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Vol 2 July/August 2010 Clinical Pharmacist 261

There are a limited number of licensed treatments available for the management of gout. Febuxostat

SPOTLIGHT ON MEDICINES
is the first new agent for the prophylaxis of gout to reach the market in the past 40 years

Febuxostat
By Scott Mercer, DipClinPharm, Place in therapy
MRPharmS
VERDICT Febuxostat is licensed in the UK for the
Febuxostat is a useful treatment option treatment of chronic hyperuricaemia in

G
out affects 1–2% of adults in for patients who require gout prophylaxis conditions where urate deposition has
developed countries and it is the most but are unable to use allopurinol. already occurred (including a history, or
common type of inflammatory Evidence shows that febuxostat presence, of tophi or gouty arthritis). The
arthritis in men1 (see Box “About gout”, p263). reduces serum uric acid levels more aim of therapy is to reduce serum urate
The first-line treatment for acute effectively than allopurinol. In clinical levels below target (see Box, p263). Acute
attacks of gout, providing there are no trials, febuxostat has been generally attacks of gout should have resolved before
contraindications, is a maximum dose of well tolerated. initiating febuxostat.3
non-steroidal anti-inflammatory drug
(NSAID), continued for one to two weeks. National guidance The National Institute
Colchicine is also effective for acute gout prophylaxis when allopurinol is for Health and Clinical Excellence (NICE)
but it is slower to work than NSAIDs. inappropriate. Sulfinpyrazone is one such issued a technology appraisal for febuxostat
Corticosteroids are an alternative treatment option. Other options are unlicensed (eg, in December 2008 (the EU licence was
for patients unable to tolerate NSAIDs and probenecid, benzbromarone) or used “off- granted in May 2008).7 NICE recommends
for patients who do not respond to other label” (eg, losartan, rasburicase). febuxostat as an option for the management
treatments.3 Febuxostat, launched in the UK in March of chronic hyperuricaemia in gout, but only
Long-term prophylaxis against gout is 2010, is therefore a welcome addition to for people who are intolerant of allopurinol
not recommended after one attack. Dietary the therapeutic group. or for whom allopurinol is contraindicated.
changes (eg, reducing intake of red meat), Intolerance to allopurinol is defined as
abstaining from alcohol, losing weight and Mechanism of action “adverse effects that are sufficiently severe
limiting diuretic use might reduce Febuxostat is a novel, non-purine, selective, to warrant its discontinuation or to prevent
uricaemia and control gout.1 Long-term xanthine oxidase inhibitor. Xanthine full dose escalation for optimal effect”.
prophylaxis is indicated for patients with oxidase inhibitors reduce serum uric acid At the time of writing, the Scottish
recurrent gout attacks, chronic arthropathy, concentrations by blocking the Medicines Consortium had not issued
tophi and gout with uric acid kidney transformation of hypoxanthine to guidance on the use of febuxostat. Current
stones.2,3 xanthine and of xanthine to uric acid. guidelines from the British Society for
Allopurinol is used first line as urate-
lowering therapy.2,3 Severe allopurinol-
induced toxic effects (eg, Stevens-Johnson The pain and inflammation of gout depicted in a cartoon by James Gillray (1799)
syndrome or toxic epidermal necrolysis)
occur in less than 2% of patients but can be
life-threatening (mortality rate about
20%).1 Severe reactions usually develop
early in treatment and are more common in
patients receiving high doses, taking
concomitant diuretics or with renal failure.
They are also more likely if allopurinol is
reintroduced after a patient has had a
previous skin reaction to the medicine.6
Therefore, patients with a history of severe
skin rash should never be given allopurinol
again. There are few remaining options for

Scott Mercer is principal pharmacist for

specialist medicine at Guy’s and St
Jean-Loup Charmet | SPL

Thomas’ NHS Foundation Trust.

