Rheumatology 2009;48:ii15–ii19 doi:10.

1093/rheumatology/kep088

Febuxostat: a new treatment for hyperuricaemia in gout

N. Lawrence Edwards1

Febuxostat is a new non-purine xanthine oxidase inhibitor that is more potent than allopurinol 300 mg daily. In two Phase III trials, significantly
more febuxostat-treated gout patients met the primary endpoint [serum urate (sUA) <6 mg/dl (<360 mmol/l) at the last three visits] (48 and
53% with 80 mg; 65 and 62% with 120 mg), compared with those receiving allopurinol 300 mg (22 and 21%; P < 0.001 in both studies).
Febuxostat was more effective than allopurinol in the subset with impaired renal function; no dose adjustment is required in mild-to-moderate

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renal impairment. Long-term extension studies confirmed the efficacy and tolerability of febuxostat. In patients who achieved the sUA target of
6 mg/dl (360 mmol/l), the incidence of gout flares fell steadily and tophi resolved in many patients. The incidence of adverse events such as
dizziness, diarrhoea, headache and nausea with febuxostat was similar to allopurinol. The incidence of cardiovascular side-effects
(Antiplatelet Trialists Collaboration events) was numerically higher with febuxostat than with allopurinol, but this was not statistically
significant. Co-administration of febuxostat with AZA or 6-mercaptopurine is not recommended. Prophylaxis (colchicine and/or NSAIDs)
against acute attacks should be used for at least the first 6 months, since early mobilization flares were observed in the clinical trials. In
conclusion, febuxostat is more effective than allopurinol 300 mg daily in reducing sUA levels <6 mg/dl (360 mmol/l), the target recommended
by EULAR, and offers a new option for the long-term treatment of gout.

KEY WORDS: Gout, Urate-lowering therapy, Allopurinol, Febuxostat, Clinical studies, sUA target, Adverse events.

Introduction effects, is excreted predominantly by the kidneys and hence it

Gout is a form of inflammatory arthritis, associated with hyper-
uricaemia, in which the formation of monosodium urate crystals
in the joints and periarticular tissues causes acute inflammatory
attacks as well as long-term tissue damage. The strategy for the
long-term management of gout is to lower the serum urate (sUA)
level and hence the level in the tissues, and maintain it below
the saturation point (6.8 mg/dl or 410 mmol/l) so that existing
monosodium urate crystals dissolve and no further crystals
form. A target level for sUA of 46 mg/dl (360 mmol/l) is
recommended in recent evidence-based recommendations from
the European League against Rheumatism (EULAR) [1].
The British Society for Rheumatology (BSR) has also published
guidelines for gout, which recommend a lower sUA target level
of 5 mg/dl (300 mmol/l) [2].
For many years, allopurinol has been the most widely used
urate-lowering agent in gout patients. It is recommended that
allopurinol be initiated at a low dose of 100 mg, which is then
titrated upwards in 100 mg increments every few weeks to achieve
the therapeutic target [2]. However, this is rarely done in clinical
practice, for reasons that are unclear, and the vast majority of
physicians give allopurinol at the standard dose of 300 mg/day
without titration. Moreover, there is increasing evidence to show
that the 300 mg dose is relatively ineffective in achieving the target
sUA level and that higher doses (or combination therapy) may be
needed to attain this [3, 4]. There has never been a systematic
evaluation of the use of higher doses of allopurinol nor has a
controlled clinical trial been carried out comparing fixed dosing
with titration to achieve a target sUA.
Side-effects including rashes occur in a small proportion of
patients receiving allopurinol, and a more severe reaction
described as allopurinol hypersensitivity syndrome is believed to
affect around 1 in 300 treated patients [2]. Characterized by symp-
toms such as severe skin rash, fever and deterioration in renal
function [5], allopurinol hypersensitivity syndrome is potentially
life-threatening, and is associated with significant mortality
and morbidity. Oxypurinol, which is the main metabolite of
allopurinol and is responsible for most of its urate-lowering
1
Department of Medicine, University of Florida, Gainesville, FL, USA.
Submitted 18 December 2008; revised version accepted 18 March 2009.
