum recommended human daily oral dose on a mg/m2 basis is given in brackets): mice 1600 mg/kg/day (160 times); rats 2000 mg/kg/day (400 times); cynomolgus monkeys 2000 mg/kg/day (800 times).
At these doses, maternal toxicity was manifested in rats (as deaths and increased incidence of early fetal resorption), and cynomolgus monkeys (as spontaneous abortions). There are no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, zafirlukast should be used during pregnancy only if clearly needed.
Caution is required in treating patients with severe asthma when steroid reduction is being considered. In rare cases, patients on zafirlukast therapy may present with systemic eosinophilia, eosinophilic pneumonia or clinical features of systemic vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Presentations may involve various body systems including vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between zafirlukast and these underlying conditions has not been established (see Adverse Effects).
The efficacy and safety of zafirlukast in children under 12 years have not been established.
Carcinogenesis and Mutagenicity: In 2-year oral carcinogenicity studies, zafirlukast was administered at daily doses of 10 to 300 mg/kg to mice and 40 to 2000 mg/kg to rats. At 300 mg/kg/day male mice had an increased incidence of hepatocellular adenomas and female mice showed an increased incidence of whole body histocytic sarcomas as compared to concurrent controls. The plasma concentrations at these tumorigenic doses were approximately 220 times maximum recommended human daily oral dose. Male and female rats given 2000 mg/kg/day had an increased incidence of urinary bladder transitional cell papillomas as compared to concurrent controls. The plasma concentrations at these tumorigenic doses were approximately 200 times the plasma concentrations in humans at the maximum recommended human daily oral dose. The data for both the mouse and rat demonstrate: large safety margins, a clear threshold over the no-effect level, and findings that are applicable or restricted to only one species. Further, zafirlukast has no evident genotoxic potential. The bladder tumor induction seen in rats and liver tumor induction seen in mice are therefore unlikely to be relevant to humans.
No mutagenic potential was evident in point mutation assays or chromosomal aberrations clastogenic assays.
Reproduction and Fertility: Reproduction and fertility studies in rats showed no effect on fertility due to zafirlukast at doses up to 2000 mg/kg (approximately 400 times the maximum recommended human daily oral dose on mg/m2 basis). In the 1-year toxicity studies in dogs, zafirlukast produced an increase in absolute and relative uterine and ovarian weights at an oral dose of 150 mg/kg, resulting in approximately 85 times the systemic exposure (AUC0-12h) in humans at the maximum recommended human oral daily dose.
Supplied
Each white to off-white, round, biconvex, film-coated, intagliated tablet contains: zafirlukast 20 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and titanium dioxide. Calendar packs of 60. Store between 15 and 30°C.
Contraindications
Zafirlukast is contraindicated in patients who have previously experienced hypersensitivity to the product or any of its ingredients.
Zafirlukast is also contraindicated in patients with hepatic impairment including hepatic cirrhosis and patients in whom zafirlukast is discontinued due to hepatotoxicity where no other attributable cause is identified.
Warnings
Zafirlukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus.
Warfarin Interaction: Warfarin coadministration with zafirlukast produces clinically significant increases in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see Precautions, Drug Interactions).
Hepatic Effects: Clinical Trials: Rarely, elevations of one or more liver enzymes have occurred in patients receiving zafirlukast in controlled clinical trials. In clinical trials, most of these cases have been observed in asymptomatic patients at doses four times higher than the recommended dose.
Post-Marketing Experience: The reporting rates of adverse events from the post-marketing experience are generally considered to significantly underestimate the incidence of the events.
Elevations in serum transaminases can occur during treatment with zafirlukast. These were usually asymptomatic and transient but could represent early evidence of hepatotoxicity and have very rarely (less than 1 case/10 000 patient years) been associated with more severe hepatocellular injury, fulminant hepatitis and liver failure resulting in some cases of liver transplantation and death. In some post-marketing cases of more severe hepatic injury, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede these observations. The following hepatic events (which have occurred predominantly in females) have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of zafirlukast (40 mg/day): very rare (less than 1 case/10 000 patient years) cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and very rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all, post-marketing reports, the patient's symptoms abated and the liver enzymes returned to normal or near normal after stopping zafirlukast.
