Xanthine oxidase inhibitor (uric-lowering)
Febuxostat is a medicine used in the chronic treatment of gout, to lower uric acid in the blood. It is an alternative to allopurinol when this is ineffective or not tolerated. It is not recommended for asymptomatic hyperuricaemia. Like all uric-acid-lowering drugs, it can precipitate gout flares at the start.
Also known as: Adenuric, febuxostat
Two xanthine oxidase inhibitors: no benefit and increased risk of hypersensitivity reactions.
Allopurinol and febuxostat act by the same mechanism — xanthine oxidase inhibition — and combining them adds no efficacy in controlling hyperuricaemia, but can increase the risk of hypersensitivity reactions (including hypersensitivity syndrome and, rarely, severe skin reactions). In practice the combination is not used: the patient should be on a single xanthine oxidase inhibitor, at the titrated dose, with gout flare prophylaxis in the first months and uric acid monitoring. If intolerance to one occurs, switching to the other is considered, never combining them.
Two xanthine oxidase inhibitors: no benefit and increased risk of hypersensitivity reactions. Do not combine.
Overlapping mechanism (xanthine oxidase inhibition) and risk profile of severe cutaneous reactions.
Watch for skin rash and hypersensitivity symptoms.
Skin rash, pruritus, fever, hypersensitivity syndrome symptoms.
Do not combine; choose only one xanthine oxidase inhibitor.
DailyMed (FDA) — approved Allopurinol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6c5b5c0-b1cb-44c0-a849-5d317e6fa300 ; approved Febuxostat label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f2c338dc-5bab-49f4-a4ac-d8dea8afeea5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Xanthine oxidase inhibitor + azathioprine: risk of severe, potentially fatal marrow suppression.
Like allopurinol, febuxostat inhibits xanthine oxidase and blocks the inactivation of 6-mercaptopurine derived from azathioprine, markedly increasing the cytotoxic 6-thioguanine metabolites — the approved febuxostat label formally contraindicates co-administration with azathioprine or mercaptopurine due to the risk of severe and potentially fatal myelosuppression. There is no documented safe dose; if azathioprine therapy is indispensable, another urate-lowering agent should be chosen and, failing that, a marked azathioprine dose reduction with very close haematological monitoring should be discussed.
Xanthine oxidase inhibitor + azathioprine: risk of severe and potentially fatal myelosuppression. Febuxostat is contraindicated with azathioprine — do not combine; choose an alternative urate-lowering agent.
Febuxostat (like allopurinol) inhibits xanthine oxidase, the enzyme that degrades the active 6-mercaptopurine from azathioprine; levels rise markedly.
Weekly full blood count in the first weeks of the combination.
Fever, severe infections, pancytopenia, bleeding.
Combination contraindicated. Reduce azathioprine dose by about 75% only if clinically essential, with tight full blood count monitoring.
DailyMed (FDA) — approved Azathioprine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5116b22b-1460-5535-e063-6394a90acbe5 ; approved Febuxostat label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f2c338dc-5bab-49f4-a4ac-d8dea8afeea5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Food does not significantly alter absorption.
May take with or without food.
EMC-UK (MHRA) — approved Febuxostat SmPC: https://www.medicines.org.uk/emc/product/487/smpc
Alcohol raises serum urate and may trigger gout flares.
Limit or avoid alcohol, especially beer, during treatment.
EMC-UK (MHRA) — approved Febuxostat SmPC: https://www.medicines.org.uk/emc/product/487/smpc
Reduced renal excretion increases febuxostat exposure.
Use with caution and monitor renal function.
EMC-UK (MHRA) — approved Febuxostat SmPC: https://www.medicines.org.uk/emc/product/487/smpc
In trials, febuxostat was associated with higher cardiovascular risk versus allopurinol.
Use with caution in patients with prior cardiovascular disease.
EMC-UK (MHRA) — approved Febuxostat SmPC: https://www.medicines.org.uk/emc/product/487/smpc
No adequate human data; animal studies showed adverse effects.
Avoid during pregnancy unless benefit justifies risk.
Unknown; prefer to avoid during breastfeeding.
Use effective contraception given uncertainty about risk.
EMC-UK (MHRA) — approved Febuxostat SmPC: https://www.medicines.org.uk/emc/product/487/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Selective (non-purine) xanthine oxidase inhibitor, indicated for the treatment of chronic hyperuricaemia with urate deposition (gout, tophaceous gout, urate urolithiasis) in adults. Reduces serum uric acid dose-dependently (40-55% at 40-80 mg/day) and increases serum xanthine. No effect on the QTc interval up to 300 mg/day. Apparent terminal half-life of 5-8 hours.
Selective xanthine oxidase inhibitor: lowers serum uric acid by blocking the oxidation of hypoxanthine and xanthine to uric acid; not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations. Increases urinary xanthine excretion and decreases urinary uric acid excretion.
Peak plasma concentrations between 1-1.5 hours after dosing; absorption is at least 49% (radioactivity recovered in urine). At 40 mg and 80 mg/day, Cmax of ~1.6 and ~2.6 mcg/mL. With a high-fat meal Cmax decreases 49% and AUC 18% (no clinical change in effect); antacids delay absorption ~1 hour (-31% Cmax, -15% AUC, not clinically significant). Apparent volume of distribution ~50 L.
Metabolised by glucuronide conjugation (via UGT, including UGT1A1, 1A3, 1A9, 2B7) and oxidation by CYP (CYP1A2, 2C8, 2C9) and non-P450 enzymes. Approximately 49% of the dose is recovered in urine (as drug, acylglucuronide and oxidative metabolites) and 45% in faeces; less than 1% excreted unchanged in urine.
Mean apparent terminal half-life of approximately 5-8 hours; Cmax and AUC dose-proportional between 10-120 mg, with no accumulation with daily administration. In patients with severe hepatic impairment (Child-Pugh C) exposure increases — not recommended.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