Correspondence to: N. Lawrence Edwards, Department of Medicine, University
of Florida, Gainesville, FL 32610, USA. E-mail: edwarnl@medicine.ufl.edu
ii15
ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
has been recommended that the dosage of allopurinol be reduced
in patients with renal impairment.
It has become increasingly obvious that alternative therapeutic
options may have a significant impact on the future of successful
gout management, especially in those patients with renal impair-
ment or who are unresponsive or intolerant to allopurinol.
Febuxostat is a new oral non-purine xanthine oxidase (XO)
inhibitor that has recently been approved in Europe for the treat-
ment of chronic hyperuricaemia and gout. It has been evaluated in
an extensive clinical trials programme, and results have shown
that it is an effective therapy for lowering sUA levels. This article
reviews the evidence to show that febuxostat is a valuable treat-
ment option that may provide considerable benefits for patients
with gout and hyperuricaemia.
Pharmacodynamics
Febuxostat is structurally different from allopurinol and lacks the
purine ring (Fig. 1). It is a more selective and potent inhibitor
of XO than allopurinol and has no effect on other enzymes
involved in purine or pyrimidine metabolism. Animal studies
have demonstrated that the potency of febuxostat is 10–30 times
that of allopurinol [6]. Febuxostat showed potent mixed-type
inhibition of XO from purified bovine milk, with Ki and Ki0
values of 0.6 and 3.1 nM, respectively, suggesting that both the
oxidized and reduced forms of XO were inhibited [7]. The IC50 of
febuxostat for bovine milk XO is 20 nmol/l, making it 10-fold
more potent than allopurinol in this assay. The onset of action
of febuxostat is sufficiently fast that sUA levels can be re-tested
within 2 weeks of initial dosing [8].
Pharmacokinetics
Febuxostat is well absorbed after oral administration (84% oral
bioavailability). The effects of food or antacids on absorption are
not considered to be clinically relevant and febuxostat can be
given without regard to food intake [9]. The half-life is 5–8 h,
and the volume of distribution at steady state ranges from 29
to 75 l after an oral dose of 10–300 mg. Febuxostat is almost
completely bound to plasma proteins (99% binding), primarily
albumin. The active metabolites of febuxostat are 82–91% protein
bound [8].
ii16
FIG. 1. Unlike allopurinol, febuxostat is a non-purine XO inhibitor.
The main route of elimination of febuxostat is metabolism in
the liver followed by excretion of metabolites in the urine and
faeces. It is metabolized via the uridine diphosphate glucuronosyl-
transferase system and oxidized by the cytochrome P450 system.
The pharmacokinetics of febuxostat are unaffected in subjects
with mild-to-moderate hepatic impairment (Child–Pugh Classes
A and B) [10]. Less than 5% of the dose of febuxostat is excreted
unchanged in the urine. The area under the time–concentration
curve (AUC) is increased by a factor of 1.8 in patients with severe
renal dysfunction, but no dose adjustment is required in mild-to-
moderate renal impairment (creatinine clearance 30–80 ml/min)
[11]. The safety and efficacy of febuxostat have not been
fully evaluated in patients with creatinine clearance <30 ml/min.
Neither age nor gender had any significant effect on the pharma-
cokinetics, pharmacodynamics or safety profile of febuxostat [12].
Drug interactions
Studies of drug interactions between febuxostat and a variety of
other medicinal agents have reported that febuxostat can be
co-administered with colchicine (0.6 mg b.i.d.), certain NSAIDs
(naproxen and indometacin), hydrochlorothiazide, warfarin and
desipramine or other CYP2D6 substrates, without any dose
adjustment, and without any clinically significant effects on the
pharmacokinetics of either agent [8]. No drug interaction studies
have been undertaken with AZA or 6-mercaptopurine, but since
these drugs are metabolized by XO, co-administration with
febuxostat is not recommended.
Phase II studies and dose selection
A Phase II randomized double-blind dose–response study
in 153 patients with gout compared febuxostat 40, 80 and
120 mg/day with placebo over 28 days, with colchicine prophylaxis
in all groups [13]. The study population was predominantly
male (89%) with mean baseline sUA >8.0 mg/dl (480 mmol/l).
