BLACK BOX WARNING
- increased cardiovascular death in the CARES trial; prescribe to patients for whom allopurinol treatment had failed or was not tolerated
febuxostat
Brand: Uloric
⚠ BBW Prototype: allopurinol
Drug Class: xanthine oxidase inhibitor
Drug Family: uric acid agent
Subclass: non-purine selective xanthine oxidase inhibitor
Organ Systems: endocrinemusculoskeletal
Mechanism of Action
Non-purine selective xanthine oxidase inhibitor that blocks both the oxidized and reduced forms of XO, providing more complete enzyme inhibition than allopurinol. Lowers serum urate via reduced uric acid synthesis without requiring dose adjustment for mild-to-moderate renal impairment.
xanthine oxidase (XO) — both oxidized and reduced forms
Indications
- chronic gout in patients with hyperuricemia (when allopurinol has failed or is not tolerated)
Contraindications
- patients treated with azathioprine or 6-mercaptopurine (same as allopurinol interaction)
- hypersensitivity
Adverse Effects
Common
- gout flares (during initiation)
- liver function test abnormalities
- nausea
- arthralgia
Serious
- cardiovascular events (increased MACE vs. allopurinol in CARES trial)
- serious skin reactions (SJS — rare, but class risk)
Pharmacokinetics (ADME)
| Absorption | oral bioavailability ~49% |
| Distribution | 99.2% protein bound (albumin) |
| Metabolism | hepatic via CYP1A2, CYP2C8, CYP2C9, UGT |
| Excretion | renal (49%) and fecal (45%) |
| Half-life | 5–8 hours |
| Onset | days to weeks |
| Peak | 1–1.5 hours |
| Duration | continuous |
| Protein Binding | 99.2% |
| Vd | 29–75 L |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| azathioprine, 6-MP | xanthine oxidase inhibition causes azathioprine/6-MP accumulation; potentially fatal; contraindicated | contraindicated |
| theophylline | XO inhibition increases theophylline levels | major |
Nursing Considerations
- Reserve for patients who have failed allopurinol or have documented allergy/intolerance — do not use as first-line due to CARES trial CV mortality signal.
- Initiate with colchicine or NSAID prophylaxis for the first 6 months to prevent gout flares.
- Monitor LFTs at 2 and 4 months after initiation; discontinue if significant LFT elevation.
- Educate patients about same azathioprine/6-MP interaction risk as allopurinol — equally dangerous.
Clinical Pearls
- The CARES cardiovascular outcomes trial showed febuxostat was associated with increased all-cause mortality (primarily cardiovascular) versus allopurinol, prompting the FDA boxed warning and restriction to second-line use.
- Unlike allopurinol, febuxostat does not require dose adjustment in mild-to-moderate CKD, which can be clinically advantageous in gout patients with concurrent renal disease.
Safety Profile
Pregnancy insufficient-data
Lactation avoid
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Guideline Update pending
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.