ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C 16 H 16 N 2 O 3 S. The chemical structure is: Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C. ULORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium croscarmellose. ULORIC tablets are coated with Opadry II, green. Chemical Structure

ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult patients with gout who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in adult patients with gout who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. Limitations of Use : ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. Limitations of Use : ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

40 mg tablets, light green to green, round, debossed with "TAP" and "40" 80 mg tablets, light green to green, teardrop shaped, debossed with "TAP" and "80" Tablet: 40 mg, 80 mg.

Recommended dosage is 40 mg or 80 mg once daily. The recommended starting dosage is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after 2 weeks, the recommended dosage is 80 mg once daily. Patients with severe renal impairment: Limit the dosage to 40 mg once daily. Flare prophylaxis is recommended upon initiation of ULORIC. Can be administered without regard to food or antacid use

Recommended Dosage The recommended ULORIC dosage is 40 mg or 80 mg once daily. The recommended starting dosage of ULORIC is 40 mg once daily. For patients who do not achieve a serum uric acid (sUA) less than 6 mg/dL after two weeks, the recommended ULORIC dosage is 80 mg once daily. ULORIC can be taken without regard to food or antacid use . Concurrent prophylactic treatment with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended

Dosage Recommendations in Patients with Renal Impairment and Hepatic Impairment The recommended dosage of ULORIC is limited to 40 mg once daily in patients with severe renal impairment. No dose modification is necessary when administering ULORIC in patients with mild or moderate renal impairment . No dosage modification is necessary in patients with mild to moderate hepatic impairment

Serum Uric Acid Level Monitoring Testing for the target serum uric acid level of less than 6 mg/dL may be performed as early as two weeks after initiating ULORIC therapy

Recommended Prophylaxis for Gout Flares Gout flares may occur after initiation of ULORIC due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months . If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient .

Gout Flares : An increase in gout flares is frequently observed after initiation of ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti-inflammatory drug or colchicine) upon initiation of treatment may be beneficial for up to six months. Hepatic Effects : Cases of hepatic failure, some fatal, have been reported. If liver injury is detected, promptly interrupt ULORIC and treat cause, if possible, to resolution or stabilization. Permanently discontinue ULORIC if liver injury is confirmed, and no alternate etiology can be found. Serious Skin Reactions : Serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms and toxic epidermal necrolysis have been reported in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected. 5.1 Cardiovascular Death In a cardiovascular (CV) outcome study, gout patients with established CV disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol. Sudden cardiac death was the most common cause of adjudicated CV deaths, 2.7% in the ULORIC group (83 of 3,098) as compared to 1.8% in the allopurinol group (56 of 3,092). ULORIC was similar to allopurinol for nonfatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization . Because of the increased risk of CV death, ULORIC should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable . Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC. Consider use of prophylactic low-dose aspirin therapy in patients with a history of CV disease. Monitor patients for the development of CV events. Inform patients about the symptoms of serious CV events and the steps to take if they occur

Gout Flares 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

Hepatic Effects Cases of fatal and nonfatal hepatic failure in patients taking ULORIC have been reported. During randomized controlled studies, transaminase elevations greater than three 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 . Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient presents abnormal liver tests (ALT or AST greater than three times the upper limit of the reference range), interrupt ULORIC treatment while investigating the probable cause. Permanently discontinue ULORIC if liver injury is confirmed, and no alternate etiology can be found. Permanently discontinue ULORIC in patients who have serum ALT or AST greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies because they are at risk for severe drug-induced liver injury. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with close monitoring

Serious Skin Reactions Serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported postmarketing in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected . Many of these patients had reported previous similar skin reactions to allopurinol. ULORIC should be used with close monitoring in these patients.

Concomitant administration of ULORIC with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity

Xanthine Oxidase Substrate Drugs ULORIC is an XO inhibitor. Based on a drug interaction study in healthy patients, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans . Therefore, use with caution when coadministering ULORIC with theophylline. A drug interaction study of ULORIC and azathioprine, also metabolized by XO, showed an increase in exposure of 6-mercaptopurine which may lead to toxicity . Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine) have not been conducted. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine

Cytotoxic Chemotherapy Drugs Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy

In Vivo Drug Interaction Studies Based on drug interaction studies in healthy patients, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine . Therefore, ULORIC may be used concomitantly with these medications.