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Accolate (Zafirlukast) Side Effects, Interactions, Warning, Dosage


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3.11.2017 | Logan Miers
Accolate
Accolate (Zafirlukast) Side Effects, Interactions, Warning, Dosage

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

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

ACCOLATE is not a bronchodilator and should not be used to treat acute episodes of asthma. Patients should be instructed to notify their physician if neuropsychiatric events occur while using ACCOLATE (see PRECAUTIONS, Neuropsychiatric Events ). ACCOLATE is indicated for the chronic treatment of asthma and should be taken regularly as prescribed, even during symptom-free periods. Patients receiving ACCOLATE should be instructed not to decrease the dose or stop taking any other antiasthma medications unless instructed by a physician. Alternative antiasthma medication should be considered in such patients. Women who are breast-feeding should be instructed not to take ACCOLATE (see PRECAUTIONS, Nursing Mothers ).

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

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 immediay if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.

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 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 ).

The possibility that ACCOLATE may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see ADVERSE REACTIONS ). 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.

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

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 rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death (see WARNINGS, Hepatotoxicity and PRECAUTIONS, PATIENT INFORMATION ). 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.

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

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

Zafirlukast exposure is likely to be increased by other moderate and strong CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast. The clinical significance of this interaction is unknown. Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast, by approximay 58% (90% CI:28, 95).

Find Lowest Prices on ACCOLATE (zafirlukast) Tablets.

Adverse Event ACCOLATE N=4058 PLACEBO 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%

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Nov 2013.

Call your doctor at once if you have a serious side effect such as:

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.

No teratogenicity was observed at oral doses up to 1600 mg/kg/day in mice (approximay 160 times the maximum recommended daily oral dose in adults on a mg/m² basis), up to 2000 mg/kg/day in rats (approximay 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 approximay 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). Spontaneous abortions occurred in cynomolgus monkeys at the maternally toxic oral dose of 2000 mg/kg/day. Because animal reproductive studies are not always predictive of human response, ACCOLATE should be used during pregnancy only if clearly needed. There are no adequate and well-controlled trials in pregnant women. At an oral dose of 2000 mg/kg/day in rats, maternal toxicity and deaths were seen with increased incidence of early fetal resorption.

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

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. ACCOLATE has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. 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.

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 (approximay 410 times the maximum recommended daily oral dose in adults on a mg/m² basis).

Dosage adjustment is not required for patients with renal impairment.

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 ).

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 total of 671 patients received ACCOLATE for 1 year or longer. 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.

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

These events have usually, but not always, been associated with reductions and/or withdrawal of steroid therapy. 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. The possibility that ACCOLATE may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see PRECAUTIONS, Eosinophilic Conditions ).

The empirical formula is: C 31 H 33 N 3 O 6 S.

2.3%). 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.

No other 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.

Patients should be instructed to notify their prescriber if these changes occur. Patients and prescribers should be alert for neuropsychiatric events. 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. Prescribers should carefully evaluate the risks and benefits of continuing treatment with ACCOLATE if such events occur (see ADVERSE REACTIONS ). Neuropsychiatric events have been reported in adult, adolescent and pediatric patients taking ACCOLATE.

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 approximay 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.

The clinical significance of these findings for the longterm use of ACCOLATE is unknown. Zafirlukast was not tumorigenic at oral doses up to 100 mg/kg (approximay 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 approximay 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. 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 (approximay 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 approximay 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 values) of zafirlukast showed an increased incidence of urinary bladder transitional cell papillomas.

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

Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with ACCOLATE therapy. Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have also been reported in association with ACCOLATE therapy. Neuropsychiatric adverse events, including insomnia and depression, have been reported in association with ACCOLATE therapy (see PRECAUTIONS, Neuropsychiatric Events ).

home drugs a-z list side effects drug center accolate (zafirlukast) drug.

The molecular weight of zafirlukast is 575.7 and the structural formula is:. 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-otolylsulfonylbenzamide.

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 approximay 40% due to a decrease in zafirlukast bioavailability.

In extremely rare postmarketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations. 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 rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. Cases of life-threatening hepatic failure have been reported in patients treated with ACCOLATE. 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.

The clinical significance of this finding is unknown. A similar finding was not observed in other age groups studied. In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. 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 recommended dose of ACCOLATE in children 5 through 11 years of age is 10 mg twice daily.

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

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 approximay 30%, but no effect on plasma theophylline levels was observed.

ACCOLATE 10 mg Tablets, ( NDC white, unflavored, round, biconvex, film-coated, minitablets identified with “ACCOLATE 10” debossed on one side are supplied in opaque HDPE bottles of 60 tablets.

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

Visit the FDA MedWatch website or call 1-800-FDA-1088. You are encouraged to report negative side effects of prescription drugs to the FDA.

The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that the Cmax and AUC are approximay 50 - 60% greater than those of normal adults. ACCOLATE is contraindicated in patients with hepatic impairment including hepatic cirrhosis (see CONTRAINDICATIONS ). ACCOLATE has not been evaluated in patients with hepatitis or in long-term studies of patients with cirrhosis.

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.

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 ). Liver function tests, in particular serum ALT, should be measured immediay and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, ACCOLATE therapy should not be resumed.

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.

ACCOLATE 20 mg Tablets, ( NDC white, round, biconvex, coated tablets identified with “ACCOLATE 20” debossed on one side are supplied in opaque HDPE bottles of 60 tablets.

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).

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.

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

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

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. Patients on oral warfarin anticoagulant therapy and ACCOLATE should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see WARNINGS, Concomitant Warfarin Administration ). 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 approximay 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system.

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 vitro metabolism data and the results of two clinical drug interaction studies (see CLINICAL PHARMACOLOGY and PRECAUTIONS: DRUG INTERACTIONS ).

Accolate