Brand:  Uloric®

Generic:  febuxostat

Manufacturer:  Takeda Pharmaceuticals¹

Drug Class:  Antigout Agent²

Uses: 

Labeled: Gout – Hyperuricemia in adults³

Unlabeled: N/A

Mechanism of Action:          

Febuxostat is a xanthine oxidase inhibitor.  This results in a decrease of serum uric acid.^2,3,4

Pharmacokinetics:

Metabolism: Febuxostat is metabolized by conjugation through the uridine diphosphate glucuronosyltransferase (UGT) enzymes: 1A1, 1A3, 1A9, and 2B7.  It is also metabolized by oxidation through the cytochrome P450 (CYP) enzymes: 1A2, 2C8 and 2C9 as well as by some non-P450 enzymes.^3,4,5   Conjugation creates an acyl glucuronide metabolite, and oxidation creates the following active hydroxyl metabolites: 67M-1, 67M-2, 67M-4.^3,5

Elimination: Febuxostat undergoes renal and hepatic elimination.  Approximately 49% undergoes renal elimination: 3% unchanged, 30% acyl glucuronide metabolite, 13% oxidative metabolites and their conjugates, and 3% as unknown metabolites.  Approximately 45% of the drug is eliminated in the feces: 12% unchanged, 1% acyl glucuronide metabolite, 25% oxidative metabolites and their conjugates, and 7% as unknown metabolites.^3,4

Efficacy:

Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, et al.  Febuxostat compared with allopurinol in patients with hyperuricemia and gout.  N Eng J Med 2005; 353(23):2450-61. ⁷

Study Design: This study was a randomized, multi-center, controlled, double blinded trial.

Description:  762 patients with gout (serum urate concentration of at least 8.0mg/dL) were obtained from 112 centers in the United States and Canada.  Subjects were randomized into one of three groups: febuxostat 80mg, febuxostat 120mg, or allopurinol 300mg once daily for one year.  The primary endpoint was a serum urate concentration <6.0mg/dL at each of the last three monthly measurements.  Of the subjects taking 80mg of febuxostat, 53% achieved the primary endpoint.  Of those taking 120mg of febuxostat, 62% achieved the primary endpoint, and of those taking 300mg of allopurinol, 21% achieved the primary endpoint (P<0.001 for both febuxostat groups versus allopurinol).  A significantly higher proportion of subjects receiving 120mg of febuxostat required treatment for a gout flair during the prophylaxis period as compared to those on the 80mg dose and allopurinol (P<0.001 for each). More patients discontinued the study in the 120mg febuxostat group as compared to the allopurinol group (P=0.003).  The adverse event leading to the most withdrawal was an abnormal liver-function test result, which was significantly higher for the 120mg febuxostat group compared to the 80mg febuxostat group and the allopurinol group (P=0.04 for each).

Limitations:  Most of the authors had an association or were employed by the manufacturing company of febuxostat.  The two week washout period may not have been enough time to eliminate the effects of the previous drugs, resulting in a carry-over effect.  The allopurinol was not administered by a titration method as indicated by its package insert in an effort to prevent unblinding.  However, this prevented the most effective dosage schedule from being used and may have resulted in poorer outcomes.

Conclusions:  Despite some limitations to this study, febuxostat appears to be safe and efficacious for the use of gout based on the results of this study, but it is unknown if febuxostat is more effective than the optimal dose of allopurinol.  Treatment with febuxostat should be initiated at the lowest dose possible to achieve desired outcomes based on the facts that more subjects on the 120mg dose discontinued due to adverse events, were withdrawn due to abnormal liver-function tests, and experienced acute gouty flares as compared to the 80mg dose and allopurinol.  An NSAID or colchicine should be used with febuxostat to prevent acute gouty flare upon initiation of therapy.

Schumacher RH, Becker MA, Wortmann RL, MacDonald PA, 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 and Rheumatism (Arthritis Care and Research). 2009;59(11):1540-8. ⁸

Study Design:  This was a multi-center, randomized, double-blind, parallel-group, allopurinol- and placebo-controlled trial.

Description:  Patients were enrolled in this study from 167 United States sites between February 2003 and April 2004.  They were randomized to receive febuxostat 80mg, febuxostat 120mg, febuxostat 240mg, allopurinol, or placebo on a 2:2:1:2:1 ratio.  The randomization was stratified by renal function, and the allopurinol dose was dependent on renal function.  The primary endpoint was the proportion of subjects with the last 3 serum urate levels <6.0mg/dL.  A significantly higher proportion of patients in all three febuxostat groups achieved the primary endpoint of <6.0mg/dL serum urate levels during the last three monthly versus allopurinol and placebo (P<0.001 for each).  Patients with impaired renal function who took febuxostat 80mg, febuxostat 120 mg, and febuxostat 240mg achieved the primary endpoint 44%, 46%, and 60%, respectively.  No subjects with renal impairment who received allopurinol or placebo achieve the primary outcome endpoint.  The most common reasons for withdrawal included abnormal liver function tests and diarrhea.  Dizziness occurred significantly more in the 240mg febuxostat group compared to the others, as well.  Authors conclude that febuxostat at doses of 80mg, 120mg, and 240mg reduces serum urate levels in hyperuricemic patients significantly more than allopurinol or placebo.

