ZAFIRLUKAST (Generic for ACCOLATE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer at least 1 hour before or 2 hours after meals. Bioavailability is substantially decreased when taken with food.
-Advise patients and caregivers not to stop or decrease the use of other asthma treatments when starting zafirlukast unless otherwise directed by their health care prescriber.

The most common adverse reactions with oral zafirlukast, seen in one adult clinical trial in patients with asthma, were headache, gastritis, pharyngitis, and rhinitis. One patient was withdrawn from the study due to fever and weakness. In a study of 39 children (6-14 years old) receiving a single dose of zafirlukast 20 mg or placebo for exercise-induced bronchoconstriction, dizziness (13% vs. 10% placebo) and pharyngitis (7.7% vs. 7.7%) were reported. In pediatric patients receiving zafirlukast in multi-dose clinical trials, headache (4.5% vs. 4.2% placebo) and abdominal pain (2.8% vs. 2.3% placebo) occurred most frequently. Adverse reactions reported by the manufacturer in zafirlukast-treated children >= 12 years old and adults, at rates greater than placebo-treated patients, include: headache (13% zafirlukast vs. 12% placebo), nausea/vomiting (3.1%/1.5% vs. 2%/1.1%), diarrhea (2.8% vs. 2.1%), pain (generalized) (1.9% vs. 1.7%), asthenia (1.8% vs. 1.6%), abdominal pain (1.8% vs. 1.1%), dizziness (1.6% vs. 1.5%), myalgia (1.6% vs. 1.5%), fever (1.6% vs. 1.1%), back pain (1.5% vs. 1.1%), and dyspepsia (1.3% vs. 1.2%). Side effects resulting from the use of zafirlukast in children 5 years of age and older appear to be similar to those for adults and adolescents. Infection was reported in 3.5% of patients (compared to 3.4% of placebo treated patients), but was reported in an increased proportion of patients over the age of 55. The infections were generally mild to moderate and affected the upper respiratory tract. Arthralgia has also been reported post-marketing.

In controlled clinical trials elevated hepatic enzymes (asymptomatic) have occurred in patients taking oral zafirlukast; most of these have been observed at doses four times higher than the recommended dose. In clinical trials involving children >= 12 years of age and adults, SGPT elevation (1.5% vs. 1.1% placebo) has been reported. In a study of 39 children (6-14 years old) receiving a single dose of zafirlukast 20 mg or placebo for exercise-induced bronchoconstriction, no clinically significant abnormalities in laboratory tests or other clinical assessments associated with treatment were found for any of the children during this study. The post-marketing experience in pediatric patients is similar to that seen in adults, including hepatic dysfunction, which may lead to liver failure. In post-marketing reports, cases of symptomatic hepatitis and hyperbilirubinemia or jaundice, not due to other causes, have occurred in patients receiving zafirlukast within the recommended dosage range. In most, but not all post-marketing reports, the patient's symptoms abated and liver enzymes returned to normal or near normal after stopping zafirlukast. In rare cases, patients have presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation, and death. If hepatic dysfunction is suspected based on clinical signs and symptoms (e.g., right upper quadrant abdominal pain, nausea/vomiting, lethargy, jaundice, and flu-like symptoms), zafirlukast should be discontinued. Liver function tests (LFTs), in particular serum ALT, should be measured immediately and the patient managed accordingly. If LFTs are consistent with hepatic dysfunction, zafirlukast therapy should not be resumed. Patients in whom zafirlukast was discontinued due to hepatic dysfunction, where no other attributable course is identified should not be re-exposed to zafirlukast. The manufacturer states that hepatic events have occurred predominately in females.

Hypersensitivity reactions, including angioedema, rash (unspecified), and urticaria, have been reported infrequently in association with zafirlukast use. In some cases, the rashes have involved blistering (vesicular rash). There are also rare reports of patients experiencing agranulocytosis, bleeding, bruising (ecchymosis), pruritus, or edema in association with zafirlukast therapy; the reactions may be immune-mediated.

Neuropsychiatric adverse events such as insomnia, depression, and suicidal ideation have been reported with zafirlukast and other leukotriene inhibitors. Other post-marketing reports among patients on leukotriene inhibitor therapy have included agitation, aggressive behavior, dream abnormalities, drowsiness/sedation, hallucinations, irritability and restlessness, anxiety, tremor, and malaise. Advise patients and caregivers to immediately report changes in behavior and mood; consider alternate therapy if patients develop neuropsychiatric symptoms.

