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FOCUS ON RHEUMATOLOGIC DISORDERS Arthur A. Schuna,
Section Advisor
Febuxostat for hyperuricemia in patients with gout
Key point: Two recently published studies examined
the efficacy and safety of febuxostat (Uloric—Takeda), which was
recently approved for the chronic management of hyperuricemia in
patients with gout. The approval of this product marks the first new
treatment option for the chronic management of this condition in more
than 40 years.
Finer points: The first study—a Phase III,
randomized, double-blind, parallel group trial—was conducted at
167 sites in the United States between February 2003 and April 2004. A
total of 1,072 patients with hyperuricemia (serum urate level ≥
8.0 mg/dL) and gout with both normal and impaired renal function (serum
creatinine > 1.5 to ≤ 2.0 mg/dL) were randomized to receive
either once-daily febuxostat (80 mg [n = 267], 120 mg [n = 269], or 240
mg [n = 134]), allopurinol (300 mg [n = 258] or 100 mg [n = 10], based
on renal function), or placebo [n = 134] for 28 weeks. The primary
endpoint of the study was the proportion of patients with serum urate
levels < 6.0 mg/dL for the last 3 months.
At the end of the 28-week study, significantly more patients who
received febuxostat (48%, 65%, and 69% of patients receiving febuxostat
80 mg, 120 mg, and 240 mg, respectively) achieved the primary endpoint
compared with 22% of patients receiving allopurinol and 0% of patients
who were treated with placebo (P ≤ 0.05). In addition, a
significantly higher percentage of patients with impaired renal function
treated with febuxostat (44%, 45%, and 60% of patients receiving
febuxostat 80 mg, 120 mg, and 240 mg, respectively) achieved the primary
endpoint compared with 0% of patients treated with allopurinol 100 mg
(P < 0.05). Adverse events occurred similarly between
treatment groups and were generally mild to moderate in
severity.
The second study assessed the clinical efficacy and safety of
long-term febuxostat therapy in patients with gout. A total of 116
patients who had completed a previous 28-day study with febuxostat were
enrolled in this open-label extension study, conducted at 23 sites in
the United States. All patients initially received febuxostat 80 mg
daily. However, febuxostat dosing could be adjusted to 40 mg or 120 mg
between weeks 4 and 24. Thirty-eight percent of patients (n = 44)
required febuxostat dosage adjustments. Eight patients received 40 mg,
79 patients received 80 mg, and 29 patients received 120 mg daily
maintenance dosing of the drug.
At 5 years, 50% of patients (n = 58) had prematurely discontinued
participating in the study, with 13 patients withdrawing because of
adverse events. Of the remaining 58 patients, 93% had maintained serum
urate levels < 6.0mg/dL. This sustained reduction in serum urate
levels was associated with a nearly complete elimination of gout
attacks. Adverse events were reported by 91% of patients (n = 106)
during the study. The majority of adverse events were mild to
moderate.
The primary goal in the treatment of hyperuricemia and gout is the
reduction and maintenance of serum uric acid levels to less than 6.0
mg/dL. Data from various clinical trials, including the two studies
examined above, suggest that febuxostat effectively lowers serum uric
acid levels in patients with hyperuricemia who also suffer from symptoms
of gout.
What you need to know: Although the first study
above suggested a fixed dose of allopurinol was less effective than
febuxostat in achieving goal uric acid of < 6.0, in clinical
practice, doses of allopurinol are adjusted to achieve goal uric acid
concentrations. Allopurinol remains an effective drug for most patients
with gout, given appropriate dosage. Febuxostat may be advantageous for
patients with a history of rash or hypersensitivity to allopurinol.
Additionally, febuxostat dose does not need to be adjusted for patients
with mild to moderate renal impairment. There are insufficient data in
patients with severe renal insufficiency (CrCl < 30 ml/minute) and
the drug should be used with caution in this setting. Because liver
enzyme elevations have been reported with febuxostat, transaminase
laboratory assessment should be done at 2 months, 4 months, and
periodically thereafter.
What your patients need to know: Explain to patients
that febuxostat is only indicated for patients with hyperuricemia who
also suffer from gout. It is not indicated for patients with
hyperuricemia who do not suffer from gout.
Tell patients that gout typically flares up when therapy with an
antihyperuricemic agent, such as febuxostat, is initiated. The uric acid
levels in the blood decrease, causing uric acid crystals in or around
the joints to dissolve. For this reason, prophylactic treatment with
colchicine or NSAIDs is generally recommended when antihyperuricemic
agents are initiated. These prophylactic therapies should be continued
for at least 6 months. If an acute gout attack should occur, remind
patients not to discontinue therapy with febuxostat.
Sources:
Beth Farnstrom (bfarnstrom@aphanet.org)
Posted March 17, 2009
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