Limitations:  Authors of this study had associations or were employed by the manufacturer of febuxostat, Takeda Pharmaceuticals.  Takeda not only provided much of the funding, but they also helped design the study, collect data, and conduct statistical analyses.  The washout period of two weeks may not have been enough time, and subjects may have experienced carry-over effects from previous anti-gout medications.  This study evaluated how renal impairment affects the efficacy of these drugs, and patients in the allopurinol group with renal impairment received a dose of 100mg.  It is recommended to titrate this dose up as needed to achieve desired outcomes, which was not done in these cases. 

Conclusions:  It is difficult to conclude if febuxostat is superior to allopurinol based on the limitations of this study.  Febuxostat does not require dosage adjustment in renal impairment, which may be one of its benefits over allopurinol.  The use of prophylactic medications like an NSAID or colchicine to prevent gout flares upon initiation of febuxostat or allopurinol should be used.  It appears that some of the adverse effects may occur with higher dosages of febuxostat, so patients would likely benefit best by starting at a lower dose of febuxostat and titrating upwards as needed.

Khosravan R, Grabowski BA, Mayer MD, Wu JT, et al.  The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuoxstat, a novel nonpurine selective inhibitor of xanthine oxidase.  J Clin Pharmacol. 2006;46:88-102.⁹

Study Design:  This was a phase I, parallel-group, open-label, multiple-dose study of the pharmacokinetics, pharmacodynamics, and safety of febuxostat in patients with normal, mild, and moderately impaired hepatic function. 

Description:  This study assigned subjects into 3 groups based on hepatic function.  Each subject received an 80mg oral dose of febuxostat, given as four 20mg tablets daily for 7 consecutive days after an overnight fast.  Blood, urine, and plasma samples were obtained on a scheduled basis daily to evaluate metabolites and protein binding.  Safety and tolerability were evaluated based on vital signs, ECG, physical exam, clinical laboratory parameters, and adverse event monitoring.  Those with mild (63%, 5 of 8) and moderate (75%, 6 of 8) hepatic impairment had a higher incidence of adverse events than those with normal hepatic function (25%, 3 of 12).  After once-daily multiple dosing with febuxostat 80mg, the serum uric acid values decreased for normal, mild, and moderately impaired hepatic function groups by a mean of 62% (4.77 to 1.83mg/dL), 48.9% (4.95 to 2.66mg/dL), and 47.8% (5.45 to 2.85mg/dL), respectively.  The authors concluded that no dosage adjustment of febuxostat is necessary in patients who are mild or moderately hepatically impaired.

Limitations:  This study is limited by the fact that the subjects did not have gout since it was a phase I trial looking at pharmacodynamics, pharmacokinetics, and safety in healthy subjects.  Another limitation was the very small sample size.  Only 29 subjects were enrolled, and there were unequal numbers of patients in the normal, moderate, or mild hepatic impairment groups.  Even though adverse events appeared to occur more in those with mild or moderate hepatic impairment, a significance value was not indicated.  This study is also limited in that it primarily was focused on the pharmacokinetics, pharmacodynamics, and safety of this drug and not on its efficacy. 

Conclusions: This study did not focus on efficacy of the drug, but it did show that there were no serious adverse events associated with the drug despite hepatic function.  Those who are more hepatically impaired may experience more adverse events, but this is difficult to conclude based on this study due to its small sample size.  Further controlled studies are needed in subjects who are hepatically impaired and have gout to further support the authors’ statement that dosage adjustments are not needed in hepatically impaired patients.

Contraindications:

This use of this drug is contraindicated with simultaneous use of     azathioprine, mercaptopurine, or theophylline^3,4,5

Precautions: 

Acute Gout Flare:  Initiation of febuxostat  may cause a flare of gout.  When serum uric acid is reduced, this results in urate mobilization from the tissue.  This may be prevented by using an NSAID or colchicine (up to 6 months of therapy).^4,5 

Cardiovascular Events:  Some studies have shown a higher rate of cardiovascular thromoembolic events with use of febuxostat when compared to allopurinol.  Patients should be monitored for signs and symptoms of a myocardial infarction and stroke.^4,5 

Liver Enzyme Elevations:  Febuxostat may increase the liver enzyme transaminase.  Patients using febuxostat should have their liver function monitored at two and four months, and periodically thereafter.^4,5 

Hepatic Impairment:  This drug should be used cautiously in patients with hepatic impairment.⁵

Renal Impairment:  This drug should be used cautiously in patients with renal      impairment (Cl_Cr <30mL/min).⁵

Pediatrics:  Febuoxstat’s safety and efficacy have not been studied in children.⁵

Other Precautions:  Febuxostatis not recommended for patients with conditions which have increased urate formation rates such as those patients with a malignant disease and treatment, organ transplant recipients, or those with Lesch-Nyhan syndrome.^4,5 

Adverse effects:

>1% incidence:         

