ACCOLATE

DESCRIPTION

Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. 

The empirical formula is: C31H33N3O6S

Zafirlukast, a fine white to pale yellow amorphous powder, is practically insoluble in water. It is slightly soluble in methanol and freely soluble in tetrahydrofuran, dimethylsulfoxide, and acetone.

ACCOLATE is supplied as 10 and 20 mg tablets for oral administration.

Inactive Ingredients: Film-coated tablets containing croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, hypromellose, and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action:

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.

Clinical Pharmacokinetics and Bioavailability:

Clinical Studies:

Three U.S. double-blind, randomized, placebo-controlled, 13-week clinical trials in 1380 adults and children 12 years of age and older with mild-to-moderate asthma demonstrated that ACCOLATE improved daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta2-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 beta2-agonist requirement of approximately 4-5 puffs of albuterol per day. The results of the largest of the trials are shown in the table below.

Mean Change from Baseline at Study End Point
 

ACCOLATE

20 mg twice daily

N=514

Placebo

N=248

Daytime Asthma symptom score

(0-3 scale)

-0.44p<0.05, compared to placebo

-0.25

Nightime Awakenings

(number per week)

-1.27

-0.43

Mornings with Asthma Symptoms

(days per week)

-1.32

-0.75

Rescue β2-agonist use

(puffs per day)

-1.15

-0.24

FEV1 (L)

+0.15

+0.05

Morning PEFR (L/min)

+22.06

+7.63

Evening PEFR (L/min)

+13.12

+10.14

In a second and smaller study, the effect of ACCOLATE on most efficacy parameters was comparable to the active control (inhaled cromolyn sodium 1600 mcg four times per day) and superior to placebo at end point for decreasing rescue beta2-agonist use.

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.

INDICATIONS AND USAGE

ACCOLATE is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.

CONTRAINDICATIONS

ACCOLATE is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients.

WARNINGS

Hepatotoxicity:

Cases of life-threatening hepatic failure have been reported in patients treated with ACCOLATE. Cases of liver injury without other attributable cause have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of ACCOLATE (40 mg/day). 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 rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death.

Physicians may consider the value of liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery.

Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia) and to contact their physician immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.

If liver dysfunction is suspected based upon clinical signs or symptoms (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver), ACCOLATE should be discontinued.

Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, ACCOLATE therapy should not be resumed. Patients in whom ACCOLATE was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to ACCOLATE (see PRECAUTIONS, Information for Patients and ADVERSE REACTIONS).

Bronchospasm:

ACCOLATE is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with ACCOLATE can be continued during acute exacerbations of asthma.

Concomitant Warfarin Administration:

Coadministration of zafirlukast with warfarin results in a clinically significant increase 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).

PRECAUTIONS

Information for Patients:

Patients should be told that a rare side effect of ACCOLATE is hepatic dysfunction, and to contact their physician immediately if they experience symptoms of hepatic dysfunction (eg. right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia). Liver failure resulting in liver transplantation and death has occurred in patients taking zafirlukast (see WARNINGS, Hepatotoxicity and ADVERSE REACTIONS).

ACCOLATE 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. Women who are breast-feeding should be instructed not to take ACCOLATE (see PRECAUTIONS, Nursing Mothers). Alternative antiasthma medication should be considered in such patients.

The bioavailability of ACCOLATE may be decreased when taken with food. Patients should be instructed to take ACCOLATE at least 1 hour before or 2 hours after meals.

Eosinophilic Conditions: In rare cases, patients on ACCOLATE therapy may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. These events usually, but not always, have been associated with the reduction of oral steroid 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 ADVERSE REACTIONS).

Drug Interactions:

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 (seeWARNINGS),Concomitant Warfarin Administration). No formal drug-drug interaction studies with ACCOLATE and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme (eg, tolbutamide, phenytoin, carbamazepine) have been conducted; however, care should be exercised when ACCOLATE is coadministered with these drugs.

In a drug interaction study in 11 asthmatic patients, coadministration 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.

Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline.

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, 18 to 44 years of age, resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed.

Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of ACCOLATE to an existing theophylline regimen have been reported. The mechanism of the interaction between ACCOLATE and theophylline in these patients is unknown (see ADVERSE REACTIONS).

Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%.

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.

No formal drug-drug interaction studies between ACCOLATE and marketed drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As ACCOLATE is known to be an inhibitor of CYP3A4 in vitro, it is reasonable to employ appropriate clinical monitoring when these drugs are coadministered with ACCOLATE.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

In two-year carcinogenicity studies, zafirlukast was administered at dietary doses of 10, 100, and 300 mg/kg to mice and 40, 400, and 2000 mg/kg to rats. Male mice at an oral dose of 300 mg/kg/day (approximately 30 times the maximum recommended daily oral dose in adults and in children on a mg/m2 basis) showed an increased incidence of hepatocellular adenomas; female mice at this dose showed a greater incidence of whole body histocytic sarcomas. Male and female rats at an oral dose of 2000 mg/kg/day (resulting in approximately 160 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma area-under the curve [AUC] values) of zafirlukast showed an increased incidence of urinary bladder transitional cell papillomas. Zafirlukast was not tumorigenic at oral doses up to 100 mg/kg (approximately 10 times the maximum recommended daily oral dose in adults and in children on a mg/m2 basis) in mice and at oral doses up to 400 mg/kg (resulting in approximately 140 times the exposure to drug plus metabolites from the maximum recommended daily oral dose in adults and in children based on a comparison of the plasma AUC values) in rats. The clinical significance of these findings for the long-term use of ACCOLATE is unknown.

