Benzbromarone in Gout and Hyperuricemia
Primary Recommendation
Benzbromarone is an effective uricosuric agent for gout management, particularly valuable in patients with moderate renal impairment (eGFR 30-60 mL/min) where it can be used without dose adjustment, but it is contraindicated when eGFR falls below 30 mL/min. 1
Clinical Positioning and Indications
When to Consider Benzbromarone
Benzbromarone should be considered when allopurinol or febuxostat alone fails to achieve target serum uric acid <6 mg/dL, either as monotherapy or in combination with a xanthine oxidase inhibitor 1
It is particularly useful in patients with moderate renal impairment (eGFR 30-60 mL/min) because it is predominantly metabolized by the liver rather than renally excreted 1, 2
Standard dosing of benzbromarone (100 mg/day) produces greater hypouricemic effects than standard doses of allopurinol (300 mg/day) or probenecid (1000 mg/day) 3
Combination Therapy Strategy
The EULAR guidelines explicitly recommend combining benzbromarone with allopurinol or febuxostat in patients who cannot reach target serum uric acid with monotherapy, especially when newer agents like pegloticase are not available or appropriate 1
Clinical evidence demonstrates that combination therapy with 300 mg allopurinol plus 60 mg benzbromarone achieves sustained normalization of uric acid levels, with levels remaining therapeutic even 3 months after discontinuation 4
Renal Function Considerations
Dosing by Kidney Function
Benzbromarone can be used without dose adjustment in mild to moderate renal insufficiency (eGFR 30-60 mL/min) 1, 2
It is absolutely contraindicated when eGFR drops below 30 mL/min due to increased risk of adverse effects and reduced efficacy 1
This represents a significant advantage over allopurinol, which requires careful dose reduction starting at 50-100 mg daily in stage 3-4 CKD 2
Efficacy Profile
Uric Acid Reduction
Benzbromarone achieves average reductions in serum uric acid of approximately 54% from baseline 5
In patients with refractory gout despite optimal conventional therapy, benzbromarone reduced uric acid levels from 0.61 mmol/L to 0.46 mmol/L after 1 year (p=0.01) 6
Most patients normalize their plasma urate levels with benzbromarone therapy 3
Clinical Outcomes
The severity and incidence of gout attacks are reduced by 75% before the end of the first year of treatment 5
Tophaceous deposits typically disappear within 6-18 months of therapy 5
In refractory gout patients, acute attack frequency decreased from 16 attacks to 7.3 attacks annually (p=0.01) 6
Safety Profile and Hepatotoxicity Risk
The Hepatotoxicity Controversy
Benzbromarone was withdrawn from some markets in 2003 due to reports of serious hepatotoxicity, though a comprehensive benefit-risk analysis suggests this withdrawal was not in patients' best interests 3
Only 4 cases of benzbromarone-induced hepatotoxicity were identified in the published literature, with only 1 demonstrating clear causality on rechallenge 3
The estimated risk of hepatotoxicity in Europe was approximately 1 in 17,000 patients, which compares favorably to allopurinol's hypersensitivity syndrome risk of 1 in 56,000 3
Risk Mitigation Strategies
Employ graded dosage increases rather than starting at full dose to minimize hepatotoxicity risk 3
Monitor liver function tests regularly during therapy, particularly in the first 6 months 3
Ensure adequate fluid intake and urinary alkalinization to prevent urolithiasis, as 35% of patients may be urate overexcretors 5
Common Adverse Effects
Side effects are usually mild and primarily gastrointestinal in nature 7
The drug was well tolerated by 96% of patients in long-term studies 5
Urinary complications occur in only 3% of patients when adequate hydration and urinary alkalinization are maintained 5
Drug Interactions
CYP2C9 Considerations
Benzbromarone is an inhibitor of CYP2C9, which can lead to clinically significant drug interactions with warfarin and other drugs metabolized by this enzyme 3
Consider determining CYP2C9 polymorphism status before initiating therapy, as the active metabolite 6-hydroxybenzbromarone is metabolized by CYP2C9 and its activity may vary between patients 3
Adjust doses of CYP2C9 substrates accordingly and monitor INR closely in patients on warfarin 3
Practical Dosing Recommendations
Standard Regimen
Typical dosing ranges from 75-120 mg daily, with 100 mg/day being the most common therapeutic dose 3, 5
Lower doses (60 mg) can be effective when combined with allopurinol 300 mg 4
The drug has a short half-life of approximately 3 hours, but its active metabolite 6-hydroxybenzbromarone has a half-life up to 30 hours, allowing once-daily dosing 3, 7
Critical Pitfalls to Avoid
Do not use benzbromarone in patients with eGFR <30 mL/min - this is an absolute contraindication 1
Do not overlook potential drug interactions with warfarin and other CYP2C9 substrates - these require careful monitoring and dose adjustments 3
Do not start at full dose - use graded dose escalation to minimize hepatotoxicity risk 3
Do not neglect liver function monitoring - regular LFT checks are essential, particularly in the first 6 months 3
Do not forget urinary alkalinization and adequate hydration - these measures reduce the 35% baseline risk of urolithiasis to only 3% 5
Availability Considerations
Benzbromarone is not available in all countries, having been withdrawn from some markets but remaining available in others throughout Asia, South America, and Europe 3
The EULAR task force acknowledges that not all uricosurics are readily available in all European countries but emphasizes that these drugs could benefit patients without adequate control on xanthine oxidase inhibitors alone 1