What is the difference between Allopurinol and Febuxostat in the management of gout?

Allopurinol vs. Febuxostat for Gout Management

Allopurinol is strongly recommended as the first-line urate-lowering therapy for gout management, with febuxostat as an alternative when allopurinol is not tolerated or ineffective. 1

Mechanism of Action

• Both allopurinol and febuxostat are xanthine oxidase inhibitors that reduce uric acid production 1, 2
• Allopurinol is converted to oxypurinol, its active metabolite, which is primarily excreted by the kidneys 3, 4
• Febuxostat is a nonpurine selective inhibitor of xanthine oxidase with a different chemical structure than allopurinol 2, 5

Efficacy Comparison

• Febuxostat (80-120 mg) is more effective than fixed-dose allopurinol (300 mg) in achieving target serum urate levels <6 mg/dL 6, 7
• In clinical trials, 48-69% of patients on febuxostat (80-240 mg) achieved target serum urate levels compared to 22% on allopurinol (300 mg) 7
• However, when allopurinol is properly up-titrated (beyond the common 300 mg dose), 97% of patients can achieve target urate levels 8
• Both medications show similar efficacy in reducing gout flares and tophi size over time 5

Dosing Considerations

• Allopurinol should be started at a low dose (100 mg/day) and gradually increased by 100 mg increments every 2-4 weeks until target serum urate levels are achieved 6, 1
• Maximum FDA-approved dose of allopurinol is 800 mg/day 1
• Febuxostat starting dose is 40 mg/day, which can be increased to 80 mg/day if target urate levels are not achieved after 2 weeks 2

Special Populations

Renal Impairment

• Allopurinol requires dose adjustment in renal impairment, starting at ≤100 mg/day (lower in CKD stage ≥3) 1, 3
• Febuxostat may be preferred in patients with chronic kidney disease as it does not require dose adjustment in mild to moderate renal impairment 1, 3, 2
• Febuxostat has demonstrated greater efficacy in patients with renal impairment compared to renally-adjusted allopurinol doses 3, 7

Cardiovascular Risk

• Febuxostat carries an FDA black box warning regarding cardiovascular risk 3
• The American College of Rheumatology conditionally recommends switching to an alternative urate-lowering therapy for patients taking febuxostat with a history of cardiovascular disease or new cardiovascular events 3

Safety Profile

• Both medications have similar overall safety profiles with comparable rates of adverse events 4, 7, 5
• Common side effects for both include liver function abnormalities, rash, nausea, and arthralgias 2
• Allopurinol is associated with rare but serious hypersensitivity reactions, particularly in patients with renal impairment 3
• Withdrawal rates due to adverse events are similar between allopurinol and febuxostat 4, 7

Clinical Algorithm for Selection

1. First-line therapy: Start with allopurinol at low dose (100 mg/day), titrate up by 100 mg every 2-4 weeks to achieve target serum urate <6 mg/dL 6, 1

2. For patients with renal impairment:

   • Mild-moderate CKD: Consider febuxostat or dose-adjusted allopurinol 1, 3
   • Severe CKD (eGFR <30 ml/min): Febuxostat is preferred 3

3. Switch to febuxostat if:

   • Allopurinol is not tolerated 6
   • Target serum urate levels cannot be achieved despite appropriate allopurinol dose titration 6
   • Patient has significant renal impairment 3, 2

4. Avoid febuxostat or use with caution in:

   • Patients with established cardiovascular disease 3

Important Considerations for Both Medications

• Always provide prophylaxis against acute gout flares when initiating either medication, typically with colchicine (0.5-1 mg/day) for the first 6 months 6, 1
• Continue urate-lowering therapy during acute gout flares 1
• Monitor serum urate levels regularly to ensure target levels (<6 mg/dL) are maintained 6
• For patients with tophi, a lower target serum urate level (<5 mg/dL) is recommended 6

Common Pitfalls to Avoid

• Inadequate allopurinol dosing: Many patients remain on 300 mg without appropriate up-titration to achieve target urate levels 1, 8
• Starting urate-lowering therapy without flare prophylaxis 1
• Discontinuing urate-lowering therapy during acute flares 1
• Failing to adjust allopurinol dose in patients with renal impairment 3
• Not considering cardiovascular risk when prescribing febuxostat 3