Zafirlukast showed no evidence of mutagenic potential in the reverse microbial assay, in 2 forward point mutation (CHO-HGPRT and mouse lymphoma) assays or in two assays for chromosomal aberrations (the in vitro human peripheral blood lymphocyte clastogenic assay and the in vivo rat bone marrow micronucleus assay).

No evidence of impairment of fertility and reproduction was seen in male and female rats treated with zafirlukast at oral doses up to 2000 mg/kg (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m2 basis).

ADVERSE REACTIONS

Adults and Children 12 years of age and older

The safety database for ACCOLATE consists of more than 4000 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.

 

ACCOLATE

PLACEBO

Adverse Event

N=4058

N=2032

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%

SGPT Elevation

1.5%

1.1%

Dyspepsia

1.3%

1.2%

The frequency of less common adverse events was comparable between ACCOLATE and placebo.

Rarely, elevations of one or more liver enzymes have occurred in patients receiving ACCOLATE in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of ACCOLATE (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all postmarketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping ACCOLATE. In rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death (see WARNINGS, Hepatotoxicity and PRECAUTIONS, Information for Patients).

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.

In rare cases, patients on ACCOLATE therapy may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. These events usually, but not always, have been associated with the reduction of oral steroid 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 (seePRECAUTIONS, Eosinophilic Conditions).

Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without bulering, have been reported in association with ACCOLATE therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, insomnia, malaise, and pruritus in association with ACCOLATE therapy.

Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of ACCOLATE to an existing theophylline regimen have been reported. The mechanism of the interaction between ACCOLATE and theophylline in these patients is unknown and not predicted by available in vitrometabolism data and the results of two clinical drug interaction studies (see CLINICAL PHARMACOLOGY andPRECAUTIONS, Drug Interactions).

Pediatric Patients 5 through 11 years of age

ACCOLATE has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with ACCOLATE 10 mg twice daily or higher for at least 6 months, and 113 of them were treated for one year or longer in clinical trials. The safety profile of ACCOLATE 10 mg twice daily-versus placebo in the 4- and 6-week double-blind trials was generally similar to that observed in the adult clinical trials with ACCOLATE 20 mg twice daily.

In pediatric patients receiving ACCOLATE in multi-dose clinical trials, the following events occurred with a frequency of ≥ 2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: headache (4.5 vs. 4.2%) and abdominal pain (2.8 vs. 2.3%).

The post-marketing experience in this age group is similar to that seen in adults, including hepatic dysfunction, which may lead to liver failure.

OVERDOSAGE

No deaths occurred at oral zafirlukast doses of 2000 mg/kg in mice (approximately 210 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis), 2000 mg/kg in rats (approximately 420 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis), and 500 mg/kg in dogs (approximately 350 times the maximum recommended daily oral dose in adults and children on a mg/m2 basis).

Overdosage with ACCOLATE has been reported in four patients surviving reported doses as high as 200 mg. The predominant symptoms reported following ACCOLATE overdose were rash and upset stomach. There were no acute toxic effects in humans that could be consistently ascribed to the administration of ACCOLATE. It is reasonable to employ the usual supportive measures in the event of an overdose; eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

DOSAGE AND ADMINISTRATION

Because food can reduce the bioavailability of zafirlukast, ACCOLATE should be taken at least 1 hour before or 2 hours after meals.

Adults and Children 12 years of age and older

The recommended dose of ACCOLATE in adults and children 12 years and older is 20 mg twice daily.

Pediatric Patients 5 through 11 years of age

The recommended dose of ACCOLATE in children 5 through 11 years of age is 10 mg twice daily.

Elderly Patients: Based on cross-study comparisons, the clearance of zafirlukast is reduced in elderly patients (65 years of age and older), such that Cmax and AUC are approximately twice those of younger adults. In clinical trials, a dose of 20 mg twice daily was not associated with an increase in the overall incidence of adverse events or withdrawals because of adverse events in elderly patients.

Patients with Hepatic Impairment: The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that the Cmax and AUC are approximately 50 – 60% greater than those of normal adults. ACCOLATE has not been evaluated in patients with hepatitis or in long-term studies of patients with cirrhosis.

Patients with Renal Impairment: Dosage adjustment is not required for patients with renal impairment.

HOW SUPPLIED

ACCOLATE 10 mg Tablets, (NDC 0310-0401) white, unflavored, round, biconvex, film-coated, mini-tablets identified with “ACCOLATE 10” debossed on one side are supplied in opaque HDPE bottles of 60 tablets and Hospital Unit Dose buler packages of 100 tablets.

ACCOLATE 20 mg Tablets, (NDC 0310-0402) white, round, biconvex, coated tablets identified with “ACCOLATE 20” debossed on one side are supplied in opaque HDPE bottles of 60 tablets and Hospital Unit Dose buler packages of 100 tablets.

Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Protect from light and moisture. Dispense in the original air-tight container.

ACCOLATE is a trademark of the AstraZeneca group of companies.

©AstraZeneca 2001, 2004

Manufactured for:

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

By: IPR Pharmaceuticals, Inc.

Carolina, PR 00984

30013-00

Rev . 07/04

THIS TOOL DOES NOT PROVIDE MEDICAL ADVICE. It is intended for informational purposes only. It is not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the site. If you think you may have a medical emergency, immediately call your doctor or dial 911.

a/item/39-accolatea/item/39-accolate

Leave a Reply

Your email address will not be published. Required fields are marked *