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 dosage is 80 mg once daily.
Febuxostat 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 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 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 therapy.

2.4 Recommended Prophylaxis for Gout Flares

Gout flares may occur after initiation of febuxostat 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 febuxostat. Prophylactic therapy may be beneficial for up to six months [see Clinical Studies (14.1)].

If a gout flare occurs during febuxostat treatment, febuxostat need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see Warnings and Precautions (5.2)].

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 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 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.

5.2 Gout Flares

After initiation of febuxostat, 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 febuxostat is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended [see Dosage and Administration (2.4)].

5.3 Hepatic Effects

Cases of fatal and nonfatal hepatic failure in patients taking febuxostat, 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 febuxostat and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted [see Clinical Pharmacology (12.3)].

Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating febuxostat.

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 febuxostat treatment while investigating the probable cause.. Permanently discontinue febuxostat if liver injury is confirmed, and no alternate etiology can be found.

Permanently discontinue febuxostat 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 febuxostat can be used with close monitoring.

5.4 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 in postmarketing patients taking febuxostat. Discontinue febuxostat if serious skin reactions are suspected [see Patient Counseling Information (17)]. Many of these patients had reported previous similar skin reactions to allopurinol. Febuxostat should be used with close monitoring in these patients.

5.5 Risk of Allergic Reactions due to Tartrazine

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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.

Table 1: Adverse Reactions Occurring in ≥1% of Patients Treated with Febuxostat and at Least 0.5% Greater than in Patients Receiving Placebo in Controlled Studies

*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.

The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of febuxostat 40 mg, 1.2% of febuxostat 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 febuxostat although not at a rate more than 0.5% greater than placebo.

In the CARES study, liver function abnormalities and diarrhea were reported in more than 1% of patients treated with febuxostat, although not at a rate more than 0.5% greater than allopurinol.

Less Common Adverse Reactions
In 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 febuxostat. 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, hematemesis, 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-Barré 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of febuxostat. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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.

7.1 Xanthine Oxidase Substrate Drugs

Febuxostat is an XO inhibitor.
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.

8.1 Pregnancy

Risk Summary
Limited available data with febuxostat use in pregnant women are insufficient to inform a 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 a 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 a 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 2 to 4% and 15 to 20%, respectively.

Data
Animal Data
In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7 - 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 6 - 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 a pre-and postnatal development study in pregnant female rats dosed orally from gestation Day 7 through lactation Day 20, febuxostat had no effects on delivery or growth and development of offspring at a dose approximately 11 times the MRHD (on an AUC basis at a maternal oral dose of 12 mg/kg/day). However, increased neonatal mortality and a reduction in neonatal body weight gain were observed in the presence of maternal toxicity at a dose approximately 40 times the MRHD (on an AUC basis at a 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.

8.2 Lactation

Risk Summary
There 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 mother's clinical need for febuxostat and any potential adverse effects on the breastfed child from febuxostat or from the underlying maternal condition.

Data
Animal Data
Orally administered febuxostat was detected in the milk of lactating rats at up to approximately 7 times the plasma concentration.

8.4 Pediatric Use

Safety and effectiveness of febuxostat in pediatric patients have not been established.

8.5 Geriatric Use

No dose adjustment is necessary in elderly patients. Of the total number of patients in Studies 1, 2, and 3 (clinical studies of febuxostat in the treatment of gout) [see Clinical Studies (14.1)], 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 febuxostat in geriatric patients (≥65 years) were similar to those in younger patients (18 to 40 years) [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (Clcr 30 to 89 mL/min). For patients with severe renal impairment (Clcr 15 to 29 mL/min), the recommended dosage of febuxostat is limited to 40 mg once daily [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A 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)].

8.8 Secondary Hyperuricemia

No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); febuxostat 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.

12.1 Mechanism of Action

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

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.

12.3 Pharmacokinetics

In healthy patients, maximum plasma concentrations (Cmax) and AUC of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg (0.25 times the lowest recommended dosage) to 120 mg (1.5 times the maximum recommended dosage). 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 5 to 8 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 1 and 1.5 hours postdose. 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 a high fat meal, there was a 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, febuxostat 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 febuxostat has been shown to delay absorption of febuxostat (approximately one hour) and to cause a 31% decrease in Cmax and a 15% decrease in AUC∞. As AUC rather than Cmax was related to drug effect, change observed in AUC was not considered clinically significant. Therefore, febuxostat may be taken without regard to antacid use.

Distribution
The mean apparent steady state volume of distribution (Vss/F) of febuxostat was approximately 50 L (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.

