What alternative urate‑lowering therapies can be used in gout when allopurinol is contraindicated due to intolerance, hypersensitivity, severe renal impairment, or inadequate response?

Alternatives to Allopurinol in Gout

Febuxostat is the preferred first-line alternative to allopurinol for urate-lowering therapy, with uricosuric agents (probenecid, benzbromarone) as second-line options depending on renal function. 1, 2

First-Line Alternative: Febuxostat

Febuxostat should be your go-to alternative when allopurinol cannot be used. This non-purine xanthine oxidase inhibitor demonstrates superior efficacy compared to standard-dose allopurinol, with 53-62% of patients achieving target serum uric acid levels below 6 mg/dL. 2

Key Advantages of Febuxostat:

• No dose adjustment required in mild-to-moderate renal impairment (eGFR 30-59 mL/min/1.73m²), making it particularly valuable in patients with kidney disease 2, 3
• Does not cause allopurinol hypersensitivity syndrome, eliminating the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis 2
• Starting dose is 40 mg daily, which can be increased to 80 mg after 2 weeks if serum uric acid remains ≥6 mg/dL 4, 5

Critical Cardiovascular Warning:

Switch from febuxostat to an alternative therapy in patients with established cardiovascular disease or new cardiovascular events. The FDA issued a black box warning regarding cardiovascular risk, and the ACR conditionally recommends this approach. 2, 3 More cardiovascular thromboembolic events occurred in randomized trials with febuxostat, though causality remains unestablished. 5

Second-Line Alternatives: Uricosuric Agents

When febuxostat is contraindicated or in combination therapy for severe disease, uricosuric agents provide effective alternatives. 1

Probenecid:

• Use in patients with normal renal function (creatinine clearance >50 mL/min) 1
• Dose: 1-2 g/day 2
• Contraindicated in urolithiasis due to increased kidney stone risk 2, 6
• Recommended as an alternative first-line option when at least one xanthine oxidase inhibitor is contraindicated or not tolerated 1

Benzbromarone:

• Can be used in mild-to-moderate renal insufficiency without dose adjustment, unlike probenecid 1, 2
• Dose: 400 mg/day (where available) 2
• Carries a small risk of hepatotoxicity requiring monitoring 2, 3
• Demonstrates significantly greater serum uric acid reduction compared to allopurinol in patients with renal impairment 6
• Not available in all countries, including the United States 3

Sulphinpyrazone:

• Dose: 400 mg/day 2
• Less potent than allopurinol but effective in patients with normal renal function 6

Combination Therapy for Refractory Cases

For severe tophaceous gout not controlled by monotherapy, combine a xanthine oxidase inhibitor (febuxostat) with a uricosuric agent (probenecid or benzbromarone). 1, 2 This EULAR recommendation applies when the serum uric acid target cannot be achieved with maximum doses of single agents. 1

Pegloticase for Severe Refractory Disease

Reserve pegloticase for crystal-proven, severe debilitating chronic tophaceous gout with poor quality of life when the serum uric acid target cannot be reached with any other available drug at maximal dosage (including combinations). 1 This is not a first-line alternative but represents the final option for treatment-refractory disease. 3

Mandatory Prophylaxis During Initiation

Always initiate anti-inflammatory prophylaxis when starting any urate-lowering therapy. 2, 3

• Colchicine 0.5 mg daily is the preferred prophylactic agent 1, 2
• Continue prophylaxis for 3-6 months after initiating therapy 2, 3
• Reduce colchicine dose in renal impairment and monitor for neurotoxicity/muscular toxicity, especially with concurrent statin use 1
• If colchicine is contraindicated, use low-dose NSAIDs (if not contraindicated) 1

Starting urate-lowering therapy without prophylaxis significantly increases flare risk, a common and preventable pitfall. 3

Treatment Targets

Maintain serum uric acid below 6 mg/dL (360 μmol/L) for all patients. 1, 3

For severe gout with tophi, chronic arthropathy, or frequent attacks, target <5 mg/dL (300 μmol/L) until total crystal dissolution occurs. 1 This lower target facilitates faster dissolution of crystals. 1

Monitor serum urate every 2-5 weeks during titration, then every 6 months once target is achieved. 1 This monitoring is particularly useful for assessing adherence, which is commonly poor in gout patients. 1

Special Populations

Renal Impairment Algorithm:

• Mild-moderate impairment (eGFR 30-59 mL/min/1.73m²): Febuxostat 40 mg daily (first choice), can increase to 80 mg if needed 3
• Severe impairment (eGFR <30 mL/min/1.73m²): Febuxostat 40 mg daily (limited data but appears safe) 3
• Do NOT use probenecid if creatinine clearance <50 mL/min 1

Allopurinol Desensitization:

Consider allopurinol desensitization only for patients with prior mild allergic reactions who cannot be treated with other oral urate-lowering therapies. 6 Never attempt this in patients with severe reactions or allopurinol hypersensitivity syndrome. 6

Adjunctive Lifestyle Modifications

Always implement lifestyle modifications alongside pharmacologic therapy: weight loss if appropriate, avoid alcohol (especially beer and spirits), avoid sugar-sweetened drinks and high-fructose foods, reduce meat and seafood intake, encourage low-fat dairy products, and discontinue diuretics if possible. 1, 2 However, recognize that diet and lifestyle measures alone provide insufficient serum urate-lowering (only ~10-18% decrease) for most patients with sustained hyperuricemia substantially above 7 mg/dL. 1