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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, 2023. 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

Drug

Interaction

Comments

Antihistamines (terfenadine and astemizole [no longer commercially available in US])

Increased plasma terfenadine concentrations; no substantial changes in QTc interval

Possible increased plasma astemizole concentrations

Terfenadine: Concomitant use not recommended

Astemizole: Concomitant use not evaluated; appropriate monitoring recommended with concomitant use

Calcium channel blockers, dihydropyridine

Possible increased plasma concentrations of dihydropyridine calcium-channel blocking agents

Concomitant use not evaluated; appropriate monitoring recommended with concomitant use

Cisapride (no longer commercially available in US)

Possible increased plasma cisapride concentrations

Concomitant use not evaluated; appropriate monitoring recommended with concomitant use

Contraceptives, oral (ethinyl estradiol)

Pharmacokinetic interactions unlikely

Cyclosporine

Possible increased plasma cyclosporine concentrations

Concomitant use not evaluated; appropriate monitoring recommended with concomitant use

Digoxin

Pharmacokinetic interactions unlikely

Naproxen

Pharmacokinetic interactions unlikely

Phenytoin

Pharmacokinetic interactions unlikely

Prednisone

Pharmacokinetic interactions unlikely

Propranolol

Substantial increase in plasma propranolol concentrations resulting in increased β-adrenergic blockade

Close monitoring recommended; reduce propranolol dosage as necessary

Sulfasalazine

Pharmacokinetic interactions unlikely

Theophylline

Substantial increase in plasma theophylline concentrations

Reduce theophylline dosage by approximately 50% and monitor plasma theophylline concentrations; adjust dosage and/or dosing interval if indicated

Warfarin

Possible increased plasma warfarin concentrations and clinically important increases in PT

Closely monitor PT; adjust anticoagulant dosage if indicated

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

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.

Zileuton

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

600 mg

Zyflo (scored)

Cornerstone Therapeutics

Tablets, film-coated, extended-release

600 mg

Zyflo CR

Cornerstone Therapeutics

AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 24, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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