ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. Adverse reactions occurring in at least 1% of patients treated with ULORIC, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 patients 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 patients were treated for >=6 months, 674 patients were treated for >=1 year and 515 patients were treated for >=2 years.. Most Common Adverse ReactionsIn three randomized, controlled clinical studies (Studies 1, and 3), which were six to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table summarizes adverse reactions reported at 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 Patients Treated with ULORIC and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled StudiesPlaceboULORICallopurinolOf the patients who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. Adverse Reactions(N=134)40 mg daily(N=757)80 mg daily(N=1279)(N=1277)Liver Function Abnormalities0.7%6.6%4.6%4.2%Nausea 0.7%1.1%1.3%0.8%Arthralgia 0%1.1%0.7%0.7%Rash0.7%0.5%1.6%1.6%The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of patients treated with allopurinol.In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of patients treated with ULORIC although not at rate more than 0.5% greater than placebo.. Less Common Adverse ReactionsIn Phase and clinical studies the following adverse reactions occurred in less than 1% of patients and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of patients) associated with organ systems from Warnings and Precautions.Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia. Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia.Ear and Labyrinth Disorders: deafness, tinnitus, vertigo.Eye Disorders: vision blurred.Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting.General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst.Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.Immune System Disorder: hypersensitivity.Infections and Infestations: herpes zoster. Procedural Complications: contusion.Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor.Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change. Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence.Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia. Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection.Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria.Vascular Disorders: flushing, hot flush, hypertension, hypotension. Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.. Cardiovascular SafetyCardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo (95% CI 0.00-6.16), ULORIC 40 mg (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53).In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).Overall, higher rate of APTC events was observed in ULORIC than in patients treated with allopurinol. causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke.. 6.2Postmarketing Experience. The following adverse reactions have been identified during post approval use of ULORIC. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System Disorders: agranulocytosis, eosinophilia.Hepatobiliary Disorders: hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.Immune System Disorders: anaphylaxis, anaphylactic reaction.Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis.Psychiatric Disorders: psychotic behavior including aggressive thoughts.Renal and Urinary Disorders: tubulointerstitial nephritis.Skin and Subcutaneous Tissue Disorders: generalized rash, Stevens-Johnson Syndrome, hypersensitivity skin reactions, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.


13.2Animal Toxicology. 12 month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately times the MRHD on an AUC basis). similar effect of calculus formation was noted in rats in six-month study due to deposition of xanthine crystals at 48 mg/kg (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. ULORIC is xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout.ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.. ULORIC is xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. (1)ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. (1).

STORAGE AND HANDLING SECTION.


