Febuxostat (Uloric), A New Treatment Option

for Gout
Carmela Avena-Woods, PharmD and Olga Hilas, PharmD, MPH, BCPS, CGP
Author information Copyright and License information
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INTRODUCTION
Gout is a rheumatic condition resulting from the deposition of monosodium urate crystals (tophi)
in the joints or soft tissues. It is usually associated with elevated serum uric acid levels (greater
than 7 mg/dL). The diagnosis is based on uric acid crystals found in the joints, tissues, or body
fluids, as well as on gouty attacks or flares characterized by intense pain, swelling, redness, and
heat.
14
The peak incidence of gout occurs between 30 and 50 years of age. Approximately 1% to
2% of Americans are affected, with an equal prevalence in men and women; however, men are
more likely to have elevated serum uric acid levels (hyperuricemia).
2,4,5

Hyperuricemia results from the accumulation of uric acid, the end product of purine metabolism,
which possesses no physiological role.
2,6
It has been associated with a high-purine diet (i.e.,
meats, seafood), alcohol use, diuretic therapy, reduced renal clearance, hypertriglyceridemia, and
diabetes mellitus.
2,6,7
Non-steroidal anti-inflammatory medications (NSAIDs), colchicine,
corticosteroids, and analgesics are commonly used in the acute treatment of gout. Goals of
therapy include controlling acute attacks, preventing recurrent attacks, and preventing or
reversing complications.
6,8

Chronic management of gout may include the long-term use of urate-lowering agents after an
attack is treated and prophylactic therapy has been considered. Antihyperuricemic therapy is
indicated in patients who have had two or more gouty attacks per year, tophaceous gout, erosive
arthritis on radiographs, or uric acid kidney disease.
9,10
In most patients, a serum uric acid level
of below 6 mg/dL is the initial target for therapy. Urate-lowering agents should be started after
the complete resolution of a gouty attack because a rapid decrease in serum urate levels
sometimes exacerbates a subsequent attack.
2,8

Underexcretion of uric acid is responsible for gout in approximately 90% of patients; therefore,
uricosuric agents should be used in most patients after ongoing urate deposition has been
confirmed and attempts to correct or reverse other causes of hyperuricemia have been made.
6,7,11

Inhibitors of uric acid synthesis are also used, particularly for patients who produce excessive
amounts of urate (more than 800 mg in 24 hours).
8

Allopurinol (Zyloprim, Prometheus), a potent purine xanthine oxidase (XO) inhibitor, is the most
commonly used drug in the treatment of hyperuricemia. Until recently, it was the only available
inhibitor of uric acid synthesis. In February 2009, the FDA approved febuxostat (Uloric, Takeda
Pharmaceutics America), a structurally unrelated non-purine XO inhibitor, for the chronic
management of hyperuricemia in patients with gout.
12,13

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PHARMACOLOGY AND MECHANISM OF
ACTION
4,12,1417

Patients with gout can be categorized into two groups: (1) overproducers of uric acid or (2)
underexcreters of uric acid. Hyperuricemia can thus result from the endogenous production of
uric acid, a high rate of renal urate reabsorption, or a diet high in purines. XO inhibitors are
effective in treating patients with both categories of gout as a result of their inhibition of uric
acid synthesis by impairing the conversion of hypoxanthine to xanthine, which results in uric
acid formation.
As a non-purine selective XO inhibitor, febuxostat inhibits both oxidized and reduced types of
XO. It does not inhibit enzymes involved in purine or pyrimidine metabolism, as does
allopurinol. Febuxostat is also structurally unrelated to allopurinol; its structure does not
resemble a pyrimidine or a purine. The drugs active ingredient is 2-(3-cyano-4[2-
methylpropoxy] phenyl)-4-methylthiazole-5-carboxylic acid. The empirical formula is
C
16
H
16
N
2
O
3
S, with a molecular weight of 316.38. As a result of its selectivity and structural
differences, febuxostat tends to cause fewer adverse events when compared with allopurinol.
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PHARMACOKINETICS AND
PHARMACODYNAMICS
12,14,18,19

