(zafirlukast tablets) Leukotriene Receptor Antagonist
AstraZeneca Canada Inc. 1004 Middlegate Road Mississauga, Ontario
Date of Preparation: January 19, 2000
L4Y
1M4 Date of Revision:
Submission Control No. 105558
ACCOLATE(r) is a trade-mark of the AstraZeneca group of companies.
ACCOLATE(r) (zafirlukast tablets) Tablets 20 mg
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 one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three 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.
Three double-blind, randomized, placebo-controlled, 13-week clinical trials in 1,380 patients with mild-to-moderate asthma demonstrated that ACCOLATE (zafirlukast) improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta2- agonist use, FEV1, and morning peak expiratory flow rate (PEFR). In these studies, the patients had a mean baseline FEV1 of approximately 75% of predicted normal and a mean baseline beta-agonist requirement of approximately 4-5 puffs of salbutamol per day. The results of the largest of the trials are shown in the table below.
| ACCOLATE 20 mg twice daily | Placebo | ||
| Parameter | N=514 | N=248 | |
| Daytime Asthma symptom score | (0-3 scale) | -0.44 * | -0.25 |
| Nighttime Awakenings | (number per week) | -1.27 * | -0.43 |
| Mornings with Asthma Symptoms | (days per week) | -1.32 * | -0.75 |
| Rescue b 2 -agonist use FEV 1 Morning PEFR | (puffs per day) (L) (L/min) | -1.15 * +0.15 * +22.06 * | -0.24 +0.05 +7.63 |
| Evening PEFR | (L/min) | +13.12 | +10.14 |
| *p<0.05, compared to placebo | |||
In a second and smaller study, the effect of ACCOLATE on most efficacy parameters was comparable to the active control (inhaled sodium cromoglycate 1600 ug four times per day) and superior to placebo at endpoint for decreasing rescue beta-agonist use (figure below).
Mean ss2 -agonist use (puffs/day)
Placebo
ss2 -agonist Use (Puffs/Day) Adjusted Treatment Means
ACCOLATE 20 mg
twice a day
Cromolyn sodium
1600 ug four times
a day
2 4 6 8
Trial Week
10 12 14
In these trials, improvement in asthma symptoms occurred within one week of initiating treatment with ACCOLATE. The role of ACCOLATE in the management of patients with more severe asthma, patients receiving antiasthma therapy other than as-needed, inhaled beta2- agonists, or as an oral or inhaled corticosteroid-sparing agent remains to be fully characterized.
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 two separate studies, one using a high fat and the other a high protein meal, administration of ACCOLATE 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 0.25-10 ug/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.
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 50-60% 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.
ACCOLATE (zafirlukast) is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. ACCOLATE 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 ACCOLATE must be based on assessing its risks and benefits for each individual patient.
ACCOLATE (zafirlukast) is contraindicated in patients who have previously experienced hypersensitivity to the product or any of its ingredients. ACCOLATE is also contraindicated in patients with hepatic impairment including hepatic cirrhosis and patients in whom ACCOLATE is discontinued due to hepatotoxicity where no other attributable cause is identified.
ACCOLATE (zafirlukast) is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus.
: Warfarin coadministration with zafirlukast produces clinically significant increases in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and ACCOLATE should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see PRECAUTIONS, Drug Interactions).
Clinical Trials: Rarely, elevations of one or more liver enzymes have occurred in patients receiving ACCOLATE 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 ACCOLATE. 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 ACCOLATE (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 ACCOLATE. 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 ACCOLATE. The table below lists the number and the main outcomes of post-marketing reports of specific hepatic events in patients receiving ACCOLATE 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.
| Type of Hepatic Event | Number of Reports | Recovered | Resolving / Not fully recovered at the time of the report | Death | Transplant | Unknown |
| Liver Failure * | 14 | 2 | 4 | 5 | 2 (1 died) | 1 |
| Hepatitis * * | 46 | 16 | 22 | 1 | 0 | 7 |
| Other significant liver dysfunction | 59 | 20 | 20 | 1 | 0 | 18 |
* 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.