Protect from light. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS No studies have been conducted in patients with severe hepatic impairment. Caution should be exercised in these patients. (8.6, 8.7)No studies have been conducted in patients with secondary hyperuricemia (including patients being treated for Lesch-Nyhan syndrome or malignant disease, or in organ transplant recipients); therefore, ULORIC is not recommended for use in these patients. (8.8). No studies have been conducted in patients with severe hepatic impairment. Caution should be exercised in these patients. (8.6, 8.7). No studies have been conducted in patients with secondary hyperuricemia (including patients being treated for Lesch-Nyhan syndrome or malignant disease, or in organ transplant recipients); therefore, ULORIC is not recommended for use in these patients. (8.8). 8.1Pregnancy. Risk SummaryLimited available data with ULORIC use in pregnant women are insufficient to inform drug associated risk of adverse developmental outcomes. No adverse developmental effects were observed in embryo-fetal development studies with oral administration of febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in pre- and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure approximately 11 times the MRHD (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days - 17, febuxostat was not teratogenic and did not affect fetal development or survival at exposures up to approximately 40 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days - 18, febuxostat was not teratogenic and did not affect fetal development at exposures up to approximately 51 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day).In pre- and postnatal development study in pregnant female rats dosed orally from gestation Day through lactation Day 20, febuxostat had no effects on delivery or growth and development of offspring at dose approximately 11 times the MRHD (on an AUC basis at maternal oral dose of 12 mg/kg/day). However, increased neonatal mortality and reduction in neonatal body weight gain were observed in the presence of maternal toxicity at dose approximately 40 times the MRHD (on an AUC basis at maternal oral dose of 48 mg/kg/day).Febuxostat crossed the placental barrier following oral administration to pregnant rats and was detected in fetal tissues.. 8.2Lactation. Risk SummaryThere are no data on the presence of febuxostat in human milk, the effects on the breastfed infant, or the effects on milk production. Febuxostat is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ULORIC and any potential adverse effects on the breastfed child from ULORIC or from the underlying maternal condition.. Data. Animal DataOrally administered febuxostat was detected in the milk of lactating rats at up to approximately times the plasma concentration.. 8.4Pediatric Use. Safety and effectiveness in pediatric patients under 18 years of age have not been established.. 8.5Geriatric Use. No dose adjustment is necessary in elderly patients. Of the total number of patients in clinical studies of ULORIC, 16% were 65 and over, while 4% were 75 and over. Comparing patients in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric patients (>=65 years) were similar to those in younger patients (18 to 40 years) [see Clinical Pharmacology (12.3)]. 8.6Renal Impairment. No dose adjustment is necessary in patients with mild to moderate renal impairment (Clcr 30 to 89 mL/min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve sUA less than mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended. For patients with severe renal impairment (Clcr 15 to 29 mL/min), the dose of ULORIC is limited to 40 mg once daily [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.7Hepatic Impairment. No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients [see Clinical Pharmacology (12.3)]. 8.8Secondary Hyperuricemia. No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. Gout Flare: An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti-inflammatory drug [NSAID] or colchicine upon initiation of treatment) may be beneficial for up to six months. (2.4, 5.1)Cardiovascular Events: higher rate of cardiovascular thromboembolic events was observed in patients treated with ULORIC than allopurinol in clinical trials. Monitor for signs and symptoms of MI and stroke. (5.2)Hepatic Effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt ULORIC and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart ULORIC if liver injury is confirmed and no alternate etiology can be found. (5.3)Serious Skin Reactions: Postmarketing reports of 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 in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected. (5.4). Gout Flare: An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti-inflammatory drug [NSAID] or colchicine upon initiation of treatment) may be beneficial for up to six months. (2.4, 5.1). Cardiovascular Events: higher rate of cardiovascular thromboembolic events was observed in patients treated with ULORIC than allopurinol in clinical trials. Monitor for signs and symptoms of MI and stroke. (5.2). Hepatic Effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt ULORIC and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart ULORIC if liver injury is confirmed and no alternate etiology can be found. (5.3). Serious Skin Reactions: Postmarketing reports of 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 in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected. (5.4). 5.1Gout 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)]. 5.2Cardiovascular Events In the randomized controlled studies, there was 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)]. causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.. 5.3Hepatic Effects There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ULORIC, although the reports contain insufficient information necessary to establish the probable cause. 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 [see Clinical Pharmacology (12.3)].Obtain liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as 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 is found to have abnormal liver tests (ALT greater than three times the upper limit of the reference range), ULORIC treatment should be interrupted and investigation done to establish the probable cause. ULORIC should not be restarted in these patients without another explanation for the liver test abnormalities.Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury and should not be restarted on ULORIC. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with caution.. 5.4Serious Skin Reactions. Postmarketing reports of 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 in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected [see Patient Counseling Information (17)]. Many of these patients had reported previous similar skin reactions to allopurinol. ULORIC should be used with caution in these patients.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of the urinary bladder was observed at 24 mg/kg (25 times the MRHD on an AUC basis and 18.75 mg/kg (12.5 times the MRHD on an AUC basis) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.Febuxostat showed positive clastogenic response in chromosomal aberration assay in Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in human peripheral lymphocytes, the L5178Y mouse lymphoma cell line assay, the in vivo mouse micronucleus assay, and the rat unscheduled DNULL synthesis assay.Fertility and reproductive performance were unaffected in male or female rats that received febuxostat at oral doses up to 48 mg/kg/day (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY 12.1Mechanism of Action. ULORIC, xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.. 12.2Pharmacodynamics. Effect on Uric Acid and Xanthine ConcentrationsIn healthy patients, ULORIC resulted in 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 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 RepolarizationThe effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy patients and in patients with gout. ULORIC in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval.. 12.3Pharmacokinetics. In healthy patients, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately to hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy patients.. Absorption The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between and 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 +- 0.6 mcg/mL (N=30), and 2.6 +- 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied.Following multiple 80 mg once daily doses with high fat meal, there was 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, ULORIC may be taken without regard to food.Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of ULORIC has been shown to delay absorption of febuxostat (approximately one hour) and to cause 31% decrease in Cmax and 15% decrease in AUC. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, ULORIC may be taken without regard to antacid use.. DistributionThe mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 (CV ~40%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses.. MetabolismFebuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at much lower extent than febuxostat.In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo.. EliminationFebuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).The apparent mean terminal elimination half-life (t1/2) of febuxostat was approximately to hours.. Special Populations. Pediatric UseThe pharmacokinetics of ULORIC in patients under the age of 18 years have not been studied.. Geriatric UseThe Cmax and AUC of febuxostat and its metabolites following multiple oral doses of ULORIC in geriatric patients (>=65 years) were similar to those in younger patients (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger patients. No dose adjustment is necessary in geriatric patients [see Use in Specific Populations (8.5)]. Renal ImpairmentIn dedicated phase pharmacokinetics study, following multiple 80 mg doses of ULORIC in healthy patients with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to patients with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for patients with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).Based on population pharmacokinetic analysis, following multiple 40 mg or 80 mg doses of ULORIC, the mean oral clearance (CL/F) values of febuxostat in patients with gout and mild (n=334), moderate (n=232) or severe (n=34) renal impairment were decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.ULORIC has not been studied in end stage renal impairment patients who are on dialysis. Hepatic ImpairmentFollowing multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to patients with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations (8.7)]. GenderFollowing multiple oral doses of ULORIC, the Cmax and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender.. RaceNo specific pharmacokinetic study was conducted to investigate the effects of race.. Drug-Drug Interactions. Effect of ULORIC on Other Drugs. Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine, and TheophyllineFebuxostat is an XO inhibitor. drug-drug interaction study evaluating the effect of ULORIC upon the pharmacokinetics of theophylline (an XO substrate) in healthy patients showed that coadministration of febuxostat with theophylline resulted in an approximately 400-fold increase in the amount of 1-methylxanthine, one of the major metabolites of theophylline, excreted in the urine. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline.Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications (4) and Drug Interactions (7)]. Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Although ULORIC drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because ULORIC is xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity.. P450 Substrate DrugsIn vitro studies have shown that febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between ULORIC and drugs metabolized by these CYP enzymes are unlikely.. Effect of Other Drugs on ULORIC Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between ULORIC and drug that inhibits or induces one particular enzyme isoform is in general not expected.. In Vivo Drug Interaction Studies. TheophyllineNo dose adjustment is necessary for theophylline when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax and 6.5% in AUC of theophylline. These changes were not considered statistically significant. However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as result of XO inhibition by ULORIC. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister ULORIC and theophylline.. Colchicine No dose adjustment is necessary for either ULORIC or colchicine when the two drugs are coadministered. Administration of ULORIC (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in Cmax and 7% in AUC24 of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with ULORIC (120 mg daily) resulted in less than 11% change in Cmax or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant.. Naproxen No dose adjustment is necessary for ULORIC or naproxen when the two drugs are coadministered. Administration of ULORIC (80 mg once daily) with naproxen (500 mg twice daily) resulted in 28% increase in Cmax and 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the Cmax or AUC of naproxen (less than 2%). IndomethacinNo dose adjustment is necessary for either ULORIC or indomethacin when these two drugs are coadministered. Administration of ULORIC (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in Cmax or AUC of febuxostat or indomethacin (less than 7%).. HydrochlorothiazideNo dose adjustment is necessary for ULORIC when coadministered with hydrochlorothiazide. Administration of ULORIC (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in Cmax or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected.. WarfarinNo dose adjustment is necessary for warfarin when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy patients. INR and Factor VII activity were also not affected by the coadministration of ULORIC.. DesipramineCoadministration of drugs that are CYP2D6 substrates (such as desipramine) with ULORIC are not expected to require dose adjustment. Febuxostat was shown to be weak inhibitor of CYP2D6 in vitro and in vivo. Administration of ULORIC (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES. serum uric acid level of less than mg/dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout.. 14.1Management of Hyperuricemia in Gout. The efficacy of ULORIC was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as baseline serum uric acid level >=8 mg/dL.Study randomized patients to: ULORIC 40 mg daily, ULORIC 80 mg daily, or allopurinol (300 mg daily for patients with estimated creatinine clearance (Clcr) >=60 mL/min or 200 mg daily for patients with estimated Clcr >=30 mL/min and <=59 mL/min). The duration of Study was six months. Study randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 240 mg daily or allopurinol (300 mg daily for patients with baseline serum creatinine <=1.5 mg/dL or 100 mg daily for patients with baseline serum creatinine greater than 1.5 mg/dL and <=2 mg/dL). The duration of Study was six months.Study 3, 1 year study, randomized patients to: ULORIC 80 mg daily, ULORIC 120 mg daily, or allopurinol 300 mg daily. Patients who completed Study and Study were eligible to enroll in Phase long-term extension study in which patients received treatment with ULORIC for over three years.In all three studies, patients received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study the duration of prophylaxis was six months; in Study and Study the duration of prophylaxis was eight weeks.The efficacy of ULORIC was also evaluated in four week dose ranging study which randomized patients to: placebo, ULORIC 40 mg daily, ULORIC 80 mg daily, or ULORIC 120 mg daily. Patients who completed this study were eligible to enroll in long-term extension study in which patients received treatment with ULORIC for up to five years.Patients in these studies were representative of the patient population for which ULORIC use is intended. Table summarizes the demographics and baseline characteristics for the patients enrolled in the studies.Table 2: Patient Demographics and Baseline Characteristics in Study 1, Study and Study 3Male95%Race: Caucasian80% African American10%Ethnicity: Hispanic or Latino7%Alcohol User67%Mild to Moderate Renal Insufficiency(percent with estimated Clcr less than 90 mL/min)59%History of Hypertension49%History of Hyperlipidemia38%BMI >=30 kg/m2 63%Mean BMI33 kg/m2 Baseline sUA >=10 mg/dL36%Mean baseline sUA9.7 mg/dLExperienced gout flare in previous year85%. Serum Uric Acid Level less than mg/dL at Final VisitULORIC 80 mg was superior to allopurinol in lowering serum uric acid to less than mg/dL at the final visit. ULORIC 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than mg/dL at the final visit (Table 3).Table 3: Proportion of Patients with Serum Uric Acid Levels less than mg/dL at Final VisitDifference in Proportion(95% CI)StudyRandomization was balanced between treatment groups, except in Study in which twice as many patients were randomized to each of the active treatment groups compared to placebo. ULORIC40 mg dailyULORIC80 mg dailyallopurinolPlaceboULORIC 40 mg vs allopurinolULORIC 80 mg vs allopurinolStudy 1(6 months)(N=2268)45%67%42%3%(-2%, 8%)25%(20%, 30%)Study 2(6 months)(N=643)72%39%1%33%(26%, 42%)Study 3(12 months)(N=491)74%36%38%(30%, 46%)In 76% of ULORIC 80 mg patients, reduction in serum uric acid levels to less than mg/dL was noted by the Week visit. Average serum uric acid levels were maintained at mg/dL or below throughout treatment in 83% of these patients.In all treatment groups, fewer patients with higher baseline serum urate levels (>=10 mg/dL) and/or tophi achieved the goal of lowering serum uric acid to less than mg/dL at the final visit; however, higher proportion achieved serum uric acid less than mg/dL with ULORIC 80 mg than with ULORIC 40 mg or allopurinol.Study evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this sub-group of patients are shown in Table 4.Table 4: Proportion of Patients with Serum Uric Acid Levels less than mg/dL in Patients with Mild or Moderate Renal Impairment at Final VisitDifference in Proportion(95% CI)ULORIC 40 mg daily(N=479)ULORIC80 mg daily(N=503)allopurinolAllopurinol patients (n=145) with estimated Clcr >=30 mL/min and Clcr <=59 mL/min were dosed at 200 mg daily. 300 mg daily(N=501)ULORIC 40 mg vs allopurinolULORIC 80 mg vs allopurinol50%72%42%7%(1%, 14%)29%(23%, 35%).

