5 WARNINGS AND PRECAUTIONS
5.1 Gout Flare
After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits.

In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended [see Dosage and Administration (2.4)].

5.2 Cardiovascular Events
In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% Confidence Interval (CI) 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions (6.1)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.

5.3 Liver Enzyme Elevations
During randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter.

6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for ≥ 6 months. For ULORIC 80 mg, 1377 subjects were treated for ≥ 6 months, 674 patients were treated for ≥ 1 year and 515 patients were treated for ≥ 2 years.

Most Common Adverse Reactions

In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo.

Table 1: Adverse Reactions Occurring in ≥ 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies
Adverse Reactions Placebo ULORIC allopurinol*
(N=134) 40 mg daily
(N=757) 80 mg daily
(N=1279)
(N=1277)
*
Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. 
Liver Function Abnormalities 0.7% 6.6% 4.6% 4.2%
Nausea 0.7% 1.1% 1.3% 0.8%
Arthralgia  0% 1.1% 0.7% 0.7%
Rash 0.7% 0.5% 1.6% 1.6%
Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. 
Liver Function Abnormalities 0.7% 6.6% 4.6% 4.2%
Nausea 0.7% 1.1% 1.3% 0.8%
Arthralgia  0% 1.1% 0.7% 0.7%
Rash 0.7% 0.5% 1.6% 1.6%

The most common adverse reaction leading to discon