In very rare (less than 1 case/100 000 patient years) cases, patients have progressed to fulminant hepatitis and/or hepatic failure despite early detection of liver enzyme elevations or signs and symptoms and/or discontinuation of zafirlukast.
Table 2 lists the number and the main outcomes of post-marketing reports of specific hepatic events in patients receiving zafirlukast through 23 December 2003 only and is not an illustration of any causality assessments of these outcomes. The reports are listed irrespective of pre-existing conditions and/or of concomitant therapies that may have contributed to the outcomes.
Table 2: AccolateNumber and Main Outcomes of Post-Marketing Reports of Specific Hepatic Events in Patients Receiving Accolate through 23 December 2003 | Type of Hepatic Event | Number of Reports | Recovered | Resolving/Not fully recovered at the time of the report | Death | Transplant | Unknown |
| Liver Failurea | 14 | 2 | 4 | 5 | 2 (1 died) | 1 |
| Hepatitisb | 46 | 16 | 22 | 1 | 0 | 7 |
| Other significant liver dysfunction | 59 | 20 | 20 | 1 | 0 | 18 |
a. Includes 3 reports of fulminant hepatitis that progressed to liver failure; Two of these patients have died and one was not fully recovered at the time of the report.
b. Hepatitis includes: hepatitis, hepatitis acute, hepatitis cholestatic, possible autoimmune hepatitis, hepatitis chronic active and chronic hepatitis.
For all patients who are to be treated with zafirlukast, serum transaminase testing should be done at baseline and periodically during the treatment. However, note that periodic serum transaminase testing has not proven to prevent idiosyncratic liver injury. Particular caution should be used when patients are using a combination of zafirlukast and concomitant medications known to be hepatotoxic. Such patients should be closely monitored for possible hepatotoxicity.
It is important that physicians be informed and subsequently inform their patients to be alert to the signs and symptoms of hepatic injury [e.g., right upper quadrant abdominal pain (enlarged liver), nausea, vomiting, fatigue, lethargy, pruritus, jaundice, “flu-like” symptoms, anorexia, dark urine, discoloured and/or pale stools], and to seek immediate medical attention if these signs or symptoms develop. The appearance of signs and symptoms of hepatotoxicity or development of abnormal aminotransferase and/or bilirubin levels while on treatment is an indication for immediate termination of zafirlukast treatment and close monitoring of patient. The serum transaminases, in particular serum ALT, should be measured immediately and the patient managed accordingly. In very rare (less than 1 case/100 000 patient years) cases, patients have progressed to fulminant hepatitis and/or hepatic failure despite early detection of liver enzyme elevations or signs and symptoms and/or discontinuation of zafirlukast. If liver function tests are consistent with hepatic dysfunction, zafirlukast therapy should not be resumed. Patients in whom zafirlukast is discontinued due to hepatotoxicity where no other attributable cause is identified, should not be re-exposed to zafirlukast. Zafirlukast is contraindicated for patients with hepatic impairment including hepatic cirrhosis (see Contraindications).
Adverse Effects
The safety database for zafirlukast consists of more than 4000 healthy volunteers and patients who received zafirlukast, of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received zafirlukast for 1 year or longer. The majority of the patients were 18 years of age or older; however 222 patients between the age of 12 and 18 years received zafirlukast. A comparison of adverse events reported by ≥1% of zafirlukast-treated patients, and at rates numerically greater than in placebo-treated patients, is shown for all trials in Table 3.
