英文药名: Uloric(Febuxostat Tablets) 中文药名: 非布索坦片 生产厂家：武田北美制药 药品介绍 美国FDA批准了近40年来的第一个用于治疗高尿酸症的痛风药物——武田制药的非布索坦（febuxostat；ULORIC）。 非布索坦通过降低患者血液中的尿酸水平改善来痛风患者的症状。此外，武田制药北美公司还是该产品在美国市场中的独立开发商与销售商。 　　 根据武田公司的一项声明：该产品的结构与40年前开发的黄嘌呤氧化酶抑制剂药物完全不同，它是一种全新的高效的非嘌呤类黄嘌呤氧化酶选择性抑制剂。黄嘌呤氧化酶则是促进尿酸生成的关键酶。 　　 非布索坦可以降低高尿酸血症痛风患者血液中的尿酸水平，在临床研究中已经证明了非布索坦的安全性和有效性，而且在中、重度肝肾功能不全的患者中也不需要进行剂量调整。该产品的服用剂量为每日一次，一次40毫克或者80毫克，但是该产品不推荐用于无高尿酸血症的痛风患者。 　　 非布索坦的原研厂家为日本的另一家公司，日本帝人制药（TeijinPharma）。在帝人制药公司总裁最近的一份声明中，我们可以了解到该公司对该产品采取的全球战略。他说，在本品获得FDA的许可之前，Ipsen公司的产品也获得了欧盟的上市许可。Ipsen公司是帝人制药关于该产品在欧盟的许可公司，而武田北美制药是本品在美国的许可公司。所以公司在全球已经取得了里程碑式的战略意义。同时他还指出，在亚洲市场，帝人制药将采取自主开发或联合开发的形式。 　　 据专家介绍，痛风是一组异质性疾病，是遗传性和（或）获得性引起的尿酸排泄减少和（或）嘌呤代谢障碍。临床特点：高尿酸血症，以及尿酸盐结晶，沉积所致的特征性急性关节炎、痛风石、间质性肾炎、严重者呈关节畸形及功能障碍；常伴尿酸性尿路结石。假性痛风常常与痛风混淆，因为其症状非常相似，假性痛风是由磷酸钙的代谢障碍引起，而不是尿酸代谢障碍引起。 　　　 根据美国国家关节肌肉骨骼疾病与皮肤病研究所（NIAMS）的研究数据表明，在美国有600万20岁及其以上的人生平有患痛风的经历。通常40~50岁的男性患者较为常见，而绝经前的女性患者少见。经历过器官移植的患者也容易患痛风。 药理作用特点　　 痛风的发生是由于体内产生尿酸过多及肾脏清除能力下降，尿酸体内蓄积，导致尿酸盐结晶在关节及各脏器沉积。因此，痛风的治疗通常采取的手段是：促进尿酸排泄和抑制尿酸生成，并采用适当措施改善相关症状。 　　 体内尿酸的生成与嘌呤代谢有关，在嘌呤代谢的最后步骤中，次黄嘌呤在黄嘌呤氧化还原酶（XOR）的作用下生成黄嘌呤，再进一步生成尿酸，抑制该酶的活性可以有效的减少尿酸的生成。非布索坦为目前世界上最新研制的XOR抑制剂，其通过高度选择性地作用于该氧化酶，减少体内尿酸合成，降低尿酸浓度，从而有效治疗通风疾病。 　　 30年来，别嘌呤醇是临床上唯一一个用于抑制尿酸生成的药物，并作为痛风的黄金治疗药物广泛用于临床，在抗痛风的治疗中取得了不俗的成绩。 　　 与别嘌呤相比，非布索坦具有明显优势： 　　 （1）别嘌呤醇只对还原型的XOR有抑制作用，而非布索坦对氧化型和还原型的XOR均有显著的抑制作用，因而其降低尿酸的作用更强大、持久； 　　 （2）由于别嘌呤醇为嘌呤类似物，不可避免的造成涉及嘌呤及吡啶代谢其他酶活性的影响。因此别嘌呤醇治疗中，需要重复大剂量给药来维持较高的药物水平。由此也带来由于药物蓄积所致的严重甚至致命的不良反应。而非布索坦为非嘌呤类XOR抑制剂，因此具有更好的安全性。 临床评价　　 一项多中心、双盲、随机Ⅱ期临床研究评价了非布索坦的安全性和对痛风的疗效。总共有136名男性和17名女性痛风病人随机接受安慰剂或本品(40、80或120mg/d),4周后检测发现,本品各剂量组病人血清尿酸浓度较治疗前均显著降低,按剂量由低至高各组分别平均降低37%、44%和59%,而安慰剂组病人仅降低了2%；绝大多数病人坚持完成了试验,本品和安慰剂组不良反应发生率相近，并且这些不良反应大多轻微,具有自限性,常见的有腹泻、疼痛、背痛、头痛和关节痛。 　　 一项Ⅲ期临床试验平行比较了本品(80和120mg/d)和别嘌醇(300mg/d)的疗效。对760名病人进行的为期1年的研究显示,与别嘌醇组相比,本品组中有更多的病人达到主要试验疗效指标－最后3个月均测得sUA浓度低于60mg/L(所有受试者均为痛风病人,且试验前sUA浓度均在80mg/L以上)；在治疗52周后,本品未能显著减少痛风石面积(痛风石是痛风特有的尿酸盐结晶的聚集体),但在试验早期的高剂量组,该作用较明显；各治疗组中,sUA浓度达标(<60mg/L)的病人较少再突发痛风，且其痛风石面积有更明显的减少；各治疗组的不良反应及其发生率相似,不良反应包括肝功能异常、腹泻、头痛、关节相关征和症状及肌骨骼/结缔组织症状。 HIGHLIGHTS OF PRESCRIBING INFORMATION These HIGHLIGHTS do not include all the information needed to use ULORIC safely and effectively. See full prescribing information for ULORIC. ULORIC (febuxostat) tablet for oral use Initial U.S. Approval: 2009 Dosage and Administration  Special Populations (2.2) 8/2017 Warnings and Precautions  Serious Skin Reactions (5.4) 8/2017 INDICATIONS AND USAGE ULORIC is a 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) DOSAGE 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 a serum uric acid (sUA) less than 6 mg/dL after 2 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) DOSAGE FORMS AND STRENGTHS Tablet: 40 mg, 80 mg. (3) CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine. (4) WARNINGS AND PRECAUTIONS Gout Flare: An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a 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: A 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) ADVERSE 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. DRUG INTERACTIONS Concomitant administration of ULORIC with XO substrate drugs, azathioprine or mercaptopurine could increase plasma concentrations of these drugs resulting in severe toxicity. (7) USE 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) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 8/2017 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ULORIC is a 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. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended 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 a serum uric acid (sUA) less than 6 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)]. 2.2 Special 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 a sUA less than 6 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)]. 2.3 Uric Acid Level Testing for the target serum uric acid level of less than 6 mg/dL may be performed as early as two weeks after initiating ULORIC therapy. 2.4 Gout Flares Gout flares may occur after initiation of ULORIC due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended upon initiation of ULORIC. Prophylactic therapy may be beneficial for up to six months [see CLINICAL STUDIES (14.1)]. If a gout flare occurs during ULORIC treatment, ULORIC need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient [see WARNINGS AND PRECAUTIONS (5.1)]. 