近日，FDA批准Xtandi（enzalutamide）扩大治疗非转移性去势抵抗性前列腺癌（CRPC）。本品为每日一次的雄激素受体抑制剂，成为美国批准的非转移性和转移性CRPC的第一种口服型治疗药物。
批准日期：2018年7月13日 公司：辉瑞和安斯泰来
XTANDI（恩杂鲁胺[enzalutamide]）胶囊，用于口服
首次美国批准：2012
近期重大变化
适应症及用法：7/2018
剂量和给药，
重要行政指导：7/2018
禁忌症：7/2018
警告和预防措施：7/2018
警告和注意事项，超敏反应：7/2018
警告和注意事项，缺血性心脏病：7/2018
警告和预防措施，Falls和裂缝：7/2018
警告和预防措施，胚胎胎儿毒性：7/2018
作用机理
恩他鲁胺是雄激素受体抑制剂，其作用于雄激素受体信号通路的不同步骤。恩扎鲁胺已被证明竞争性地抑制雄激素与雄激素受体的结合，并因此抑制雄激素受体的核移位及其与DNA的相互作用。一个主要代谢物，N-去甲基泽兰酰胺，表现出类似的体外活性Zealutut酰胺。在异种小鼠前列腺癌移植模型中，恩扎鲁胺在体外抑制了前列腺癌细胞的增殖和诱导细胞死亡，并降低了肿瘤体积。
适应症及用法
XTANDI是一种雄激素受体抑制剂，用于治疗去势抗性前列腺癌患者。
剂量与给药
XTANDI 160mg（四40mg胶囊）每日口服1次。全脂胶囊。XTANDI可以携带或不带食物。
接受XTANDI的患者也应同时接受促性腺激素释放激素（GnRH）类似物或应进行双侧睾丸切除术。
剂型和强度
40mg胶囊
禁忌症
没有。
警告和注意事项
在接受XTANDI的患者中有0.4%发生癫痫发作。在易感因素患者中，2.2%的患者有癫痫发作。在治疗期间发生癫痫发作的患者永久停止XTANDI。
后部可逆性脑病综合征（PRES）：停止XTANDI。
超敏反应：停止XTANDI。
缺血性心脏病：优化心血管危险因素的管理。停止XTANDI为3-4事件。
在接受XTANDI的患者中分别发生了10%和8%的跌倒和骨折。评估患者的骨折和跌倒风险，并根据既定指导方针治疗骨靶向剂。
胎儿胚胎毒性：XTANDI可引起胎儿损伤和妊娠损失。建议男性具有生殖潜能的女性使用有效的避孕方法。
不良反应
XTANDI患者出现的最常见的不良反应（10%以上）为乏力/乏力、食欲减退、潮热、关节痛、头晕/眩晕、高血压、头痛和体重下降。
为了报告可能的不良反应，请联系Astellas Pharma US Inc.在1-800-727-7003或FDA 1-800-FDA-1088或WWW.FDA.GOV/MEDWATCH。
药物相互作用
避免强的CYP2C8抑制剂，因为它们可以增加血浆对XTANDI的暴露。如果联合用药是必要的，减少XTANDI的剂量。
避免强CYP3A4诱导剂，因为它们可以降低血浆暴露于XTANDI。如果联合用药是必要的，增加XTANDI的剂量。
避免CYP3A4、CYP2C9和CYP2C19底物具有狭窄的治疗指数，因为XTANDI可能降低这些药物的血浆暴露。如果XTANDI与华法林（CY2C9底物）联合使用，则进行额外的INR监测。
包装供应/储存和搬运
XTANDI(enzalutamide)40mg胶囊以白色至灰白色长圆形软明胶胶囊的形式提供，用黑色墨水用ENZ压印。XTANDI胶囊有以下包装尺寸：
120瓶胶囊（NDC 04690125-99）
建议储存：XTANDI胶囊在20℃至25℃（68°F至77°F）干燥处储存，并保持容器密闭。允许从15°C到30°C（59°F到86°F）的偏移。
XTANDI不应由患者及其护理人员以外的人处理，尤其是怀孕或可能怀孕的妇女。不要溶解或打开胶囊。
XTANDI(enzalutamide)capsules
XTANDI(enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
Important Safety Information
Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.
Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Permanently discontinue XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES)  In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.
Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from the two placebo-controlled 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. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.
In the placebo-controlled study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.
Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).
Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.
Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.
Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. 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.
Drug Interactions
Effect of Other Drugs on XTANDI  Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.
Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.
Effect of XTANDI on Other Drugs  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 .
https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf