Yes, allopurinol (Zyloric) and uricosuric agents can be given together in gout treatment
Combining allopurinol with a uricosuric agent is explicitly recommended by major international guidelines as a second-line strategy when allopurinol monotherapy fails to achieve target serum uric acid levels. This combination approach is particularly valuable for patients with refractory gout who cannot reach the therapeutic goal of serum uric acid <6 mg/dL (360 μmol/L) with allopurinol alone.
Guideline-Based Recommendations
The 2016 EULAR guidelines clearly state: "If the SUA target cannot be reached by an appropriate dose of allopurinol, allopurinol should be switched to febuxostat or a uricosuric or combined with a uricosuric" 1. This recommendation is echoed across multiple authoritative sources.
The 2012 ACR guidelines similarly recommend that "effective therapeutic options include addition of a uricosuric agent (e.g., probenecid, fenofibrate, or losartan) to an XOI drug" as a second-line approach for refractory disease 2. The guidelines emphasize this combination therapy should be attempted after upward dose titration of allopurinol to its maximum appropriate dose has failed to achieve target serum urate levels 2.
Clinical Algorithm for Combination Therapy
Step 1: Optimize allopurinol first
- Start allopurinol at 100 mg/day (50 mg/day if stage 4 or worse CKD)
- Titrate upward by 100 mg every 2-4 weeks
- Target serum uric acid <6 mg/dL (or <5 mg/dL for severe gout with tophi) 1
Step 2: Consider combination if target not achieved
- If maximum tolerated allopurinol dose fails to reach target
- Add a uricosuric agent (probenecid, benzbromarone, or agents with uricosuric effects like fenofibrate or losartan) 1, 2
Step 3: Monitor appropriately
- Check serum uric acid every 2-5 weeks during titration
- Continue monitoring every 6 months once target achieved 2
Important Caveats and Contraindications
Do NOT use uricosuric agents as first-line monotherapy in patients with:
- Creatinine clearance <50 mL/min (probenecid specifically) 2
- History of urolithiasis 2
- Uric acid overproduction (>1000 mg/24 hours urinary uric acid) 2
When combining therapies:
- Measure urinary uric acid before initiating uricosuric therapy 2
- Consider urine alkalinization (e.g., potassium citrate) with increased fluid intake to reduce urolithiasis risk 2
- Continue monitoring urinary uric acid during treatment 2
- Provide adequate patient education about the combination approach 2
Specific Uricosuric Options
The guidelines recommend several uricosuric options for combination:
- Probenecid: First choice among dedicated uricosurics 2
- Benzbromarone: Can be used in mild-to-moderate renal insufficiency (except GFR <30 mL/min), though carries small hepatotoxicity risk 1, 3
- Fenofibrate and losartan: Have clinically significant uricosuric effects and can be useful as components of comprehensive urate-lowering strategy 2
Evidence Quality
The recommendation for combination therapy is based on moderate-quality evidence 2. While the published data on optimal combinations are somewhat limited 2, the consensus across EULAR, ACR, and BSR guidelines strongly supports this approach for refractory disease.
Critical pitfall to avoid: Fixed-dose combinations of allopurinol and uricosurics should NOT be used 4. Each agent should be titrated individually to optimize efficacy and minimize adverse effects.
The combination approach allows dual targeting of hyperuricemia—reducing uric acid production (allopurinol) while increasing renal excretion (uricosuric)—which can accelerate dissolution of urate crystal deposits and improve disease control in patients who fail monotherapy 2.