Febuxostat: a new treatment for

hyperuricaemia in gout
1. N. Lawrence Edwards1

+ Author Affiliations
1
1. Department of Medicine, University of Florida, Gainesville, FL, USA

1. Correspondence to: N. Lawrence Edwards, Department of Medicine, University of

Florida, Gainesville, FL 32610, USA. E-mail: edwarnl@medicine.ufl.edu

 Received December 18, 2008.

 Revision received March 18, 2009.

 
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Abstract
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 μmol/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 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 μmol/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 μmol/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

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Introduction
Gout is a form of inflammatory arthritis, associated with hyperuricaemia, 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 μmol/l) so that existing monosodium urate crystals dissolve
and no further crystals form. A target level for sUA of ⩽6 mg/dl (360 μmol/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 μmol/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 symptoms 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 effects, is
excreted predominantly by the kidneys and hence it 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
impairment 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
treatment 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 treatment option that may
provide considerable benefits for patients with gout and hyperuricaemia.

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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 Ki′ 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].

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Fig. 1.

Unlike allopurinol, febuxostat is a non-purine XO inhibitor.

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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].

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
glucuronosyltransferase 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
pharmacokinetics, pharmacodynamics or safety profile of febuxostat [12].

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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.

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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 μmol/l). The primary endpoint was the proportion of patients reaching the target sUA
level of <6 mg/dl (<360 μmol/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.

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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 difference were the inclusion of a
placebo arm in APEX but not FACT, and a difference in renal function criteria. In the FACT
study, patients were required to have serum creatinine ⩽1.5 mg/dl and a creatinine clearance of
⩾50 ml/min. In APEX, the criteria were ⩽2.0 mg/dl and ⩾20 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 μmol/l). In both trials, patients received
prophylaxis with either colchicine 0.6 mg once daily or 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 μmol/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 μmol/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 μmol/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).

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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 μmol/l) at the last three visits. Adapted from
Becker et al. [3] and Schumacher et al. [14].

In the FACT study, significantly more patients receiving 80 and 120 mg febuxostat achieved the
lower sUA level of <5 mg/dl (<300 μmol/l) at the final visit (47 and 66%, respectively),
compared with 300 mg allopurinol (13%; P ⩽0.001) [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 ⩾10 mg/dl (⩾600 μmol/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 ⩾8 mg/dl (⩾480 μmol/l),
18.2% experienced flares compared with 4.5% of patients with sUA <4 mg/dl (<240 μmol/l)
(Fig. 3) [15].

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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].

The APEX study included a small subset of patients with significantly impaired renal function
(serum creatinine >1.5 to ⩽2.0 mg/dl); febuxostat was safe and well tolerated in this population.
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 μmol/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% with allopurinol (P ⩽0.01). Treatment was well tolerated in this
population [16].

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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 μmol/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 experienced 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 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 μmol/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 recommended, 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 ⩽6 mg/dl (⩽360 μmol/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].
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Fig. 4.

Complete freedom from gout attacks after 2 years in patients achieving the EULAR target for
sUA < 6 mg/dl (< 360 μmol/l).

Patients not achieving a reduction in sUA level <6 mg/dl (360 μmol/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 prevented by using a longer duration of prophylaxis than
that used in the FACT, APEX and open-label studies.

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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 μIU/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,
hyperuricaemia is considered to be part of the metabolic syndrome, a clustering of risk factors
associated with high CV risk [30, 31].

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Conclusions
Febuxostat reduced and maintained sUA levels <6 mg/dl (360 μmol/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 μmol/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, increasing to 120 mg after 2–4
weeks if sUA level has not reached the 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.

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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.

 © 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

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