Febuxostat is administered orally and is quickly absorbed; it reaches its maximum plasma
concentration in 1 to 1.5 hours after the dose is taken. Following oral absorption, approximately
85% of the drug is absorbed. Although the rate and extent of absorption may decrease with food
intake and antacid use, no clinically significant change in the effect of febuxostat has been
reported; therefore, it may be taken without regard to food or antacid consumption. There is no
accumulation when it is given in therapeutic doses in daily intervals (once every 24 hours). It is
approximately 99.2% protein-bound, primarily to albumin.
Febuxostat is metabolized primarily by uridine diphosphate glucuronosyl-transferase (UGT)
enzymes by means of conjugation. A small portion also undergoes oxidation via cytochrome P
(CYP) 450 isoenzymes. However, oxidation via CYP 450 is clinically insignificant in terms of
the drugs pharmacokinetics. Febuxostat does not inhibit any major CYP isoenzymes, other than
CYP 2D6, to which it exerts a mild inhibitory effect for which no dose adjustments are required.
Febuxostat is eliminated by both renal and hepatic pathways. However, renal clearance is not
significant. Only a small amount of unchanged drug or metabolites is excreted in the urine. The
half-life is approximately five to eight hours. Over a 24-hour period, febuxostat results in a dose-
dependent decrease in serum uric acid concentrations. As a result, total daily urinary uric acid
excretions are reduced with an increase in total daily urinary xanthine excretion.
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CLINICAL EFFICACY
The FDAs approval of febuxostat was based on three randomized, double-blind, controlled
clinical trials involving patients with hyperuricemia (i.e., 8 mg/dL or higher) and gout.
FACT
20

The Febuxostat versus Allopurinol Controlled Trial (FACT) was conducted to compare the
safety and efficacy of febuxostat with that of allopurinol. In this phase 3, 52-week, multicenter
trial, 762 patients were randomly assigned to receive either febuxostat 80 mg, febuxostat 120
mg, or allopurinol 300 mg once daily for the study period. All participants receiving any urate-
lowering therapy were required to undergo a two-week washout period prior to randomization.
During this two-week period, as well as during the first eight weeks of the trial, patients were
also given 250 mg of naproxen (Naprosyn, Roche) twice daily or 0.6 mg of colchicine once daily
as a preventative measure against any associated acute gouty attacks. Any subsequent attacks
were treated according to the discretion of the investigators. Patients underwent physical
examination, laboratory testing, monitoring of vital signs, measurement of serum urate
concentration, assessment of renal function, and evaluation of compliance at two weeks, four
weeks, and monthly thereafter.
The primary endpoint was a serum urate concentration below 6 mg/dL at each of the last three
monthly measurements.
Secondary endpoints included the proportion of patients with serum urate concentrations of less
than 6 mg/dL at each visit and the percentage reduction of serum urate concentrations from
baseline to each visit. The researchers also evaluated clinical endpoints such as the percentage
reduction in tophus area, the number of tophi, and the proportion of subjects requiring treatment
for acute gouty attacks.
Of the 756 patients who were included in the final analysis, 53% of patients receiving 80 mg of
febuxostat, 62% of those receiving 120 mg of febuxostat, and 21% of those receiving allopurinol
reached the primary efficacy endpoint. Higher proportions of patients treated with febuxostat (as
opposed to allopurinol at all ranges of initial urate levels tested) also reached this endpoint.
All results were determined to be statistically significant. The secondary endpoints were also
achieved more frequently with febuxostat than with allopurinol. However, no statistically
significant differences among the groups were seen in the percentage reduction in tophus area or
in the reduction in number of tophi or gouty flares.
Adverse event rates were similar in all treatment groups. The most frequently reported adverse
events among all patients included liver function abnormalities, diarrhea, headaches, joint-related
signs and symptoms, and musculoskeletal and connective tissue signs and symptoms. Four
deaths were reported in the two febuxostat groups, but they were determined to be unrelated to
the drug.
APEX
21