* * 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 ACCOLATE, 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 ACCOLATE 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 ACCOLATE treatment and close monitoring of patient. The serum transaminases, in particular serum ALT, should be measured immediately and the patient managed accordingly. Serum transaminase testing should be done at baseline and periodically during ACCOLATE treatment. Periodic serum transaminase testing has not proven to prevent serious injury. 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 ACCOLATE. If liver function tests are consistent with hepatic dysfunction, ACCOLATE therapy should not be resumed. Patients in whom ACCOLATE is discontinued due to hepatotoxicity where no other attributable cause is identified, should not be re-exposed to ACCOLATE. ACCOLATE is contraindicated for patients with hepatic impairment including hepatic cirrhosis (see CONTRAINDICATIONS).
ACCOLATE (zafirlukast) tablets should be taken regularly as prescribed, even during symptom-free periods. ACCOLATE therapy can be continued during acute exacerbations of asthma. ACCOLATE is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients receiving ACCOLATE should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician.
Caution is required in treating patients with severe asthma when steroid reduction is being considered. In rare cases, patients on ACCOLATE 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 ACCOLATE and these underlying conditions has not been established. (see ADVERSE REACTIONS).
See WARNINGS.
The efficacy and safety of ACCOLATE in children under 12 years has not been established.
In two-year oral carcinogenicity studies, zafirlukast was administered at daily doses of 10-300 mg/kg to mice and 40-2000 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, ACCOLATE has no evident genotoxic potential. The bladder tumour induction seen in rats and liver tumour induction seen in mice are therefore unlikely to be relevant to humans (see TOXICOLOGY, Carcinogenicity and Mutagenicity). No mutagenic potential was evident in point mutation assays or chromosomal aberrations clastogenic assays (see TOXICOLOGY, Carcinogenicity and Mutagenicity).
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 one-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.
The safety of ACCOLATE in human pregnancy has not been established. The potential risks should be weighed against the benefits of continuing therapy during pregnancy; ACCOLATE 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, ACCOLATE should be used during pregnancy only if clearly needed (see TOXICOLOGY, Reproduction and Teratology).
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.
A total of 8,094 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 Accolate 20 mg given twice daily in three patient age groups, adolescents (12-17 years), adults (18-65 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.
ACCOLATE may be administered with other therapies routinely used in the management of asthma and allergy. Examples of agents which have been co-administered with ACCOLATE without adverse interaction include inhaled steroids, inhaled and oral bronchodilator therapy, antihistamines and antibiotics. Co-administration with: erythromycin will result in decreased plasma levels of zafirlukast. In a drug interaction study in 11 asthmatic patients, co-administration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three 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. acetylsalicylic acid (e.g., Aspirin(r)) may result in increased plasma levels of zafirlukast. Co-administration of zafirlukast (40 mg/day) with acetylsalicylic acid (650 mg four times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%. theophylline may result in decreased plasma levels of zafirlukast, without effect on plasma theophylline levels. Co-administration 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, post-marketing surveillance revealed rare cases of patients experiencing increased theophylline levels (with or without theophylline toxicity symptoms) when ACCOLATE was co-administered. The mechanism of action for this interaction is unknown. terfenadine decreases zafirlukast AUC, but has no effect on plasma terfenadine levels. In a drug interaction study in 16 healthy male volunteers, co-administration 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 ACCOLATE. No effect of zafirlukast on terfenadine plasma concentrations or ECG parameters (i.e., QTc interval) was seen. No formal drug-drug interaction studies between ACCOLATE and other drugs known to be metabolized by the P450 3A4 (CYP 3A4) isoenzymes have been conducted. (see Cytochrome P450 enzyme inhibition below). 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 ACCOLATE should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see WARNINGS). Oral contraceptives may be administered with ACCOLATE 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.