CONTRAINDICATIONS SECTION.


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

DESCRIPTION SECTION.


11DESCRIPTION. ULORIC (febuxostat) is xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with molecular weight of 316.38. The empirical formula is C16H16N2O3S.The chemical structure is:Febuxostat is 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 205C to 208C.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 lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. ULORIC is recommended at 40 mg or 80 mg once daily. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve serum uric acid (sUA) less than mg/dL after weeks with 40 mg, ULORIC 80 mg is recommended. (2.1)ULORIC can be administered without regard to food or antacid use. (2.1)Limit the dose of ULORIC to 40 mg once daily in patients with severe renal impairment. (2.2, 8.6). ULORIC is recommended at 40 mg or 80 mg once daily. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve serum uric acid (sUA) less than mg/dL after weeks with 40 mg, ULORIC 80 mg is recommended. (2.1). ULORIC can be administered without regard to food or antacid use. (2.1). Limit the dose of ULORIC to 40 mg once daily in patients with severe renal impairment. (2.2, 8.6). 2.1Recommended Dose. For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily.The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve serum uric acid (sUA) less than mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.ULORIC can be taken without regard to food or antacid use [see Clinical Pharmacology (12.3)]. 2.2Special Populations. No dose adjustment is necessary when administering ULORIC in patients with mild or moderate renal impairment. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve sUA less than mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.The dose of ULORIC is limited to 40 mg once daily in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].No dose adjustment is necessary in patients with mild to moderate hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. 2.3Uric Acid Level. Testing for the target serum uric acid level of less than mg/dL may be performed as early as two weeks after initiating ULORIC therapy.. 2.4Gout 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 non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months [see Clinical Studies (14.1)].If gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Warnings and Precautions (5.1)].