The primary endpoint was the proportion of patients reaching
the target sUA level of <6 mg/dl (<360 mmol/l) on Day 28. The
proportion of patients successfully achieving the endpoint
was significantly greater with 40, 80 and 120 mg febuxostat
(56, 76 and 94% of patients, respectively) than with placebo
(0% of patients; P < 0.001 for each comparison).
Based on the results of the Phase II study, doses of 80 and
120 mg were selected for evaluation in the Phase III programme.
Phase III studies comparing febuxostat, allopurinol and
placebo
Two Phase III randomized double-blind trials with febuxostat
have been conducted together in the USA—APEX (Allopurinol
and Placebo-Controlled Efficacy Study of Febuxostat) [14]
and FACT (Febuxostat versus Allopurinol Control Trial) [3]—
including a total of 1832 patients. Both studies had similar
designs, endpoints and inclusion and exclusion criteria allowing
the results to be analysed together. Two important points of dif-
ference were the inclusion of a placebo arm in APEX but not
FACT, and a difference in renal function criteria. In the FACT
N. Lawrence Edwards
study, patients were required to have serum creatinine 41.5 mg/dl
and a creatinine clearance of 550 ml/min. In APEX, the criteria
were 42.0 mg/dl and 520 ml/min, respectively; hence, patients
with significant renal impairment were eligible for this trial.
The APEX study compared febuxostat 80, 120 and 240 mg/day
with allopurinol 100 or 300 mg/day (depending on renal function)
and placebo over 28 weeks [14]. The FACT study compared
febuxostat 80 and 120 mg/day with allopurinol 300 mg/day over
1 year [3]. The patients in these studies were mostly male (
95%),
with a long history of gout (average 11.9 years) and mean sUA at
baseline of 9.85 mg/dl (590 mmol/l). In both trials, patients
received prophylaxis with either colchicine 0.6 mg once daily or
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naproxen 250 mg twice daily for the first 8 weeks of urate-lowering
therapy.
The primary endpoint for both studies was the percentage of
patients reaching an sUA level of <6 mg/dl (<360 mmol/l) at the
last three monthly visits, the sUA target recommended in the
EULAR guidelines (although these trials were initiated before
the EULAR guidelines were published). The secondary endpoints
included the percentage of patients attaining an sUA level of
<6 mg/dl (<360 mmol/l) at the final visit, the incidence of gouty
flares requiring treatment, and the change in primary tophus size.
Both trials showed that febuxostat was significantly more
effective than the conventional dose of 300 mg/day allopurinol
in lowering sUA, as shown by the higher proportion of patients
achieving the primary endpoint of sUA <6 mg/dl (<360 mmol/l) at
the last three visits (Fig. 2). Significantly more febuxostat-treated
patients met the primary endpoint in both studies (48% with
80 mg febuxostat and 65% with 120 mg febuxostat in APEX;
53 and 62%, respectively in FACT), compared with those
receiving allopurinol 300 mg (22% in APEX and 21% in FACT;
P < 0.001 in both studies).
In the FACT study, significantly more patients receiving 80 and
120 mg febuxostat achieved the lower sUA level of <5 mg/dl
(<300 mmol/l) at the final visit (47 and 66%, respectively), com-
pared with 300 mg allopurinol (13%; P 40.001) [3]. This more
stringent endpoint corresponds to the BSR target for sUA [2].
The FACT and APEX studies also showed that febuxostat was
significantly more effective than allopurinol in reducing sUA in
patients with very high pre-treatment sUA levels: of those
with sUA at baseline of 510 mg/dl (5600 mmol/l), 41% met the
primary endpoint with the 80 mg dose and 48% with the 120 mg
dose compared with 9% with allopurinol [3, 14].
There was no significant difference in the incidence of gout
flares between the patients in the three treatment arms of
the FACT study. Immediately after the end of prophylaxis, the
incidence of acute gout attacks requiring treatment was higher in
patients with lower sUA levels, probably reflecting continued
mobilization of pre-existing urate crystals and implying that
a longer period of prophylaxis was required. However, when the
incidence of gout flares was analysed according to the sUA level in
the last 4 weeks of the study, it was clear that patients with
lower sUA levels were less likely to experience flares at 1 year;
in patients with sUA 58 mg/dl (5480 mmol/l), 18.2% experienced
flares compared with 4.5% of patients with sUA <4 mg/dl
(<240 mmol/l) (Fig. 3) [15].