: Aside from warfarin and terfenadine, no formal ACCOLATE drug-drug interaction studies have been conducted with other drugs known to be metabolized by cytochrome P450 isoenzymes. However, care should be exercised when ACCOLATE is co-administered with metabolised drugs such as:
tolbutamide, phenytoin, carbamazepine (isozyme 2C9) dihydropyridine calcium-channel blockers, cyclosporin, cisapride, astemizole (isozyme CYP 3A4).
ACCOLATE bioavailability may be altered when taken with a meal (see ACTIONS, CLINICAL PHARMACOLOGY, Pharmacokinetics).
The safety database for ACCOLATE (zafirlukast) consists of more than 4,000 healthy volunteers and patients who received ACCOLATE, of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received ACCOLATE 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 ACCOLATE. 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 the table below.
| Number of Patients Adverse Event | ACCOLATE 4058 Percent (%) | PLACEBO 2032 Percent (%) |
| 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 |
| Number of Patients Adverse Event | ACCOLATE 4058 Percent (%) | PLACEBO 2032 Percent (%) |
| Myalgia | 1.6 | 1.5 |
| Fever | 1.6 | 1.1 |
| Back Pain | 1.5 | 1.2 |
| Vomiting | 1.5 | 1.1 |
| SGPT 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 ACCOLATE 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 ACCOLATE (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 ACCOLATE. 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 milligrams 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 ACCOLATE 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 ACCOLATE 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 ACCOLATE 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 ACCOLATE. These events usually resolved after cessation of therapy.
Edema:
Cases of edema (uncommon) have been reported. The condition usually resolved after ACCOLATE was discontinued.
Arthralgia & myalgia:
Rare cases of non-specific arthralgia and non-specific myalgia have been reported. The condition usually improved following discontinuation of ACCOLATE.
Other:
The following have also been reported in association with the administration of ACCOLATE :
Insomnia, malaise (common) Pruritus (uncommon) These events have usually resolved following cessation of therapy.
TREATMENT OF OVERDOSAGE
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 ACCOLATE (zafirlukast) have been received. In reports with excessive ACCOLATE 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.
ACCOLATE (zafirlukast) is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. ACCOLATE is not a bronchodilator, and should not be used to treat acute episodes of asthma. Patients receiving ACCOLATE should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician.
The recommended dose of ACCOLATE is 20 mg, twice daily for a total daily dose of 40 mg. Since food reduces the bioavailability of zafirlukast, ACCOLATE should be taken at least 1 hour before or 2 hours after meals.
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 ACTIONS AND CLINICAL PHARMACOLOGY)
The safety and efficacy in children under 12 years have not been established.
Dosage adjustment is not required in patients with renal impairment.
ACCOLATE 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 - 60% greater than those of normal adults.
Trade Name: ACCOLATE(r)
Proper Name: zafirlukast
Chemical Name: 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethyl)-3- methoxy-N-o-tolylsulfonylbenzamide
Structural Formula:
Molecular Formula: C31H33N3O6S Molecular Weight: 575.7
Physical Form: White to off-white amorphous powder
Solubility: Practically insoluble in water. Slightly soluble in methanol. pKa: 5.5 in water with 1% acetonitrile (amorphous form) Melting Point: 119degC to 199degC (amorphous form)
Inactive Ingredients:
The tablets are film coated and include croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, hypromellose and titanium dioxide.
Store between 15 and 30degC.
ACCOLATE (zafirlukast) 20 mg tablets are white to off-white, round, biconvex, film-coated tablets. The tablets are intagliated. Available in calendar packs of 60.
ACCOLATE(r) (zafirlukast tablets) PLEASE READ THIS LEAFLET CAREFULLY BEFORE YOU START TO TAKE YOUR MEDICINE. For further information or advice, ask your doctor or pharmacist.