In rare cases, patients taking zafirlukast have developed a systemic eosinophilia, eosinophilic pneumonia, and/or vasculitis consistent with Churg-Strauss syndrome; such patients are usually, but not always, undergoing steroid therapy dosage reductions or withdrawal. Symptoms include eosinophilia, vasculitic rash, worsening pulmonary symptoms (such as sinusitis, dyspnea, or worsening wheezing), cardiac complications (such as chest pain (unspecified) or irregular heartbeat), and/or peripheral neuropathy. Although a causal relationship between Churg-Strauss syndrome and zafirlukast therapy has not been established; physicians should be alert to such symptoms and caution is advised when oral corticosteroid reduction is being considered. Churg-Strauss syndrome is a disorder marked by inflammation of the blood vessels, primarily those of the lungs, and commonly treated with systemic steroid therapy; asthma and allergic rhinitis, conditions which may be treated with zafirlukast, are hallmarks of the syndrome.

Animal data suggest that very high doses of zafirlukast may cause clastogenesis leading to malignancy. Some evidence of carcinogenesis (hepatocellular adenomas, histocytic sarcomas, and urinary bladder transitional cell papillomas) was noted in mice at roughly 30 times the maximum recommended human daily dosage and in rats at 160 times the maximum recommended human daily dosage based on comparative drug AUCs. No tumorigenic effects were noted in mice at doses 10 times the maximal recommended daily human oral dose. The clinical significance of these findings for the long-term use of zafirlukast is not known.

In a study of 39 children (6-14 years old) receiving a single dose of zafirlukast 20 mg or placebo for exercise-induced bronchoconstriction, fatigue (10% vs. 5%) was reported more often in the zafirlukast group. Fatigue, when accompanied by other symptoms such as abdominal pain, nausea, and flu-like symptoms, may be indicative of liver injury; if fatigue is persistent and other symptoms are present, prompt evaluation of hepatic function is warranted.

Zafirlukast is contraindicated in any patient with a known hypersensitivity to this agent or the inactive products in the formulation.

Zafirlukast is not effective for the treatment of acute asthma attacks, including status asthmaticus or acute bronchospasm. Zafirlukast is also not recommended to be used as monotherapy for exercise-induced bronchospasm (EIB). Advise patients to have appropriate rescue medication (e.g., inhaled beta-agonist) available. Zafirlukast therapy may be continued during the treatment of an acute asthmatic event. Patients should be advised not to stop taking or decrease the use of other asthma treatments when starting zafirlukast unless otherwise directed by their health care prescriber.

Zafirlukast is contraindicated in patients with hepatic impairment (hepatic disease). Similarly, do not use in patients with hepatitis or hepatic encephalopathy. Liver dysfunction is expected to result in significantly increased drug exposure. In addition, cases of elevated liver enzymes, hepatitis, and life-threatening hepatic failure have been reported with zafirlukast use. In most cases, the patient's symptoms and liver enzymes returned to normal or near normal after discontinuing zafirlukast, but in rare cases, patients have progressed to fulminant hepatitis or liver failure, which required transplantation or resulted in death. In extremely rare cases, patients had no clinical signs or symptoms of liver dysfunction preceding hepatic failure. Consider periodic serum transaminase (LFT) testing to monitor for possible hepatic injury, and advise patients to immediately report signs and symptoms of liver dysfunction (e.g., abdominal pain, jaundice, nausea, vomiting, dark urine). If such symptoms occur, discontinue therapy, assess liver function tests (LFTs), in particular serum ALT, and manage the patient accordingly. Do not resume zafirlukast if LFTs are consistent with hepatic dysfunction. Patients in whom zafirlukast was discontinued due to hepatic dysfunction, where no other attributable course is identified, should not be re-exposed to zafirlukast. The manufacturer states that reported hepatic events have occurred predominately in females.

Neuropsychiatric events, including insomnia, depression, suicidal ideation, and completed suicide, have been reported during use of leukotriene-receptor antagonist therapy in pediatric and adult patients. After a review of safety data by the FDA, the agency concluded that such events may be drug-related, possibly related to the leukotriene pathway. Available data are insufficient to characterize at-risk patients; however, it may be prudent to use these agents cautiously in patients with a history of depression or other psychiatric condition. Advise patients and caregivers to immediately report any neuropsychiatric events.