The Allopurinol and Placebo-Controlled, Efficacy Study of Febuxostat (APEX) was a phase 3,
28-week, multicenter trial designed to compare the efficacy and safety of febuxostat, allopurinol,
and placebo in patients with normal and impaired renal function. Impairment was defined as a
serum creatinine level of 1.5 to 2 mg/dL.
A total of 1,072 patients received once-daily febuxostat (80, 120, or 240 mg), allopurinol (100 or
300 mg, based on renal function), or placebo. Participants receiving any urate-lowering therapy
underwent a two-week washout period prior to randomization. During this two-week period, as
well as during the first eight weeks of the trial, patients were also given either naproxen or
colchicine as prophylaxis for gout flares. Any subsequent flares were treated at the discretion of
the investigators. Serum urate levels, laboratory testing, gout flares, adverse events, concomitant
medication use, and the number and size of palpable tophi were evaluated at the every-four-week
visit.
The primary endpoint was the proportion of patients with the last three monthly serum urate
levels of below 6 mg/dL. Secondary endpoints included the proportion of patients with a serum
urate level of below 6 mg/dL at each visit, the percentage of reduction of serum urate from the
baseline value at each visit, the proportion of patients requiring treatment for gout flares between
weeks 8 and 28, the reduction in the number of tophi at each visit for patients with palpable tophi
at baseline, and the percentage of reduction in primary tophus size at each visit in patients with a
primary palpable tophus at the baseline evaluation.
Of the 1,067 patients who were included in the final analysis, higher and statistically significant
percentages of patients attained the primary endpoint. Forty-eight percent of the febuxostat 80-
mg group, 65% of the 120-mg group, and 69% of the 240-mg group achieved serum urate levels
below 6 mg/dL at the last three monthly visits, compared with the 22% of patients in both
allopurinol groups and none (0%) of the patients in the placebo group.
A significantly higher percentage of patients with impaired renal function who received
febuxostat 80 mg (44%), 120 mg (45%), and 240 mg (60%) also achieved the primary endpoint,
compared with patients receiving allopurinol 100 mg (0%). The febuxostat-treated patients also
attained the secondary endpoints more often compared with the allopurinol or placebo patients.
Higher and significant proportions of patients with serum urate levels of below 6 mg/dL at week
28 (or at the final visit) were observed with febuxostat therapy than with allopurinol or placebo.
None of the patients with renal impairment who received allopurinol 100 mg reached this
endpoint.
All febuxostat groups also experienced significantly greater decreases in serum urate levels from
baseline at week 28 (or at the final visit) compared with patients receiving allopurinol or placebo.
However, no significant differences among the groups were seen in the proportion of patients
requiring treatment for gout flares between weeks 8 and 28, in the number of tophi, or in the
percentage of reduction in tophus area.
The occurrence of adverse events was similar for all study groups. As in FACT, liver function
abnormalities, diarrhea, headaches, joint-related signs and symptoms, and musculoskeletal and
connective tissue signs and symptoms, as well as upper respiratory infections, were the most
frequently experienced events. Cardiovascular events were also similar in all groups. No deaths
were reported during the study period.
CONFIRMS
22

A study called The Efficacy and Safety of Oral Febuxostat in Subjects with Gout (CONFIRMS)
was the largest phase 3, 28-week, multicenter trial to compare daily febuxostat with allopurinol.
A total of 2,269 patients received febuxostat 40 mg, febuxostat 80 mg, or allopurinol 300 mg.
Patients with an estimated creatinine clearance [CrCl] of 30 to 59 mL/minute received 200 mg.
Prophylaxis of gout flares was provided at the investigators discretion throughout the study.
The primary endpoint was the proportion of patients who achieved final serum urate levels below
6 mg/dL. The secondary endpoint was the proportion of patients with mild chronic kidney
disease (CrCl, 6089 mL/minute) or moderate chronic kidney disease (CrCl, 3059 mL/minute)
who achieved final serum urate levels of less than 6 mg/dL.
Forty-five percent of patients who received febuxostat 40 mg, 67% of those receiving febuxostat
80 mg, and 42% of those receiving allopurinol achieved the primary endpoint. Urate-lowering
efficacy was similar for the febuxostat 40-mg and allopurinol groups, although the 80-mg dose
was superior to both the 40-mg dose and allopurinol.
In patients with chronic kidney disease (n =1,483), febuxostat 80 mg had greater urate-lowering
efficacy compared with the 40-mg dose and allopurinol; however, febuxostat 40 mg provided
greater urate-lowering efficacy than allopurinol in these patients. Overall, patients with baseline
tophi or serum urate levels higher than 10 mg/dL had a greater response to the 80-mg dose than
the 40-mg dose and allopurinol. All data were determined to be statistically significant.
The rates of adverse events (including cardiovascular events) were comparable for all groups and
levels of renal function. During the study, one patient in each febuxostat group died and three
allopurinol patients died.
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ADVERSE DRUG REACTIONS
12

Compared with allopurinol and placebo in clinical trials, febuxostat at doses of 40 mg and 80 mg
daily was associated with a higher percentage of liver function abnormalities, the most common
adverse reaction that resulted in discontinuation of therapy. Of those subjects taking febuxostat
40 mg, 1.2% experienced liver abnormalities, compared with 1.8% of patients who were
receiving 80 mg. In the allopurinol group, 0.9% discontinued therapy because of hepatic
abnormalities, compared with 0.7% of patients in the placebo group. Other common adverse
reactions that were experienced in 1% or more of subjects taking febuxostat and that occurred at
least 0.5% more often than in those receiving placebo were nausea, arthralgia, and rash.
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DRUG INTERACTIONS
12,14