ACCOLATE is used to control asthma symptoms, and prevent your asthma from getting worse. The effect of ACCOLATE lasts for up to 12 hours. That's why it is important to take ACCOLATE twice a day, in the morning and evening. Regular ACCOLATE use will help to control your symptoms; all day and all night.
You should take your ACCOLATE tablets on an empty stomach (at least 1 hour before or 2 hours after meals). This will ensure you absorb as much medicine as possible each time.
ACCOLATE does not act quickly enough to be used as a relief medication. If you get a sudden attack of wheezing and breathlessness between doses of ACCOLATE, you should take one or two puffs from a fast-acting relief medication (e.g., formoterol, terbutaline, salbutamol) that your doctor has given you. Remember, if you have an attack that does not get better when you take the relief medication you should see your doctor right away. You may need emergency treatment. You should tell your doctor as soon as possible if you: are getting more attacks of wheezing, breathlessness or chest tightness, are using an increasing amount of fast-acting relief medication, start to wake up at night with chest tightness, wheezing or shortness of breath.
ACCOLATE is a leukotriene receptor antagonist that blocks substances called leukotrienes. Leukotrienes cause narrowing and swelling of airways in your lungs. Blocking leukotrienes improves asthma symptoms and helps prevent asthma attacks.
Have you ever had to stop taking another medication for your breathing problems because it caused problems or you were allergic to it? Have you ever been told that you have problems with your liver? If the answer is YES to either of these questions, make sure your doctor or pharmacist knows as soon as possible. Make sure your doctor knows about all other medicines you are taking (including non- prescription or over the counter products), especially blood thinners (e.g. COUMADIN(r), allergy medications (e.g., SELDANE(r), HISMANAL(r)), acetylsalicylic acid (e.g., Aspirin(r)), antibiotics, and theophylline. You should tell your doctor if you have ever had a bad, unusual or allergic reaction to zafirlukast or any of the other ingredients in ACCOLATE tablets.
Do not take ACCOLATE during pregnancy or while breast-feeding without discussing this with your doctor first. Similarly, let your doctor know about future pregnancies you are planning.
Follow your doctor's instructions about when and how to take your tablets. Please READ THE LABEL on the package. Ask your doctor or pharmacist if you are not sure. For patients 12 years of age and older: the usual treatment with ACCOLATE is 20 mg twice daily. Swallow each tablet whole with a full glass of water. Do not take your tablet(s) with a meal (at least 1 hour before or 2 hours after meals). Try to take your medicine at the same times each day. Using ACCOLATE twice a day, regularly, is very important. Your tablets come in blister cards of 15, enough for 7 days, plus one extra tablet. (So, two cards supply exactly 15 days, 4 cards supply 30 days). All tablets in each card are the same. To help you remember your schedule, fourteen tablets are labelled with the days of the week, 2 spots per day, (a.m. and p.m.). You can start ACCOLATE at any time. When starting a card, punch out and take the tablet labelled 'Start' noting the day and time you took it. Take your next tablet approximately 12 hours later, punching out the tablet that corresponds with that date and time (a.m. or p.m.). Continue following the calendar system to ensure that you take a morning and evening dose every day. When you finish a card, begin another approximately 12 hours later, at 'Start', and follow the calendar system again. As you get to the end of your last card, call your pharmacist for a refill, preferably before using the last four tablets.
Do not stop taking your tablets even if you are feeling well, unless your doctor tells you.