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. 40 mg tablets, light green to green, round, debossed with TAP and 4080 mg tablets, light green to green, teardrop shaped, debossed with TAP and 80. 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. (3).

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. Concomitant administration of ULORIC with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity. (7). 7.1Xanthine Oxidase Substrate Drugs. ULORIC is an XO inhibitor. Based on 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 ULORIC with theophylline.Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology (12.3)]. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications (4)]. 7.2Cytotoxic 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.. 7.3In 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 [see Clinical Pharmacology (12.3)]. Therefore, ULORIC may be used concomitantly with these medications.

GERIATRIC USE SECTION.


8.5Geriatric Use. No dose adjustment is necessary in elderly patients. Of the total number of patients in clinical studies of ULORIC, 16% were 65 and over, while 4% were 75 and over. Comparing patients in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric patients (>=65 years) were similar to those in younger patients (18 to 40 years) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. ULORIC 40 mg tablets are light green to green in color, round, debossed with TAP on one side and 40 on the other side and supplied as:NDC NumberSize64764-918-11Hospital Unit Dose Pack of 100 Tablets64764-918-30Bottle of 30 Tablets64764-918-90Bottle of 90 Tablets64764-918-18Bottle of 500 TabletsULORIC 80 mg tablets are light green to green in color, teardrop shaped, debossed with TAP on one side and 80 on the other side and supplied as:NDC NumberSize64764-677-11Hospital Unit Dose Pack of 100 Tablets64764-677-30Bottle of 30 Tablets64764-677-13Bottle of 100 Tablets64764-677-19Bottle of 1000 Tablets. Protect from light. Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information)Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered.Patients should be instructed to inform their healthcare professional if they develop rash, chest pain, shortness of breath or neurologic symptoms suggesting stroke. Some serious skin and allergic reactions such as rash, skin reddening, pain, swelling or blistering of lips, eyes or mouth, skin peeling and flu-like symptoms have been reported in patients taking ULORIC. Patients who had previous reactions to allopurinol may be at greater risk for these skin conditions [see Warnings and Precautions (5.4)]. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications.

LACTATION SECTION.


8.2Lactation. Risk SummaryThere are no data on the presence of febuxostat in human milk, the effects on the breastfed infant, or the effects on milk production. Febuxostat is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ULORIC and any potential adverse effects on the breastfed child from ULORIC or from the underlying maternal condition.. Data. Animal DataOrally administered febuxostat was detected in the milk of lactating rats at up to approximately times the plasma concentration.

MECHANISM OF ACTION SECTION.


12.1Mechanism of Action. ULORIC, xanthine oxidase inhibitor, achieves its therapeutic effect by decreasing serum uric acid. ULORIC is not expected to inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic concentrations.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of the urinary bladder was observed at 24 mg/kg (25 times the MRHD on an AUC basis and 18.75 mg/kg (12.5 times the MRHD on an AUC basis) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.Febuxostat showed positive clastogenic response in chromosomal aberration assay in Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in human peripheral lymphocytes, the L5178Y mouse lymphoma cell line assay, the in vivo mouse micronucleus assay, and the rat unscheduled DNULL synthesis assay.Fertility and reproductive performance were unaffected in male or female rats that received febuxostat at oral doses up to 48 mg/kg/day (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).. 13.2Animal Toxicology. 12 month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately times the MRHD on an AUC basis). similar effect of calculus formation was noted in rats in six-month study due to deposition of xanthine crystals at 48 mg/kg (approximately 31 and 40 times the MRHD on an AUC basis in males and females respectively).

OVERDOSAGE SECTION.


10OVERDOSAGE. ULORIC was studied in healthy patients in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 40mg. NDC 43353-305 Uloric (Febuxostat) 40mg Rx Only Bottle Label 40mg.

PEDIATRIC USE SECTION.


8.4Pediatric Use. Safety and effectiveness in pediatric patients under 18 years of age have not been established.

PHARMACODYNULLMICS SECTION.


12.2Pharmacodynamics. Effect on Uric Acid and Xanthine ConcentrationsIn healthy patients, ULORIC resulted in 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 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 RepolarizationThe effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy patients and in patients with gout. ULORIC in doses up to 300 mg daily, at steady-state, did not demonstrate an effect on the QTc interval.

