Accolate (Zafirlukast)
zafirlukast
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Asthma — prophylaxis and chronic treatment | Adults and children ≥5 years | Controller (monotherapy or adjunctive) | FDA Approved |
Zafirlukast is positioned as a controller medication for persistent asthma. According to the GINA guidelines, leukotriene receptor antagonists serve as an alternative to low-dose inhaled corticosteroids for mild persistent asthma or as add-on therapy when inhaled corticosteroids alone provide insufficient control. Zafirlukast is not a bronchodilator and has no role in treating acute bronchospasm or status asthmaticus. Improvement in symptoms typically begins within the first week of regular use.
Chronic urticaria — Used as adjunctive therapy when antihistamines provide inadequate relief. Evidence quality: Low.
Exercise-induced bronchospasm (prevention) — Single pre-exercise dose may attenuate bronchoconstriction. Evidence quality: Moderate.
Allergic rhinitis — Limited data supporting use as adjunct to intranasal corticosteroids. Evidence quality: Low.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Persistent asthma — adults and adolescents (≥12 yr) | 20 mg BID | 20 mg BID | 40 mg/day | No titration required; flat-dose regimen Take 1 h before or 2 h after meals |
| Persistent asthma — children (5–11 yr) | 10 mg BID | 10 mg BID | 20 mg/day | Dose reflects higher weight-adjusted clearance in children Same food-timing requirement applies |
| Asthma in elderly (≥65 yr) | 20 mg BID | 20 mg BID | 40 mg/day | Clearance reduced 2–3-fold; Cmax and AUC elevated No formal dose reduction but monitor closely for adverse effects |
| Exercise-induced bronchospasm prevention (off-label) | 20 mg BID | 20 mg BID | 40 mg/day | Scheduled dosing; not suitable for as-needed pre-exercise use Adjunctive to rescue inhaler |
Food reduces zafirlukast bioavailability by approximately 40%. The consistent instruction is to take each dose on an empty stomach, at least one hour before or two hours after eating. Poor adherence to this timing is a common cause of sub-optimal response.
Pharmacology
Mechanism of Action
Zafirlukast is a selective, competitive antagonist of the cysteinyl leukotriene receptors CysLT1. It blocks the binding of leukotriene D4 (LTD4) and leukotriene E4 (LTE4), which are potent pro-inflammatory mediators released from mast cells, eosinophils, and other cells in the asthmatic airway. These leukotrienes are key components of the slow-reacting substance of anaphylaxis (SRSA) and drive bronchoconstriction, mucosal edema, increased vascular permeability, and eosinophil recruitment. By occupying the CysLT1 receptor, zafirlukast attenuates both early- and late-phase asthmatic responses to allergen challenge and reduces bronchial hyperresponsiveness to a range of provocative stimuli including cold air, sulfur dioxide, and inhaled antigens. Asthmatic individuals are 25–100 times more sensitive to inhaled LTD4 than non-asthmatic subjects, underscoring the clinical relevance of this pathway.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid oral absorption; Tmax ~3 h; absolute bioavailability unknown; food reduces exposure ~40% | Must be taken on an empty stomach to ensure consistent drug levels |
| Distribution | Vss/F ~70 L; >99% protein bound (albumin); minimal CNS penetration | High protein binding means interactions with other highly bound drugs are theoretically possible but not clinically significant at usual doses |
| Metabolism | Extensive hepatic metabolism via CYP2C9; hydroxylated metabolites ≥90-fold less potent; also inhibits CYP3A4 and CYP2C9 | CYP2C9 inhibitors (e.g., fluconazole) increase zafirlukast exposure; zafirlukast itself can potentiate warfarin and other CYP2C9 substrates |
| Elimination | CL/f ~20 L/h; t½ ~10 h (range 8–16 h); ~10% urinary (as metabolites), ~90% faecal (biliary excretion); ~45% accumulation at steady state | Twice-daily dosing achieves stable steady-state levels; no dose adjustment needed for renal impairment |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | 12.9% | Similar to placebo rate (11.7%); rarely treatment-limiting; consider analgesics if persistent |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Infection | 3.5% | Mostly mild upper and lower respiratory tract infections; higher in patients >55 yr and those on concurrent inhaled corticosteroids |
| Nausea | 3.1% | Often transient; may improve by ensuring the tablet is taken with water despite fasting requirement |
| Diarrhoea | 2.8% | Typically mild and self-limiting |
| Generalised pain | 1.9% | Non-specific; similar rate to placebo (1.7%) |
| Asthenia | 1.8% | Consider hepatic evaluation if fatigue is progressive or persistent |
| Abdominal pain | 1.8% | Right upper quadrant pain warrants immediate hepatic work-up |
| Dizziness | 1.6% | Similar to placebo; usually does not limit activity |
| Myalgia | 1.6% | Monitor for features of systemic eosinophilia or vasculitis if accompanied by rash |
| Fever | 1.6% | Evaluate for intercurrent infection; higher background infection rate exists in this population |
| Vomiting | 1.5% | May reduce drug absorption; re-dose if vomiting occurs within 1 hour of administration |
| ALT (SGPT) elevation | 1.5% | Most elevations occurred at supra-therapeutic doses; any elevation warrants close follow-up given hepatotoxicity risk |
| Back pain | 1.5% | Non-specific musculoskeletal complaint; comparable to placebo |
| Dyspepsia | 1.3% | Taking with a full glass of water on an empty stomach may help |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatotoxicity (hepatitis, fulminant hepatic failure) | Rare | Weeks to months; reported predominantly in females | Discontinue immediately; measure serum ALT urgently; do not rechallenge. Liver transplant and death have been reported. |
| Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) | Very rare | Weeks to months; often coinciding with corticosteroid taper | Discontinue zafirlukast; obtain eosinophil count, CRP, and chest imaging; refer to rheumatology; systemic corticosteroids typically required |
| Hypersensitivity reactions (angioedema, urticaria, blistering rash) | Rare | Any time during therapy | Discontinue permanently; manage with antihistamines/epinephrine as needed |
| Neuropsychiatric events (insomnia, depression, suicidal ideation) | Rare (class-wide signal) | Variable; reported at any point | Evaluate risk-benefit; consider discontinuation if mood/behavioural changes persist; refer for psychiatric assessment if indicated |
| Agranulocytosis | Very rare (post-marketing) | Variable | Obtain urgent CBC; discontinue zafirlukast; infection precautions |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Hepatic events | Rare | Elevations more frequent at supra-therapeutic doses (4x recommended); permanent discontinuation required if hepatic dysfunction confirmed |
| Gastrointestinal intolerance | Uncommon | Nausea, diarrhoea, and abdominal pain occasionally led to withdrawal |
| Hypersensitivity | Rare | Angioedema, urticaria, or blistering rash requires permanent cessation |
Educate every patient about symptoms of liver injury: right upper quadrant pain, nausea, fatigue, dark urine, pruritus, and jaundice. If any of these develop, zafirlukast must be stopped immediately and serum ALT measured urgently. Patients withdrawn for hepatotoxicity should never be re-exposed to the drug. Periodic liver function testing has not been proven to prevent serious liver injury but may allow earlier detection.
Drug Interactions
Zafirlukast is metabolised primarily by CYP2C9 and is itself an inhibitor of CYP2C9 and CYP3A4 at clinically relevant concentrations. This dual role—as both substrate and inhibitor—creates interactions in both directions.
Monitoring
-
Liver Function (ALT)
Consider at baseline; urgently if symptoms develop
Trigger-based Periodic LFT screening has not been proven to prevent severe hepatic injury, but early detection of transaminase elevation allows prompt drug withdrawal. Measure ALT immediately if the patient reports right upper quadrant pain, fatigue, nausea, jaundice, or pruritus. -
INR / Prothrombin Time
At initiation (if on warfarin), then closely thereafter
Routine Zafirlukast increases S-warfarin exposure substantially. Check INR within 3–5 days of starting or stopping zafirlukast in warfarin-treated patients and adjust the anticoagulant dose accordingly. -
Asthma Control
Every 1–3 months
Routine Assess symptom frequency, rescue inhaler use, and lung function (FEV1 or PEF). If control is inadequate after 4–6 weeks, consider stepping up therapy (e.g., adding or increasing inhaled corticosteroid). -
Eosinophil Count
If vasculitis symptoms arise
Trigger-based New-onset rash, worsening pulmonary symptoms, neuropathy, or cardiac complications—especially during corticosteroid taper—should prompt a full blood count with differential to exclude eosinophilic granulomatosis with polyangiitis (EGPA). -
Neuropsychiatric Status
Each visit
Routine Ask about mood changes, insomnia, and depression at every follow-up. Instruct patients and caregivers (especially for paediatric patients) to report behavioural or mood changes promptly. -
Theophylline Levels
Within 1–2 weeks of co-initiation
Trigger-based Rare post-marketing cases of elevated theophylline levels have been reported despite formal studies showing no pharmacokinetic effect. Check theophylline levels if toxicity symptoms (tremor, tachycardia, nausea) appear.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to zafirlukast or any inactive ingredient (croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, povidone, hypromellose, titanium dioxide)
- Hepatic impairment including hepatic cirrhosis—zafirlukast is extensively hepatically metabolised and has caused life-threatening liver failure
- Breastfeeding—zafirlukast is excreted in breast milk and the manufacturer contraindicates use during lactation due to tumourigenicity signals in animal studies
Relative Contraindications (Specialist Input Recommended)
- History of hepatic enzyme elevation on any LTRA—rechallenge not recommended; consider alternative controller therapy
- Concurrent high-dose warfarin therapy—if unavoidable, requires very close INR monitoring and likely dose adjustment
- Patients undergoing corticosteroid taper—unmasking of eosinophilic conditions (EGPA) has been reported; taper corticosteroids cautiously and monitor for systemic eosinophilia
Use with Caution
- Elderly patients (≥65 yr)—drug clearance is 2–3-fold lower, resulting in higher systemic exposure; increased infection risk observed
- Pregnancy—Category B; use only if clearly needed; no adequate human data
- Children <5 years—safety and efficacy not established
- Co-administration with CYP2C9 substrates (phenytoin, tolbutamide)—monitor for increased substrate effects
Cases of life-threatening hepatic failure, including cases requiring liver transplantation and resulting in death, have been reported in patients receiving zafirlukast at the recommended dose of 40 mg/day. Hepatic events have occurred predominantly in females. Patients should be instructed to report symptoms of hepatic dysfunction immediately. If hepatic dysfunction is suspected, zafirlukast should be discontinued and liver function tests obtained. Patients should not be re-exposed to zafirlukast after hepatotoxicity.