Tell your doctor or pharmacist if you think you have any of these or any other problems. As with all medicines, undesirable effects are sometimes experienced. With ACCOLATE these may include headache or gastrointestinal disturbances (indigestion or stomach upsets). These are usually mild. Feeling of discomfort, infections and sleeplessness have also been reported. Allergic reactions including skin rash and itching, blood disorders, edema (swelling caused by a build-up of fluid) and pain in the joints and muscles have been seen in a very small number of patients given ACCOLATE. Tell your doctor if any of these problems occur. Tell your doctor if you start to bruise easily, have unusual bleeding or experience persistent fever or sore throat. Rarely ACCOLATE may cause some changes to occur in your liver, which may be of a serious nature. If you think you have any of the following, tell your doctor immediately. feel sick, feel tired or lacking energy, feel like you have flu, feel like you have lost your appetite, feel itchy, have pain on the right side of your stomach, just below your ribs, have a yellow colouring of your skin and eyes (jaundice) have dark urine have discoloured and/or pale stools. Consult your doctor immediately if you experience any of the above signs or symptoms. Very rarely severe liver injury, including liver failure (which may result in liver transplantation or death), has been observed. A condition, which includes a combination of certain persistent or worsening symptoms, has been reported rarely in patients given ACCOLATE. These symptoms may include: a flu-like illness, rash, pins and needles or numbness of arms or legs, and severe sinusitis. These have occurred usually, but not always, in patients whose oral corticosteroid medicine for asthma is being reduced. Although ACCOLATE has not been shown to cause this condition, you must tell your physician immediately if you experience a combination of these symptoms.
IF YOU TAKE TOO MUCH
If you accidentally take a larger dose than recommended, tell your doctor as soon as possible. For an excessive overdose tell your doctor immediately or contact your hospital emergency department.
IF YOU MISS A DOSE
If you forget to take a dose, do not worry. Take another tablet just as soon as you remember. BUT if it is near the time for the next dose, wait until this dose is due. Then go on as before. Do not take a double dose.
STORING YOUR MEDICINE
Keep your medicine where children cannot reach it. Your medicine can harm them. You should store your tablets between 15 and 30degC (room temperature). Keep your tablets in the original package. If your doctor decides to stop your treatment, return your tablets to the pharmacist for disposal. Do not take your tablets after the expiry date on the package. Return the tablets to your pharmacist for disposal.
WHAT'S IN YOUR ACCOLATE TABLET
Each ACCOLATE tablet contains 20 mg of zafirlukast. Each tablet is film coated and also contains the inactive ingredients: croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, hypromellose and titanium dioxide. REMEMBER: This medicine was prescribed only for YOU. Only a doctor knows who can use it safely. Never give it to someone else. It may harm them, even if their symptoms are the same as yours.
FURTHER INFORMATION
If you go into hospital, let the medical staff know that you are taking ACCOLATE. If you have any questions or are not sure about anything to do with your medicine, then ask your doctor or pharmacist. You may need to read this leaflet again. PLEASE DO NOT THROW IT AWAY until you have finished your medicine. This leaflet alerts you to some of the times you should call your doctor. Other situations which cannot be predicted may arise. Nothing about this leaflet should stop you from calling your doctor or pharmacist with any questions or concerns you have about using ACCOLATE.
NOTE: This INFORMATION FOR THE CONSUMER leaflet provides you with the most current information at the time of printing. Please refer to the ACCOLATE INFORMATION FOR THE CONSUMER leaflet located at:
under the heading "Patients with Prescriptions", to see if more up-to-date information has been posted. , www.astrazeneca.ca
Customer Inquiries: 1 800 668 6000
ACCOLATE(r) and the AstraZeneca logo are trade-marks of the AstraZeneca group of companies.
(c) AstraZeneca 2000 AstraZeneca Canada Inc.
Mississauga, ON
L4Y 1M4 Last revised: December 21, 2005
In Vitro
and Animal Pharmacology
Zafirlukast is a potent, selective antagonist of receptors for the cysteinyl leukotrienes, LTC4, LTD4, and LTE4 on human membranes, as demonstrated by direct receptor binding and functional studies in isolated tissues.
