新一类型晚期前列腺癌新药Xtandi被美国FDA批准上市 近日，美国食品和药物管理局(FDA)批准Xtandi(enzalutamide)用于治疗晚期转移性或复发的去势抵抗性前列腺癌患者，和为了减少睾酮已进行了药物或手术治疗的患者。 Xtandi通过FDA的优先审查程序获准，适用于抗肿瘤药多西他赛治疗后的前列腺癌患者，Xtandi是被证实可延长患者生命的治疗该疾病的最新方法。 一项纳入1199名既往接受多西他赛治疗的转移性去势抵抗性前列腺癌患者的临床试验评估了Xtandi的安全性和有效性。该研究旨在评估接受Xtandi治疗与接受安慰剂(糖丸)治疗的男性患者的总生存期(至死亡前的时间长度)。结果显示，接受Xtandi治疗患者的中位总生存期为18.4个月，接受安慰剂治疗患者为13.6个月。 临床试验中观察到的最常见不良反应为虚弱或疲劳，腰痛，腹泻，关节痛，潮热，组织肿胀、肌肉骨骼疼痛，头晕、头痛，上、下呼吸道感染，脊髓压迫和马尾神经综合征，肌无力，失眠，尿血、刺痛感、焦虑和高血压。 约1%接受Xtandi治疗的患者出现癫痫。该研究中的癫痫患者停止了Xtandi治疗。Xtandi临床研究排除了有癫痫史、有意识丧失的潜在脑损伤、过去12个月内有暂时性大脑供血减少、卒中、脑转移瘤、脑部动脉和静脉的异常连接或服用可能会降低癫痫发作阈值药物的患者，这些患者应用Xtandi的安全性未知 批准日期：2012年8月31日；公司：Medivation Inc.和Astellas Pharma Inc 适应证和用途 XTANDI是一种雄激素受体抑制剂适用于治疗有转移去势耐受前列腺癌既往曾接受多西他奇[docetaxel]患者。 剂量和给药方法 XTANDI 160mg(四40mg胶囊)口服给药每天1次。吞服整个胶囊。XTANDI可与或无食物服用。 剂型和规格 胶囊40mg HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XTANDI ® safely and effectively. See full prescribing information for XTANDI. XTANDI ® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 RECENT MAJOR CHANGES Indications and Usage (1)                                  09/2014 Contraindications (4)                                         09/2014 Warnings and Precautions (5.1)                         09/2014 INDICATIONS AND USAGE XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer. (1)  DOSAGE AND ADMINISTRATION XTANDI 160 mg (four 40 mg capsules) administered orally once daily. Swallow capsules whole. XTANDI can be taken with or without food. (2.1)  DOSAGE FORMS AND STRENGTHS Capsule 40mg (3)  CONTRAINDICATIONS Pregnancy (4, 8.1) WARNINGS AND PRECAUTIONS Seizure occurred in 0.9% of patients receiving XTANDI who previously received docetaxel and in 0.1% of patients who were chemotherapy-naive. There is no clinical trial experience with XTANDI in patients who have had a seizure. Permanently discontinue XTANDI in patients who develop a seizure during treatment. (5.1) ADVERSE REACTIONS The most common adverse reactions (≥ 10%) are asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. ( 2.2, 7.1) • Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the plasma exposure to XTANDI. ( 7.1, 7.2) • Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. ( 7.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 9/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of XTANDI is 160 mg (four 40 mg capsules) administered orally once daily. XTANDI can be taken with or without food [see Clinical Pharmacology (12.3)]. Swallow capsules whole. Do not chew, dissolve, or open the capsules. 2.2 Dose Modifications If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted. Concomitant Strong CYP2C8 Inhibitors The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the XTANDI dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].  3 DOSAGE FORMS AND STRENGTHS XTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. 4 CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.  6 ADVERSE REACTIONS The following is discussed in more detail in other sections of the labeling: • Seizure [see Warnings and Precautions (5.1)] 6.1 Clinical Trial 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. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in Study 1 XTANDI N = 800 Placebo N = 399 Grade 1-4a (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) General Disorders     Asthenic Conditionsb 50.6 9.0 44.4 9.3     Peripheral Edema 15.4 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders     Back Pain 26.4 5.3 24.3 4.0     Arthralgia 20.5 2.5 17.3 1.8     Musculoskeletal Pain 15.0 1.3 11.5 0.3     Muscular Weakness 9.8 1.5 6.8 1.8     Musculoskeletal Stiffness 2.6 0.3 0.3 0.0 Gastrointestinal Disorders     Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders     Hot Flush 20.3 0.0 10.3 0.0     Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders     Headache 12.1 0.9 5.5 0.0     Dizzinessc 9.5 0.5 7.5 0.5     Spinal Cord Compression     and Cauda Equina Syndrome 7.4 6.6 4.5 3.8     Paresthesia 6.6 0.0 4.5 0.0     Mental Impairment Disordersd 4.3 0.3 1.8 0.0     Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations     Upper Respiratory Tract     Infectione 10.9 0.0 6.5 0.3     Lower Respiratory Tract And     Lung Infectionf 8.5 2.4 4.8 1.3 Psychiatric Disorders     Insomnia 8.8 0.0 6.0 0.5     Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders     Hematuria 6.9 1.8 4.5 1.0     Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications     Fall 4.6 0.3 1.3 0.0     Non-pathologic Fractures 4.0 1.4 0.8 0.3 Skin And Subcutaneous Tissue Disorders     Pruritus 3.8 0.0 1.3 0.0     Dry Skin 3.5 0.0 1.3 0.0 Respiratory Disorders     Epistaxis 3.3 0.1 1.3 0.3 a    CTCAE v4 b    Includes asthenia and fatigue. c    Includes dizziness and vertigo. d    Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e    Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f    Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in Study 2  XTANDI N = 871 Placebo N = 844 Grade 1-4a (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) General Disorders     Asthenic Conditionsb 46.9 3.4 33.0 2.8     Peripheral Edema 11.5 0.2 8.2 0.4 Musculoskeletal And Connective Tissue Disorders     Back Pain 28.6 2.5 22.4 3.0     Arthralgia 21.4 1.6 16.1 1.1 Gastrointestinal Disorders     Constipation 23.2 0.7 17.3 0.4     Diarrhea 16.8 0.3 14.3 0.4 Vascular Disorders     Hot Flush 18.0 0.1 7.8 0.0     Hypertension 14.2 7.2 4.1 2.3 Nervous System Disorders     Dizzinessc 11.3 0.3 7.1 0.0     Headache 11.0 0.2 7.0 0.4     Dysgeusia 7.6 0.1 3.7 0.0     Mental Impairment Disordersd 5.7 0.0 1.3 0.1     Restless Legs Syndrome 2.1 0.1 0.4 0.0 Respiratory Disorders     Dyspneae 11.0 0.6 8.5 0.6 Infections And Infestations     Upper Respiratory Tract     Infectionf 16.4 0.0 10.5 0.0     Lower Respiratory Tract And     Lung Infectiong 7.9 1.5 4.7 1.1 Psychiatric Disorders     Insomnia 8.2 0.1 5.7 0.0 Renal And Urinary Disorders     Hematuria 8.8 1.3 5.8 1.3 Injury, Poisoning And Procedural Complications     Fall 12.7 1.6 5.3 0.7     Non-Pathological Fracture 8.8 2.1 3.0 1.1 Metabolism and Nutrition Disorders     Decreased Appetite 18.9 0.3 16.4 0.7 Investigations     Weight Decreased 12.4 0.8 8.5 0.2 Reproductive System and Breast disorders     Gynecomastia 3.4 0.0 1.4 0.0 a    CTCAE v4 b    Includes asthenia and fatigue. c    Includes dizziness and vertigo. d    Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e    Includes dyspnea, exertional dyspnea, and dyspnea at rest. f    Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g    Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. 7 DRUG INTERACTIONS 7.1 Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co‑administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)]. 7.3 Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4)]. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). 8.3 Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. 8.5 Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. 8.7 Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].  10 OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. 11 DESCRIPTION Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. The structural formula is: Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model. 12.3 Pharmacokinetics The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption. Absorption Following oral administration (XTANDI 160 mg daily) in patients with metastatic CRPC, the median time to reach maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively. With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg. A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1. Distribution and Protein Binding The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro, there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations. Metabolism  Following single oral administration of 14C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14C-AUC0-inf. In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro, N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5. Elimination Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of 14C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide). The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h). The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days. Pharmacokinetics in Special Populations Renal Impairment: A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient [see Use in Specific Populations (8.6)]. Hepatic Impairment: The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N = 8, Child-Pugh B) hepatic impairment. XTANDI was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7)]. Body Weight and Age: Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalutamide. Gender: The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated. Race: The majority of XTANDI-treated patients in the randomized clinical trials were Caucasian (85%). Based on pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no clinically relevant differences in exposure between Japanese and Caucasians. