Allopurinol vs Febuxostat: Which?
Allopurinol and febuxostat block the same enzyme and chase the same blood target, yet almost every guideline still puts allopurinol first. The reasons are a mix of cost, decades of familiarity, and an unresolved argument about cardiovascular safety that two large trials answered differently. Here is what actually separates them, and where each one earns its place.
Same enzyme, different key
Both drugs inhibit xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Block it and less urate is made, the blood level falls, and crystals already deposited in joints slowly dissolve.
They do it differently. Allopurinol is a purine analogue: it looks like the enzyme’s natural substrate, and its active metabolite oxypurinol binds the enzyme and stays bound. Because it resembles a purine, it also brushes against other purine-handling enzymes, which is part of why it has a broader interaction profile. Febuxostat is a non-purine inhibitor designed specifically for the job. It wedges into the channel leading to the enzyme’s active site and blocks it whether the enzyme is oxidised or reduced — a more selective, more complete block.
Side by side
| Allopurinol | Febuxostat | |
|---|---|---|
| Mechanism | Purine-analogue xanthine oxidase inhibitor | Non-purine selective xanthine oxidase inhibitor |
| Potency at licensed doses | Reaches target in most people when titrated properly; often under-dosed in practice | Generally more potent milligram for milligram; reaches target in a higher share of patients in head-to-head trials |
| Clearance | Mainly renal — dose adjusted in kidney impairment | Mainly hepatic — less dose adjustment needed in mild to moderate kidney impairment |
| Hypersensitivity | Rare but serious syndrome, linked to HLA-B*5801 | Not associated with HLA-B*5801; severe reactions reported but rarer |
| Cardiovascular signal | Comparator in both major trials; no excess signal | Contested — see below |
| Cost | Very cheap; generic everywhere | Generic in most markets now, but usually still the more expensive of the two |
| Guideline position | First line for nearly everyone, including chronic kidney disease | Second line, or first where allopurinol is unsuitable |
| Early flares | Common; prophylaxis co-prescribed | Common, possibly more so given the faster drop; prophylaxis co-prescribed |
Potency, and why it matters less than it sounds
In head-to-head trials, febuxostat at its licensed doses got more patients below 6 mg/dL (360 µmol/L) than allopurinol did. That result is real, but it comes with a caveat that is often skipped: many of those trials capped allopurinol at 300 mg, a dose plenty of people need to exceed. Compare febuxostat against allopurinol that has genuinely been titrated to effect, and the gap narrows considerably.
That is the practical lesson. A very large share of “allopurinol didn’t work for me” is really “allopurinol was never increased”. If your urate is still above target, the first question is what your dose is and when it was last reviewed — not whether to switch drugs. Both are decisions for your prescriber, and neither should be made on your own. The titration logic is set out in our practical guide to allopurinol, and what the target means in the uric acid target that actually matters.
Kidneys
Allopurinol and its active metabolite are cleared renally, so reduced kidney function means a lower starting dose and slower steps upward. That is a reason for caution, not avoidance: modern guidance is clear that allopurinol can be used in chronic kidney disease, started low and titrated carefully to target.
Febuxostat is metabolised mainly by the liver, so mild to moderate kidney impairment needs less adjustment. For someone with meaningfully reduced kidney function who has not tolerated or responded to allopurinol, that simplicity is a genuine advantage.
The hypersensitivity difference
Allopurinol carries a rare but potentially life-threatening hypersensitivity syndrome, strongly associated with the HLA-B*5801 gene variant — common enough in people of Han Chinese, Thai, Korean and some African ancestries that guidelines recommend testing before starting. Febuxostat is not linked to that variant, which makes it the usual choice for someone who tests positive, and for anyone who has had a genuine allopurinol reaction. Details are in allopurinol side effects: an honest look.
The cardiovascular question, honestly
In 2018 the CARES trial reported on more than six thousand people with gout and established cardiovascular disease. Febuxostat matched allopurinol on the primary composite outcome of major cardiovascular events — but all-cause death and cardiovascular death were higher in the febuxostat group. The US regulator responded with a boxed warning and a recommendation to reserve febuxostat for people who cannot use allopurinol.
CARES had weaknesses. A large proportion of participants stopped treatment early and a substantial number were lost to follow-up, and many of the deaths occurred after people had already come off the study drug — which makes attributing them to it difficult.
In 2020 the FAST trial, a European study of over six thousand patients followed for several years, was designed partly to test the same question. It found febuxostat non-inferior to allopurinol for cardiovascular events, with no excess in death. European regulators took a more relaxed view as a result.
So the honest position is: the two best trials disagree, FAST is methodologically the stronger of the two, and most rheumatologists now consider the alarm overstated without regarding the question as closed. If you have existing heart disease and are on febuxostat, that is worth a specific conversation at your next review rather than a change made unilaterally.
Worth raising at your next appointment: if you are on allopurinol and still above target, ask whether the dose has ever been increased, and what your last urate reading was. Switching drugs when the first one was never pushed to an effective dose trades a cheap, familiar option for a dearer one without solving the problem.
Who each one suits
- Allopurinol — most people starting urate-lowering therapy, including those with chronic kidney disease, provided it is titrated to target and HLA-B*5801 testing is used where ancestry indicates it.
- Febuxostat — people who cannot tolerate allopurinol, who have reacted to it, who test positive for HLA-B*5801, or who remain above target on the maximum tolerated allopurinol dose.
- Neither alone — people with severe tophaceous disease may need combination treatment or, rarely, pegloticase. That territory is covered in gout medications compared.
Frequently Asked Questions
Can you switch from allopurinol to febuxostat directly?
Switching is done in clinical practice and does not usually require a washout, but the changeover raises the chance of a flare because urate shifts again. Prophylaxis is often continued or restarted around a switch for that reason. The timing and the cover are for your prescriber to arrange.
Is febuxostat safe if I have had a heart attack?
This is exactly the question CARES and FAST disagree about, and it is not settled. In the US the label advises reserving febuxostat for people who cannot use allopurinol, partly on that basis. Someone with established cardiovascular disease should have the choice discussed individually rather than decided from a general rule.
Which one causes more flares when you start?
Both do, because both lower urate and both cause existing crystals to shed. A faster or deeper drop tends to mean more early flares, which is an argument for starting low and using prophylaxis with either drug rather than for preferring one over the other.
Do I still need to watch my diet on either drug?
Diet helps but does not replace them. Whole-diet change shifts serum urate by roughly 0.3–1.3 mg/dL (about 18–78 µmol/L), which for established gout is a useful contribution rather than a treatment. Weight loss and cutting alcohol are the two biggest levers you control.
What to read next
- Allopurinol for gout: a practical guide
- Allopurinol side effects: an honest look
- Gout medications compared
- The uric acid target that actually matters