In vitro Studies
Zafirlukast competed with binding of the cysteinyl leukotriene receptor agonists [3H]LTD4 and [3H]LTE4 in membranes prepared from guinea pig and human lungs, with Ki values of 0.4 nM to 1.4 nM. Zafirlukast competitively antagonized the contractile activity of both LTD4 and LTE4 on guinea pig isolated trachea. Zafirlukast also blocked the activity of LTC4 in this preparation; however, when the metabolic conversion of LTC4 to LTD4 and LTE4 was inhibited, zafirlukast failed to antagonize LTC4-induced contractions. In contrast to the effects on guinea pig trachea, zafirlukast blocked the contractile activity of LTC4 and LTD4 with similar potency on human isolated bronchial smooth muscle. Zafirlukast was evaluated in a range of in vitro tests in order to assess potential pharmacological actions unrelated to its intended therapeutic use. Concentrations ranged to 10,000 times the concentrations that cause 50% antagonism of the effects of the EC50 concentration of exogenous LTD4. Zafirlukast had no effects at cholinergic, adrenergic, histaminergic or serotonergic receptors at a concentration of 0.1 uM. At 10 uM, zafirlukast caused relaxation of the guinea pig isolated trachea and noncompetitive antagonism of agonist responses in other smooth muscle preparations. Since this concentration is some 10,000 times that required to antagonize the effects of cysteinyl leukotrienes, these effects are unlikely to be observed after administration to animals or humans.
In vivo
Studies
In conscious guinea pigs exposed to an aerosol of LTD4 to induce dyspnea, zafirlukast exhibited dose-related prolongation of time to dyspnea, when administered orally (0.17 to 0.58 mg/kg). The pharmacologic half-life was 916 min. Oral dosing of Zafirlukast (0.58 mg/kg per day) for 5 days provided no evidence of tolerance. In studies of leukotriene-induced alterations of pulmonary mechanics in anaesthetized, spontaneously-breathing guinea pigs, zafirlukast in doses of 0.17 to 5.8 mg/kg orally produced significant dose-related antagonism in the i.v. LTC4, LTD4, and LTE4 dose-response curves. Zafirlukast inhibited LTD4-induced eosinophil accumulation and tracheal edema in guinea pigs. Increases in pulmonary resistance and decreases in dynamic lung compliance in response to aerosol ovalbumin antigen administered to the guinea pig were prevented as well as reversed by zafirlukast. Zafirlukast inhibited LTD4-induced bronchoconstriction and lavagable protein in sheep in a dose-dependent manner. Zafirlukast, administered prior to, 4 hours after, and 24 hours after antigen in Ascaris suum-sensitive sheep, inhibited acute bronchoconstriction, late bronchoconstriction, and nonspecific airways hyper-reactivity. Zafirlukast was evaluated in a range of in vivo tests covering the major physiological systems in order to assess potential pharmacological actions unrelated to its intended therapeutic use. Doses in vivo were approximately 10 times the projected therapeutic dose for antagonism of the effects of LTD4. Zafirlukast was found to be without effect on autonomic, cardiovascular, central nervous system, gastrointestinal, renal, or reproductive function, at doses at least 10 times those effective in pharmacological tests.
Human Pharmacodynamics
The specificity of ACCOLATE (zafirlukast) was shown in clinical studies by its action on leukotriene receptors and not on prostaglandin, thromboxane, cholinergic or histamine receptors. ACCOLATE diminished the airway inflammatory response 48 hours after allergen challenge as demonstrated in a single placebo-controlled trial involving broncho-alveolar lavage following segmental allergen provocation. Compared to placebo, 20 mg of ACCOLATE led to a reduction in basophil (p<0.01) and lymphocyte (p<0.01) number and histamine release (p<0.05) in broncho-alveolar lavage fluid on day 7 of treatment (2 days after allergen challenge). ACCOLATE inhibited superoxide anion production from purified alveolar macrophages on day 7 (p< 0.01). ACCOLATE attenuated the increase in bronchial hyperresponsiveness that follows inhaled allergen challenge and the bronchoconstriction induced by platelet activating factor (PAF). Furthermore, methacholine sensitivity was diminished by long-term dosing with ACCOLATE 20 mg b.i.d. ACCOLATE shows a dose-dependent inhibition of bronchoconstriction induced by inhaled leukotriene D4 (LTD4). ACCOLATE, at recommended doses, enables an asthmatic patient to inhale 100 times more LTD4 and continues to show significant protection at 12 and 24 hours after a single oral dose. (See also ACTIONS, CLINICAL PHARMACOLOGY.)
