Zileuton

Zileuton is an oral 5-lipoxygenase inhibitor used as add-on controller therapy in chronic asthma in adults and adolescents from 12 years. It is not a reliever, has a limited role, and is marketed in few countries.

Classification. Leukotriene synthesis inhibitor.

Mechanism. Inhibits 5-lipoxygenase, blocking formation of all leukotrienes (LTB4 and the cysteinyl leukotrienes), which reduces bronchoconstriction, mucus production and eosinophil recruitment.

Pharmacokinetics. Well absorbed orally. Half-life about 2.5 hours for the immediate-release form. Metabolised by CYP1A2, CYP2C9 and CYP3A4. It inhibits CYP1A2, which drives its interactions. Excreted mainly as glucuronide in urine.

Add-on, chronic asthma, adults and adolescents from 12 years.

• Immediate-release: 600 mg four times daily.

• Extended-release: 1200 mg twice daily within 1 hour after the morning and evening meals.

• Maximum 2400 mg daily. Tablets are swallowed whole.

Alternative. Used when montelukast or zafirlukast has failed or when a leukotriene synthesis inhibitor is specifically wanted. An inhaled corticosteroid is more effective.

Emergency. Not used.

Titration and loading. None. Dose adjustment is by switching formulation only.

Contraindications. Active liver disease or alanine aminotransferase (ALT) at 3 times the upper limit of normal or more. Hypersensitivity.

Serious adverse effects. Hepatotoxicity (ALT elevation in about 2% of patients, usually within 3 months), neuropsychiatric events including sleep disorder and behavioural change, eosinophilic granulomatosis with polyangiitis unmasked as corticosteroid doses fall, leucopenia.

Common adverse effects. Headache, nausea, dyspepsia, abdominal pain, myalgia.

Interactions. Theophylline: zileuton roughly doubles serum theophylline, so reduce the theophylline dose by about half and check levels. Warfarin: raises INR, so monitor closely. Propranolol: raises levels and effect.

Common prescribing errors. Missing liver monitoring. Giving with theophylline or warfarin without dose reduction and monitoring.

Special groups.

• Pregnancy: limited data; use only if the benefit outweighs risk. Breastfeeding: no data; avoid.

• Children: not licensed under 12 years.

• Older adults: no adjustment.

• Kidney impairment: no adjustment. Liver impairment: contraindicated in active disease.

• East Africa: availability is very limited; montelukast is the usual alternative.

Formulations. Tablets 600 mg immediate-release and 600 mg extended-release.

Administration. Immediate-release with meals and at bedtime. Extended-release after meals.

Baseline. ALT, symptom score.

Monitoring. ALT before starting, monthly for the first 3 months, every 2 to 3 months for the rest of the first year, then periodically. Control and reliever use at each review.

Stop and reduce rules. Stop for ALT over 5 times the upper limit of normal or for symptoms of liver injury (nausea, right upper quadrant pain, jaundice, pruritus). Stop for neuropsychiatric symptoms. Therapeutic drug monitoring is not used.

Referral and escalation. Refer for liver injury or vasculitis features.