What alternative medication to allopurinol (xanthine oxidase inhibitor) can be used for gout management in patients who cannot tolerate it?

Alternative Medications to Allopurinol for Gout Management

Febuxostat is the recommended alternative medication to allopurinol for gout management in patients who cannot tolerate allopurinol. 1

First-Line Alternative: Febuxostat

Febuxostat is a non-purine selective xanthine oxidase inhibitor that offers several advantages for patients who cannot tolerate allopurinol:

• Dosing: Start at 40 mg/day and titrate up to 80 mg daily as needed 1
• Efficacy: More potent in lowering serum uric acid levels compared to allopurinol at standard doses 2, 3
• Renal function: Can be used in patients with mild to moderate renal impairment without dose adjustment 1
• Safety profile: Different from allopurinol, making it suitable for patients with allopurinol hypersensitivity 2

Cardiovascular Considerations

While earlier concerns existed about cardiovascular safety, more recent evidence from the FAST trial showed febuxostat is non-inferior to allopurinol with respect to cardiovascular outcomes 4. However, use with caution in patients with pre-existing cardiovascular disease 1.

Second-Line Alternatives: Uricosuric Agents

If febuxostat is not tolerated or contraindicated, uricosuric agents can be considered:

1. Probenecid:

   • Starting dose: 500 mg once or twice daily 1
   • Best for patients with normal renal function
   • Less effective when creatinine clearance <50 ml/min 1

2. Benzbromarone:

   • Can be used in mild to moderate renal insufficiency 1
   • Caution: carries hepatotoxicity risk

3. Sulfinpyrazone:

   • Alternative to probenecid in patients with normal renal function 1

Combination Therapy

For patients with inadequate response to monotherapy:

• XOI + Uricosuric: Combining a xanthine oxidase inhibitor (febuxostat or allopurinol) with a uricosuric agent (probenecid) is recommended when target serum urate levels are not achieved with monotherapy 5, 1
• Other potential additions to XOI therapy include fenofibrate or losartan, which have mild uricosuric effects 1

Third-Line Option: Pegloticase

For severe, refractory cases:

• Indication: Severe debilitating chronic tophaceous gout that has failed or cannot tolerate appropriately dosed oral ULT options 1, 6
• Dosing: 8 mg IV infusion every two weeks 6
• Monitoring: Check serum uric acid levels before each infusion; consider discontinuation if levels increase above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed 6
• Administration: Must be given in healthcare settings prepared to manage potential anaphylaxis and infusion reactions 6

Treatment Approach Algorithm

1. First attempt: Febuxostat 40 mg daily, titrate up to 80 mg if needed
2. If ineffective or not tolerated: Add or switch to a uricosuric agent (probenecid, benzbromarone, or sulfinpyrazone) based on renal function
3. If still inadequate control: Consider combination therapy with XOI + uricosuric
4. For severe refractory cases: Consider pegloticase

Important Considerations

• Target serum urate level: <6 mg/dL for most patients, <5 mg/dL for those with severe or tophaceous gout 1
• Anti-inflammatory prophylaxis: Essential when initiating any urate-lowering therapy to prevent flares (colchicine, NSAIDs, or low-dose prednisone) for at least 3-6 months 1
• Monitoring: Check serum urate every 2-4 weeks during dose titration, then every 6 months once target is achieved 1

Pitfalls to Avoid

• Underdosing of alternative agents
• Failure to provide anti-inflammatory prophylaxis when initiating therapy
• Discontinuing therapy during flares
• Inadequate monitoring of serum urate levels
• Not considering combination therapy when monotherapy fails

By following this evidence-based approach, patients who cannot tolerate allopurinol can still achieve effective management of their gout with appropriate alternative medications.