What is the recommended next step in managing a patient with chronic hyperuricemia >520 µmol/L despite taking febuxostat 80 mg tablets at 1½ tablets daily (total 120 mg)?

Management of Refractory Hyperuricemia on Febuxostat 120 mg Daily

You should add a uricosuric agent (probenecid, fenofibrate, or losartan) to the current febuxostat regimen rather than switching medications, provided the patient has adequate renal function (eGFR >50 mL/min) and no history of kidney stones. 1, 2

Verify Treatment Adequacy First

Before escalating therapy, confirm the following:

• Check medication adherence - Non-adherence is widespread in gout patients and is the most common reason for treatment failure 3, 2
• Verify the patient is actually taking 120 mg daily (1.5 tablets of 80 mg) - This dose exceeds the FDA-approved maximum of 80 mg in the United States but is approved internationally 1, 3
• Measure serum uric acid every 2-5 weeks during any dose adjustments to guide therapy 3, 4

Combination Therapy Strategy

Since the patient is already on febuxostat 120 mg (the maximum international dose), the next step is combination therapy:

• Add probenecid 500 mg once or twice daily, then titrate upward to achieve target serum uric acid <6 mg/dL (360 µmol/L) 1, 2
• This addresses hyperuricemia through dual mechanisms: reduced uric acid production (febuxostat) and increased renal excretion (probenecid) 2
• Alternative uricosuric agents include fenofibrate or losartan if the patient has comorbid hyperlipidemia or hypertension 1

Critical Contraindications to Uricosuric Therapy

Do NOT add a uricosuric agent if:

• eGFR <50 mL/min 2
• History of kidney stones 2
• Moderate-to-severe chronic kidney disease 1, 2

Target Serum Uric Acid Level

• Standard target: <6 mg/dL (360 µmol/L) maintained lifelong 1, 4, 2
• For severe disease with tophi or chronic arthropathy: <5 mg/dL (300 µmol/L) until complete crystal dissolution occurs, then relax to <6 mg/dL 1, 4
• The current level of >520 µmol/L (>8.7 mg/dL) is well above target and requires intervention 1

Mandatory Flare Prophylaxis During Escalation

• Continue or initiate colchicine 0.5-1 mg daily, low-dose NSAIDs, or prednisone/prednisolone for at least 6 months after any therapy changes 3, 4
• Dose-adjust colchicine for renal function if applicable 3
• Changing urate-lowering therapy mobilizes tissue urate deposits and increases flare risk 4, 5

Alternative Options if Combination Therapy Fails

If febuxostat 120 mg plus uricosuric therapy fails to achieve target:

• Switch to allopurinol (if not previously tried or contraindicated), starting at 100 mg/day and titrating up to 800 mg/day maximum 1
• Consider pegloticase only for severe refractory disease with tophi and poor quality of life when all oral options have failed at maximum doses 1, 5

Important Cardiovascular Consideration

• Febuxostat carries an FDA black box warning regarding cardiovascular risk 3
• If the patient has a history of cardiovascular disease or experiences a new cardiovascular event, consider switching to alternative urate-lowering therapy rather than continuing febuxostat 3, 2
• Shared decision-making is recommended for patients at high cardiovascular risk 3

Monitoring Protocol

• Measure serum uric acid every 2-5 weeks during dose titration of the added uricosuric agent 3, 4
• Once target is achieved, monitor every 6 months to assess adherence 3, 2
• Continue monitoring for gout flares and adjust prophylaxis accordingly 4

Common Pitfalls to Avoid

• Do not combine febuxostat with allopurinol - they have redundant mechanisms and increase toxicity risk without therapeutic benefit 3
• Do not use uricosurics in patients with significant renal impairment (eGFR <50 mL/min) 2
• Do not discontinue flare prophylaxis prematurely - continue for at least 6 months after achieving target 3, 4
• Do not assume treatment failure without verifying adherence first 2