Use caution whenever oral corticosteroid withdrawal or dosage reduction is being considered in asthmatic patients. In rare cases, a systemic eosinophilic vasculitis consistent with Churg-Strauss syndrome has occurred in asthmatic patients receiving leukotriene-receptor antagonists. These events have most often been reported in association with oral corticosteroid dose reduction or corticosteroid withdrawal. Although a causal relationship to zafirlukast has not been established, prescribers should be alert to the presentation of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy in patients receiving montelukast. In addition, zafirlukast should not be abruptly substituted for inhaled or oral corticosteroids in asthma therapy. Inhaled corticosteroids are the preferred treatment for persistent asthma.

Description: Zafirlukast is an oral leukotriene receptor antagonist (LTRA). It is FDA-approved for the maintenance treatment of asthma, but it is also used off-label for the prevention of exercise-induced bronchoconstriction and the relief of allergic rhinitis. LTRAs are less effective than inhaled corticosteroids (ICSs) for asthma maintenance therapy; however, they may be of benefit in patients who are unwilling or unable to use ICS, experience intolerable ICS side effects, or have concomitant allergic rhinitis. LTRAs are an add-on therapy for severe asthma in adolescents and adults. In young children with asthma, LTRA therapy reduces symptoms and need for oral corticosteroids when compared with placebo. For the prevention of exercise-induced bronchoconstriction (EIB), LTRAs may be considered a first-line choice to add as a controller agent to an inhaled short-acting beta-2 agonist (SABA) to control EIB symptoms in patients who cannot be controlled by an inhaled SABA alone. Rhinitis guidelines suggest that LTRA not be used for initial treatment of allergic rhinitis due to reduced efficacy when compared to other agents. However, in patients with allergic rhinitis and comorbid asthma, LTRA could be an option after weighing the benefits of LTRA monotherapy versus an inhaled corticosteroid for asthma and an antihistamine or intranasal corticosteroid for allergic rhinitis. Zafirlukast has been shown to inhibit the activity of several hepatic cytochrome isoenzymes, which increases the risk of drug-drug interactions; the drug is also associated with rare, but sometimes serious, hepatic toxicity. Zafirlukast is FDA-approved for use in pediatric patients as young as 5 years of age.

For asthma maintenance treatment:
Oral dosage:
Children 5 to 11 years: 10 mg PO twice daily.
Children and Adolescents 12 to 17 years: 20 mg PO twice daily.

For exercise-induced bronchospasm prophylaxis*:
Oral dosage:
Children 5 to 11 years: Efficacy data are limited. 10 mg PO twice daily is the recommended dosing for controller therapy. Other regimens have been studied. Zafirlukast 5 to 40 mg PO as a single dose given 4 hours before an exercise challenge was studied in a double-blind, crossover study of 40 children 6 to 14 years old. Some experts recommend administration at least 2 hours before exercise for best effect.
Children and Adolescents 12 to 17 years: Efficacy data are limited. 20 mg PO twice daily is the recommended dosing for controller therapy. Other regimens have been studied. Zafirlukast 5 to 40 mg PO as a single dose given 4 hours before an exercise challenge was studied in a double-blind, crossover study of 40 children 6 to 14 years old. Some experts recommend administration at least 2 hours before exercise for best effect.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
Less than 5 years: Safety and efficacy have not been established.
5 to 11 years: 20 mg/day PO.
12 years: 40 mg/day PO.
-Adolescents
40 mg/day PO.

Patients with Hepatic Impairment Dosing
Use is contraindicated in patients with hepatic impairment.

Patients with Renal Impairment Dosing
It appears that no dosage adjustments are needed; zafirlukast is not significantly eliminated via the renal route.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Zafirlukast is a potent and selective and competitive antagonist of leukotriene types D4 (LTD4) and E4 (LTE4) at the cysteinyl leukotriene receptor, CysLT1, found in the human airway. The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are important intermediaries of allergic airway disease. They are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils, in response to allergens. The binding of cysteinyl leukotrienes to CysLT has been associated with asthma pathophysiology, including chemoattraction of eosinophils, stimulation of inflammatory mediators, increased endothelial membrane permeability leading to airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. Zafirlukast improves the signs and symptoms of asthma by inhibiting the physiologic actions of LTD4 at the CysLT1 receptor. Additionally, blockage of the LTD4 receptors results in bronchial relaxation.