The APEX study included a small subset of patients with
significantly impaired renal function (serum creatinine >1.5 to
42.0 mg/dl); febuxostat was safe and well tolerated in this popu-
lation. It was effective in controlling sUA in this renally impaired
population: with 44 and 45% reaching the primary endpoint with
the 80 and 120 mg doses, respectively, compared with none in the
placebo or allopurinol groups [14].
Febuxostat was also very effective in patients aged >65 years,
as shown by a subanalysis of the FACT and APEX trials. The
primary endpoint of sUA level <6 mg/dl (360 mmol/l) at the last
three visits was achieved in >75% of febuxostat-treated patients
(72% at 80 mg and 78% at 120 mg) compared with 46%
 Febuxostat: a new treatment for hyperuricaemia in gout
FIG. 2. Febuxostat at both 80 and 120 mg daily was significantly more effective than allopurinol in achieving the primary endpoint, sUA 6 mg/dl (360 mmol/l) at the last three
visits. Adapted from Becker et al. [3] and Schumacher et al. [14].
FIG. 3. Proportion of patients requiring treatment for a gout flare in the last 4 weeks
of the FACT study by average sUA level. Adapted from Becker et al. [15].
with allopurinol (P 40.01). Treatment was well tolerated in this
population [16].
Long-term open-label extension studies
A total of 116 patients who completed the Phase II study were
entered into FOCUS, a long-term, open-label extension study
(up to 4 years) [17]. Febuxostat 80 mg/day was administered to
all subjects initially (with colchicine prophylaxis), with dose
adjustment up to 40 or 120 mg/day as appropriate up to Week
28 of the study with the aim that patients would be on stable
therapy for the remainder of the 4-year study. The reduction in
sUA to <6 mg/dl (<360 mmol/l), as observed in the majority of
subjects treated with febuxostat during the Phase II study, was
maintained throughout the open-label study, and was associated
with stable renal function as measured by glomerular filtration
rate, and serum creatinine level [18]. The number of gout flares
fell steadily and, after the first year on stable dose, patients experi-
enced less than one flare per year. By the third year, flares had
virtually ceased to occur in both febuxostat 80 and 120 mg/day
groups [17].
Patients successfully completing the Phase III FACT and
APEX studies could be entered into an open-label extension
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study [febuxostat/allopurinol comparative extension long-term
study (EXCEL)], in which they were re-randomized to 80 or
120 mg febuxostat, or allopurinol (300 or 100 mg depending on
renal function), in a 2 : 2 : 1 ratio, with colchicine or naproxen as
prophylaxis against mobilization flares in the first 8 weeks [19, 20].
The target sUA was <6 mg/dl (360 mmol/l) and investigators were
allowed to adjust the dose of febuxostat or switch the medication
in the first 6 months to meet this target. The EXCEL protocol did
not allow for dose adjustments of allopurinol >300 mg/day
to achieve the target sUA because this approach, although recom-
mended, is not commonly done in clinical practice. The aim was
that patients should be on stable therapy with good control
of sUA for the remainder of the study period; after the first
6 months, the investigator could only switch therapy with the
sponsor’s permission.
The long-term response rate was similar to that observed in the
randomized trials. In patients who achieved the sUA target of
46 mg/dl (4360 mmol/l), the incidence of gout flares fell steadily
over the period of the study (Fig. 4). Two-year data from EXCEL
showed that by maintaining sUA level at this target, over 97%
of the patients required no treatment for gout flares at months
16–24. Tophus size was also reduced and 54% of the patients with
tophi experienced complete resolution by month 24 [8].
Patients not achieving a reduction in sUA level <6 mg/dl
(360 mmol/l) were permitted to switch therapy from allopurinol
to febuxostat, or vice versa, within the first 6 months of
the study. The switch from allopurinol to febuxostat resulted
in successful lowering of sUA level for 67% of the patients,
whereas only 9% of the patients who switched from febuxostat
to allopurinol lowered their sUA level <6 mg/dl.
