zafirlukast
Brand: Accolate
Prototype: montelukast
Drug Class: leukotriene receptor antagonist (LTRA)
Drug Family: leukotriene modifier
Subclass: oral competitive cysteinyl leukotriene receptor antagonist
Organ Systems: respiratory
Mechanism of Action
Competitive antagonist at CysLT1 receptors in airway smooth muscle and inflammatory cells; blocks leukotriene D4 and E4 (products of the 5-lipoxygenase pathway acting on arachidonic acid), preventing bronchoconstriction, airway edema, increased mucus secretion, and eosinophil recruitment.
cysteinyl leukotriene CysLT1 receptor
Indications
- persistent asthma (maintenance therapy, adults and children 5 years and older)
- prophylaxis of exercise-induced bronchospasm
Contraindications
- hepatic impairment (metabolized by CYP2C9; increased hepatotoxicity risk)
- hypersensitivity
Adverse Effects
Common
- headache
- nausea
- diarrhea
- infection
Serious
- hepatotoxicity (rare but potentially fatal — cases reported)
- Churg-Strauss syndrome (eosinophilic vasculitis — with corticosteroid tapering)
- neuropsychiatric events (rare: insomnia, behavioral changes)
Pharmacokinetics (ADME)
| Absorption | oral; reduced by food (40% reduction in Cmax and AUC) — take on empty stomach |
| Distribution | Vd approximately 70 L; >99% protein bound |
| Metabolism | extensive hepatic CYP2C9 metabolism to inactive hydroxylated metabolites; also a CYP2C9 inhibitor |
| Excretion | fecal (~89%) and renal (~10%) |
| Half-life | approximately 10 hours |
| Onset | days for optimal anti-inflammatory effect |
| Peak | 3 hours |
| Duration | 12 hours (requires twice-daily dosing — unlike montelukast) |
| Protein Binding | >99% |
| Vd | approximately 70 L |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| warfarin | zafirlukast inhibits CYP2C9; increases warfarin plasma levels and anticoagulant effect — monitor INR | major |
| aspirin | increases zafirlukast plasma levels by approximately 45% | moderate |
| erythromycin and theophylline | decrease zafirlukast plasma levels; may reduce efficacy | moderate |
Nursing Considerations
- Administer on an empty stomach (1 hour before or 2 hours after meals) as food significantly reduces drug absorption; this twice-daily fasting requirement is a key adherence challenge compared with once-daily montelukast.
- Monitor liver enzymes at baseline and if symptoms of hepatotoxicity develop (jaundice, right upper quadrant pain, fatigue); discontinue if hepatotoxicity is confirmed.
- Closely monitor warfarin INR when zafirlukast is initiated or discontinued; CYP2C9 inhibition raises warfarin levels and may require warfarin dose reduction.
- Educate patients about neuropsychiatric risks (insomnia, anxiety, behavioral changes) — though primarily associated with montelukast, any LTRA can potentially cause these effects; report changes promptly.
Clinical Pearls
- Zafirlukast requires twice-daily fasting administration, placing it at an adherence disadvantage compared with once-daily montelukast; most prescribers prefer montelukast for long-term LTRA therapy, reserving zafirlukast for specific cases or formulary requirements.
- The CYP2C9 inhibitory effect of zafirlukast on warfarin metabolism is clinically significant and has caused serious bleeding events; the warfarin interaction is a key differentiator from montelukast and a priority patient safety consideration.
Safety Profile
Pregnancy generally-safe
Lactation use-with-caution
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.