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Accolate

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Accolate

Warnings
Precautions

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. In extremely rare post-marketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations.

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 Patients in whom ACCOLATE was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to ACCOLATE (see PRECAUTIONS, PATIENT INFORMATION and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. Patients should be instructed to notify their physician if neuropsychiatric events occur while using ACCOLATE (see PRECAUTIONS, Neuropsychiatric Events). 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 with asthma on ACCOLATE 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. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. The possibility that ACCOLATE may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see ADVERSE REACTIONS).

Neuropsychiatric Events

Neuropsychiatric events have been reported in adult, adolescent and pediatric patients taking ACCOLATE. Post-marketing reports with ACCOLATE include insomnia and depression. The clinical details of some post-marketing reports involving ACCOLATE appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with ACCOLATE if such events occur (see ADVERSE REACTIONS).

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).

Pregnancy Category B

No teratogenicity was observed at oral doses up to 1600 mg/kg/day in mice (approximately 160 times the maximum recommended daily oral dose in adults on a mg/m² basis), up to 2000 mg/kg/day in rats (approximately 410 times the maximum recommended daily oral dose in adults on a mg/m² basis) and up to 2000 mg/kg/day in cynomolgus monkeys (which resulted in approximately 20 times the exposure to drug plus metabolites compared to that from the maximum recommended daily oral dose in adults based on comparison of the AUC values). At an oral dose of 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 the maternally toxic oral dose of 2000 mg/kg/day. There are no adequate and well-controlled trials in pregnant women. Because animal reproductive studies are not always predictive of human response, ACCOLATE should be used during pregnancy only if clearly needed.

Nursing Mothers

Zafirlukast is excreted in 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.

Pediatric Use

The safety of ACCOLATE at doses of 10 mg twice daily has been demonstrated in 205 pediatric patients 5 through 11 years of age in placebo-controlled trials lasting up to six weeks and with 179 patients in this age range participating in 52 weeks of treatment in an open label extension.

The effectiveness of ACCOLATE for the prophylaxis and chronic treatment of asthma in pediatric patients 5 through 11 years of age is based on an extrapolation of the demonstrated efficacy of ACCOLATE in adults with asthma and the likelihood that the disease course, and pathophysiology and the drug's effect are substantially similar between the two populations. The recommended dose for the patients 5 through 11 years of age is based upon a cross-study comparison of the pharmacokinetics of zafirlukast in adults and pediatric subjects, and on the safety profile of zafirlukast in both adult and pediatric patients at doses equal to or higher than the recommended dose.

The safety and effectiveness of zafirlukast for pediatric patients less than 5 years of age has not been established. The effect of ACCOLATE on growth in children has not been determined.

Geriatric Use

Based on cross-study comparison, 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 (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY).

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 infections 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.

Last reviewed on RxList: 8/18/2011
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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