Table 3: AccolateComparison of Adverse Events Reported by ≥1% of Zafirlukast-treated Patients vs Placebo-treated Patients | | Accolate | Placebo |
| Number of Patients | 4058 | 2032 |
| Adverse Event | (%) | (%) |
| Headache | 12.9 | 11.7 |
| Infection | 3.5 | 3.4 |
| Nausea | 3.1 | 2.0 |
| Diarrhea | 2.8 | 2.1 |
| Pain (Generalized) | 1.9 | 1.7 |
| Asthenia | 1.8 | 1.6 |
| Abdominal Pain | 1.8 | 1.1 |
| Accidental Injury | 1.6 | 1.5 |
| Dizziness | 1.6 | 1.5 |
| Myalgia | 1.6 | 1.5 |
| Fever | 1.6 | 1.1 |
| Back Pain | 1.5 | 1.2 |
| Vomiting | 1.5 | 1.1 |
| ALT Elevation | 1.5 | 1.1 |
| Dyspepsia | 1.3 | 1.2 |
Liver Enzymes: Rarely, elevations of one or more liver enzymes have occurred in patients receiving zafirlukast in controlled clinical trials. In clinical trials, most of these cases have been observed in asymptomatic patients at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from post-marketing adverse event surveillance of patients (total exposure of more than 1.9 million patient years) who have received the recommended dose of zafirlukast (40 mg/day): very rare (less than 1 case/10 000 patient years) cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and very rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all, post-marketing reports, the patient's symptoms abated and the liver enzymes returned to normal or near normal after stopping zafirlukast. In very rare (less than 1 case/100 000 patient years) cases, patients have progressed to fulminant hepatitis and/or hepatic failure in some cases resulting in liver transplantation and/or death (see Warnings).
Infections and Age: In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. A similar finding was not observed in other age groups studied. These infections were mostly mild or moderate in intensity and predominantly affected the respiratory tract. Infections occurred equally in both sexes, were dose-proportional to total mg of zafirlukast exposure, and were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown.
Eosinophilic Conditions: In rare cases, patients on zafirlukast therapy may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between zafirlukast and these underlying conditions has not been established (see Precautions).
Hypersensitivity Reactions: Rarely, cases of hypersensitivity reactions including urticaria, angioedema and rashes, with or without blistering, have been reported in association with zafirlukast therapy. These events usually resolved following cessation of therapy.
Hematological Disorders: Rarely, bruising and bleeding disorders (including thrombocytopenia, haemoptysis, haematemesis, haemorrhage and rectal bleeding), and very rarely agranulocytosis and neutropenia have been reported in association with zafirlukast. These events usually resolved after cessation of therapy.
Edema: Cases of edema (uncommon) have been reported. The condition usually resolved after zafirlukast was discontinued.
Arthralgia and Myalgia: Rare cases of nonspecific arthralgia and nonspecific myalgia have been reported. The condition usually improved following discontinuation of zafirlukast.
Other: The following have also been reported in association with the administration of zafirlukast: Insomnia, malaise (common); pruritus (uncommon). These events have usually resolved following cessation of therapy.
Overdose
No deaths occurred at oral zafirlukast doses of 2000 mg/kg in mice (approximately 200 times the maximum recommended human daily oral dose on a mg/m2 basis), 2000 mg/kg in rats (approximately 400 times the maximum recommended human daily oral dose on a mg/m2 basis), and 500 mg/kg in dogs (approximately 330 times the maximum recommended human daily oral dose on a mg/m2 basis).
Reports of overdose with zafirlukast have been received. In reports with excessive zafirlukast doses, no significant symptoms have been observed. It is reasonable to employ the usual supportive measures in the event of an overdose; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
Dosage
The clearance of zafirlukast is reduced in patients 65 years of age and older such that Cmax and AUC are approximately 2- to 3-fold greater than those of younger patients. However, accumulation of zafirlukast is not evident in elderly patients.
No overall difference in adverse events was seen in the elderly patients, except for an increase in the frequency of infection among zafirlukast-treated elderly patients compared to placebo-treated elderly patients (7.0% vs 2.9%). The infections were not severe, occurred mostly in the lower respiratory tract and did not necessitate withdrawal of therapy (see also Precautions and Pharmacology).
The safety and efficacy in children under 12 years have not been established.
Renal Impairment: Dosage adjustment is not required in patients with renal impairment.
Hepatic Impairment: Zafirlukast is contraindicated in patients with hepatic impairment, including hepatic cirrhosis.
The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that Cmax and AUC are approximately 50 to 60% greater than those of normal adults.