3 DOSAGE FORMS AND STRENGTHS 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" 4 CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine or mercaptopurine [see DRUG INTERACTIONS (7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Gout 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)]. 5.2 Cardiovascular Events In the randomized controlled studies, there was a 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)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke. 5.3 Hepatic 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 a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient 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. 5.4 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 [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. 6 ADVERSE REACTIONS 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. 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 Reactions In three randomized, controlled clinical studies (Studies 1, 2 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 1 summarizes adverse reactions reported at a 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 Studies 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 a rate more than 0.5% greater than placebo. Less Common Adverse Reactions In Phase 2 and 3 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-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. Cardiovascular Safety Cardiovascular 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 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (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, a higher rate of APTC events was observed in ULORIC than in patients treated with allopurinol. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ULORIC. 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 DRUG INTERACTIONS 7.1 Xanthine Oxidase Substrate Drugs ULORIC is an XO inhibitor. Based on a drug interaction study in healthy patients, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans [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)]. 7.2 Cytotoxic Chemotherapy Drugs Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy. 7.3 In Vivo Drug Interaction Studies Based on drug interaction studies in healthy patients, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine [see CLINICAL PHARMACOLOGY (12.3)]. Therefore, ULORIC may be used concomitantly with these medications. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited available data with ULORIC 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 ULORIC and any potential adverse effects on the breastfed child from ULORIC 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 in pediatric patients under 18 years of age have not been established. 8.5 Geriatric 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)]. 8.6 Renal 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 a sUA less than 6 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)]. 8.7 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); 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. 10 OVERDOSAGE 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. 11 DESCRIPTION ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S. The chemical structure is: Chemical Structure Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C. ULORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ULORIC, a 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. 12.2 Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations In healthy patients, ULORIC 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 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. 12.3 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 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 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 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 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, 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 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, ULORIC 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. Special Populations Pediatric Use The pharmacokinetics of ULORIC in patients under the age of 18 years have not been studied. Geriatric Use The 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 Impairment In a dedicated phase I 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 Impairment Following 