Mixing Febuxostat and Allopurinol
No, febuxostat and allopurinol should never be combined or mixed together. Both medications are xanthine oxidase inhibitors that work through the same mechanism to lower uric acid, and combining them provides no additional benefit while potentially increasing toxicity risk 1.
Why Combination is Not Recommended
Redundant mechanism of action: Both drugs inhibit the same enzyme (xanthine oxidase) through different binding mechanisms, making combination therapy pharmacologically illogical 1, 2.
No evidence of additive benefit: All major clinical trials compared these medications head-to-head as monotherapy alternatives, never as combination therapy 3, 2, 4, 5.
Increased adverse event risk: Combining two xanthine oxidase inhibitors would expose patients to the adverse effect profiles of both medications simultaneously without therapeutic justification 1.
Choosing Between Febuxostat and Allopurinol
Select one medication and titrate it to achieve target serum uric acid <6 mg/dL 1, 6.
When to Choose Allopurinol:
- First-line for most patients with normal to mildly impaired renal function (eGFR ≥60 mL/min) 1.
- Lower cardiovascular risk compared to febuxostat, making it preferable in patients with established cardiovascular disease 6, 7.
- More extensive safety data with over 40 years of clinical experience 1.
- Recent evidence shows lower gout flare rates in CKD patients during maintenance phase compared to febuxostat 5.
When to Choose Febuxostat:
- Preferred in moderate-to-severe CKD (eGFR <60 mL/min) as it requires no dose adjustment and maintains efficacy 6.
- Allopurinol hypersensitivity or contraindication, particularly in patients with HLA-B*5801 haplotype (prevalent in Asian populations) 1, 6.
- Failure to achieve target uric acid with maximally titrated allopurinol 6, 8.
Critical Pitfalls to Avoid
Never use both medications simultaneously - this is the most important point 1.
Do not switch between medications without washout consideration - if switching from one to the other, stop the first medication before starting the second 1.
Always provide flare prophylaxis with colchicine (0.5-1 mg daily) or low-dose NSAIDs for at least 6 months when initiating either medication, as both can paradoxically increase gout flares initially 1, 6, 8.
Febuxostat carries FDA black box warning for cardiovascular mortality - strongly consider allopurinol instead in patients with history of myocardial infarction, stroke, or established cardiovascular disease 6, 7.
If Target Uric Acid Not Achieved with Monotherapy
Maximize the dose of your chosen xanthine oxidase inhibitor first (allopurinol up to 800-900 mg/day with normal renal function; febuxostat up to 80 mg/day in US, 120 mg/day elsewhere) 6, 8.
Add a uricosuric agent (probenecid, fenofibrate, or losartan) to the xanthine oxidase inhibitor rather than combining two xanthine oxidase inhibitors 8.
Switch to the alternative xanthine oxidase inhibitor if the first fails at maximum dose 8.
Consider pegloticase only for severe refractory disease with tophi when all oral options have failed 8.