Introduction
Zyflo (zileuton) is an oral leukotriene synthesis inhibitor approved for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. As a first-in-class 5-lipoxygenase inhibitor, Zyflo represents a unique therapeutic approach to asthma management by targeting the leukotriene pathway, which plays a significant role in the inflammatory process of asthma.
Mechanism of Action
Zileuton inhibits 5-lipoxygenase, the enzyme that catalyzes the conversion of arachidonic acid to leukotriene A4 (LTA4). This action prevents the formation of leukotriene B4 (LTB4) and the cysteinyl leukotrienes (LTC4, LTD4, and LTE4). These inflammatory mediators contribute to asthma pathophysiology through bronchoconstriction, increased vascular permeability, mucus secretion, and eosinophil recruitment. By blocking their production, zileuton reduces airway inflammation and bronchoconstriction.
Indications
- Prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older
- Not indicated for use in the reversal of acute asthma attacks
Dosage and Administration
Standard dosing: 600 mg orally four times daily Formulations: 600 mg extended-release tablets (Zyflo CR) Administration: Should be taken regularly, even during symptom-free periods Special populations:- Hepatic impairment: Contraindicated in patients with active liver disease
- Renal impairment: No dosage adjustment necessary
- Geriatric patients: Use with caution
- Pediatric patients: Safety and effectiveness not established in children <12 years
Pharmacokinetics
Absorption: Rapidly absorbed after oral administration; bioavailability approximately 94% Distribution: 93% protein-bound, primarily to albumin Metabolism: Extensively metabolized hepatically via cytochrome P450 enzymes (primarily CYP1A2, 2C9, and 3A4) Elimination: Primarily renal excretion (94.5%) with mean elimination half-life of 2.5 hours Food effects: No significant effect on absorptionContraindications
- Active liver disease or persistent ALT elevations ≥3 times ULN
- History of hypersensitivity to zileuton or any component of the formulation
- Concurrent use with terfenadine, theophylline, or warfarin (due to potential interactions)
Warnings and Precautions
Hepatotoxicity: Can cause elevated liver enzymes; monitor ALT before treatment, once monthly for first 3 months, every 2-3 months for remainder of first year, and periodically thereafter Neuropsychiatric events: May cause sleep disturbances, behavior changes, agitation, or depression Not for acute attacks: Should not be used to treat acute bronchospasm Churg-Strauss syndrome: Rare cases of eosinophilic conditions have been reported with leukotriene modifiers Pregnancy: Category C - use only if potential benefit justifies potential risk Lactation: Excreted in breast milk; use caution when administering to nursing womenDrug Interactions
Theophylline: Zileuton increases theophylline concentrations by approximately 75% Warfarin: Increases prothrombin time; monitor INR closely Propranolol: Increases propranolol concentrations by approximately 40% Terfenadine: Contraindicated due to increased terfenadine concentrations CYP1A2, 2C9, and 3A4 substrates: May increase concentrations of drugs metabolized by these enzymesAdverse Effects
Common (≥5%):- Headache (18%)
- Dyspepsia (8%)
- Nausea (5%)
- Abdominal pain (5%)
- Asthenia (5%)
- Hepatotoxicity (elevated transaminases)
- Neuropsychiatric events (agitation, depression, suicidal ideation)
- Hypersensitivity reactions
- Eosinophilic conditions
Monitoring Parameters
- Liver function tests (ALT) at baseline, monthly for 3 months, then every 2-3 months for first year, periodically thereafter
- Asthma symptoms and pulmonary function
- Mental status and behavior changes
- INR in patients taking warfarin
- Theophylline levels if co-administered
- Signs of hypersensitivity reactions
Patient Education
- Take medication regularly as prescribed, even when feeling well
- Do not use for acute asthma attacks; keep rescue medication available
- Report any signs of liver problems (nausea, fatigue, jaundice, dark urine)
- Report mood changes, depression, or unusual behaviors
- Inform all healthcare providers about all medications being taken
- Do not stop taking without consulting your healthcare provider
- Regular follow-up appointments are necessary for monitoring
References
1. Zyflo [package insert]. Lexington, MA: Chiesi USA, Inc.; 2021. 2. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07-4051. Bethesda, MD: National Institutes of Health; 2007. 3. Drugs.com. Zileuton Professional Monograph. Updated 2023. 4. Micromedex Solutions. Zileuton Drug Information. Truven Health Analytics, Inc. 5. Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007;357(18):1841-1854. 6. US Food and Drug Administration. Zyflo approval documents. Accessed through Drugs@FDA.