E: scott.mercer@nhs.net
CP, Jul_Aug, p261-63, SpOM_Layout 1 08/07/2010 11:49 Page 263
Rheumatology do not include specific
recommendations on the use of febuxostat.3
The European League Against Rheumatism
recommends that, in patients with allopurinol
toxicity, other xanthine oxidase inhibitors
can be considered as a treatment option.2
Clinical evidence
Febuxostat was studied in two randomised,
double-blind trials involving 1,834 patients
with hyperuricaemia and gout. Both studies
showed the medicine to be more effective at
lowering serum uric acid levels than a fixed
allopurinol dose of 300mg once daily.
APEX The “Allopurinol placebo-controlled
efficacy study of febuxostat” (APEX) trial8
was designed to examine the urate-lowering
efficacy and safety of febuxostat,
allopurinol and placebo in subjects with
gout (including those with renal
impairment). It enrolled 1,072 patients and
compared several once-daily doses of
febuxostat (80mg, 120mg and 240mg)
against placebo and with allopurinol over a
six-month period. Allopurinol was
administered at a dose of 300mg once daily
except for patients with renal impairment,
who received 100mg daily. All participants
received either colchicine or naproxen for
the first eight weeks to prevent gout flares.
Higher percentages of patients treated
with febuxostat achieved uric acid levels
below target, compared with those
receiving placebo or allopurinol. However,
febuxostat was associated with more gout
flares than the other groups.
FACT The “Febuxostat versus allopurinol
controlled trial” (FACT)9 compared two
doses of febuxostat (80mg and 120mg daily)
with allopurinol in 762 patients over one
year. Similar to APEX, the proportion of
patients achieving target serum urate levels
was higher with febuxostat than with
allopurinol. There were no significant
differences between any of the groups in
the rate of gout flare or the median
reduction in tophus area.
Dose
Febuxostat is available as 80mg and 120mg
film-coated tablets. The recommended
starting dose is 80mg orally once daily,
taken with or without food. The dose can
be increased to 120mg daily after two to
four weeks if serum uric acid levels have
not fallen below target. No dose adjustment
is necessary for patients with mild or
moderate renal impairment or for the elderly.
The recommended dose for patients with
mild hepatic impairment is 80mg daily.10
Vol 2 July/August 2010 Clinical Pharmacist 263
About gout
SPOTLIGHT ON MEDICINES
Gout is caused by chronic hyperuricaemia and subsequent deposition of monosodium
urate crystals within joints. When serum uric acid concentrations fall below the
monosodium urate saturation point the crystals dissolve and gout can be cured. The
European League Against Rheumatism guidelines2 recommend that plasma urate should
be maintained at a concentration less than 360µmol/L whereas the British guidelines3
recommend less than 300µmol/L.
The main causes of primary gout are diet and genetic polymorphisms of renal urate
transporters. Secondary gout is caused by therapy with particular medicines (eg, diuretics
or tacrolimus) or develops during the course of other disorders (eg, renal failure).1
The prevalence of gout is much higher in men than in women and rises with age.1
Obesity, diabetes mellitus, hyperlipidaemia, hypertension and renal and cardiovascular
diseases are common comorbidities for patients with gout and hyperuricaemia.2 Although
the pathophysiology of gout is well understood and effective treatments are available,
many patients with gout experience recurrent attacks.4 These can cause pain, joint
damage and functional limitation.5
Safety considerations NSAID or colchicine. Febuxostat can be
Adverse effects According to the summary continued if a flare occurs but an NSAID,
of product characteristics for febuxostat the colchicine or corticosteroid should be used
most common adverse effects of the drug to treat the acute attack.10
are liver function abnormalities, diarrhoea,
headache, nausea and rash. Diarrhoea, nausea Drug interactions No direct interaction
and vomiting are more common in patients studies have been performed for febuxostat.
treated concomitantly with colchicine. The SPC includes details of drug
Febuxostat is not recommended for interactions that occur for other xanthine
patients with ischaemic heart disease or oxidase inhibitors.10 Concomitant use of
congestive cardiac failure because of febuxostat and mercaptopurine or
concerns over cardiovascular safety. azathioprine is not recommended because
Although there were more investigator- febuxostat may increase blood levels of the
reported cardiovascular events in the other medicines. Febuxostat can increase
combined febuxostat groups than in the theophylline levels and therefore blood
allopurinol group, this finding did not reach levels of theophylline should be monitored.
statistical significance and no causal
relationship has been established.10 References
1 Richette P, Bardin T. Seminar: gout. Lancet
Abnormalities in liver and thyroid 2010;375:318–28.
function test results for patients taking 2 Zhang W, Doherty M, Bardin T, et al. EULAR evidence
based recommendations for gout. Part II: management.
febuxostat in clinical trials were observed, Report of a task force of the EULAR Standing
so it is recommended that these parameters Committee for International Clinical Studies Including
Therapeutics (ESCISITT). Annals of Rheumatic Disease
are monitored at baseline and then 2006;65:1312–24.
periodically during treatment.10 3 Jordan KM, Cameron JS, Snaith M, et al. British Society
for Rheumatology and British Health Professionals in
Rheumatology guideline for the management of gout.
Gout flare As with allopurinol, gout flares Rheumatology 2007;46:1372–74.
may occur during initiation of treatment 4 Hande KR, Noone RM, Stone WJ. Severe allopurinol
toxicity. Description and guidelines for prevention in
with febuxostat because of changing serum patients with renal insufficiency. American Journal of
uric acid levels, resulting in mobilisation of Medicine 1984;76:47–56.
5 Neogi T, Hunder D, Chaisson C, et al. Frequency and
urate from tissue deposits. The SPC for predictors of inappropriate management of recurrent
febuxostat recommends prophylaxis against gout attacks in a longitudinal study. The Journal of
Rheumatology 2006;33:1104–9.
a gout flare for at least six months with an 6 Terkeltaub RA. Clinical practice: gout. New England
Journal of Medicine 2003;349:1647–55.
7 National Institute for Health and Clinical Excellence.
Febuxostat for the management of hyperuricaemia in
Write about medicines people with gout. December 2008.
www.nice.org.uk/ta164 (accessed 1 June 2010).
This Clinical Pharmacist series looks at 8 Schumacher HR, Becker MA, Wortman RL, et al.
Febuxostat vs allopurinol and placebo in subjects with
prominent or recently launched hyperuricaemia and gout: the 28-week APEX study.
medicines or classes of drugs. Arthritis and Rheumatism 2008;59:1540–48.
9 Becker MA, Schumacher HR, Wortman RL, et al.
Pharmacists who have ideas for the
Febuxostat compared with allopurinol in patients with
series or wish to write about medicines hyperuricaemia and gout. New England Journal of
are invited to contact the editor. Medicine 2005;353:2450–61.
E: clinicalpharmacist@pharmj.org.uk 10 A.Menarini Pharma. Summary of product
characteristics: Adenuric. 2010. www.medicines.org.uk/
T: 020 7572 2425 emc/medicine/22830/SPC/Adenuric+film-
coated+tablets/#ORIGINAL (accessed 1 June 2010).