What are the dosing recommendations for 5-lipoxygenase (5-LOX) inhibitors, such as zileuton (5-lipoxygenase inhibitor), for inflammatory conditions like asthma?

Zileuton Dosing for Asthma

The recommended dose of zileuton for asthma is 2400 mg daily, administered as two 600 mg extended-release tablets twice daily within one hour after morning and evening meals. 1

Specific Dosing Instructions

• Zileuton extended-release tablets: 1200 mg (two 600 mg tablets) twice daily with food - total daily dose of 2400 mg 1
• Tablets must be taken within one hour after morning and evening meals 1
• Tablets should not be chewed, cut, or crushed 1
• If a dose is missed, take the next dose at the scheduled time - do not double the dose 1

Age and Population Restrictions

• Zileuton is indicated for adults and children 12 years of age and older 1
• Not approved for children under 12 years of age 2

Role in Asthma Management

Zileuton is positioned as an alternative (not preferred) adjunctive therapy in the stepwise approach to asthma management. 2

Specific Treatment Steps:

• Step 2 (mild persistent asthma): Alternative to low-dose inhaled corticosteroids, but leukotriene receptor antagonists (LTRAs) are preferred over zileuton 2
• Step 3: Alternative adjunctive therapy with low-dose inhaled corticosteroids (along with LTRA or theophylline), but long-acting beta-agonists (LABAs) are preferred 2
• Step 4: Alternative adjunctive therapy with medium-dose inhaled corticosteroids, but LABAs remain preferred 2

Critical Monitoring Requirements

Liver function monitoring is essential and mandatory with zileuton therapy. 2, 1

Monitoring Schedule:

• Assess hepatic function enzymes (ALT/SGPT) before initiating treatment 1
• Monthly for the first 3 months 1
• Every 2-3 months for the remainder of the first year 1
• Periodically thereafter for long-term therapy 1

When to Discontinue:

• Immediately discontinue if ALT elevations ≥5 times the upper limit of normal (ULN) 1
• Discontinue if clinical signs of liver dysfunction develop (right upper quadrant pain, nausea, fatigue, lethargy, pruritus, jaundice, or flu-like symptoms) 1
• Follow hepatic enzymes until normal after discontinuation 1

Contraindications

• Active liver disease 1
• Persistent hepatic enzyme elevations ≥3 times ULN 1
• History of allergic reaction to zileuton 1

Important Clinical Considerations

Why Zileuton is Less Preferred:

• Zileuton is a less desirable alternative because of limited studies as adjunctive therapy and the need to monitor liver function 2
• In clinical trials, 4.4% of patients developed ALT elevations >3 times ULN, with 1.3% having levels >8 times ULN 3
• The majority (64.2%) of ALT elevations occurred within the first 3 months of treatment 3

Drug Interactions:

• Zileuton is a microsomal P450 enzyme inhibitor that can inhibit metabolism of warfarin and theophylline - doses of these drugs must be monitored accordingly 2

Efficacy Considerations:

• Zileuton produces both acute bronchodilatory effects (within 2-5 hours) and sustained improvements over 6 months in mild to moderate asthma 4
• Response rates are modest, with approximately 28% of patients showing significant response 5
• Severe asthma is associated with poorer response to zileuton (OR 0.12, p=0.004) 5
• Obesity may also be associated with reduced response, though this did not reach statistical significance 5

Clinical Pitfalls to Avoid

• Do not use zileuton as first-line therapy - inhaled corticosteroids are consistently more effective 2
• Do not prescribe without establishing a liver monitoring plan - hepatotoxicity risk requires vigilant surveillance 1
• Do not use in patients who consume substantial alcohol or have history of liver disease without extreme caution 1
• Zileuton is NOT indicated for acute asthma attacks or reversal of bronchospasm - it is for prophylaxis and chronic treatment only 1
• Therapy can be continued during acute exacerbations, but short-acting beta-agonists should be used for acute relief 1