Febuxostat is an inhibitor of the enzyme xanthine oxidase and is FDA-approved for the chronic management of hyperuricemia in patients diagnosed with gout. Due to the finding of an increased risk of death with febuxostat versus allopurinol, the FDA recently recommended limiting the use of febuxostat to patients for which allopurinol is not efficacious or patients who experience severe side effects with allopurinol.
Febuxostat is a non-purine selective inhibitor of the enzyme xanthine oxidase, which is involved in purine catabolism. The xanthine oxidase enzyme catalyzes two reactions that ultimately generate uric acid from hypoxanthine. Febuxostat is a potent, selective inhibitor of xanthine oxidase, forming a stable complex with both the reduced and oxidized form of the enzyme, thereby inhibiting its function. Treatment with febuxostat leads to lower serum uric acid levels in animals and humans. The therapeutic effect of febuxostat has as its basis the ability to lower serum uric acid levels in patients with hyperuricemia, defined by the uric acid serum concentration that exceeds the solubility of uric acid (approximately 7 mg/dL). The chemical structure of febuxostat does not resemble either purines or pyrimidine structures, and it does not appear to inhibit other enzymes in the nucleotide catabolic pathways.
Febuxostat is administered orally with an initial dose of 40 mg per day. Its administration can be without regard to food or antacid use. The clinician can increase the dose of febuxostat 80 mg per day in patients that do not achieve a serum uric acid level of less than 6 mg/dL after two weeks of treatment with 40 mg so long as the patient does not have severe renal impairment (defined as a clearance of 15 to 29 mL/min). Febuxostat is available in both 40 mg and 80 mg tablet formulations, and estimates are that greater than 49% of the dose is absorbed when taken orally. Upon initiating treatment with febuxostat, gout flares may occur. Therefore, flare prophylaxis with either a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended concurrently with febuxostat treatment and may continue for up to six months.
Common adverse drug effects (greater than 1% of the febuxostat-treated group based on multiple randomized, controlled clinical studies ranging in length from 6 to 12 months) :
Warnings and Precautions
An increase in gout flares frequently occurs after the initiation of febuxostat. This increase is likely due to the reduction of serum uric acid levels, which mobilizes the urate crystals in tissue deposits. Therefore, flare prophylaxis with either a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended concurrently with febuxostat treatment and may continue for up to six months. Febuxostat should not be used to treat secondary hyperuricemia or asymptomatic hyperuricemia.
In randomized controlled studies, there was a higher rate of cardiovascular deaths as well as non-fatal myocardial infarctions and strokes in the febuxostat-treated group compared with the allopurinol-treated group. Based on this new information, the FDA is limiting the use of febuxostat to patients for which allopurinol is not efficacious or patients who experience severe side effects with allopurinol, and there is now a boxed warning of cardiovascular death.
In randomized controlled studies, liver function abnormalities were reported, including transaminase elevations greater than three times the upper limit of normal. Although this effect has not demonstrated that it is clinically significant, recommendations include a liver test panel, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and total bilirubin, prior to initiating febuxostat treatment as a baseline measurement as well as periodically during treatment and in patients experiencing any signs of hepatic injury.
Febuxostat contraindications include patients that are treated with azathioprine or mercaptopurine since xanthine oxidase inhibition enhances serious toxicity such as myelosuppression.
Patient monitoring should include signs and symptoms of MI and stroke as well as liver injury, as described above in the warnings and precautions section. Patients with impaired renal function appear to tolerate febuxostat well, and no dose adjustments are necessary. Febuxostat may actually slow the progress of mild or moderate chronic kidney disease.
There is no known human toxicity with febuxostat treatment.
As with many medications, interprofessional communication and teamwork are necessary when it comes to the administration and monitoring of febuxostat. With the recent revisions of the FDA guidelines, physicians, nurses and pharmacists need to be particularly aware of current prescribing information.
As of early 2019, febuxostat is now recommended only for patients with gout who are unable to tolerate allopurinol or if allopurinol lacks efficacy; this is particularly pertinent in patients with cardiovascular disease. Pharmacists should familiarize themselves with the patient's gout medication history, and verify that febuxostat is appropriate. They can also confirm dosing and perform medication reconciliation, alerting the patient's clinician to any concerns or potential interactions. Nursing will be in a position to assess treatment efficacy, patient compliance, and look for medication side effects, reporting any concerns to the treating physician. The healthcare team, consisting of physicians, specialists, specialty-trained nursing, and pharmacy, must work together to ensure that proper dosing and dispensing protocols are in place and be aware of the possibility of adverse effects, which includes informing the patient of the increased risk of gout flares upon treatment with febuxostat and treating the flares appropriately. [Level 5]
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