Zileuton (Monograph)

Brand names: Zyflo, Zyflo CR
Drug class: Leukotriene Modifiers
- Leukotriene Synthesis Inhibitors
VA class: RE109
Molecular formula: C₁₁H₁₂N₂O₂S
CAS number: 111406-87-2

Medically reviewed by Drugs.com on Apr 14, 2025. Written by ASHP.

Introduction

Antiasthmatic agent; a leukotriene synthesis inhibitor.

Uses for Zileuton

Asthma

Prevention and long-term symptomatic management of asthma; used as an alternative, but not preferred adjunctive therapy.

In patients with mild persistent asthma, low-dose orally inhaled corticosteroids considered first-line agents for long-term control. Alternative agents, including certain leukotriene modifiers (i.e., montelukast, zafirlukast), may be used but are less effective than inhaled corticosteroids and are not preferred as initial therapy.

In patients with moderate persistent asthma, low-dose inhaled corticosteroids with a long-acting inhaled β₂-agonist bronchodilator (e.g., salmeterol, formoterol) or monotherapy with medium-dose inhaled corticosteroids preferred. However, the National Asthma Education and Prevention Program recommends that the beneficial effects of long-acting inhaled β₂-agonists be weighed carefully against increased risk of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.

Alternative agents, including certain leukotriene modifiers (i.e., montelukast, zafirlukast), can be added to a low dosage of inhaled corticosteroid for treatment of moderate persistent asthma, but these options are less effective. Considerations favoring combination with orally inhaled corticosteroids include intolerance to long-acting β₂-adrenergic agonists, marked preference for oral therapy, and demonstration of superior responsiveness to these leukotriene modifiers.

Not recommended for relief of acute bronchospasm; however, may continue therapy during acute asthma exacerbations. (See Acute Asthma under Cautions.)

Zileuton Dosage and Administration

Administration

Oral Administration

Conventional (immediate-release) tablets: Administer orally in 4 equally divided doses daily without regard to meals. May be swallowed whole or cut in half.

Extended-release tablets: Administer orally in 2 equally divided doses daily. Give within 1 hour after morning and evening meals. Swallow tablets whole; do not chew, cut, or crush. If a dose is missed, do not administer a double dose; take next dose at the regularly scheduled time.

Dosage

Pediatric Patients

Asthma

Oral

Conventional (immediate-release) tablets: 600 mg 4 times daily in children ≥12 years of age.

Extended-release tablets: 1.2 g twice daily in children ≥12 years of age.

Adults

Asthma

Oral

Conventional (immediate-release) tablets: 600 mg 4 times daily.

Extended-release tablets: 1.2 g twice daily.

Prescribing Limits

Pediatric Patients

Asthma

Oral

Children ≥12 years of age: Maximum 2.4 g daily as conventional (immediate-release) or extended-release tablets.

Adults

Asthma

Oral

Maximum 2.4 g daily as conventional (immediate-release) or extended-release tablets.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. Do not use in patients with active liver disease or transaminases ≥3 times the ULN. (See Contraindications and also Hepatic Effects under Cautions.)

Renal Impairment

Dosage adjustment not required.

Geriatric Patients

Dosage adjustment not required.

Cautions for Zileuton

Contraindications

Active liver disease or serum aminotransferase concentrations ≥3 times the ULN. (See Hepatic Effects under Cautions.)

Known hypersensitivity to zileuton or any ingredient in the formulation.

Warnings/Precautions

Warnings

Acute Asthma

Do not use for the relief of acute bronchospasm (including status asthmaticus); zileuton can be continued during acute exacerbations of asthma, but it will not provide immediate symptomatic relief.

Interactions

Possible serious and/or life-threatening events associated with concomitant use with drugs dependent on CYP isoenzymes for metabolism (e.g., theophylline, propranolol, warfarin). (See Specific Drugs under Interactions.)

General Precautions

Hepatic Effects

Associated with increases in serum aminotransferase values (e.g., serum ALT); generally occurs within the first 3 months of therapy. Possible increased risk for ALT elevations in patients with preexisting aminotransferase elevations and women ≥65 years of age receiving immediate-release zileuton.

Perform liver function tests (serum ALT) before initiating therapy, then once a month for 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter. Discontinue therapy if signs or symptoms of liver dysfunction (e.g., right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, “flu-like” symptoms) occur or serum ALT concentrations increase to ≥5 times the ULN; monitor serum ALT concentrations until they return to normal.

Use contraindicated in patients with active liver disease or serum ALT concentrations ≥3 times the ULN. (See Contraindications under Cautions.) Use with caution in patients who consume large quantities of alcohol, those with mild hepatic impairment (serum ALT <3 times the ULN), and those with history of liver disease.

