Home' Australian Pharmacist : Australian Pharmacist March 2013 Contents 40 Australian Pharmacist March 2013 I ©Pharmaceutical Society of Australia Ltd.
plasma urate concentration. Typically this
may take up to six months, or longer in
There have been recent changes in the
approach to allopurinol dosing, especially
in elderly patients and those with renal
impairment, as under-dosing and
inadequate reduction in plasma urate levels
seem to be common.2,3,10,24 Previously,
dose reduction in renal impairment
was emphasised, based on reports of a
relationship between allopurinol dose
in patients with renal impairment and
development of the potentially fatal
allopurinol hypersensitivity-like syndrome.
The adverse reaction, estimated to occur
in between one in 1,000 and one in 50,000
treated patients, results in a diffuse,
erythematous, exfoliative skin rash (often
toxic epidermal necrolysis), malaise, fever,
leukocytosis, eosinophilia, deteriorating
renal function, and hepatic damage.25
There is a mortality rate of approximately
20% in patients who develop allopurinol
hypersensitivity-like reactions.4 Most cases
occur within six weeks of commencing
allopurinol. The development of a rash
in the setting of allopurinol therapy,
especially if the duration of therapy has
been less than 12 weeks, should prompt
urgent consideration of allopurinol
hypersensitivity, regardless of the patient's
age and renal function.10
The syndrome appears to be associated
with an accumulation in the body of the
active metabolite, oxypurinol, since patients
with pre-existing renal disease are at
greatest risk.25 Hence, it was recommended
that dosage reductions of allopurinol
should occur in patients with renal disease.
In hindsight, this has frequently resulted
in inadequate reduction of plasma urate.10
There is also no clear evidence that reduced
dosing of allopurinol in patients with renal
impairment reduces the risk of serious
The allopurinol dose should be gradually
increased to achieve the target plasma
urate level (600 mg/day is not uncommonly
required and up to 900 mg/day is
occasionally required).10 In patients with
renal impairment, the same approach can
be followed, but once the plasma urate has
reached a plateau there is no advantage in
further increasing the dose of allopurinol.10
The uricosuric agent, probenecid, is usually
appropriate for patients allergic to or
intolerant of allopurinol,.8,10 Probenecid is
less effective than allopurinol in reducing
plasma urate concentrations; it may
also be added to allopurinol in those
individuals unable to achieve target levels
with monotherapy, or those with severe
tophaceous gout.8 Because of the increased
urinary excretion of uric acid that is most
marked in the early phase of treatment,
good hydration is required and urinary
alkalinisation is appropriate.3,8 As is true for
all urate-lowering therapy, the aim should
be to achieve a gradual fall in plasma urate.8
Febuxostat, a non-purine xanthine oxidase
inhibitor, has recently become available
in Australia. Clinical trials have shown
that febuxostat 80 mg or 120 mg daily is
more effective than fixed-dose allopurinol
(300 mg daily) in lowering the plasma urate
level to below 0.36 mmol/L.3,17,26 However,
no published studies have compared
febuxostat with allopurinol in doses titrated
up to a maximum of 900 mg daily to reach
this therapeutic target; so the efficacy
and safety of febuxostat compared with
the optimal administration of allopurinol
(i.e. best practice) is unknown.26
As with other urate-lowering therapies,
prophylaxis with colchicine and/or NSAIDs
against acute attacks is recommended
when initiating febuxostat therapy. Even so,
compared with allopurinol, febuxostat has
been associated with more gout flares, and
with more withdrawals from treatment,
indicating lower acceptability.26 Based on
current data on efficacy, safety and cost,
febuxostat should not be considered for
first-line therapy in patients with gout, but
could be considered for those intolerant
of allopurinol and for whom available
uricosuric drugs are either contraindicated
or have failed, or who do not achieve
the therapeutic target on allopurinol
at the highest recommended dose.26,27
The drug is much more expensive than
allopurinol. It is unlikely that febuxostat will
replace allopurinol as the preferred initial
choice for urate-lowering therapy, but for
patients intolerant of allopurinol, it is a
Finally, it should be noted that poor
adherence with therapy is a common
cause of treatment failure in gout,2,8,10,29,30
and represents an area that could benefit
substantially from greater pharmacist
involvement, through the provision
of more information for patients and
monitoring of prescription refill patterns.
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2. Bolzetta F, Veronese N, Manzato E, Sergi G. Tophaceous gout in the
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elderly. Drugs Aging 2011;28(8):591--603.
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of gout in the elderly. Geriatrics 2008;63(7):13--8,20.
5. Robinson P, Taylor W, Merriman T. A systematic review of the
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foods, dairy and protein intake, and the risk of gout in men. N Engl
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13. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol
intake and risk of incident gout in men: a prospective study.
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onset gout: a review. Rheumatol Int 2007;28(1):1--6.
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increased cardiovascular risk. Atherosclerosis 2009;202(1):11--7.
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cardiovascular disease in type 2 diabetic and non-diabetic
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17. Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of
febuxostat for urate lowering in gout patients >/=65 years of age.
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18. Oh DH, Chan SQ, Wilson AM. Myopathy and possible intestinal
dysfunction in a patient treated with colchicine and simvastatin.
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20. Sweidan M, Reeve JF, Yu K. Death and morbidity from
supratherapeutic dosing of colchicine. Med J Aust
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