Febuxostat

5 WARNINGS AND PRECAUTIONS Gout Flares : An increase in gout flares is frequently observed after initiation of febuxostat. If a gout flare occurs during treatment, febuxostat need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti-inflammatory drug or colchicine) upon initiation of treatment may be beneficial for up to six months. ( 2.4 , 5.2 ) Hepatic Effects : Cases of hepatic failure, some fatal, have been reported. If liver injury is detected, promptly interrupt febuxostat and treat cause, if possible, to resolution or stabilization. Permanently discontinue febuxostat if liver injury is confirmed, and no alternate etiology can be found. ( 5.3 ) Serious Skin Reactions : Serious skin and hypersensitivity reactions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms and toxic epidermal necrolysis have been reported in patients taking febuxostat. Discontinue febuxostat if serious skin reactions are suspected. ( 5.4 ) 5.1 Cardiovascular Death In a cardiovascular (CV) outcome study, gout patients with established CV disease treated with febuxostat had a higher rate of CV death compared to those treated with allopurinol. Sudden cardiac death was the most common cause of adjudicated CV deaths, 2.7% in the febuxostat group (83 of 3,098) as compared to 1.8% in the allopurinol group (56 of 3,092). Febuxostat was similar to allopurinol for nonfatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization [see Clinical Studies (14.2) ] . Because of the increased risk of CV death, febuxostat should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable [see Indications and Usage (1) ] . Consider the risks and benefits of febuxostat when deciding to prescribe or continue patients on febuxostat. Consider use of prophylactic low-dose aspirin 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 postmarketing in 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: Cardiovascular Death [see Warnings and Precautions (5.1) ] Hepatic Effects [see Warnings and Precautions (5.3) ] Serious Skin Reactions [see Warnings and Precautions (5.4) ] Adverse reactions in ≥ 1% of patients treated with febuxostat are liver function abnormalities, nausea, arthralgia, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Phase 2 and 3 clinical studies, a total of 2757 patients with hyperuricemia and gout were treated with febuxostat 40 mg or 80 mg daily. For febuxostat 40 mg, 559 patients were treated for ≥6 months. For febuxostat 80 mg, 1377 patients were treated for ≥6 months, 674 patients were treated for ≥1 year and 515 patients were treated for ≥2 years. In the CARES study, a total of 3098 patients were treated with febuxostat 40 mg or 80 mg daily; of these, 2155 patients were treated for ≥1 year and 1539 were treated for ≥2 years [see Clinical Studies (14.2) ] . Most Common Adverse Reactions In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in febuxostat treatment groups and at least 0.5% greater than placebo. * Of the patients who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. Table 1: Adverse Reactions Occurring in ≥1% of Patients Treated with Febuxostat and at Least 0.5% Greater than in Patients Receiving Placebo in Controlled Studies Adverse Reactions Placebo Febuxostat allopurinol* (N=134) 40 mg daily (N=757) 80 mg daily (N=1279) (N=1277) Liver Function Abnormalities 0.7% 6.6% 4.6% 4.2% Nausea 0.7% 1.1% 1.3% 0.8% Arthralgia 0% 1.1% 0.7% 0.7% Rash 0.7% 0.5% 1.6% 1.6% The most common adverse reaction leading to 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-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. 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.

8 USE IN SPECIFIC POPULATIONS Patients with severe hepatic impairment: No studies have been conducted in this patient population. Caution should be exercised in these patients. ( 8.7 ) Patients with secondary hyperuricemia (including patients being treated for Lesch-Nyhan syndrome or malignant disease, or in organ transplant recipients): Febuxostat is not recommended for use as no studies have been conducted in this patient population. ( 8.8 ) 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 to 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 to 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 C max and AUC 24 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 (Cl cr 30 to 89 mL/min). For patients with severe renal impairment (Cl cr 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.

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 to 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 to 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.