FebuxostatRx

Trade Names: Uloric

Drug Class: Xanthine oxidase inhibitor; antigout agent

Preparations: 40- and 80-mg tablets

Dose: For prophylaxis of gout, initially use 40 mg daily if do not achieve target uric acid of less than 6 mg/dL after 4 weeks increase to 80 mg daily. Some patients require 120 mg/day. No dose adjustment required for mild renal impairment but little data with more severe renal impairment (creatinine clearance less than 30 ml/min).

Indications: To treat hyperuricemia in patients with gout

Mechanism of Action: Inhibits formation of uric acid by inhibiting xanthine oxidase; has no anti-inflammatory activity.

Contraindications: Concomitant azathioprine or mercaptopurine

Precautions: When initiating therapy use NSAID or colchicine prophylaxis to reduce risk of acute  attack.

Pregnancy Risk: C

Monitoring: Monitor liver function tests before,  after 2 and 4 months, and then periodically. Uric acid level guides dose; aim to reduce uric acid concentration to <6 mg/dL.

Adverse Effects
Common: Acute gout occurs with increased frequency after starting febuxostat, rash, increased liver function tests, nausea
Rarely: Hypersensitivity, serious skin reactions, hepatic failure, myocardial infarction

Drug Interactions
Azathioprine and mercaptopurine: This is a potentially fatal interaction. Febuxostat decreases metabolism of these agents, leading to toxicity (bone marrow depression). Avoid concurrent use.
Theophylline: Increased theophylline levels
Pegloticase: Urate lowering therapies including febuxostat should be discontinued prior to the use of pegloticase and should not be initiated during  pegloticase therapy.

Patient Instructions: The drug needs to be taken every day (or as prescribed) to lower uric acid and thus prevent gout. It has no effect on the symptoms of gout and will not help when joints hurt.  Do not drink alcohol.

Comments:  Xanthine oxidase inhibitors are used primarily to lower the uric acid level in patients with recurrent attacks of acute gout (more than one per year) or patients with tophaceous gout. They are preferred over a uricosuric agent in patients with tophi, renal stones, and impaired renal function. Monitor serum uric acid and titrate dose with aim to decrease to 5–6 mg/dL. Failure to decrease uric acid often indicates poor compliance. Prevent acute attacks of gout with concurrent colchicine or NSAID treatment, particularly in first 3–6 months of therapy. High doses of aspirin are uricosuric but low  doses increase uric acid levels. Many, but not all, patients who are hypersensitive to allopurinol appear to tolerate febuxostat. Febuxostat 80 mg/day  and 120 mg /day  were more effective in lowering uric acid than a suboptimal clinical strategy of a fixed dose (300 mg/day) of allopurinol. Comparison with a titrated dose allopurinol will be of interest.

Clinical Pharmacology: Oral absorption is 50%; 99% protein bound, metabolism by uridine diphosphate glucuronosyltransferases (UGTs), half-life 5-8 hours. If xanthine oxidase inhibitor is discontinued, uric acid concentrations return to pretreatment levels in weeks.

Cost: $$$

BIBLIOGRAPHY

Becker MA, Schumacher HR Jr, Wortmann RL, et al Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450-61. PMID:16339094.

Khanna D, Fitzgerald JD, Khanna PP et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1 Arthritis Care Res2012;64:1431-46.PMID:23024028