Indications to Start Febuxostat
Febuxostat is indicated for chronic hyperuricemia in patients with gout where urate deposition has already occurred, specifically when patients have recurrent gout flares (≥2 per year), tophi, urate arthropathy, or uric acid renal stones. 1
Primary Clinical Indications
Febuxostat should be initiated in patients with gout who meet any of the following criteria:
- Recurrent gout flares: ≥2 attacks per year 1, 2
- Presence of tophi: Visible or palpable subcutaneous urate deposits 1, 2
- Radiographic damage: Joint damage attributable to gout 2
- Urate arthropathy: Chronic joint disease from urate deposition 1
- History of uric acid renal stones 1, 2
- Chronic kidney disease stage ≥3 with gout 2
- Serum uric acid >9 mg/dL with gout 2
When Febuxostat is Preferred Over Allopurinol
Febuxostat is the preferred first-line xanthine oxidase inhibitor in specific clinical scenarios:
- Moderate to severe renal impairment (eGFR <60 mL/min): Febuxostat does not require dose adjustment in renal impairment, unlike allopurinol which requires strict dose reduction based on creatinine clearance 1, 3, 4
- Allopurinol intolerance or contraindication: Including history of allopurinol hypersensitivity syndrome 1
- HLA-B*5801 allele carriers: Patients at high risk for severe cutaneous adverse reactions (SCARs) with allopurinol 1
- Failure to achieve target serum urate with appropriately dosed allopurinol: Per EULAR recommendations, febuxostat is second-line after allopurinol optimization 5
Positioning in Treatment Algorithm
The American College of Rheumatology recommends either allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy without preferential recommendation of one over the other 5. However, EULAR guidelines recommend allopurinol first, then febuxostat if the serum urate target is not achieved, based on cost-effectiveness considerations rather than efficacy differences 5.
When NOT to Start Febuxostat
Do not initiate febuxostat in the following situations:
- Asymptomatic hyperuricemia: Patients with elevated serum uric acid (>6.8 mg/dL) but no prior gout flares or tophi should not receive urate-lowering therapy 2
- Infrequent gout attacks: Patients with <2 gout flares per year do not require long-term urate-lowering therapy 2
- History of cardiovascular disease: The ACR conditionally recommends switching to alternative therapy for patients with established cardiovascular disease or new cardiovascular events due to increased CV risk with febuxostat 1, 3
Dosing and Monitoring Requirements
Start febuxostat at 40 mg daily with subsequent titration to achieve target serum urate levels 1, 2:
- Target serum urate: <6 mg/dL for most patients; <5 mg/dL may be needed for severe gout with tophi 1
- Mandatory flare prophylaxis: Colchicine (0.5-1 mg/day) or low-dose NSAIDs for at least 8 weeks, preferably 6 months, when initiating febuxostat 1, 2
- Monitor serum uric acid: Every 2-5 weeks during titration, then every 6 months once target achieved 5
- Maximum dose: 80 mg daily (120 mg in some severe cases) 3
Important Clinical Pitfalls
Febuxostat can be started during an acute gout attack if effective anti-inflammatory therapy has been initiated, contrary to older practice patterns 5. However, prophylaxis is essential as urate-lowering therapy may initially increase flare frequency in the first 6 months before reducing attacks after 1 year 2.
Cardiovascular risk is a critical consideration: Febuxostat carries an FDA black box warning regarding cardiovascular events. Shared decision-making is essential for patients at high cardiovascular risk, and switching to alternative therapy should be considered if CV events occur during treatment 1, 3.
Efficacy advantage: Febuxostat 80 mg/day is more effective than allopurinol 300 mg/day at lowering serum urate levels, though febuxostat 40 mg/day shows no major outcome differences compared to allopurinol 300 mg/day 1, 6.