Inhibition of XO by febuxostat may cause increased plasma concentrations of drugs that are
metabolized by this enzyme, although studies have not been conducted to confirm this effect.
Azathioprine (e.g., Imuran, GlaxoSmith-Kline), theophylline (Theo-Dur, Key), and
mercaptopurine (e.g., Purinethol, Gate) undergo some metabolism, mediated by XO, which has
the potential to result in toxic levels of these drugs. Therefore, the manufacturer identifies this
possibility as a contraindication for use.
There are no interactions between febuxostat and CYP 450 enzymes or CYP 1A2, 2C9, 2C19,
2D6, or 3A4. There appear to be no clinically significant effects of febuxostat on colchicine,
indomethacin, or naproxen, medications that are commonly used to treat gout. Because
hydrochlorothiazide (HCT) can cause an increase in uric acid levels, it was studied with
febuxostat. When the two agents are used together, the increase in uric acid levels has been
determined to be insignificant. No dose adjustment is necessary when febuxostat is used with
HCT, warfarin (Coumadin, Bristol-Myers Squibb), or desipramine (Norpramin, Sanofi-Aventis).
It is speculated that febuxostat is a weak inhibitor of CYP 2D6, although this property does not
seem to be clinically significant.
1
Even though febuxostat is highly protein-bound, the available
evidence is insufficient to verify the degree of displacement.
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CONTRAINDICATIONS
12

Because of the possible increases in plasma concentrations with febuxostat, this agent is
contraindicated in patients using azathioprine, mercaptopurine, or theophylline. As with other
medications, febuxostat should not be administered to patients with any hypersensitivity to any
component of the product.
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PRECAUTIONS AND WARNINGS
12

Patients should be informed that an increase in gout flares is common after the commencement
of febuxostat therapy. This is the result of the shift in urate from tissue deposits caused by the
reduction in serum uric acid levels. To help avoid such flares, prophylactic treatment with an
NSAID or colchicine is recommended when febuxostat is initiated. It may be beneficial to
continue prophylactic therapy for up to six months. Febuxostat does not need to be discontinued
if a flare occurs.
Although a causal relationship has not been established, patients should be monitored and
counseled for signs and symptoms of myocardial infarction and stroke. In randomized controlled
studies, there was a higher rate of cardiovascular thromboembolic events with febuxostat than
with allopurinol.
It is recommended that baseline liver function be assessed at two and four months and
periodically after febuxostat is initiated. Increases in liver transaminase levels are not affected by
the dose.
No adequate or well-controlled studies have been conducted on the use of febuxostat in pregnant
women. Febuxostat is a Pregnancy Category C drug. Caution should be used when this agent is
prescribed to nursing mothers because the drug has been noted to be excreted in the milk of rats.
Safety and effectiveness have not been established in patients 18 years of age or under.
Febuxostat is not recommended for patients who may have conditions that increase urate
formation. No studies have been conducted in patients with secondary hyperuricemia; however,
in rare instances, xanthine concentrations in the urine may increase and accumulate in the urinary
tract.
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DOSAGE AND ADMINISTRATION
12,14,18,19

Febuxostat is available in 40-mg and 80-mg tablets. For the treatment of gout, it is recommended
that the drug be started at 40 mg by mouth once daily. Two weeks after initiation, if serum uric
acid levels are not below 6 mg/dL, the dose can be increased to 80 mg daily.
Febuxostat can be taken with or without food. Although not clinically significant in relation to its
effects, there is a slight delay in absorption, of approximately one hour, if febuxostat is taken
with antacids that contain magnesium and aluminum hydroxide.
No dose adjustment is necessary in elderly patients or in patients with mild or moderate renal or
hepatic impairment. However, caution should be used when febuxostat is prescribed for patients
with severe renal impairment or hepatic impairment, because the data available in this regard are
inadequate.
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COST
12,23

Febuxostat (Uloric) is sold as 40-mg and 80-mg light green to green tablets. The product should
be protected from light and stored at room temperature (25C, or 77F). According to the 2009
edition of Red Book, the average wholesale price of a bottle of 30 tablets was $162, regardless of
strength.
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CONCLUSION
Febuxostat is the first drug approved and marketed for the treatment of gout in more than 40
years. It represents a new option for the management of hyperuricemia and gout, particularly in
patients who are unable to use or to tolerate the less expensive and more extensively studied
allopurinol.
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Footnotes
Disclosure: The authors report no financial or commercial relationships in regard to this article.
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