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.^{1 2 46}

Uses for Zileuton

Asthma

Prevention and long-term symptomatic management of asthma; used as an alternative, but not preferred adjunctive therapy.^{1 45 46}

In patients with mild persistent asthma, low-dose orally inhaled corticosteroids considered first-line agents for long-term control.^{21 28 29 39 45 47} 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.^{39 45 47}

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.^{39 45} 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.⁴⁵

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.^{39 45} 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.⁴⁵

Not recommended for relief of acute bronchospasm; however, may continue therapy during acute asthma exacerbations.^{1 46} (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.¹ May be swallowed whole or cut in half.¹

Extended-release tablets: Administer orally in 2 equally divided doses daily.⁴⁶ Give within 1 hour after morning and evening meals.⁴⁶ Swallow tablets whole; do not chew, cut, or crush.⁴⁶ If a dose is missed, do not administer a double dose; take next dose at the regularly scheduled time.⁴⁶

Dosage

Pediatric Patients

Asthma

Oral

Conventional (immediate-release) tablets: 600 mg 4 times daily in children ≥12 years of age.¹

Extended-release tablets: 1.2 g twice daily in children ≥12 years of age.⁴⁶

Adults

Asthma

Oral

Conventional (immediate-release) tablets: 600 mg 4 times daily.¹

Extended-release tablets: 1.2 g twice daily.⁴⁶

Prescribing Limits

Pediatric Patients

Asthma

Oral

Children ≥12 years of age: Maximum 2.4 g daily as conventional (immediate-release) or extended-release tablets.^{1 46}

Adults

Asthma

Oral

Maximum 2.4 g daily as conventional (immediate-release) or extended-release tablets.^{1 46}

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.^{46 a} Do not use in patients with active liver disease or transaminases ≥3 times the ULN.^{1 27 46} (See Contraindications and also Hepatic Effects under Cautions.)

Renal Impairment

Dosage adjustment not required.^{1 46 a}

Geriatric Patients

Dosage adjustment not required.^{1 46 a}

Cautions for Zileuton

Contraindications

Active liver disease or serum aminotransferase concentrations ≥3 times the ULN.^{1 27 46} (See Hepatic Effects under Cautions.)

Known hypersensitivity to zileuton or any ingredient in the formulation.^{1 27 46}

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.^{1 46}

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).^{1 23 27 30 46} (See Specific Drugs under Interactions.)

General Precautions

Hepatic Effects

Associated with increases in serum aminotransferase values (e.g., serum ALT);^{1 27 46} generally occurs within the first 3 months of therapy.^{1 27 46} Possible increased risk for ALT elevations in patients with preexisting aminotransferase elevations and women ≥65 years of age receiving immediate-release zileuton.^{1 27}

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.^{1 27 46} 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.^{1 27 46}

Use contraindicated in patients with active liver disease or serum ALT concentrations ≥3 times the ULN.^{1 27 46} (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.^{1 27 46}

Neuropsychiatric Effects

Neuropsychiatric events reported with zileuton during postmarketing experience.^{1 46 48 52 53} 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.⁵² FDA concluded that some neuropsychiatric events reported with zileuton (e.g., sleep disorders, behavior changes) appear consistent with a drug-induced effect.^{1 46 53}

Be alert to the potential for neuropsychiatric events in patients receiving the drug.^{1 46 53} Instruct patients to contact their clinician if behavior or mood changes occur.^{1 46 53} Carefully evaluate the risks and benefits of continuing zileuton therapy in patients who develop neuropsychiatric symptoms.^{1 46 53}

Specific Populations

Pregnancy

Conventional (immediate-release) and extended-release tablets: Category C.^{1 46}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 46} Discontinue nursing or the drug.^{1 46}

Pediatric Use

Conventional (immediate-release) tablets: Safety and efficacy not established in children <12 years of age.¹

Extended-release tablets: Safety and efficacy not established in children <12 years of age.⁴⁶ FDA has not required studies in children <12 years of age because of risk of hepatotoxicity.⁴⁶ Manufacturer states that therapy not appropriate for children <12 years of age.⁴⁶

Geriatric Use

Conventional (immediate-release) tablets: Pharmacokinetics similar to those in younger adults.¹ Possible increased risk for ALT elevations in women ≥65 years of age.^{1 27}

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.⁴⁶

Hepatic Impairment

Contraindicated in patients with active liver disease or serum ALT concentrations ≥3 times the ULN.^{1 27 46} 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.^{1 27 46} (See Hepatic Effects under Cautions.)

