New Drug Update 2009-2010 - LAFP

CONTRAINDICATIONS: Febuxostat will be contraindicated in patients with a history of hypersensitivity to
febuxostat and the other product ingredients. Febuxostat is also contraindicated in patients receiving
azathiaprine, mercaptopurine and theophylline, these agents are metabolized by xanthine oxidase and
thus levels would be significantly elevated..
WARNINGS AND PRECAUTIONS: As with allopurinol, periodic liver function tests may be advisable for
patients receiving febuxostat.
Febuxostat is not effective for the treatment of acute gouty attacks. Acute gouty attacks may be
precipitated at the start of treatment with febuxostat in new patients and these may continue even after
serum uric acid concentrations begin to fall, usually for the first 6 to 12 months. Colchicine has often been
coadministered during this time.
Cardiovascular events? A higher rate of CV and thromboembolic events was seen in the head to head
trials against allopurinol and patients should be monitored for signs of MI and stroke. A causal
relationship with febuxostat has not been established. Anti-Platelet Trialists’ Collaborative (APTC)
endpoints (CV death, non-fatal MI and non-fatal CVA) events per 100 patient-years of exposure were as
follows placebo 0, febuxostat 40mg 0, febuxostat 80 mg 1.09 and allopuriniol 0.60
ADVERSE REACTIONS: Adverse reactions reported during febuxostat therapy included liver function
test abnormalities, diarrhea, headache, nausea, flushing, dizziness, and gout flares. The concomitant use
of colchicine for acute gout flares may have influenced the overall nature of the adverse reactions.The
overall incidence of adverse reactions was similar in the febuxostat and allopurinol groups in the
comparative study.
Febuxostat 80 and 300 mg doses were not associated with a change in QT interval in a crossover
comparison with placebo and moxifloxacin enrolling 44 healthy subjects.
DRUG INTERACTIONS: Febuxostat is a significant xanthine oxidase inhibitor and would be expected to
significantly inhibit the metabolism of agents that are metabolized by this enzyme (IE azathioprine,
mercaptopurine and theophyllin).
In vitro, febuxostat exhibited no effect on CYP1A2, CYP2C9, CYP2C19, or CYP3A4, and weak inhibitory
activity on CYP2D6. When febuxostat was administered with desipramine (a CYP2D6 substrate) in 18
CYP2D6 extensive metabolizers, a slight increase in total exposure to desipramine was observed. The
effect did not appear clinically important; therefore, dose adjustments do not appear necessary when
CYP2D6 substrates are coadministered with febuxostat.
RECOMMENDED MONITORING: Periodic liver function tests may be advised in addition to monitoring of
serum uric acid.
DOSING: Febuxostat is administered orally once daily at a starting dose of 40 mg once a day. For
patients who do not achieve a serum uric acid of less than 6.0 mg/dl after 2 weeks the dose may be
increased o 80 mg once a day. Febuxostat can be administered without regard to food. No dosage
adjustment is need for mild to moderate renal or hepatic dysfunction.
PRODUCT AVAILABILITY/COST and STORAGE: An NDA for febuxostat 80 and 120 mg was submitted
to the Food and Drug Administration (FDA) in December 2004. The FDA approved the 40 and 80 mg
tablets. The cost of Uloric is $5.62 per 40 and 80 mg tablets AWP vs. $0.59 per allopurinol 300 mg
tablets.
CONCLUSION: Febuxostat offers an alternative to allopurinol. Additional studies are necessary to
compare febuxostat with recommended allopurinol doses, although serum uric acid levels were reduced
to a greater extent with febuxostat compared with low-dose allopurinol. Additional side effect information
is necessary to better determine the place of febuxostat in the treatment of hyperuricemia and gout.
Lijmited data suggest that with a different chemical structure that it may be safe to use in patients
intolerant to allopurinol.
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