What is the use and dosage of probenecid in treating gout or hyperuricemia?

Probenecid for Treating Gout and Hyperuricemia

Probenecid is recommended as a second-line uricosuric agent for gout treatment when xanthine oxidase inhibitors (XOIs) like allopurinol or febuxostat are ineffective, not tolerated, or contraindicated, with a standard dosing regimen starting at 250 mg twice daily for one week, followed by 500 mg twice daily thereafter. 1, 2

Indications and Position in Treatment Algorithm

• Probenecid is the first choice among uricosuric agents for urate-lowering therapy (ULT) monotherapy in gout patients 1
• However, it is not recommended as first-line ULT monotherapy in current treatment algorithms, as allopurinol is the preferred first-line agent for all patients, including those with moderate-to-severe chronic kidney disease (CKD) 1
• Probenecid can be used as an alternative first-line therapy when XOIs are contraindicated or not tolerated 1, 3
• Probenecid can be effectively combined with an XOI (allopurinol or febuxostat) in patients with refractory gout who fail to achieve target serum urate levels on XOI monotherapy 1, 4

Contraindications and Precautions

• Probenecid is contraindicated as first-line ULT monotherapy in patients with:
  • Creatinine clearance <50 ml/minute 1
  • History of urolithiasis 1
  • Elevated urine uric acid indicative of uric acid overproduction 1
• Probenecid is contraindicated in children under 2 years of age 2

Dosing Regimen

• Initial dosing:
  • 250 mg twice daily for one week 2
  • Then increase to 500 mg twice daily 2
• Maintenance dosing:
  • Standard maintenance dose is 500 mg twice daily (1000 mg/day) 2
  • If necessary, dosage may be increased by 500 mg increments every 4 weeks as tolerated 2
  • Maximum dose is usually not above 2000 mg per day 2
  • Once serum urate levels remain normal and acute attacks have been absent for 6 months or more, the daily dosage may be decreased by 500 mg every 6 months to find the minimum effective maintenance dose 2

Monitoring and Risk Management

• Urinary uric acid should be measured before initiation of probenecid therapy 1
• Continue monitoring urinary uric acid during probenecid treatment 1
• Maintain liberal fluid intake to prevent crystallization of uric acid 2
• Consider urine alkalinization with:
  • Sodium bicarbonate (3 to 7.5 g daily) or
  • Potassium citrate (7.5 g daily) to maintain alkaline urine 1, 2
• Gastric intolerance may indicate overdosage and can be corrected by decreasing the dosage 2
• Monitor for adverse events, which occur in approximately 13-19% of patients 5

Efficacy and Outcomes

• Probenecid has moderate efficacy as ULT in clinical management of gout 5
• Target serum urate concentrations (<0.36 mmol/l or <6 mg/dL) are achieved in approximately 33-37% of patients on probenecid monotherapy or combination therapy 5
• Baseline serum urate concentrations are predictive of achieving target levels 5
• Despite conventional recommendations against use in CKD, studies show similar efficacy and adverse event rates in patients with eGFR <50 ml/min/1.73 m² compared to those with better renal function 5, 4

Combination Therapy

• Adding probenecid to an XOI (allopurinol or febuxostat) is an effective therapeutic option for patients with refractory gout 1
• Combination therapy may achieve target serum urate levels in patients who fail to respond to monotherapy 4
• Other agents with uricosuric effects (fenofibrate, losartan) can also be therapeutically useful as components of a comprehensive ULT strategy 1

Important Clinical Considerations

• Probenecid should not be started during an acute gout attack but can be continued without changing the dosage if an acute attack occurs during therapy 2
• Probenecid may not be effective in chronic renal insufficiency, particularly when the glomerular filtration rate is 30 ml/minute or less 2
• Alkalization of urine should be continued until serum urate levels return to normal and tophaceous deposits disappear 2
• Probenecid therapy should be maintained at a dosage that keeps serum urate levels within normal limits 2