Leukotriene Receptor Antagonist
Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with asthma were found in 1 study to be 25 to 100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of 3 leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early- and late-phase response and the nonspecific hyperresponsiveness. In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.
Clinical Studies: Three double-blind, randomized, placebo-controlled, 13-week clinical trials in 1 380 patients with mild to moderate asthma demonstrated that zafirlukast improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue b2-agonist use, FEV1, and morning peak expiratory flow rate. In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline b-agonist requirement of approximately 4 to 5 puffs of salbutamol/day. The results of the largest of the trials are shown in Table I. In a second and smaller study, the effect of zafirlukast on most efficacy parameters was comparable to the active control (inhaled sodium cromoglycate 1 600 Âµg 4 times/day) and superior to placebo at endpoint for decreasing rescue b-agonist use. 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 b2-agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.
Pharmacokinetics: 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: Geriatrics: 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- to 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.
For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
In patients who have previously experienced hypersensitivity to the product or any of its ingredients.
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: Rarely, elevations of one or more liver enzymes have occurred in patients receiving zafirlukast in controlled clinical trials. Most of these cases have been observed in asymptomatic patients at doses 4 times higher than the recommended dose, and return to the normal range after a variable period of time upon discontinuation of zafirlukast therapy. Liver function test abnormalities could represent early evidence of hepatotoxicity that may occur with prolonged administration. This risk appears to be greater in women. Rare cases of symptomatic hepatitis and hyperbilirubinemia, without other attributable causes, have occurred in patients who have received the recommended doses of zafirlukast (40 mg/day). In these patients, the liver enzymes returned to normal or near normal after stopping zafirlukast. If clinical signs or symptoms of liver dysfunction (e.g., right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, and flu-like symptoms) are noted, it is reasonable to recommend that standard liver tests be obtained and the patient managed accordingly. A decision to discontinue zafirlukast should be individualized to the patient’s condition, weighing the risk of hepatic dysfunction against the clinical benefit of zafirlukast to the patient.
General: 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.
Eosinophilic Conditions: When oral steroid reduction is considered, caution is required. Reduction of the oral steroid dose, in some asthma patients on zafirlukast therapy, has been followed, in rare cases, by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy, sometimes presenting as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. A causal relationship with zafirlukast has not been established.
Hepatic Effects: See Warnings. Children: The efficacy and safety of zafirlukast in children under 12 years has 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 2 000 mg/kg to rats. At 300 mg/kg/day male mice had an increased incidence of hepatocellular adenomas and female mice showed a greater incidence of whole body histocytic sarcomas. The plasma concentrations at these tumorigenic doses were approximately 220 times maximum recommended human daily oral dose. Male and female rats given 2 000 mg/kg/day had an increased incidence of urinary bladder transitional cell papillomas. 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 clinical significance of these findings for the long-term use of zafirlukast is unknown. 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 2 000 mg/kg (approximately 400 times the maximum recommended human daily oral dose on mg/mbasis). 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.
Pregnancy: 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/mbasis is given in brackets): mice 1 600 mg/kg/day (160 times); rats 2 000 mg/kg/day (400 times); cynomolgus monkeys 2 000 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.
Lactation: 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, it should not be administered to mothers who are breast-feeding.
Drug Interactions : 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.
1) 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.
2) ASA 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%.
3) 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.
4) 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).
5) 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, cyclosporin, cisapride, astemizole (isozyme CYP 3A4).
Food Interaction: Zafirlukast bioavailability may be altered when taken with a meal (see Pharmacology, Pharmacokinetics).
The safety database for zafirlukast consists of more than 4 000 healthy volunteers and patients who received zafirlukast, of which 1 723 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.
Liver Enzymes: Rarely, elevations of one or more liver enzymes have occurred in patients receiving zafirlukast in controlled clinical trials. Most of these have been observed in asymptomatic patients at doses 4 times higher than the recommended dose and returned to the normal range after a variable period of time upon discontinuation of zafirlukast therapy. Rare cases of symptomatic hepatitis and hyperbilirubinemia, without other attributable cause, have occurred in patients who had received the recommended doses of zafirlukast (40 mg/day). In these patients, the liver enzymes returned to normal or near normal after stopping zafirlukast (See Warnings and Precautions).
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: The reduction of the oral steroid dose, in some patients on zafirlukast therapy has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. A causal relationship with zafirlukast has not been established (See Precautions). Hypersensitivity reactions, including urticaria angioedema and rashes, with or without blistering, have been reported in association with zafirlukast therapy.
Symptoms and Treatment: No deaths occurred at oral zafirlukast doses of 2 000 mg/kg in mice (approximately 200 times the maximum recommended human daily oral dose on a mg/mbasis), 2 000 mg/kg in rats (approximately 400 times the maximum recommended human daily oral dose on a mg/mbasis), and 500 mg/kg in dogs (approximately 330 times the maximum recommended human daily oral dose on a mg/mbasis). There is no experience to date with zafirlukast overdose in humans. 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.
Zafirlukast is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. 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. Adults and Children Aged 12 Years and Over: The recommended dose is 20 mg, twice daily for a total daily dose of 40 mg. Since food reduces the bioavailability of zafirlukast, the drug should be taken at least 1 hour before or 2 hours after meals.
Geriatrics: The clearance of zafirlukast is reduced in elderly patients (>65 years old), such that Cmax and AUC are approximately twice those of younger adults. However, accumulation of zafirlukast is not evident in elderly patients. In clinical trials, a dose of 20 mg b.i.d. was not associated with an increase in the incidence of adverse events or withdrawals because of adverse events in elderly patients. Children: The safety and efficacy in children under 12 years has not been established.
Renal Impairment: Dosage adjustment is not required in patients with renal impairment. Hepatic Impairment: Zafirlukast is not recommended for 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.
Information for the Patient: See Blue Section – Information for the Patient Accolate.
Each white, round, biconvex, film-coated, intagliated tablet contains: zafirlukast 20 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, polyvidone and titanium dioxide. Calendar packs of 60. Store between 15 and 30°C.
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