Accolate (zafirlukast) Side Effects, Warnings, and Drug Interactions

Accolate (zafirlukast) is an oral leukotriene receptor antagonist used to treat chronic asthma. It also is effective in preventing exercise-induced asthma and in relieving the symptoms of allergic rhinitis. 

For asthma treatment, it starts working only after 3 to 14 days of therapy. Therefore, it should not be used for the treatment an acute asthma attack when immediate relief is needed.

Leukotrienes are a group of chemicals manufactured in the body from arachidonic acid. Release of leukotrienes within the body, for example, by allergic reactions, promotes inflammation in many diseases such as asthma, a disease in which inflammation occurs in the lungs. Accolate blocks the binding of leukotriene types D4 (LTD4), and E4 (LTE4) and the promotion of inflammation.

Common side effects of Accolate include:

• headache,
• dizziness,
• nausea,
• diarrhea,
• abdominal pain,
• sore throat,
• respiratory infections, and
• runny nose.

Serious side effects of Accolate include:

• fever,
• vasculitis,
• low white blood cell count (eosinophilia),
• bleeding,
• liver failure, and
• back pain.

Drug interactions of Accolate include:

• warfarin, which increase the risk of bleeding.

Accolate also interacts with drugs metabolized by CYP3A4 including: 

• alprazolam,
• carbamazepine,
• cyclosporine,
• dihydropyridine,
• calcium channel blockers,
• lovastatin,
• simvastatin,
• quinidine,
• triazolam, and
• verapamil.

Erythromycin reduces the absorption of Accolate, potentially reducing its effect. 

Safe use of Accolate for prevention and medical treatment for asthma during pregnancy has not been established. Doctors or other health care professionals may prescribe it during pregnancy if it is felt that its benefits outweigh the potential unknown risks. Accolate is secreted into breast milk and should not be used by women who are breastfeeding.

The most common health side effects include:

• Headache
• Dizziness
• Nausea
• Diarrhea
• Abdominal pain
• Sore throat
• Respiratory infections
• Rhinitis

Other health side effects and adverse effects include:

• Fever
• Vasculitis
• Eosinophilia
• Bleeding
• Liver failure
• Back pain

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.

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.

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 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.

Neuropsychiatric adverse events, including insomnia and depression, have been reported 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.

Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, 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 vitro metabolism data and the results of two clinical drug interaction studies.

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.

• 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. 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.
• 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.
• Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this interaction is unknown. 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.
• 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.