The FDA has evaluated neuropsychiatric events associated with the leukotriene modifier class, including zafirlukast. Post-marketing reports include depression, insomnia, and behavioural changes. The FDA concluded that some neuropsychiatric events reported with zafirlukast appear consistent with a drug-induced effect. Clinicians should alert patients and caregivers to monitor for mood or behavioural changes and report them promptly.
Patient Counselling
Purpose of Therapy
Zafirlukast is a controller medication that reduces airway inflammation to prevent asthma symptoms. It works by blocking inflammatory chemicals called leukotrienes. It does not provide immediate relief during an asthma attack—patients must always carry a separate rescue inhaler (e.g., salbutamol/albuterol) for acute symptoms.
How to Take
Take one tablet twice daily, at least one hour before or two hours after eating. Food significantly reduces the amount of drug absorbed. Take the tablet with a full glass of water. Continue taking zafirlukast every day, even when feeling well. Do not stop or reduce any other asthma medications unless instructed by your prescriber.
Sources
- AstraZeneca. Accolate (zafirlukast) tablets prescribing information. Revised 11/2013. FDA Label Primary source for all dosing, pharmacokinetic parameters, adverse event incidence rates, contraindications, and drug interaction data cited in this monograph.
- FDA Drug Safety Communication: FDA Requires Boxed Warning About Serious Mental Health Side Effects for Asthma and Allergy Drug Montelukast (Singulair); Updated to Include All Leukotriene Modifiers. March 2020. FDA.gov Regulatory basis for the class-wide neuropsychiatric warning applied to all leukotriene modifiers including zafirlukast.
- Fish JE, Kemp JP, Lockey RF, et al. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. Clin Ther. 1997;19(4):675–690. doi:10.1016/S0149-2918(97)80090-3 One of the three pivotal US trials (N=1380) demonstrating efficacy of zafirlukast 20 mg BID over placebo for daytime symptoms, rescue inhaler use, and FEV1.
- Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med. 1994;150(3):618–623. doi:10.1164/ajrccm.150.3.8087329 Early dose-ranging study establishing the clinical efficacy of zafirlukast (then ICI 204,219) across multiple dose levels.
- Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2024 Update. ginasthma.org Positions LTRAs as alternative controller therapy to low-dose ICS in Step 2 of the asthma management ladder.
- National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07–4051. 2007. NHLBI US guideline positioning LTRAs as alternative (not preferred) Step 2 monotherapy in mild persistent asthma.
- ACOG Practice Bulletin No. 90: Asthma in Pregnancy. Obstet Gynecol. 2008;111(2 Pt 1):457–464. Supports use of LTRAs as alternatives to long-acting beta-agonists in pregnant women with moderate-to-severe asthma.
- Dahlen SE, Hedqvist P, Hammarstrom S, Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature. 1980;288:484–486. doi:10.1038/288484a0 Foundational study demonstrating cysteinyl leukotrienes as potent bronchoconstrictors, providing the pharmacological rationale for LTRA development.
- Lynch KR, O’Neill GP, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999;399:789–793. doi:10.1038/21658 Molecular characterisation of the CysLT1 receptor, zafirlukast’s primary pharmacological target.
- Dhaliwal A, Bajaj T. Zafirlukast. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Updated August 17, 2023. NCBI Bookshelf Comprehensive clinical review covering pharmacokinetics in special populations (paediatric, elderly, hepatic/renal impairment) and off-label applications.
- Dekhuijzen PNR, Koopmans PP. Pharmacokinetic profile of zafirlukast. Clin Pharmacokinet. 2002;41(2):105–114. doi:10.2165/00003088-200241020-00003 Detailed PK review confirming CYP2C9-mediated metabolism, food effect, protein binding, and the basis for twice-daily dosing.
- Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and Churg-Strauss syndrome: adverse effect or response to corticosteroid withdrawal? Drug Saf. 1999;21(4):241–251. doi:10.2165/00002018-199921040-00001 Critical analysis of the association between LTRA use and Churg-Strauss syndrome, concluding that unmasking during corticosteroid taper is the most likely explanation.