What are the medications for urate lowering?

Medications for Urate Lowering Therapy

Xanthine oxidase inhibitors (allopurinol and febuxostat) are the first-line medications for urate lowering therapy, with allopurinol being the recommended initial agent for most patients with gout. 1, 2

First-Line Urate Lowering Therapy

Allopurinol

• Starting dose: 100 mg daily (lower in CKD)
• Titration: Increase by 100 mg every 2-4 weeks
• Target: Serum uric acid <6 mg/dL (<5 mg/dL for tophaceous gout)
• Advantages: Extensive experience, effectiveness, low cost
• Special considerations:
  • Adjust dose in renal impairment
  • Consider HLA-B*5801 screening in high-risk populations (Korean, Han Chinese, Thai) before initiating 2

Febuxostat

• Starting dose: 40 mg daily
• Titration: Can increase to 80 mg daily if needed
• When to use: When allopurinol is not tolerated or contraindicated
• Caution: Use with caution in patients with cardiovascular disease
• Advantage: More effective than allopurinol 300 mg in achieving target urate levels 3, 4

Second-Line Urate Lowering Therapy

Uricosuric Agents

• Probenecid:

  • Dose: 500 mg once or twice daily
  • When to use: When XOIs fail or are contraindicated
  • Contraindications: Renal impairment (CrCl <50 ml/min), history of urolithiasis 1
  • Monitoring: Check urinary uric acid before initiation 1

• Other uricosurics:

  • Benzbromarone: Can be used in mild to moderate renal insufficiency but carries hepatotoxicity risk 1
  • Sulphinpyrazone: Alternative to probenecid in normal renal function 1

Combination Therapy

• XOI + uricosuric agent: Effective option when monotherapy fails 1
  • Examples: Adding probenecid, fenofibrate, or losartan to an XOI
  • Consider when target urate levels are not achieved with maximum XOI dose

Advanced Therapy for Refractory Gout

Pegloticase

• Dose: 8 mg IV infusion every two weeks 5
• Indication: Severe gout with high disease burden refractory to conventional therapy 1, 2, 6
• Mechanism: PEGylated uricase that enzymatically degrades urate 6, 7
• Important notes:
  • Not recommended as first-line therapy 1
  • Discontinue oral urate-lowering agents before starting 5
  • Administer in healthcare settings prepared to manage infusion reactions 5
  • Monitor serum uric acid levels before each infusion 5

Prophylaxis During Initiation of Urate Lowering Therapy

• Colchicine: 0.6 mg once or twice daily for at least 3-6 months 2, 8
• Alternative: NSAIDs or low-dose prednisone if colchicine contraindicated 2
• Purpose: Prevents gout flares during initial urate lowering therapy

Clinical Decision Algorithm

1. Assess patient for indications for ULT:

   • Recurrent acute attacks (≥2 per year)
   • Tophaceous gout
   • Radiographic damage due to gout
   • Chronic kidney disease stage ≥3
   • History of urolithiasis

2. Select appropriate first-line agent:

   • Standard patient: Start allopurinol 100 mg daily
   • Renal impairment: Start allopurinol at lower dose
   • Allopurinol intolerance/allergy: Use febuxostat 40 mg daily
   • High cardiovascular risk: Use allopurinol with caution regarding febuxostat

3. Titrate dose to target urate level:

   • Check serum urate every 2-4 weeks during titration
   • Increase dose until target achieved (<6 mg/dL, or <5 mg/dL for tophaceous gout)
   • Once target achieved, monitor every 6 months

4. If target not achieved with maximum XOI dose:

   • Add uricosuric agent (probenecid) if renal function normal
   • Consider switching XOIs (allopurinol to febuxostat or vice versa)

5. For severe refractory gout:

   • Consider pegloticase if failed or cannot tolerate appropriately dosed oral ULT options

Common Pitfalls and Caveats

• Underdosing: Many patients remain on initial allopurinol dose without titration to target
• Inadequate prophylaxis: Failure to provide anti-inflammatory prophylaxis during ULT initiation
• Discontinuing during flares: ULT should be continued during acute gout flares
• Monitoring: Failure to monitor serum urate levels to ensure target achievement
• Renal adjustment: Not adjusting allopurinol dose in patients with renal impairment
• Drug interactions: Not accounting for interactions (e.g., colchicine with CYP3A4 inhibitors)

The evidence strongly supports a treat-to-target approach with regular monitoring of serum urate levels to guide therapy adjustments, with the goal of maintaining levels below 6 mg/dL to promote crystal dissolution and prevent new crystal formation 1, 2.