What is the role of Zileuton (leukotriene synthesis inhibitor) in treating asthma in patients 12 years and older?

Zileuton for Asthma in Patients ≥12 Years

Zileuton is an alternative but not preferred medication for asthma management in patients 12 years and older, reserved primarily as adjunctive therapy when inhaled corticosteroids plus long-acting beta-agonists are insufficient, with mandatory liver function monitoring required due to risk of hepatotoxicity. 1

FDA-Approved Indication

• Zileuton extended-release tablets are indicated for prophylaxis and chronic treatment of asthma in adults and children ≥12 years of age 2
• Not indicated for acute asthma attacks or bronchospasm reversal 2
• Therapy can be continued during acute exacerbations 2

Position in Treatment Algorithm

Step 2 Care (Mild Persistent Asthma)

• Zileuton is an alternative but not preferred option compared to low-dose inhaled corticosteroids 1
• Leukotriene receptor antagonists (montelukast, zafirlukast) are preferred over zileuton within the leukotriene modifier class 1

Step 3-6 Care (Moderate to Severe Persistent Asthma)

• Zileuton can be used as alternative adjunctive therapy in adults only, but is less desirable than adding a long-acting beta-agonist to inhaled corticosteroids 1
• The preferred adjunctive therapy for patients ≥12 years is inhaled corticosteroids plus long-acting beta-agonists 1, 3
• Zileuton is considered a less desirable alternative due to limited studies as adjunctive therapy and the need for liver function monitoring 1

Critical Safety Requirement: Liver Monitoring

Mandatory liver function testing is essential with zileuton therapy 1

• Alanine aminotransferase (ALT) elevations ≥3 times upper limit of normal occur in approximately 2-4.6% of patients 2, 4
• Most elevations occur within the first 2-3 months of treatment 4
• Elevations are reversible with dose reduction or discontinuation 4
• Patients must be counseled to report signs of liver dysfunction: right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or flu-like symptoms 2

Dosing and Administration

• Two tablets twice daily within one hour after morning and evening meals 2
• Total daily dose: 2400 mg 5
• Tablets must be swallowed whole—do not cut, chew, or crush 2

Comparative Efficacy Evidence

Versus Placebo

• Produces acute bronchodilatory effect 2-5 hours after initial dose 6
• Improves FEV₁ by 12-16% compared to 6% with placebo at 36 days 6
• Reduces daytime symptoms by 37%, nocturnal symptoms by 31%, and beta-agonist use by 31% 6
• Decreases need for steroid rescue medication by 62% 6

Versus Montelukast

• Zileuton ER demonstrated superior PEFR improvement: 64.8 L/min versus 40.6 L/min with montelukast (p<0.001) 5
• 67.9% of zileuton patients achieved ≥12% PEFR improvement versus 51.5% with montelukast (p=0.015) 5
• Greater reduction in overall symptom intensity score with zileuton (p=0.018) 5

Versus Inhaled Corticosteroids

• Inhaled corticosteroids are significantly more effective than all leukotriene modifiers including zileuton 1, 7
• Most outcome measures clearly favor inhaled corticosteroids over leukotriene modifiers 1

Mechanism and Clinical Implications

• Zileuton is a 5-lipoxygenase inhibitor that blocks leukotriene synthesis at the pathway origin 1, 8
• This differs from leukotriene receptor antagonists (montelukast, zafirlukast) which block only cysteinyl leukotriene receptors 8
• By inhibiting 5-lipoxygenase, zileuton blocks formation of all leukotrienes including LTB₄, LTC₄, LTD₄, and LTE₄ 8

Common Pitfalls to Avoid

• Never use zileuton in patients with active liver disease or elevated liver enzymes 2
• Do not prescribe zileuton as first-line therapy when inhaled corticosteroids are more effective 1, 7
• Avoid using zileuton as monotherapy for acute asthma attacks 2
• Do not discontinue other asthma medications when starting zileuton without provider guidance 2
• Remember that zileuton requires twice-daily dosing with meals, which may affect adherence compared to once-daily alternatives 2

Drug Interactions

• Zileuton can interact with multiple medications; consult provider before starting or stopping any prescription or non-prescription medicines 2
• Dose adjustments of certain medications may be necessary during zileuton therapy 2

Neuropsychiatric Considerations

• Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using zileuton 2