Alternative Medications for Reducing Uric Acid Levels When Allopurinol Is Not an Option
For patients who cannot take allopurinol, febuxostat is the preferred alternative medication for reducing uric acid levels, followed by uricosuric agents such as probenecid, sulphinpyrazone, or benzbromarone depending on renal function and comorbidities. 1
First-Line Alternative: Febuxostat
- Febuxostat is a non-purine selective xanthine oxidase inhibitor that effectively lowers serum uric acid levels 2
- Febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment, making it advantageous for patients with kidney disease 2, 3
- The recommended starting dose is 40 mg/day, which may be increased to 80 mg/day after 2 weeks if target uric acid levels (<6 mg/dL) are not achieved 3
- In clinical trials, febuxostat demonstrated superior ability to lower and maintain serum uric acid levels below 6 mg/dL compared to conventional doses of allopurinol 4
Cardiovascular Considerations with Febuxostat
- The American College of Rheumatology conditionally recommends switching from febuxostat to an alternative urate-lowering therapy in patients with a history of cardiovascular disease or a new cardiovascular event 1
- This recommendation aligns with the FDA black box warning for febuxostat due to increased risk of cardiovascular-related death compared to allopurinol in the CARES trial 1
Second-Line Alternatives: Uricosuric Agents
Probenecid
- Probenecid can be used as an alternative to allopurinol in patients with normal renal function 1
- Typically dosed at 1-2 g/day, probenecid has shown effectiveness in reducing serum uric acid levels, though less potently than allopurinol 1
- Probenecid is relatively contraindicated in patients with urolithiasis due to increased risk of kidney stone formation 1
- While traditionally not recommended for patients with GFR <50 mL/min, some case reports suggest it may be effective when combined with febuxostat in patients with moderate renal impairment 5
Sulphinpyrazone
- Sulphinpyrazone (typically dosed at 400 mg/day) has demonstrated urate-lowering effects, though less potent than allopurinol 1
- Like probenecid, it is most appropriate for patients with normal renal function and without history of urolithiasis 1
Benzbromarone
- Benzbromarone (100-200 mg/day) can be used in patients with mild to moderate renal insufficiency 1
- It has shown significantly greater reduction of serum uric acid compared to allopurinol in patients with renal impairment 1
- However, benzbromarone carries a small risk of hepatotoxicity and may have restricted availability in some countries 1
Combination Therapy
- For patients with refractory hyperuricemia, combination therapy may be considered 5
- Adding probenecid to febuxostat has shown synergistic effects in lowering uric acid levels, even in patients with moderate renal impairment 5
Special Considerations
Genetic Testing
- For patients of Southeast Asian descent (Han Chinese, Korean, Thai) and African American patients, HLA-B*5801 testing is conditionally recommended prior to starting allopurinol due to higher risk of allopurinol hypersensitivity syndrome 1
- If these patients test positive for HLA-B*5801, febuxostat would be the preferred alternative 1
Allopurinol Desensitization
- For patients with prior mild allergic response to allopurinol who cannot be treated with other oral urate-lowering therapies, allopurinol desensitization is conditionally recommended 1
- This should not be attempted in patients with severe reactions or allopurinol hypersensitivity syndrome 1
Treatment Algorithm
First choice: Febuxostat (unless contraindicated by cardiovascular disease)
- Start at 40 mg/day, increase to 80 mg/day if needed 3
If febuxostat is contraindicated or ineffective:
For refractory cases: Consider combination therapy (e.g., febuxostat + probenecid) 5
Last resort: Allopurinol desensitization (only for patients with mild previous reactions) 1