PHARMACOKINETICS SECTION.


12.3Pharmacokinetics. In healthy patients, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in dose proportional manner following single and multiple doses of 10 mg to 120 mg. There is no accumulation when therapeutic doses are administered every 24 hours. Febuxostat has an apparent mean terminal elimination half-life (t1/2) of approximately to hours. Febuxostat pharmacokinetic parameters for patients with hyperuricemia and gout estimated by population pharmacokinetic analyses were similar to those estimated in healthy patients.. Absorption The absorption of radiolabeled febuxostat following oral dose administration was estimated to be at least 49% (based on total radioactivity recovered in urine). Maximum plasma concentrations of febuxostat occurred between and 1.5 hours post-dose. After multiple oral 40 mg and 80 mg once daily doses, Cmax is approximately 1.6 +- 0.6 mcg/mL (N=30), and 2.6 +- 1.7 mcg/mL (N=227), respectively. Absolute bioavailability of the febuxostat tablet has not been studied.Following multiple 80 mg once daily doses with high fat meal, there was 49% decrease in Cmax and an 18% decrease in AUC, respectively. However, no clinically significant change in the percent decrease in serum uric acid concentration was observed (58% fed vs. 51% fasting). Thus, ULORIC may be taken without regard to food.Concomitant ingestion of an antacid containing magnesium hydroxide and aluminum hydroxide with an 80 mg single dose of ULORIC has been shown to delay absorption of febuxostat (approximately one hour) and to cause 31% decrease in Cmax and 15% decrease in AUC. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, ULORIC may be taken without regard to antacid use.. DistributionThe mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 (CV ~40%). The plasma protein binding of febuxostat is approximately 99.2% (primarily to albumin), and is constant over the concentration range achieved with 40 mg and 80 mg doses.. MetabolismFebuxostat is extensively metabolized by both conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes including UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via cytochrome P450 (CYP) enzymes including CYP1A2, 2C8 and 2C9 and non-P450 enzymes. The relative contribution of each enzyme isoform in the metabolism of febuxostat is not clear. The oxidation of the isobutyl side chain leads to the formation of four pharmacologically active hydroxy metabolites, all of which occur in plasma of humans at much lower extent than febuxostat.In urine and feces, acyl glucuronide metabolites of febuxostat (~35% of the dose), and oxidative metabolites, 67M-1 (~10% of the dose), 67M-2 (~11% of the dose), and 67M-4, secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo.. EliminationFebuxostat is eliminated by both hepatic and renal pathways. Following an 80 mg oral dose of 14C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the drug (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to the urinary excretion, approximately 45% of the dose was recovered in the feces as the unchanged febuxostat (12%), the acyl glucuronide of the drug (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).The apparent mean terminal elimination half-life (t1/2) of febuxostat was approximately to hours.. Special Populations. Pediatric UseThe pharmacokinetics of ULORIC in patients under the age of 18 years have not been studied.. Geriatric UseThe Cmax and AUC of febuxostat and its metabolites following multiple oral doses of ULORIC in geriatric patients (>=65 years) were similar to those in younger patients (18 to 40 years). In addition, the percent decrease in serum uric acid concentration was similar between elderly and younger patients. No dose adjustment is necessary in geriatric patients [see Use in Specific Populations (8.5)]. Renal ImpairmentIn dedicated phase pharmacokinetics study, following multiple 80 mg doses of ULORIC in healthy patients with mild (Clcr 50 to 80 mL/min), moderate (Clcr 30 to 49 mL/min) or severe renal impairment (Clcr 10 to 29 mL/min), the Cmax of febuxostat did not change relative to patients with normal renal function (Clcr greater than 80 mL/min). AUC and half-life of febuxostat increased in patients with renal impairment in comparison to patients with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in patients with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for three active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for patients with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).Based on population pharmacokinetic analysis, following multiple 40 mg or 80 mg doses of ULORIC, the mean oral clearance (CL/F) values of febuxostat in patients with gout and mild (n=334), moderate (n=232) or severe (n=34) renal impairment were decreased by 14%, 34%, and 48%, respectively, compared to patients with normal (n=89) renal function. The corresponding median AUC values of febuxostat at steady-state in patients with renal impairment were increased by 18%, 49%, and 96% after 40 mg dose, and 7%, 45% and 98% after 80 mg dose, respectively, compared to patients with normal renal function.ULORIC has not been studied in end stage renal impairment patients who are on dialysis. Hepatic ImpairmentFollowing multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20% to 30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to patients with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations (8.7)]. GenderFollowing multiple oral doses of ULORIC, the Cmax and AUC24 of febuxostat were 30% and 14% higher in females than in males, respectively. However, weight-corrected Cmax and AUC were similar between the genders. In addition, the percent decrease in serum uric acid concentrations was similar between genders. No dose adjustment is necessary based on gender.. RaceNo specific pharmacokinetic study was conducted to investigate the effects of race.. Drug-Drug Interactions. Effect of ULORIC on Other Drugs. Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine, and TheophyllineFebuxostat is an XO inhibitor. drug-drug interaction study evaluating the effect of ULORIC upon the pharmacokinetics of theophylline (an XO substrate) in healthy patients showed that coadministration of febuxostat with theophylline resulted in an approximately 400-fold increase in the amount of 1-methylxanthine, one of the major metabolites of theophylline, excreted in the urine. Since the long-term safety of exposure to 1-methylxanthine in humans is unknown, use with caution when coadministering febuxostat with theophylline.Drug interaction studies of ULORIC with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity. ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine [see Contraindications (4) and Drug Interactions (7)]. Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Although ULORIC drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because ULORIC is xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity.. P450 Substrate DrugsIn vitro studies have shown that febuxostat does not inhibit P450 enzymes CYP1A2, 2C9, 2C19, 2D6, or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between ULORIC and drugs metabolized by these CYP enzymes are unlikely.. Effect of Other Drugs on ULORIC Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between ULORIC and drug that inhibits or induces one particular enzyme isoform is in general not expected.. In Vivo Drug Interaction Studies. TheophyllineNo dose adjustment is necessary for theophylline when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with theophylline resulted in an increase of 6% in Cmax and 6.5% in AUC of theophylline. These changes were not considered statistically significant. However, the study also showed an approximately 400-fold increase in the amount of 1-methylxanthine (one of the major theophylline metabolites) excreted in urine as result of XO inhibition by ULORIC. The safety of long-term exposure to 1-methylxanthine has not been evaluated. This should be taken into consideration when deciding to coadminister ULORIC and theophylline.. Colchicine No dose adjustment is necessary for either ULORIC or colchicine when the two drugs are coadministered. Administration of ULORIC (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in Cmax and 7% in AUC24 of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with ULORIC (120 mg daily) resulted in less than 11% change in Cmax or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant.. Naproxen No dose adjustment is necessary for ULORIC or naproxen when the two drugs are coadministered. Administration of ULORIC (80 mg once daily) with naproxen (500 mg twice daily) resulted in 28% increase in Cmax and 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the Cmax or AUC of naproxen (less than 2%). IndomethacinNo dose adjustment is necessary for either ULORIC or indomethacin when these two drugs are coadministered. Administration of ULORIC (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in Cmax or AUC of febuxostat or indomethacin (less than 7%).. HydrochlorothiazideNo dose adjustment is necessary for ULORIC when coadministered with hydrochlorothiazide. Administration of ULORIC (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in Cmax or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected.. WarfarinNo dose adjustment is necessary for warfarin when coadministered with ULORIC. Administration of ULORIC (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy patients. INR and Factor VII activity were also not affected by the coadministration of ULORIC.. DesipramineCoadministration of drugs that are CYP2D6 substrates (such as desipramine) with ULORIC are not expected to require dose adjustment. Febuxostat was shown to be weak inhibitor of CYP2D6 in vitro and in vivo. Administration of ULORIC (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).