Liver function abnormalities (4.6-6.6%)^4,5

Nausea (1.1-1.3%)⁴

Arthralgia (0.7-1.1%)⁴

Rash (0.5-1.6%)⁴

<1% incidence:         

Cardiovascular risks: Although rare, patients should be monitored for signs and symptoms of a myocardial infarction or stroke.^2,4

Acute gout flare: May occur upon initiation;^2,4 Patients may take an NSAID or colchicine prophylactically for up to 6 months. ²

Drug Interactions:                

Azathioprine^2,3,4,5

Mercaptopurine^2,3,4,5

Theophylline^2,3,4,5

Didanosine⁵

Use of febuxostat may increase plasma levels of the drugs listed above leading to toxicity^2,4,5  These drugs are contraindicated based on their mechanisms because studies have not been conducted with drugs that are metabolized by xanthine oxidase or with cytotoxic chemotherapy drugs.  Data is therefore not available regarding these drugs and interactions are unknown.^2,4

Dosing/Administration:

Usual Dose:  The recommended starting dose of febuxostat is 40mg once daily.  Patients may be given 80mg once daily if serum uric acid concentration (sUA) <6mg/dL is not achieved within 2 weeks.  Febuxostat may be taken without regard to meals or the use of antacids.⁴

Geriatric Dose:  The usual dose of febuxostat may be used in this population.  Although studies did not show variation between elderly patients and younger age groups, some differences may still exist.⁴

Pediatric Dose:  Febuxostat dosage has not been studied in patients under the age of 18.⁴

Renal Impairment Dose:  No dosage adjustment needed in patients with mild or moderate renal impairment (Cl_Cr 30-89mL/min).  Febuxostat should be used with caution in patients with severe renal impairment (Cl_Cr <30mL/min) since there is insufficient data regarding use in this population.⁴

Hepatic Impairment Dose:  No dosage adjustment needed for mild or moderate hepatic impairment.  Febuxostat should be used with caution in patients with severe hepatic impairment since no studies have been conducted in this population.⁴

Use in special circumstances:

Pregnancy:  Febuxostat has not been extensively studied in pregnant women.  It should only be used if potential benefits outweigh the potential risks to the fetus.  It has not been found to be teratogenic when studied in rats and rabbits.  Febuxostat is rated as a Pregnancy Category C.⁴

Lactation:  It is unknown if febuxostat is excreted in human breast milk.  It has been found to be excreted in the milk of rats.  Caution should be used in nursing mothers.⁴

Conclusions:

Febuxostat is a novel therapy indicated for treating hyperuricemia. It does not appear to have any major adverse effects, but liver function abnormalities and cardiovascular risks are some of the more serious adverse events that may occur.  Febuxostat offers a new alternative to allopurinol, a drug commonly used to treat gout.  Febuxostat does not require renal or hepatic dose adjustment unlike allopurinol, but it should still be used cautiously in these populations since limited data currently exists.  Patients beginning initial therapy should begin at the lowest dose of febuxostat and titrate up until results are observed.  Based on the limitations of available studies, it is unknown if it is superior in efficacy to allopurinol.  Even though dosage adjustment for renally or hepatically impaired patients is not required with febuxostat, the cost of a brand name drug may not outweigh its benefits over a generic like allopurinol, which can still be used in these patients with an adjusted dose. 

Recommended References:

1. Takeda Pharmaceutical Company Staff.  ULORIC® (TMX-67, febuxostat) Receives FDA Approval for the Chronic Management of Hyperuricemia in Patients with Gout [updated February 14, 2009].  Takeda Pharmaceutical Company Limited.  Available at:   http://www.takeda.com/press/article_32580.html.  Accessed March 12, 2009.
2. Febuxostat.  Clinical Pharmacology [Internet Database].  Gold Standard, Inc., 2009.  Available at: http://www.clinicalpharmacology.com.  Accessed March 12, 2009.    
3. Febuxostat.  In: DrugDex® System [Internet Databse].  Greenwood Village, Colo: Thomson Micromedex.  Updated periodically.  Accessed March 12, 2009.
4. Uloric [Package Insert].  Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2009.
5. Febuxostat.  Lexi-Drugs [Database Online].  Lexi-Comp, Inc; March 12, 2009.
6. Bruce SP.  Febuxostat: A selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout.  Ann Pharmacother.  2006;40:2187-94.
7. Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, et al.  Febuxostat compared with allopurinol in patients with hyperuricemia and gout.  N Eng J Med 2005; 353(23):2450-61.
8. Schumacher RH, Becker MA, Wortmann RL, MacDonald PA, 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 and Rheumatism (Arthritis Care and Research). 2009;59(11):1540-8.
9. Khosravan R, Grabowski BA, Mayer MD, Wu JT, et al.  The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuoxstat, a novel nonpurine selective inhibitor of xanthine oxidase.  J Clin Pharmacol. 2006;46:88-102.
10. Allopurinol.  In: DrugDex® System [Internet Databse].  Greenwood Village, Colo: Thomson Micromedex.  Updated periodically.  Accessed March 19, 2009.

Prepared by: Lindsey Koliscak, Doctor of Pharmacy Candidate