In both the long-term extension study and in the double-blind
trials, there was a relatively high incidence of acute gout flares in
the first few weeks after the initiation of febuxostat and after
the end of the prophylactic colchicine/naproxen treatment. The
number of flares then declined to very low numbers over the
period of treatment. The early acute gout attacks represented
mobilization flares which are precipitated at any time the sUA
levels rapidly increase or decrease. In studies of urate-lowering
therapies, the frequency of acute flares following the institution
of treatment directly parallels the effectiveness of the drug to
dramatically or rapidly lower sUA levels. This can be partially
ii18
FIG. 4. Complete freedom from gout attacks after 2 years in patients achieving the EULAR target for sUA < 6 mg/dl (< 360 mmol/l).
prevented by using a longer duration of prophylaxis than that
used in the FACT, APEX and open-label studies.
Tolerability and adverse events
The most commonly reported adverse drug reactions (investigator
assessment) were liver function abnormalities (3%), diarrhoea
(3%), headache (1%), nausea (2%), and dizziness and/or altered
taste (2%). The percentage of patients with mild liver function
test abnormalities was similar in the febuxostat and allopurinol
treatment arms (3 vs 4%, respectively). In addition, increased
thyroid-stimulating hormone (TSH) values (>5.5 mIU/ml) were
observed in 5% of the patients treated with febuxostat and 6%
of those treated with allopurinol. The incidence of adverse events
such as dizziness, diarrhoea, headache and nausea with febuxostat
was similar to allopurinol in the combined Phase III trials and
the long-term follow-up [3, 14, 20].
The incidence of cardiovascular (CV) side-effects (composite of
myocardial infarction, stroke and CV death as defined by the
Antiplatelet Trialists Collaboration events [21]) was numerically
higher with febuxostat than with allopurinol in both the Phase III
and long-term extension studies, but the difference between
treatments was not statistically significant.
There was no relationship between CV events and febuxostat
dose, the rates did not increase over time and the investigators
did not consider the events linked to the study drug. Subjects
experiencing CV events all had pre-existing CV disease, including
congestive heart failure and coronary artery disease, and/or
underlying risk factors. It should be noted that there is a well-
documented association between gout and CV events [22–24] and
hyperuricaemia has been considered as an independent risk
factor for CV morbidity and mortality [25–29]. Moreover, hyper-
uricaemia is considered to be part of the metabolic syndrome,
a clustering of risk factors associated with high CV risk [30, 31].
Conclusions
Febuxostat reduced and maintained sUA levels <6 mg/dl
(360 mmol/l) for up to 40 months, and was significantly more
effective than allopurinol at the usual dose of 300 mg when
assigned as an initial treatment. Febuxostat was also more
effective than allopurinol in reducing sUA levels <5 mg/dl
(300 mmol/l), the target recommended by the BSR.
Febuxostat is approved in Europe for the ‘treatment of chronic
hyperuricaemia in conditions where urate deposition has already
occurred (including a history; or presence of, tophus and/or gouty
arthritis)’. The recommended dose of febuxostat is 80 mg, increas-
ing to 120 mg after 2–4 weeks if sUA level has not reached the
N. Lawrence Edwards
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target of <6 mg/dl. It is recommended that prophylaxis (colchicine
and/or NSAIDs) against acute attacks should also be used for
at least the first 6 months.
The inadequacies of allopurinol, in terms of limited efficacy
at the usual dose of 300 mg, need for dose adjustment in
patients with renal impairment and undesirable side-effects, have
highlighted the need for an additional treatment for patients
with gout. The emergence of febuxostat as a well-tolerated and
efficacious gout therapy could prove to be an excellent solution.
Rheumatology key messages
 Febuxostat is a selective XO inhibitor, requiring no dose
adjustment in mild-to-moderate renal impairment.
 Significantly more patients achieved sUA <6 mg/dl with febuxostat
(80 or 120 mg) than with allopurinol (300 mg).
 Prophylaxis against acute flares is required for 6 months
(colchicine/NSAID); flare incidence subsequently declines with
long-term treatment.
Acknowledgements
Medical writing assistance was provided by Choice Pharma, with
financial support from Ipsen. A medical writer assisted with
searches of the literature and collation of data and supported
the author in the drafting of the text. The author was fully
involved at all stages of the preparation of the manuscript.
Supplement: This paper forms part of the supplement entitled
‘Can we make gout crystal clear?’ This supplement was supported
by an unrestricted grant from Ipsen.
Disclosure statement: The author has declared no conflicts of
interest.
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