PREGNULLNCY SECTION.


8.1Pregnancy. Risk SummaryLimited available data with ULORIC use in pregnant women are insufficient to inform drug associated risk of adverse developmental outcomes. No adverse developmental effects were observed in embryo-fetal development studies with oral administration of febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in pre- and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure approximately 11 times the MRHD (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataIn an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days - 17, febuxostat was not teratogenic and did not affect fetal development or survival at exposures up to approximately 40 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days - 18, febuxostat was not teratogenic and did not affect fetal development at exposures up to approximately 51 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day).In pre- and postnatal development study in pregnant female rats dosed orally from gestation Day through lactation Day 20, febuxostat had no effects on delivery or growth and development of offspring at dose approximately 11 times the MRHD (on an AUC basis at maternal oral dose of 12 mg/kg/day). However, increased neonatal mortality and reduction in neonatal body weight gain were observed in the presence of maternal toxicity at dose approximately 40 times the MRHD (on an AUC basis at maternal oral dose of 48 mg/kg/day).Febuxostat crossed the placental barrier following oral administration to pregnant rats and was detected in fetal tissues.

RECENT MAJOR CHANGES SECTION.


Dosage and Administration Special Populations (2.2)8/2017Warnings and Precautions Serious Skin Reactions (5.4)8/2017.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information. ULORIC (U-lor-ik)(febuxostat) tabletsRead the Patient Information that comes with ULORIC before you start taking it and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.What is ULORICULORIC is prescription medicine called xanthine oxidase (XO) inhibitor, used to lower blood uric acid levels in adults with gout.It is not known if ULORIC is safe and effective in children under 18 years of age.Who should not take ULORICDo not take ULORIC if you: take azathioprine (Azasan, Imuran)take mercaptopurine (Purinethol)It is not known if ULORIC is safe and effective in children under 18 years of age.What should tell my healthcare provider before taking ULORICBefore taking ULORIC tell your healthcare provider about all of your medical conditions, including if you:have liver or kidney problemshave history of heart disease or strokeare pregnant or plan to become pregnant. It is not known if ULORIC will harm your unborn baby. Talk with your healthcare provider if you are pregnant or plan to become pregnant.are breastfeeding or plan to breastfeed. It is not known if ULORIC passes into your breast milk. You and your healthcare provider should decide if you should take ULORIC while breastfeeding.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. ULORIC may affect the way other medicines work, and other medicines may affect how ULORIC works.Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine.How should take ULORIC Take ULORIC exactly as your healthcare provider tells you to take it.ULORIC can be taken with or without food.ULORIC can be taken with antacids.Your gout may flare up when you start taking ULORIC, do not stop taking your ULORIC even if you have flare. Your healthcare provider may give you other medicines to help prevent your gout flares.Your healthcare provider may do certain tests while you take ULORIC.What are the possible side effects of ULORICHeart problems. small number of heart attacks, strokes and heart-related deaths were seen in clinical studies. It is not certain that ULORIC caused these events.The most common side effects of ULORIC include:liver problemsnauseagout flaresjoint painrashTell your healthcare provider if you develop rash, have any side effect that bothers you, or that does not go away.Rarely, serious skin reactions can occur with ULORIC which may include rash, fever, swollen glands and other internal organ involvement such as liver, kidney, lung and heart. Tell your doctor immediately if you experience any of these signs.These are not all of the possible side effects of ULORIC. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.How should store ULORICStore ULORIC between 59F and 86F (15C to 30C).Keep ULORIC out of the light.Keep ULORIC and all medicines out of the reach of children.General information about the safe and effective use of ULORIC.Medicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use ULORIC for condition for which it was not prescribed. Do not give ULORIC to other people, even if they have the same symptoms that you have. It may harm them.This patient information leaflet summarizes the most important information about ULORIC. If you would like more information about ULORIC talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ULORIC that is written for health professionals. For more information go to www.uloric.com, or call 1-877-825-3327.What are the ingredients in ULORICActive Ingredient: febuxostatInactive ingredients include: lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide, magnesium stearate, and Opadry II, greenDistributed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015Revised: August 2017ULORIC is registered trademark of Teijin Limited registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.All other trademarks are the property of their respective owners.(C)2009-2017 Takeda Pharmaceuticals America, Inc.ULR015 R6. take azathioprine (Azasan, Imuran). take mercaptopurine (Purinethol). have liver or kidney problems. have history of heart disease or stroke. are pregnant or plan to become pregnant. It is not known if ULORIC will harm your unborn baby. Talk with your healthcare provider if you are pregnant or plan to become pregnant.. are breastfeeding or plan to breastfeed. It is not known if ULORIC passes into your breast milk. You and your healthcare provider should decide if you should take ULORIC while breastfeeding.. Take ULORIC exactly as your healthcare provider tells you to take it.. ULORIC can be taken with or without food.. ULORIC can be taken with antacids.. Your gout may flare up when you start taking ULORIC, do not stop taking your ULORIC even if you have flare. Your healthcare provider may give you other medicines to help prevent your gout flares.. Your healthcare provider may do certain tests while you take ULORIC.. liver problems. nausea. gout flares. joint pain. rash.

SPL UNCLASSIFIED SECTION.


2.1Recommended Dose. For treatment of hyperuricemia in patients with gout, ULORIC is recommended at 40 mg or 80 mg once daily.The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve serum uric acid (sUA) less than mg/dL after two weeks with 40 mg, ULORIC 80 mg is recommended.ULORIC can be taken without regard to food or antacid use [see Clinical Pharmacology (12.3)].