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races.  Drug Interactions Effect of Other Drugs on XTANDI: In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on Cmax. The results are summarized in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.1)]. In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax. The results are summarized in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.2)]. The effects of CYP2C8 and CYP3A4 inducers on the exposure of XTANDI have not been evaluated in vivo. Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI PK parameters (Cmax and AUC0-inf) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect trial, where they are for enzalutamide alone. *See Dosage and Administration (2.2). Effect of XTANDI on Other Drugs: In an in vivo phenotypic cocktail drug-drug interaction trial in patients with metastatic CRPC, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, CYP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (following at least 55 days of dosing at 160 mg daily). The results are summarized in Figure 2. Results showed that in vivo, at steady state, XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer [see Drug Interactions (7.3)]. XTANDI did not cause clinically meaningful changes in exposure to the CYP2C8 substrate. Figure 2. Effect of XTANDI on Other Drugs *See Drug Interactions (7.3). In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that XTANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful effect on CYP2C8 (see Figure 2). In vitro, enzalutamide caused time-dependent inhibition of CYP1A2. In vitro studies showed that enzalutamide induces CYP2B6 and CYP3A4 and does not induce CYP1A2 at therapeutically relevant concentrations. In vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In vitro, enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carboxylic acid metabolite is not. In vitro, enzalutamide and N-desmethyl enzalutamide do not appear to be substrates of human breast cancer resistance protein (BCRP); however, enzalutamide and N-desmethyl enzalutamide are inhibitors of human BCRP at clinically relevant concentrations. 12.6 Cardiac Electrophysiology The effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with XTANDI and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). 14 CLINICAL STUDIES The efficacy and safety of XTANDI in patients with metastatic CRPC were demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. All patients continued on GnRH therapy or had prior bilateral orchiectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy A total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N=800) or placebo orally once daily (N=399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible [see Warnings and Precautions (5.1)]. The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the XTANDI arm compared to patients on the placebo arm (Table 3 and Figure 3). Table 3. Overall Survival of Patients Treated with Either XTANDI or Placebo in Study 1 XTANDI N = 800 Placebo N = 399 Number of Deaths (%) 308 (38.5%) 212 (53.1%) Median Survival (months) (95% CI) 18.4 (17.3, NR) 13.6 (11.3, 15.8) P-valuea < 0.0001 Hazard Ratio (95% CI)b 0.63 (0.53, 0.75) a) P-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI-SF score < 4 vs. ≥ 4) b) Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors XTANDI NR denotes “not reached”. Figure 3. Kaplan-Meier Overall Survival Curves in Study 1 Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer In Study 2, 1717 chemotherapy-naive patients were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N=872) or placebo orally once daily (N=845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression. Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the XTANDI arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons. A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with XTANDI compared to those treated with placebo (Table 4, Figure 4). Forty percent of XTANDI-treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival. Table 4. Overall Survival of Patients Treated with Either XTANDI or Placebo in Study 2  XTANDI N = 872 Placebo N = 845 Pre-specified Interim Analysis     Number of Deaths (%) 241 (28%) 299 (35%)     Median Survival (months) (95% CI) 32.4 (30.1, NR) 30.2 (28.0, NR)     P-valuea < 0.0001     Hazard Ratio (95% CI)b 0.71 (0.60, 0.84) a) P-value is derived from an unstratified log-rank test b) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio <1 favors XTANDI NR denotes “not reached”. Figure 4. Kaplan-Meier Overall Survival Curves in Study 2 A statistically significant improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with placebo (Table 5, Figure 5). Table 5. Radiographic Progression-free Survival of Patients Treated with Either XTANDI or Placebo in Study 2  XTANDI N = 832 Placebo N = 801 Number of Progression or Deaths (%) 118 (14%) 320 (40%) Median rPFS (months) (95% CI) NR (13.8, NR) 3.7 (3.6, 4.6) P-valuea < 0.0001 Hazard Ratio (95% CI)b 0.17 (0.14, 0.21) a) P-value is derived from an unstratified log-rank test b) Hazard Ratio is derived from an unstratified proportional hazards model. Hazard ratio <1 favors XTANDI NR denotes “not reached”. Note: As of the cutoff date for the rPFS analysis, 1633 patients had been randomized. Figure 5. Kaplan-Meier Curves for Duration of Radiographic Progression-free Survival in Study 2 Time to initiation of cytotoxic chemotherapy was prolonged after XTANDI treatment, with a median of 28.0 months for patients on the XTANDI arm versus a median of 10.8 months for patients on the placebo arm [HR=0.35 (95% CI: 0.30, 0.40), p < 0.0001)]. The median time to first skeletal‑related event was 31.1 months for patients on the XTANDI arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. A skeletal‑related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. 16 HOW SUPPLIED/STORAGE AND HANDLING • XTANDI (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. XTANDI capsules are available in the following package sizes: • Bottles of 120 capsules (NDC 0469-0125-99) Recommended storage: Store XTANDI capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). • Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. • Inform patients receiving GnRH therapy that they need to maintain this treatment during the course of treatment with XTANDI. • Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their physician right away if they have loss of consciousness or seizure. • Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. • Apprise patients of the most common side effects associated with XTANDI: asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Inform patients that XTANDI may cause infections, falls and fall-related injuries, and hypertension. • Inform patients that XTANDI can be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI. 2014年5月6日,FDA已授予前列腺癌药物恩杂鲁胺Xtandi（Enzalutamide）补充新药申请（sNDA）优先审查资格。该药sNDA的提交，旨在扩大恩杂鲁胺Xtandi的适应症，用于既往未接受化疗的转移性去势性前列腺癌（mCRPC）男性患者的治疗。 恩杂鲁胺(Enzalutamide, Xtandi) 属于一类名为雄性激素抑制剂的新药，旨在干扰睾酮结合前列腺癌细胞的能力。睾酮是一种男性激素，能够激化前列腺癌细胞的生长。2011年，FDA批准了强 生（JNJ）的前列腺癌药物Zytiga，该药旨在癌细胞内发挥作用，阻断睾酮的产生。 --------------------------------------------------------------- 产地国家：美国 原产地英文商品名: Xtandi 40mg/cap 120caps/box 原产地英文药品名: ESCITALOPRAM 中文参考商品译名: Xtandi 40毫克/胶囊 120胶囊/盒 中文参考药品译名: 生产厂家中文参考译名: 恩杂鲁胺 安斯泰来 生产厂家英文名: ASTELLAS --------------------------------------------------------------- 产地国家：德国 原产地英文商品名: Xtandi 40mg/cap 112caps/box 原产地英文药品名: ESCITALOPRAM 中文参考商品译名: Xtandi 40毫克/胶囊 112胶囊/盒 中文参考药品译名: 生产厂家中文参考译名: 恩杂鲁胺 安斯泰来 生产厂家英文名: ASTELLAS --------------------------------------------------------------- 产地国家：英国 原产地英文商品名: Xtandi 40mg/cap 112caps/box 原产地英文药品名: ESCITALOPRAM 中文参考商品译名: Xtandi 40毫克/胶囊 112胶囊/盒 中文参考药品译名: 生产厂家中文参考译名: 恩杂鲁胺 安斯泰来 生产厂家英文名: ASTELLAS --------------------------------------------------------------- 产地国家：法国 原产地英文商品名: Xtandi 40mg/cap 112caps/box 原产地英文药品名: ESCITALOPRAM 中文参考商品译名: Xtandi 40毫克/胶囊 112胶囊/盒 中文参考药品译名: 生产厂家中文参考译名: 恩杂鲁胺 安斯泰来 生产厂家英文名: ASTELLAS --------------------------------------------------------------- 产地国家：日本 原产地英文商品名: Xtandi 40mg/cap 56caps/box 原产地英文药品名: ESCITALOPRAM 中文参考商品译名: Xtandi 40毫克/胶囊 56胶囊/盒 中文参考药品译名: 生产厂家中文参考译名: 恩杂鲁胺 安斯泰来 生产厂家英文名: ASTELLAS