Can I combine allopurinol with febuxostat?

Combining Allopurinol with Febuxostat in Gout Management

Allopurinol and febuxostat should not be used in combination with each other for gout management. 1

Rationale for Not Combining These Medications

• Both allopurinol and febuxostat are xanthine oxidase inhibitors (XOIs) that work through the same mechanism to lower serum uric acid levels 1
• The American College of Rheumatology (ACR) guidelines explicitly state in their drug label information that "febuxostat and allopurinol should not be used in combination with each other" 1
• Instead of combining these two XOIs, the recommended approach for refractory gout is to:
  • Optimize the dose of a single XOI first (either allopurinol or febuxostat) 1
  • Consider switching from one XOI to another if the first is not effective or not tolerated 1
  • Add a uricosuric agent (such as probenecid, fenofibrate, or losartan) to an XOI if target serum uric acid levels are not achieved 1

Appropriate Therapeutic Strategies for Difficult-to-Control Gout

First-Line Approach

• Start with allopurinol at a low dose (100 mg/day) and gradually increase by 100 mg increments every 2-4 weeks until target serum uric acid level is reached 1
• Target serum uric acid level should be <6 mg/dL (360 μmol/L) for most patients 1
• For patients with severe gout (tophi, chronic arthropathy, frequent attacks), consider a lower target of <5 mg/dL (300 μmol/L) 1

If First-Line Therapy Fails

• If maximum appropriate dose of allopurinol doesn't achieve target uric acid levels, consider:
  • Switching to febuxostat 1
  • Adding a uricosuric agent to allopurinol 1
• If allopurinol causes adverse effects, switch to febuxostat 1

Cardiovascular Safety Considerations

• For patients with cardiovascular disease taking febuxostat, consider switching to an alternative urate-lowering therapy due to potential increased cardiovascular risk 1, 2
• The CARES trial showed higher risk of cardiovascular-related death and all-cause mortality with febuxostat compared to allopurinol 1

Comparative Efficacy of Allopurinol vs. Febuxostat

• Febuxostat (40-80 mg/day) has been shown to be more effective than standard doses of allopurinol (300 mg/day) in lowering serum uric acid levels 3, 4
• Febuxostat may provide a more rapid decrease in serum uric acid levels compared to allopurinol 5, 4
• Febuxostat may be more effective in achieving target serum uric acid levels in patients with renal impairment 5

Alternative Approaches for Refractory Gout

• For patients with severe gout disease burden who are refractory to or intolerant of conventional urate-lowering therapy, pegloticase may be appropriate 1
• Important note: All oral urate-lowering agents should be discontinued during pegloticase therapy 1
• The combination of an XOI with a uricosuric agent is an effective therapeutic option for difficult-to-control gout 1

Conclusion

Rather than combining allopurinol and febuxostat, the evidence-based approach for managing refractory gout is to optimize one XOI, switch to the alternative XOI if needed, or add a uricosuric agent to an XOI. This strategy maximizes efficacy while minimizing potential risks of combining medications with the same mechanism of action.