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)]. Gender Following 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. Race No 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 Theophylline Febuxostat is an XO inhibitor. A 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 a 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 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 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 a drug that inhibits or induces one particular enzyme isoform is in general not expected. In Vivo Drug Interaction Studies Theophylline No 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 a 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 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 ULORIC or naproxen when the two drugs are coadministered. Administration of ULORIC (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 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%). Hydrochlorothiazide No 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. Warfarin No 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. Desipramine Coadministration of drugs that are CYP2D6 substrates (such as desipramine) with ULORIC are not expected to require dose adjustment. Febuxostat was shown to be a 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 a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC). 13 NONCLINICAL 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 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 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). 14 CLINICAL STUDIES A serum uric acid level of less than 6 mg/dL is the goal of anti-hyperuricemic therapy and has been established as appropriate for the treatment of gout. 14.1 Management 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 a baseline serum uric acid level ≥8 mg/dL. Study 1 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 1 was six months. Study 2 randomized patients to: placebo, ULORIC 80 mg daily, ULORIC 120 mg daily, ULORIC 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, a 1 year study, randomized patients to: ULORIC 80 mg daily, ULORIC 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 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 1 the duration of prophylaxis was six months; in Study 2 and Study 3 the duration of prophylaxis was eight weeks. The efficacy of ULORIC was also evaluated in a 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 a 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 2 summarizes the demographics and baseline characteristics for the patients enrolled in the studies. Table 2: Patient Demographics and Baseline Characteristics in Study 1, Study 2 and Study 3 Serum Uric Acid Level less than 6 mg/dL at Final Visit ULORIC 80 mg was superior to allopurinol in lowering serum uric acid to less than 6 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 6 mg/dL at the final visit (Table 3). Table 3: Proportion of Patients with Serum Uric Acid Levels less than 6 mg/dL at Final Visit 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. n 76% of ULORIC 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 ULORIC 80 mg than with ULORIC 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 sub-group of patients are shown in Table 4. Table 4: Proportion of Patients with Serum Uric Acid Levels less than 6 mg/dL in Patients with Mild or Moderate Renal Impairment at Final Visit Allopurinol patients (n=145) with estimated Cl cr ≥30 mL/min and Cl cr ≤59 mL/min were dosed at 200 mg daily. 16 HOW 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 Number  Size 64764-918-11  Hospital Unit Dose Pack of 100 Tablets 64764-918-30  Bottle of 30 Tablets 64764-918-90  Bottle of 90 Tablets 64764-918-18  Bottle of 500 Tablets ULORIC 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 Number  Size 64764-677-11  Hospital Unit Dose Pack of 100 Tablets 64764-677-30  Bottle of 30 Tablets 64764-677-13  Bottle of 100 Tablets 64764-677-19  Bottle of 1000 Tablets Protect from light. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. 17 PATIENT 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 a rash, chest pain, shortness of breath or neurologic symptoms suggesting a 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. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=54de10ef-fe5f-4930-b91d-6bbb04c664bd