In humans, zafirlukast inhibits inflammation and also inhibits bronchoconstriction mediated by various inhalational challenges, including: cold-air; allergens like cat dander, ragweed and grass or mixed antigen exposures; sulfur dioxide; and exercise. In patients with asthma, the clinical outcomes (improvements in FEV1 or control of symptoms) resulting from the use of zafirlukast may exhibit large inter-patient variability.

Pharmacokinetics: Zafirlukast is administered orally. Zafirlukast is moderately distributed into the tissues and has a volume of distribution of approximately 70 L in adults. It is greater than 99% protein bound, predominantly albumin. Animal studies (rat) have demonstrated minimal distribution across the blood-brain-barrier. Zafirlukast is extensively metabolized. The most common metabolic products are hydroxylated metabolites that are formed through the hepatic cytochrome P450 CYP2C9 isoenzyme. These metabolites are at least 90 times less potent than the parent drug. Hydroxylated metabolites are excreted in the feces. Urinary excretion accounts for 10% of a zafirlukast dose, but the parent drug is not detected in the urine. In adults, the apparent clearance of zafirlukast is approximately 20 L/h, and the mean terminal elimination half-life is approximately 10 hours (range, 8 to 16 hours).

Affected cytochrome P450 enzymes: CYP2C8, CYP2C9, CYP3A4, and possibly CYP1A2
Zafirlukast has been shown in vitro to inhibit the activity of CYP2C8 (potent inhibitor), CYP2C9 (moderate to potent inhibitor), and CYP3A4 (minor inhibitor) ; however, in vivo data do not substantiate clinically relevant interactions with 2C8 substrates. Pharmacokinetic alterations have been reported when zafirlukast and known 2C9 and 3A4 substrates are used in combination. Furthermore, while in vitro and in vivo study data are lacking, isolated reports of CYP1A2-metabolized medication toxicity after zafirlukast initiation have been published ; the mechanism of interaction is unknown. According to the manufacturer, zafirlukast is a substrate of the isoenzyme 2C9 in vitro. Zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP1A2, CYP2C8, CYP2C9, and CYP3A4, particularly when such drugs have narrow therapeutic ranges, and in patients also receiving medications that may affect CYP2C9 function.


-Route-Specific Pharmacokinetics
Oral Route
Zafirlukast is rapidly absorbed after oral administration; peak plasma concentrations occur within 3 hours after dosing. The absolute bioavailability of zafirlukast is unknown. Because food reduces the bioavailability of zafirlukast by roughly 40%, the drug should be taken either 1 hour before or 2 hours after meals. In clinical trials of patients with asthma, improvement of symptoms was noted within 1 week of beginning therapy.


-Special Populations
Pediatrics
Children
At an identical dosage (i.e., not weight-adjusted), children 5 years of age and older exhibit greater systemic exposure to zafirlukast and decreased clearance when compared to adults and adolescents 12 years of age and older. To maintain similar exposure compared to adults, a lower dose is recommended in children 5 to 11 years of age.

After administration of a single 20 mg dose to pediatric patients, the following mean pharmacokinetic parameters were calculated :
Children 5 to 6 years (n = 29)
Cmax: 756 ng/mL (for comparison, adult value = 326 ng/mL after the same dose)
Tmax: 2.1 hours (similar to adult mean of two hours)
AUC: 2458 ng x h/mL (for comparison, adult value = 1137 ng x h/mL after the same dose)
CL: 9.2 L/h (for comparison, adult value = 19.4 L/h after the same dose)
Children 7 to 11 years (n = 20)
Cmax: 601 ng/mL (for comparison, adult value = 326 ng/mL after the same dose)
Tmax: 2.5 hours (similar to adult mean of 2 hours)
AUC: 2027 ng x h/mL (for comparison, adult value = 1137 ng x h/mL after the same dose)
CL: 11.4 L/h (for comparison, adult value = 19.4 L/h after the same dose)

Hepatic Impairment
Patients with liver dysfunction (as studied in patients with biopsy-proven, stable alcoholic cirrhosis) have reduced drug clearance and a 50 to 60% greater Cmax and AUC of zafirlukast compared to those of normal adults. Use of this medication is contraindicated in patients with hepatic impairment.

Renal Impairment
Renal impairment does not affect the pharmacokinetics of zafirlukast.