Xanuric

1 INDICATIONS AND USAGE Febuxostat 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 : Febuxostat tablets are not recommended for the treatment of asymptomatic hyperuricemia. Febuxostat 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. ( 1 ) Limitations of Use : Febuxostat tablets are not recommended for the treatment of asymptomatic hyperuricemia. ( 1 )

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) Patients with severe renal impairment: Limit the dosage to 40 mg once daily. ( 2.2 , 8.6 ) Flare prophylaxis is recommended upon initiation of febuxostat tablets. ( 2.4 ) Can be administered without regard to food or antacid use. ( 2.1 ) 2.1 Recommended Dosage The recommended febuxostat tablets dosage is 40 mg or 80 mg once daily. The recommended starting dosage of febuxostat tablets 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 febuxostat tablets dosage is 80 mg once daily. Febuxostat tablets can be taken without regard to food or antacid use [see Clinical Pharmacology (12.3) ]. Concurrent prophylactic treatment with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended [see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ]. 2.2 Dosage Recommendations in Patients with Renal Impairment and Hepatic Impairment The recommended dosage of febuxostat tablets is limited to 40 mg once daily in patients with severe renal impairment. No dose modification is necessary when administering febuxostat tablets in patients with mild or moderate renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . No dosage modification is necessary in patients with mild to moderate hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 2.3 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 febuxostat tablets therapy. 2.4 Recommended Prophylaxis for Gout Flares Gout flares may occur after initiation of febuxostat tablets due to…

12.2 Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations In healthy patients, febuxostat resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% and 55% at the exposure levels of 40 mg and 80 mg daily doses. Effect on Cardiac Repolarization The effect of febuxostat on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy patients and in patients with gout. Febuxostat in doses up to 300 mg daily (3.75 times the maximum recommended daily dosage), at steady-state, did not demonstrate an effect on the QTc interval.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: Cardiovascular Death [see Warnings and Precautions (5.1) ] Hepatic Effects [see Warnings and Precautions (5.3) ] Serious Skin Reactions [see Warnings and Precautions (5.4) ] Adverse reactions in ≥ 1% of patients treated with febuxostat are liver function abnormalities, nausea, arthralgia, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. In Phase 2 and 3 clinical studies, a total of 2757 patients with hyperuricemia and gout were treated with febuxostat 40 mg or 80 mg daily. For febuxostat 40 mg, 559 patients were treated for ≥6 months. For febuxostat 80 mg, 1377 patients were treated for ≥6 months, 674 patients were treated for ≥1 year and 515 patients were treated for ≥2 years. In the CARES study, a total of 3098 patients were treated with febuxostat 40 mg or 80 mg daily; of these, 2155 patients were treated for ≥1 year and 1539 were treated for ≥2 years [see Clinical Studies (14.2) ] . 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 febuxostat treatment groups and at least 0.5% greater than placebo. * Of the patients who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. Table 1: Adverse Reactions Occurring in ≥1% of…

4 CONTRAINDICATIONS Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine [see Drug Interactions (7) ] . Febuxostat tablets are contraindicated in patients being treated with azathioprine or mercaptopurine. ( 4 )

5 WARNINGS AND PRECAUTIONS Gout Flares : An increase in gout flares is frequently observed after initiation of febuxostat. If a gout flare occurs during treatment, febuxostat 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. ( 2.4 , 5.2 ) Hepatic Effects : Cases of hepatic failure, some fatal, have been reported. If liver injury is detected, promptly interrupt febuxostat and treat cause, if possible, to resolution or stabilization. Permanently discontinue febuxostat if liver injury is confirmed, and no alternate etiology can be found. ( 5.3 ) 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 febuxostat. Discontinue febuxostat if serious skin reactions are suspected. ( 5.4 ) 5.1 Cardiovascular Death In a cardiovascular (CV) outcome study, gout patients with established CV disease treated with febuxostat 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 febuxostat group (83 of 3,098) as compared to 1.8% in the allopurinol group (56 of 3,092). Febuxostat was similar to allopurinol for nonfatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization [see Clinical Studies (14.2) ] . Because of the increased risk of CV death, febuxostat 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 [see Indications and Usage (1) ] . Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on febuxostat. Consider use of prophylactic low-dose aspirin…

7 DRUG INTERACTIONS Concomitant administration of febuxostat with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity. ( 7 ) 7.1 Xanthine Oxidase Substrate Drugs Febuxostat 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 [see Clinical Pharmacology (12.3) ]. Therefore, use with caution when coadministering febuxostat with theophylline. A drug interaction study of febuxostat and azathioprine, also metabolized by XO, showed an increase in exposure of 6-mercaptopurine which may lead to toxicity [see Clinical Pharmacology (12.3) ] . Drug interaction studies of febuxostat with other drugs that are metabolized by XO (e.g., mercaptopurine) have not been conducted. Febuxostat is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications (4) ]. 7.2 Cytotoxic Chemotherapy Drugs Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of febuxostat during cytotoxic chemotherapy. 7.3 In Vivo Drug Interaction Studies Based on drug interaction studies in healthy patients, febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine [see Clinical Pharmacology (12.3) ]. Therefore, febuxostat may be used concomitantly with these medications.