Metabolism
Febuxostat 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 a 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, a secondary metabolite from 67M-1 (~14% of the dose), appeared to be the major metabolites of febuxostat in vivo.

Elimination
Febuxostat 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 5 to 8 hours.

Specific Populations
Geriatric Patients
The Cmax and AUC of febuxostat and its metabolites following multiple oral doses of febuxostat 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)].

Patients with Renal Impairment
In a dedicated phase I pharmacokinetics study, following multiple 80 mg doses of febuxostat 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 two and four-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 febuxostat, 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.

Febuxostat has not been studied in end stage renal impairment patients who are on dialysis.

Patients with Hepatic Impairment
Following multiple 80 mg doses of febuxostat 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)].

Male and Female Patients
Following multiple oral doses of febuxostat, 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.

Racial Groups
No specific pharmacokinetic study was conducted to investigate the effects of race.

Drug Interaction Studies
Effect of Febuxostat on Other Drugs
Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine
Febuxostat is an XO inhibitor.
 A drug interaction study of febuxostat and azathioprine has been conducted [see Drug Interactions (7)]. Inhibition of XO by febuxostat caused increased plasma concentrations of 6-mercaptopurine, a metabolite of azathioprine, which may lead to toxicity. 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) and Drug Interactions (7)]. Azathioprine and mercaptopurine undergo metabolism via three major metabolic pathways, one of which is mediated by XO. Concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because febuxostat is a xanthine oxidase inhibitor, it could inhibit the XO-mediated metabolism of mercaptopurine leading to increased plasma concentrations of mercaptopurine that could result in severe toxicity.

P450 Substrate Drugs
In 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 febuxostat and drugs metabolized by these CYP enzymes are unlikely.

Effect of Other Drugs on Febuxostat
Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between febuxostat and a drug that inhibits or induces one particular enzyme isoform is in general not expected.

In Vivo Drug Interaction Studies

Azathioprine

Concomitant use of febuxostat and azathioprine is contraindicated. Coadministration with febuxostat (40 mg or 120 mg QD) reduced the apparent clearance of mercaptopurine, a XO substrate, by 83.2% to 83.8% following a single oral dose of azathioprine, a prodrug of 6-mercaptopurine. No significant differences were observed in the extent of inhibition of 6-mercaptopurine metabolism by febuxostat 40 mg and 120 mg

Colchicine
No dose adjustment is necessary for either febuxostat or colchicine when the two drugs are coadministered. Administration of febuxostat (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 febuxostat (120 mg daily) resulted in a 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 febuxostat or naproxen when the two drugs are coadministered. Administration of febuxostat (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in Cmax and a 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%).

Indomethacin
No dose adjustment is necessary for either febuxostat or indomethacin when these two drugs are coadministered. Administration of febuxostat (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%).

Hydrochlorothiazide
No dose adjustment is necessary for febuxostat when coadministered with hydrochlorothiazide. Administration of febuxostat (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.

Warfarin
No dose adjustment is necessary for warfarin when coadministered with febuxostat. Administration of febuxostat (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 febuxostat.

Desipramine
Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with febuxostat are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of febuxostat (120 mg once daily) with desipramine (25 mg) resulted in an increase in Cmax (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).

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 a positive clastogenic response in a chromosomal aberration assay in a 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 DNA 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).

13.2 Animal Toxicology

A 12 month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg/kg (approximately 4 times the MRHD on an AUC basis). A similar effect of calculus formation was noted in rats in a 6 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).

14.1 Management of Hyperuricemia in Gout

The efficacy of febuxostat was demonstrated in three randomized, double-blind, controlled trials in patients with hyperuricemia and gout. Hyperuricemia was defined as a baseline serum uric acid level ≥8 mg/dL.

Study 1 (ClinicalTrials.gov identifier NCT00430248) randomized patients to: febuxostat 40 mg daily, febuxostat    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 1 was six months.

Study 2 (ClinicalTrials.gov identifier NCT00174915) randomized patients to: placebo, febuxostat 80 mg daily, febuxostat 120 mg daily, febuxostat 240 mg daily or allopurinol (300 mg daily for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg daily for patients with a baseline serum creatinine greater than 1.5 mg/dL and ≤2 mg/dL). The duration of Study 2 was six months.

Study 3 (ClinicalTrials.gov identifier NCT00102440), a one year study, randomized patients to: febuxostat 80 mg daily, febuxostat 120 mg daily, or allopurinol 300 mg daily. Patients who completed Study 2 and Study 3 were eligible to enroll in a Phase 3 long-term extension study in which patients received treatment with febuxostat 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 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks.

