Asthma, maintenance therapy (alternative agent):
Note: In patients with mild asthma, may be used as an alternative first-line controller therapy in those who cannot take an inhaled corticosteroid (ICS). In patients with moderate to severe asthma, may be used as an adjunctive controller therapy in those with inadequate symptom control on an ICS (GINA 2021).
Oral: 20 mg twice daily. Some experts suggest waiting 1 to 2 months before assessing efficacy (Boyce 2021).
Chronic urticaria (off-label use): Oral: 20 mg twice daily (Bagenstose 2004).
No dosage adjustment necessary.
Use is contraindicated.
(For additional information see "Zafirlukast: Pediatric drug information")
Asthma; chronic: Oral:
Children 5 to 11 years: 10 mg twice daily
Children ≥12 years and Adolescents: 20 mg twice daily
No dosage adjustment necessary.
Use is contraindicated.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Accolate: 10 mg, 20 mg
Generic: 10 mg, 20 mg
Yes
Oral: Administer at least 1 hour before or 2 hours after a meal.
Oral: Administer at least 1 hour before or 2 hours after a meal
Asthma, maintenance therapy: Prophylaxis and chronic treatment of asthma in adults and children ≥5 years of age.
Chronic urticaria
Accolate may be confused with Accupril, Accutane, Aclovate
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidences reported in children ≥12 years and adults unless otherwise specified.
>10%: Central nervous system: Headache (13%; children 5 to 11 years: 5%)
1% to 10%:
Central nervous system: Dizziness (2%), pain (2%)
Gastrointestinal: Nausea (3%), diarrhea (3%), abdominal pain (2%; children 5 to 11 years: 3%), vomiting (2%), dyspepsia (1%)
Hepatic: Increased serum ALT (2%)
Infection: Infection (4%)
Neuromuscular & skeletal: Back pain (2%), myalgia (2%), weakness (2%)
Miscellaneous: Fever (2%)
<1%, postmarketing, and/or case reports: Agranulocytosis, angioedema, arthralgia, bruise, depression, edema, eosinophilia (systemic), eosinophilic pneumonitis, hemorrhage, hepatic failure, hepatitis, hyperbilirubinemia, hypersensitivity reaction, insomnia, malaise, pruritus, skin rash, urticaria, vasculitis (with clinical features of eosinophilic granulomatosis with polyangiitis [formerly known as Churg-Strauss]; rare)
Hypersensitivity to zafirlukast or any component of the formulation; hepatic impairment (including hepatic cirrhosis)
Canadian labeling: Additional contraindications (not in US labeling): Patients in whom zafirlukast was discontinued due to treatment related hepatotoxicity
Concerns related to adverse effects:
• Eosinophilia and vasculitis: In rare cases, patients may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss), a condition which is often treated with systemic corticosteroid therapy. Healthcare providers should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between zafirlukast and these underlying conditions has not been established.
• Hepatotoxicity: Serious hepatic adverse events (including hepatitis, hyperbilirubinemia, and hepatic failure) have been reported with use; female patients may be at greater risk. Periodic testing of liver function may be considered (early detection coupled with therapy discontinuation is generally believed to improve the likelihood of recovery). Advise patients to be alert for and to immediately report symptoms (eg, anorexia, right upper quadrant abdominal pain, nausea). If hepatic dysfunction is suspected (due to clinical signs/symptoms), discontinue use immediately and measure liver function tests (particularly ALT); resolution observed in most but not all cases upon discontinuation of therapy. Do not resume or restart if hepatic function studies indicate dysfunction. Use in patients with hepatic impairment (including hepatic cirrhosis) is contraindicated.
• Infections: An increased proportion of patients >55 years of age 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.
• Neuropsychiatric events: Postmarketing reports of behavioral changes (ie, depression, insomnia) have been noted. Instruct patients to report neuropsychiatric symptoms/events during therapy.
Concurrent drug therapy issues:
• Warfarin: Concomitant use with warfarin results in a clinically significant increase in INR; closely monitor INR with concurrent use.
Special populations:
• Elderly: Clearance is decreased in elderly patients; Cmax and AUC are increased approximately two- to threefold in adults ≥65 years compared to younger adults; however, no dosage adjustments are recommended in this age group.
Other warnings/precautions:
• Reversal of bronchospasm: Not approved for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus; therapy can be continued during acute exacerbations of asthma.
Substrate of CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C9 (weak)
Erythromycin (Systemic): May decrease the serum concentration of Zafirlukast. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Risk X: Avoid combination
Theophylline Derivatives: May decrease the serum concentration of Zafirlukast. Zafirlukast may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
TOLBUTamide: CYP2C9 Inhibitors (Weak) may increase the serum concentration of TOLBUTamide. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): CYP2C9 Inhibitors (Weak) may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Food decreases bioavailability of zafirlukast by 40%. Management: Take on an empty stomach 1 hour before or 2 hours after meals.
Information related to the use of zafirlukast in pregnancy is limited (Bakhireva 2007).
Uncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes) (ERS/TSANZ [Middleton 2020]; GINA 2020).
Agents other than zafirlukast are preferred for the treatment of asthma in pregnancy (ERS/TSANZ [Middleton 2020]; GINA 2020).
Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant females in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (1-877-311-8972 or https://mothertobaby.org). Patients may also enroll themselves.
Zafirlukast is present in breast milk.
In women receiving zafirlukast 40 mg twice daily, maternal serum concentrations were 225 ng/mL and breast milk concentrations were 50 ng/mL. Due to the potential for adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Monitor for improvements in air flow; monitor closely for sign/symptoms of hepatic injury; periodic monitoring of LFTs may be considered (not proved to prevent serious injury, but early detection may enhance recovery)
Zafirlukast is a selectively and competitive leukotriene-receptor antagonist (LTRA) 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.
Asthma symptom improvement:
Onset of action: Peak effect: 2 to 6 weeks
Duration: 12 hours
Absorption: Rapid
Distribution: Vdss: ~70 L
Protein binding: >99%, primarily to albumin
Metabolism: Extensively hepatic via CYP2C9
Bioavailability: Reduced 40% with food
Half-life elimination: ~10 hours (range: 8 to 16 hours)
Time to peak, serum: Children: 2 to 2.5 hours; Adults: 3 hours
Excretion: Feces (~90%); Urine (~10%)
Clearance: Children 5 to 6 years: 9.2 L/hour; Children 7 to 11 years: 11.4 L/hour; Adults: 20 L/hour
Hepatic function impairment: Approximately 50% to 60% greater Cmax and AUC compared with healthy subjects.
Geriatric: In patients older than 65 years of age, there are about 2- to 3-fold greater Cmax and AUC compared with young adults.
Tablets (Accolate Oral)
10 mg (per each): $4.55
20 mg (per each): $4.55
Tablets (Zafirlukast Oral)
10 mg (per each): $2.05 - $4.10
20 mg (per each): $2.05 - $4.10
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