Xanthine Oxidase Inhibitors

Xanthine oxidase inhibitors (allopurinol and febuxostat) lower serum urate by reducing its production. Allopurinol is first-line for gout and is also used for urate stones, tumour lysis prevention and hyperuricaemia from chemotherapy.

Mechanism. They inhibit xanthine oxidase, which converts hypoxanthine and xanthine to uric acid. Allopurinol is a purine analogue and its metabolite oxipurinol binds the enzyme. Febuxostat is a non-purine inhibitor.

Pharmacokinetics. Allopurinol half-life is 1 to 2 hours, oxipurinol 15 to 30 hours in normal kidney function and much longer in renal impairment. Febuxostat is metabolised in the liver.

Allopurinol. Start 100 mg daily (50 mg daily at eGFR under 30 mL/min), increase by 50 to 100 mg every 2 to 5 weeks until serum urate reaches target, usual maintenance 300 to 600 mg daily, maximum 900 mg daily. Doses over 300 mg are acceptable in renal impairment when titrated slowly.

Febuxostat. 40 mg daily, increased to 80 mg daily after 2 to 4 weeks if urate stays over 360 micromol/L, with a higher dose in some regions. No renal adjustment at eGFR over 30 mL/min.

Differences. Febuxostat has a boxed concern for cardiovascular death in patients with established heart disease, so is second-line after allopurinol failure or intolerance. Febuxostat lacks the HLA-B*58:01 link to severe skin reactions.

• Gout: allopurinol first; add a uricosuric or change to febuxostat if urate remains over target on the maximum tolerated dose.
• Tumour lysis prophylaxis: allopurinol 300 mg daily (children 10 mg/kg daily in divided doses), started 1 to 2 days before chemotherapy; rasburicase for high-risk patients.
• Urate and calcium oxalate stones: allopurinol 100 to 300 mg daily.
• Combination with thiopurines: reduce azathioprine or mercaptopurine to one quarter to one third of the usual dose and monitor the blood count closely; do not combine with febuxostat.
• Flares on starting: continue treatment and cover with colchicine, NSAID or prednisolone.

Special groups. Pregnancy: avoid unless needed. Breastfeeding: small amounts in milk; use with caution. Children: tumour lysis and enzyme disorders. Older adults: low starting doses, renal check. Kidney impairment: low start, slow titration. Liver impairment: caution with both. Regional: HIV and tuberculosis treatment are common; HLA-B*58:01 testing is seldom available, so use a low starting dose.

Adverse effects. Rash (2%), allopurinol hypersensitivity syndrome (fever, rash, eosinophilia, hepatitis, kidney injury; fatal in up to 20 to 25%, usually within 3 months), Stevens-Johnson syndrome and toxic epidermal necrolysis, hepatitis, cytopenias, gastrointestinal upset, and gout flares. Febuxostat: raised liver enzymes, cardiovascular events.

Contraindications. Previous allopurinol hypersensitivity; febuxostat with azathioprine or mercaptopurine; and febuxostat with established cardiovascular disease unless no alternative.

Interactions. Azathioprine and mercaptopurine (severe myelosuppression), ampicillin and amoxicillin (rash), ACE inhibitors (hypersensitivity), warfarin, theophylline, didanosine and cyclophosphamide.

Monitoring. Serum urate monthly during titration then 6 to 12 monthly, creatinine, liver enzymes and full blood count at baseline and 3 monthly in year 1, and skin review in the first 3 months. Stop at the first sign of rash with fever or mucosal involvement.

Referral and escalation. Skin reaction, hypersensitivity syndrome, urate not at target, tophi, or concurrent thiopurine.