The efficacy of febuxostat was also evaluated in a four week dose ranging study which randomized patients to: placebo, febuxostat 40 mg daily, febuxostat 80 mg daily, or febuxostat 120 mg daily. Patients who completed this study were eligible to enroll in a long-term extension study in which patients received treatment with febuxostat for up to five years.

Patients in these studies were representative of the patient population for which febuxostat use is intended. Table 2 summarizes the demographics and baseline characteristics for the patients enrolled in the studies.

Serum Uric Acid Level less than 6 mg/dL at Final Visit:
Febuxostat 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 mg/dL at the final visit. Febuxostat 40 mg daily, although not superior to allopurinol, was effective in lowering serum uric acid to less than 6 mg/dL at the final visit (Table 3)

*Randomization was balanced between treatment groups, except in Study 2 in which twice as many patients were randomized to each of the active treatment groups compared to placebo.

In 76% of febuxostat 80 mg patients, reduction in serum uric acid levels to less than 6 mg/dL was noted by the Week 2 visit. Average serum uric acid levels were maintained at  6 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 6 mg/dL at the final visit; however, a higher proportion achieved a serum uric acid less than 6 mg/dL with febuxostat 80 mg than with febuxostat 40 mg or allopurinol.
Study 1 evaluated efficacy in patients with mild to moderate renal impairment (i.e., baseline estimated Clcr less than 90 mL/min). The results in this subgroup of patients are shown in Table 4.

*Allopurinol patients (n=145) with estimated Clcr ≥30 mL/min and Clcr ≤59 mL/min were dosed at 200 mg daily.

14.2 Cardiovascular Safety Study

A randomized, double-blind, allopurinol-controlled CV outcomes study (CARES) was conducted to evaluate the CV risk of febuxostat (NCT01101035). The study compared the risk of MACE between patients treated with febuxostat (N=3098) and allopurinol-treated patients (N=3092). The primary endpoint was the time to first occurrence of a MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. An independent committee conducted a blinded evaluation of serious CV adverse events according to predefined criteria (adjudication) for determination of MACE. The study was event driven and patients were followed until a sufficient number of primary outcome events accrued. The median on-study follow-up time was 2.6 years.

Patients randomized to febuxostat initially received 40 mg once daily which was increased to 80 mg once daily, if their sUA was ≥6mg/dL at Week 2. For patients randomized to allopurinol, those who had normal renal function or mild renal impairment (estimated creatinine clearance (eClcr) ≥ 60 to <90 mL/minute) initially received 300 mg once daily with 100 mg/day dose increments monthly until either sUA <6mg/dL or an allopurinol dosage of 600 mg once daily was achieved; those who had moderate renal impairment (eClcr ≥30 to <60 mL/minute) initially received 200 mg once daily with 100 mg/day dose increments monthly until either a sUA <6 mg/dL or an allopurinol dosage of 400 mg once daily was achieved.

The mean age of the population was 65 years (range: 44 to 93 years). Most patients were male (84%) and Caucasian (69%). Patients had a diagnosis of gout for approximately 12 years, a mean baseline sUA of 8.7 mg/dL, and 90% had experienced at least one gout flare in the past year. CV history included MI (39%), hospitalization for unstable angina (28%), cardiac revascularization (37%), and stroke (14%). The most prevalent comorbid conditions were hypertension (92%), hyperlipidemia (87%), diabetes mellitus (55%), diabetes mellitus with micro-or macrovascular disease (39%), and renal impairment [92% with an eClcr 30 to 89 mL/minute]. The use of CV disease medication was balanced across treatment groups. Baseline CV disease medications included: ACE inhibitors or ARBs (70%), lipid modifying agents (74%), aspirin (62%), beta-blockers (59%), calcium channel blockers (26%), and nonaspirin antiplatelet medications (31%).

Table 5 shows the study results for the primary MACE composite endpoint and its individual components. For the composite primary endpoint, the febuxostat group was non-inferior compared with the allopurinol group. The rates of nonfatal MI, stroke, and unstable angina with urgent coronary revascularization were similar. There was a higher rate of CV deaths in patients treated with febuxostat (134 CV deaths; 1.5 per 100 PY) than in allopurinol-treated patients (100 CV deaths; 1.1 per 100 PY). Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). The biological plausibility of CV death associated with febuxostat is unclear.

All-cause mortality was higher in the febuxostat group (243 deaths [7.8%]; 2.6 per 100 PY) than the allopurinol group (199 deaths [6.4%]; 2.2 per 100 PY) [Hazard Ratio: 1.22, 95% CI: 1.01, 1.47], due to a higher rate of CV deaths.

Table 5: Patients with MACE in CARES (Cardiovascular Outcomes Study in Patients with Gout

* Patient Years (PY)