THE LD50 values for zafirlukast in acute toxicity studies is summarized below:
Route Species Sex LD50 (mg/kg)
Oral Mouse
Intraperitoneal Mouse Rat
Intravenous Mouse Rat
Male Female Male Female Male Female
Male Female Male Female
Male Female Male Female
> 2000
> 2000
> 2000
> 2000
> 500
> 500
> 100
> 100
> 100
> 100
> 75
> 75
> 60
> 60
Zafirlukast was well tolerated in the sub-acute and chronic studies in rats, dogs and mice. Liver enlargement was the most consistent observation and it was much greater in mice than rats and dogs. Hepatic changes in dogs were limited to increased glycogen deposition and, at very high exposures, hepatocyte degeneration. Microscopic granulomatous infiltrates consisting primarily of enlarged histiocytic cells occurred in a wide range of tissues in dogs. They were not associated with any functional change, were not seen in any other species and were rarely reported in studies of more than six weeks duration. The granulomatous infiltrates may represent an enhancement of a normal macrophage response to inflammatory stimuli in this species. For adult animals, the no toxic effect dose level after 12 months was 40 mg/kg for dogs and rats which corresponds to an exposure to zafirlukast of AUC(0-24h) of 50 +/- 12 ug.h/mL for dogs and AUC(3-24h) of 105 and 155 ug.h/mL for male and female rats respectively. These exposures afford a safety margin of approximately 20-fold over the AUC(0-24h) of 2.51 ug.h/mL for 20 mg ACCOLATE (zafirlukast) bid in humans.
In two-year carcinogenicity studies, zafirlukast was administered at oral daily doses of 10, 100, and 300 mg/kg to mice and 40, 400, and 2000 mg/kg to rats. Male mice given 300 mg/kg/day of zafirlukast had a greater incidence of hepatocellular adenomas as compared to concurrent controls; female mice at this dose showed a greater incidence of whole body histocytic sarcomas. Male and female rats given 2000 mg/kg/day of zafirlukast had a greater incidence of urinary bladder transitional cell papillomas as compared to concurrent controls. Pharmacokinetic data show that the plasma concentrations in mice at non-tumorigenic (100 mg/kg) and tumorigenic (300 mg/kg) doses of zafirlukast were approximately 70 times and 220 times, respectively, the plasma concentrations at the maximum recommended human daily oral dose. For rats, plasma concentrations at the non-tumorigenic (400 mg/kg) and tumorigenic (2000 mg/kg) doses of zafirlukast were approximately 170 times and 200 times, respectively, 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 ACCOLATE is unknown. In mutagenicity studies, there was no evidence of mutagenic potential in reverse (S. typhimurium and E. coli) or forward point mutation (CHO-HGPRT) assays or in two assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenesis assay and the rat bone marrow erythrocyte micronucleus assay).
No teratogenicity was observed at oral doses up to 1600 mg/kg/day in mice (approximately 160 times the maximum recommended human daily oral dose on a mg/m2 basis), 2000 mg/kg/day in rats (approximately 400 times the maximum recommended human daily oral dose on a mg/m2 basis) and 2000 mg/kg/day in cynomolgus monkeys (approximately 800 times the maximum recommended human daily oral dose on a mg/m2 basis). At 2000 mg/kg/day in rats, maternal toxicity and deaths were seen with increased incidence of early fetal resorption. Spontaneous abortions occurred in cynomolgus monkeys at a maternally toxic dose of 2000 mg/kg/day orally. There are no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, ACCOLATE should be used during pregnancy only if clearly needed.
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