Renal Impairment

Pharmacokinetics not altered.^{1 46} Dosage adjustment not necessary.^{1 46}

Common Adverse Effects

Conventional (immediate-release) tablets: Dyspepsia, nausea, abdominal pain, pain (unspecified), headache.¹

Extended-release tablets: Sinusitis, nausea, pharyngolaryngeal pain.⁴⁶

Drug Interactions

Metabolized principally by CYP1A2, CYP2C9, and CYP3A4;^{1 46} may inhibit CYP1A and CYP3A.^{1 27 30}

Specific Drugs

Zileuton Pharmacokinetics

Absorption

Bioavailability

Conventional (immediate-release) tablets: Rapidly absorbed following oral administration; however, absolute bioavailability is not known.¹

Onset

Conventional (immediate-release) tablets: Following oral administration, improvement in asthma symptoms and/or lung function evident within 2–5 hours.^{1 5 6 8 14 17 19}

Food

Conventional (immediate-release) tablets: Food increases peak plasma concentration but does not affect extent of absorption.¹

Extended-release tablets: Food increases peak plasma concentration and extent of absorption.⁴⁶

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.^{1 46}

Plasma Protein Binding

93% (mainly albumin).^{1 46}

Elimination

Metabolism

Oxidatively metabolized to inactive metabolites principally via CYP1A2, CYP2C9, and CYP3A4.^{1 46}

Elimination Route

Excreted in urine (94.5%) and in feces (2.2%) as metabolites and unchanged drug.^{1 46}

Half-life

Conventional (immediate-release) tablets: Terminal half-life averages 2.5 hours.¹

Extended-release tablets: Terminal half-life averages 3.2 hours.⁴⁶

Stability

Storage

Oral

Tablets

Conventional (immediate-release) tablets: 20–25°C; protect from light.¹

Extended-release tablets: 20–25°C (may be exposed to 15–30°C); protect from light.⁴⁶

Actions

• Inhibits 5-lipoxygenase, the first dedicated enzyme active in the conversion of arachidonic acid to leukotrienes;^{3 4 12 19} results in inhibition of leukotriene B₄ (LTB₄), and the cysteinyl leukotrienes C₄ (LTC₄), D₄ (LTD₄), and E₄ (LTE₄).^{1 13 15 18 19 22}

• May reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.^{3 4 6 8 14 17} 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.^{21 31 32 33}

• 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.^{3 4 7 10 11 12 13 15 18 22}

• Does not appear to produce appreciable bronchodilation in healthy individuals.¹⁴

• Importance of taking zileuton at regular intervals, when asymptomatic as well as during periods of worsening asthma.^{1 46}

• Importance of swallowing zileuton extended-release tablets whole and not chewing, cutting, or crushing the tablets.⁴⁶

• 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.⁴⁶

• 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.^{1 46}

• Importance of not using zileuton for the relief of bronchospasm.^{1 46} 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.^{1 46}

• Importance of not discontinuing or reducing the dosage of other antiasthmatic agents unless instructed to do so by the clinician.^{1 46}

• Risk of liver toxicity; importance of immediately informing clinician if right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or “flu-like” symptoms occur.^{1 46}

• Importance of informing clinicians if behavior or mood changes occur.^{1 46 53}

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 46}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption.^{1 46}

• Importance of informing patients of other important precautionary information.^{1 46} (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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