Neuropsychiatric Effects

Neuropsychiatric events reported with zileuton during postmarketing experience. Data from placebo-controlled trials with leukotriene modifiers indicate that suicidal ideation occurred in 0.01% of 9929 patients treated with montelukast and in none of those receiving other leukotriene modifiers; no completed suicide occurred during therapy with any leukotriene modifier. FDA concluded that some neuropsychiatric events reported with zileuton (e.g., sleep disorders, behavior changes) appear consistent with a drug-induced effect.

Be alert to the potential for neuropsychiatric events in patients receiving the drug. Instruct patients to contact their clinician if behavior or mood changes occur. Carefully evaluate the risks and benefits of continuing zileuton therapy in patients who develop neuropsychiatric symptoms.

Specific Populations

Pregnancy

Conventional (immediate-release) and extended-release tablets: Category C.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Conventional (immediate-release) tablets: Safety and efficacy not established in children <12 years of age.

Extended-release tablets: Safety and efficacy not established in children <12 years of age. FDA has not required studies in children <12 years of age because of risk of hepatotoxicity. Manufacturer states that therapy not appropriate for children <12 years of age.

Geriatric Use

Conventional (immediate-release) tablets: Pharmacokinetics similar to those in younger adults. Possible increased risk for ALT elevations in women ≥65 years of age.

Extended-release tablets: No substantial differences in ALT elevations observed in patients ≥65 years of age compared with younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Contraindicated in patients with active liver disease or serum ALT concentrations ≥3 times the ULN. Use with caution in patients with mild hepatic impairment (serum ALT <3 times the ULN), those with history of liver disease, and/or those who consume large quantities of alcohol. (See Hepatic Effects under Cautions.)

Renal Impairment

Pharmacokinetics not altered. Dosage adjustment not necessary.

Common Adverse Effects

Conventional (immediate-release) tablets: Dyspepsia, nausea, abdominal pain, pain (unspecified), headache.

Extended-release tablets: Sinusitis, nausea, pharyngolaryngeal pain.

Drug Interactions

Metabolized principally by CYP1A2, CYP2C9, and CYP3A4; may inhibit CYP1A and CYP3A.

Specific Drugs

Zileuton Pharmacokinetics

Absorption

Bioavailability

Conventional (immediate-release) tablets: Rapidly absorbed following oral administration; however, absolute bioavailability is not known.

Onset

Conventional (immediate-release) tablets: Following oral administration, improvement in asthma symptoms and/or lung function evident within 2–5 hours.

Food

Conventional (immediate-release) tablets: Food increases peak plasma concentration but does not affect extent of absorption.

Extended-release tablets: Food increases peak plasma concentration and extent of absorption.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

93% (mainly albumin).

Elimination

Metabolism

Oxidatively metabolized to inactive metabolites principally via CYP1A2, CYP2C9, and CYP3A4.

Elimination Route

Excreted in urine (94.5%) and in feces (2.2%) as metabolites and unchanged drug.

Half-life

Conventional (immediate-release) tablets: Terminal half-life averages 2.5 hours.

Extended-release tablets: Terminal half-life averages 3.2 hours.

Stability

Storage

Oral

Tablets

Conventional (immediate-release) tablets: 20–25°C; protect from light.

Extended-release tablets: 20–25°C (may be exposed to 15–30°C); protect from light.

Actions

• Inhibits 5-lipoxygenase, the first dedicated enzyme active in the conversion of arachidonic acid to leukotrienes; results in inhibition of leukotriene B₄ (LTB₄), and the cysteinyl leukotrienes C₄ (LTC₄), D₄ (LTD₄), and E₄ (LTE₄).

• May reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control. May also reduce markers of airway inflammation (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, cytokines) in airway tissue or airway secretions and reduce the intensity of airway hyperresponsiveness.

• Does not inhibit either the acute bronchoconstrictor response (immediate/early asthmatic response [IAR, EAR]) or the delayed inflammatory response (late asthmatic response [LAR]) to inhaled antigen and irritants.

• Does not appear to produce appreciable bronchodilation in healthy individuals.

• Importance of taking zileuton at regular intervals, when asymptomatic as well as during periods of worsening asthma.

• Importance of swallowing zileuton extended-release tablets whole and not chewing, cutting, or crushing the tablets.

• Importance of advising patient that if a dose of zileuton extended-release tablets is missed, not to double the dose, but to take the next dose at the regularly scheduled time.

• Importance of contacting clinician if asthma is not well controlled; seek medical attention if short-acting, inhaled β₂-adrenergic bronchodilators are needed more often than usual or if more than the maximum number of inhalations for a 24-hour period are needed.

• Importance of not using zileuton for the relief of bronchospasm. Patients should be provided with and instructed in the use of a short-acting, inhaled β₂-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms.

• Importance of not discontinuing or reducing the dosage of other antiasthmatic agents unless instructed to do so by the clinician.

• Risk of liver toxicity; importance of immediately informing clinician if right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms occur.

• Importance of informing clinicians if behavior or mood changes occur.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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