Introduction
Febuxostat is a novel xanthine oxidase inhibitor used for the management of hyperuricemia in patients with gout. Unlike its predecessor allopurinol, febuxostat is a non-purine selective inhibitor of xanthine oxidase that offers an alternative treatment option for patients who cannot tolerate or have inadequate response to conventional urate-lowering therapy.
Mechanism of Action
Febuxostat selectively inhibits xanthine oxidase, the enzyme responsible for catalyzing the conversion of hypoxanthine to xanthine and xanthine to uric acid. By inhibiting this enzyme, febuxostat reduces the production of uric acid without affecting other enzymes in the purine or pyrimidine metabolic pathways. The drug demonstrates potent inhibition of both the oxidized and reduced forms of xanthine oxidase.
Indications
- Management of hyperuricemia in patients with gout
- Approved for patients who have not achieved target serum uric acid levels with allopurinol or who are intolerant to allopurinol
Dosage and Administration
Initial dose: 40 mg orally once daily May increase to: 80 mg once daily if serum uric acid remains above 6 mg/dL after 2 weeks Maximum dose: 80 mg daily Special Populations:- Renal impairment: No dose adjustment necessary for mild to moderate impairment (CrCl 30-89 mL/min)
- Hepatic impairment: Use with caution in severe hepatic impairment
- Geriatric patients: No dose adjustment required
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Well absorbed with approximately 85% bioavailability; Tmax: 1-1.5 hours Distribution: Volume of distribution: ~50 L; Protein binding: >99% (primarily to albumin) Metabolism: Extensive hepatic metabolism via conjugation by uridine diphosphate glucuronosyltransferase (UGT) enzymes and oxidation via cytochrome P450 system (CYP2C8, CYP1A2, CYP2C9) Elimination: Half-life: 5-8 hours; Excretion: Approximately 49% in urine and 45% in feces as metabolitesContraindications
- Concomitant use with azathioprine, mercaptopurine, or theophylline
- History of hypersensitivity reaction to febuxostat or any component of the formulation
- Asymptomatic hyperuricemia
Warnings and Precautions
Cardiovascular Risk: Increased risk of cardiovascular death has been observed in clinical trials Hepatic Effects: Transaminase elevations reported; monitor liver function tests Gout Flares: May occur during initiation due to changing serum uric acid levels; concurrent prophylaxis with NSAIDs or colchicine recommended Renal Impairment: Use caution in severe renal impairment (CrCl <30 mL/min) Hypersensitivity Reactions: Rare but serious reactions including Stevens-Johnson syndrome reportedDrug Interactions
Significant interactions:- Azathioprine/mercaptopurine: Contraindicated due to increased toxicity risk
- Theophylline: Contraindicated due to increased theophylline concentrations
- Warfarin: Monitor INR closely due to potential increased anticoagulant effect
- NSAIDs: Possible increased risk of NSAID-related adverse effects
Adverse Effects
Common (≥2%):- Liver function abnormalities
- Nausea
- Arthralgia
- Rash
- Gout flare
- Cardiovascular events
- Severe hepatic injury
- Hypersensitivity reactions
- Stevens-Johnson syndrome
Monitoring Parameters
- Serum uric acid levels (target <6 mg/dL)
- Liver function tests at baseline and periodically during treatment
- Renal function assessment
- Signs and symptoms of cardiovascular events
- Monitoring for gout flares during initiation
- Signs of hypersensitivity reactions
Patient Education
- Take medication as prescribed, typically once daily
- Continue taking even during gout flares unless directed otherwise by healthcare provider
- Report any signs of allergic reaction (rash, itching, swelling) immediately
- Be aware of potential for increased gout attacks when starting treatment
- Inform all healthcare providers about febuxostat use
- Regular follow-up appointments are important for monitoring
- Do not take with azathioprine, mercaptopurine, or theophylline
References
1. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. 2. FDA Prescribing Information: Uloric (febuxostat). Revised 2019. 3. White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018;378(13):1200-1210. 4. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446. 5. Schumacher HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-1548.