What is the recommended use and dosage of Febuxostat (febuxostat) for patients with gout?

Febuxostat for Gout Management

Febuxostat should be used as a second-line agent for gout at a starting dose of 40 mg/day, which can be increased to 80 mg/day after two weeks if target serum uric acid levels (<6 mg/dL) are not achieved, with caution in patients with cardiovascular disease. 1

Indications and Positioning in Therapy

Febuxostat is a non-purine selective xanthine oxidase inhibitor indicated for the management of hyperuricemia in patients with gout. According to current guidelines:

• Allopurinol remains the first-line urate-lowering therapy for all patients with gout 1
• Febuxostat should be considered as an alternative when:
  • Patients cannot tolerate allopurinol due to hypersensitivity or intolerance
  • Allopurinol fails to achieve target uric acid levels
  • Patients have renal impairment (no dose adjustment needed with mild to moderate renal impairment) 1, 2

Dosing Recommendations

• Starting dose: 40 mg orally once daily 1, 2
• Dose titration: If serum uric acid remains ≥6 mg/dL after two weeks, increase to 80 mg once daily 1, 2
• Monitoring: Check serum uric acid levels every 2-4 weeks during dose titration and every 6 months once target is achieved 1
• Target: Maintain serum uric acid <6 mg/dL for most patients with gout, or <5 mg/dL for patients with severe gout (tophi, frequent flares, joint damage) 1

Efficacy

Febuxostat demonstrates superior urate-lowering efficacy compared to standard doses of allopurinol:

• At 80 mg/day, febuxostat achieves target serum uric acid levels (<6 mg/dL) in 67% of patients compared to 42% with allopurinol 300 mg/day 3
• At 40 mg/day, febuxostat is non-inferior to allopurinol 300 mg/day (45% vs 42% achieving target levels) 3
• Long-term treatment with febuxostat (up to 4 years) has been shown to reduce gout flare incidence to near zero 4

Cardiovascular Safety Concerns

A critical consideration when prescribing febuxostat is the cardiovascular safety profile:

• The 2020 American College of Rheumatology guidelines conditionally recommend switching from febuxostat to an alternative urate-lowering therapy in patients with a history of cardiovascular disease or new cardiovascular events 5
• This recommendation is based on the CARES trial, which showed higher risk of cardiovascular-related death and all-cause mortality with febuxostat compared to allopurinol, although the primary composite cardiovascular endpoint showed no difference 5
• The high dropout rate in the CARES trial and deaths occurring after treatment discontinuation complicate interpretation of these results 5

Flare Prophylaxis

When initiating febuxostat:

• Anti-inflammatory prophylaxis is strongly recommended to prevent gout flares during the first 3-6 months of therapy 1
• Options include low-dose colchicine, NSAIDs, or low-dose prednisone/prednisolone 1

Monitoring and Safety

• No dosage adjustments are needed for elderly patients or those with mild to moderate renal or hepatic impairment 6, 2
• Most common adverse effects include:
  • Liver function abnormalities (4.6-6.6%)
  • Nausea (1.1-1.3%)
  • Arthralgias (0.7-1.1%)
  • Rash (0.5-1.6%) 3
• Monitor for signs and symptoms of myocardial infarction and stroke, particularly in patients with pre-existing cardiovascular disease 6

Clinical Pearls

• Unlike allopurinol, febuxostat does not require dose adjustment in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/min) 2, 3
• Febuxostat may be particularly valuable for patients with very high serum urate levels or refractory tophi 7
• The cost of febuxostat is higher than allopurinol, which may influence treatment decisions 7
• Febuxostat should be continued long-term, as discontinuation will lead to recurrence of hyperuricemia 1