What is the recommended treatment and dosage of Febuxostat (xanthine oxidase inhibitor) for a 40-70 year old adult patient with gout and hyperuricemia, potentially with impaired renal function or cardiovascular disease?

Febuxostat for Gout and Hyperuricemia

Febuxostat is indicated as first-line urate-lowering therapy alongside allopurinol for chronic hyperuricemia in gout patients, with a starting dose of 40 mg daily, titrating to 80 mg daily if serum urate remains ≥6 mg/dL after 2 weeks, and offers particular advantages in patients with moderate-to-severe renal impairment or allopurinol intolerance. 1, 2, 3

Primary Indications and Patient Selection

Febuxostat is appropriate for:

• Chronic hyperuricemia where urate deposition has already occurred, including patients with recurrent gout flares (≥2 per year), tophi, urate arthropathy, or uric acid renal stones 2
• Patients with moderate-to-severe renal impairment (eGFR <60 mL/min), where febuxostat offers an advantage as it does not require dose adjustment in mild-to-moderate renal dysfunction 2, 4, 5
• Patients who cannot tolerate allopurinol due to hypersensitivity reactions or those with HLA-B*5801 allele positivity 2
• Patients who fail to achieve target serum urate with appropriately titrated allopurinol (up to maximum tolerated doses) 1

Dosing Strategy

Initial Dosing

• Start at 40 mg once daily 2, 4, 6
• Assess serum urate after 2 weeks; if still ≥6 mg/dL, increase to 80 mg once daily 2, 4
• No dose adjustment needed in elderly patients or those with mild-to-moderate renal or hepatic impairment 4, 5, 7

Target Serum Urate Levels

• <6 mg/dL (360 μmol/L) for all gout patients as the minimum target 8, 2, 3
• <5 mg/dL (300 μmol/L) for severe gout with tophi, chronic arthropathy, or frequent attacks to hasten crystal dissolution 8, 2, 3

Monitoring

• Check serum urate every 2-5 weeks during dose titration, then every 6 months once target is achieved 2
• Monitor liver function tests as liver enzyme abnormalities occur in approximately 5-7% of patients 4, 6

Efficacy Compared to Allopurinol

• Febuxostat 80 mg daily is superior to allopurinol 300 mg daily at achieving serum urate <6 mg/dL (67% vs 42%, P<0.001) 6, 9
• Febuxostat 40 mg daily is noninferior to allopurinol 300 mg daily (45% vs 42% achieving target) 6
• Long-term treatment (3-5 years) maintains target serum urate in most patients with near elimination of gout flares and improved tophus resolution 5, 9

Critical Cardiovascular Safety Consideration

If your patient has established cardiovascular disease or develops a new cardiovascular event while on febuxostat, switch to alternative urate-lowering therapy (typically allopurinol). 8, 2

• More cardiovascular thromboembolic events occurred in randomized trials with febuxostat, though causality is not definitively established 4
• Monitor patients for signs and symptoms of myocardial infarction and stroke 4
• The American College of Rheumatology conditionally recommends switching from febuxostat in patients with cardiovascular disease history 2

Mandatory Flare Prophylaxis

Always initiate anti-inflammatory prophylaxis when starting febuxostat, continuing for at least 3-6 months. 8, 2

Options include:

• Colchicine (preferred if not contraindicated) 2, 6
• Low-dose NSAIDs (if colchicine contraindicated) 2
• Low-dose corticosteroids (if both above contraindicated) 8

This is essential because aggressive urate lowering triggers acute gout flares for a prolonged period after initiation 6, 7

Role in Treatment Algorithm

First-Line Therapy

• Febuxostat and allopurinol are both recommended as first-line xanthine oxidase inhibitors without preferential recommendation of one over the other based on efficacy alone 1, 2, 3
• However, allopurinol remains preferred initially due to extensive clinical experience and cost-effectiveness 3

When to Choose Febuxostat Over Allopurinol

1. Moderate-to-severe renal impairment (CrCl 30-60 mL/min) where dose simplicity is advantageous 2, 5
2. Allopurinol hypersensitivity or intolerance 1, 2, 7
3. HLA-B*5801 positive patients at high risk for severe allopurinol hypersensitivity 2
4. Failure to achieve target serum urate despite appropriate allopurinol dose titration (including doses >300 mg daily) 1

Refractory Disease Strategy

• If febuxostat monotherapy fails to achieve target serum urate, add a uricosuric agent (probenecid, fenofibrate, or losartan) rather than increasing febuxostat beyond 80 mg 1, 3
• Never combine febuxostat with allopurinol—both are xanthine oxidase inhibitors working through identical mechanisms 1, 3

Common Pitfalls to Avoid

• Do NOT use febuxostat to treat acute gout attacks—it is maintenance therapy only and does not reduce attack risk within the first 6 months 2
• Do NOT stop febuxostat once target serum urate is achieved—continue indefinitely for sustained benefit 8
• Do NOT fail to provide flare prophylaxis—this is the most common reason for treatment discontinuation 2, 6
• Do NOT ignore cardiovascular history—febuxostat may not be appropriate for patients with established CV disease 8, 2, 4
• Do NOT combine with allopurinol—this provides no additional benefit and is explicitly contraindicated 1, 3

Adverse Event Profile

Most common adverse events (generally mild-to-moderate):

• Liver function abnormalities (5-7%) 4, 6, 7
• Nausea and gastrointestinal symptoms 4, 5, 7
• Arthralgias 4
• Rash (1-2%) 4, 6
• Cardiovascular events (most common serious adverse event, under continued surveillance) 4, 5