YONDELIS(ET-743, TRABECTEDIN  曲贝替定)POWDER IV (INFUSION)获美国FDA及欧盟为软组织肉瘤和卵巢癌的上市新药。用于包括脂肪肉瘤和平滑肌肉瘤亚型在内的晚期软组织肉瘤 (STS)及卵巢癌患者。这些患者前期曾接受过含一种蒽环类药物的化疗。 处方修改批准日期：2016年7月 公司：强生制药公司 Yondelis（曲贝替 trabectedin）冻干粉注射剂，用于静脉内使用 美国初始批准：2015年 目前的主要变化 剂量和给药方法  07/2016 警告和注意事项  07/2016 作用机理 是一种烷基化药物曲贝替结合在DNA的小沟鸟嘌呤残基，形成加合物和在朝向大沟DNA螺旋的弯曲所致。加合物的形成触发事件可以影响DNA的后续活动结合蛋白，治疗包括一些转录因子，和DNA修复途径的级联，在细胞周期和最终的细胞死亡的扰动所致。 适应症和用法 Yondelis是表明治疗晚期或转移性脂肪肉瘤或平滑肌肉瘤的治疗烷基化药物接受含有世卫组织方案事先蒽环类药物。 用法用量 在1.5毫克/m2体表面积辖为24小时静脉滴注，每3周通过中心静脉导管。 术前用药：地塞米松20毫克静脉，每次输注前30分钟。 肝损伤：管理在0.9毫克/ m2体表面积为24小时静脉滴注，每3周通过中心静脉导管在中度肝功能损害。 剂型和规格 注射：1毫克无菌冻干粉末在单一剂量小瓶。 禁忌症 已知过敏曲贝。 警告和注意事项 中性粒细胞减少败血症：严重和致命的败血症中性粒细胞减少可能会出现。在中性粒细胞计数监测治疗。扣压Yondelis 2级或更高的中性粒细胞减少 横纹肌溶解症：横纹肌溶解症，可能会出现;扣压Yondelis在水平严重或危及生命的肌酸磷酸激酶增加。 肝：肝毒性发生。监控和​​延迟和/​​或如果需要减少剂量。 心肌病可发生严重和致命性心肌病。 Yondelis在患者与扣住左心功能不全。 胚胎 - 胎仔毒性：可引起胎儿造成伤害。潜在风险提醒到胎儿，并使用有效的避孕 不良反应 最常见的（≥20％）的不良反应有恶心，乏力，呕吐，便秘，食欲下降，腹泻，血管神经性水肿，呼吸困难和头痛。最常见（≥5％）3-4级实验室检查异常有：白细胞减少，ALT升高，血小板减少，贫血，增加AST，肌酸磷酸激酶和增加。 药物相互作用 CYP3A酶抑制剂：避免随之而来的强CYP3A酶抑制剂 CYP3A诱导：避免强CYP3A诱导伴随 特殊人群中使用 哺乳期：哺乳期不建议 不要给予YONDELIS给患者带来严重的肝功能损害 修订：7/2016 包装规格 1mg、0.25mg 注：本品目前在美国、德国、瑞士、英国均有销售，采购请注明上市国家 完整处方资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472bd78e-be17-4b9d-90f4-9482c3aec9ff Trabectedin(Yondelis)Ecteinascidin-743-曲贝替冻干粉注射剂 原研厂家：PharmaMar (Orphan Drug), University of Illinois (Originator), Ortho Biotech (Licensee), PharmaMar (Licensee), Zeltia (Licensee) 作用类别：Breast Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Apoptosis Inducers, DNA-Intercalating Drugs 研发状态：Pre-Registered 曲贝替定(Trabectedin，强生制药公司)是首个海洋来源抗肿瘤药，为在海鞘中提取的四氢喹啉类生物碱的半合成品。除了可阻滞肿瘤细胞在G1／G2周期的分化外，还可抑制血管内皮细胞生长因子(VEGF)的分泌及VEGF受体(VEGFR)-1的表达。2004年，其在欧、美已被指定为治疗急性淋巴母细胞白血病、软组织肉瘤和卵巢癌的孤儿药。2007年，EMEA正式批准其用于进展型软组织肉瘤的二线治疗 临床试验获益： 软组织肉瘤：欧盟研究共入组了266名晚期或转移性脂肪肉瘤与晚期或转移性平滑肌肉瘤患者，这些患者先前均接受过蒽环霉素与异环磷酰胺治疗并且治疗失效。研究对比了两组用药剂量，一组每月给药3次，另一组每3周给药1次。结果显示，每3周给药1次的患者平均无疾病进展期为3.8个月，每月给药3次的患者为2.1个月。 美国研究显示，对于转移性或复发性平滑肌肉瘤或脂肪肉瘤，平均而言，Yondelis治疗组患者的无进展生存期约为4.2个月，相比之下，dacarbazine治疗组患者只有1.5个月的无进展生存期。 卵巢癌：研究共入组了672名治疗后卵巢癌复发或疾病进展的患者，试验对比了脂质体阿霉素单药与Yondelis联合脂质体阿霉素，结果显示Yondelis联合脂质体阿霉素更有效，使用联合疗法的患者无疾病进展期为7.3个月，而使用脂质体阿霉素单药的患者无疾病进展期为5.8个月。 YONDELIS® was studied in patients with unresectable or metastatic liposarcoma and leiomyosarcoma who had been treated with a prior anthracycline-containing regimen Important Safety Information CONTRAINDICATIONS — YONDELIS® (trabectedin) is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin. WARNINGS AND PRECAUTIONS Neutropenic sepsis, including fatal cases, can occur. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, was 43% (161/378). Median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months). Median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%). Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS® and periodically throughout the treatment cycle. Withhold YONDELIS® for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS® for life‐ hreatening or prolonged, severe neutropenia in the preceding cycle. Rhabdomyolysis — YONDELIS® can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS®, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS® with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). Median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). Median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS®. Withhold YONDELIS® for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS® for rhabdomyolysis. Hepatotoxicity, including hepatic failure, can occur. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 x ULN were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3‐4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378). Median time to development of Grade 3‐4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3 to 4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months). In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378). ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients. Assess LFTs prior to each administration of YONDELIS® and as clinically indicated based on underlying severity of pre-existing hepatic impairment. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality. Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS® and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS® and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS® and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS® was 5.3 months (range: 26 days to 15.3 months). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS® and at 2- to 3-month intervals thereafter until YONDELIS® is discontinued. Withhold YONDELIS® for LVEF below lower limit of normal. Permanently discontinue YONDELIS® for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks. Extravasation Resulting in Tissue Necrosis — Extravasation of YONDELIS®, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS®. Administer YONDELIS® through a central venous line. Embryofetal Toxicity — Based on its mechanism of action, YONDELIS® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS®. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS®. Adverse Reactions — The most common (≥20%) adverse reactions are nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%), and headache (25%). The most common (≥5%) grades 3‐4 laboratory abnormalities are: neutropenia (43%), increased ALT (31%), thrombocytopenia (21%), anemia (19%), increased AST (17%), and increased creatine phosphokinase (6.4%). DRUG INTERACTIONS Effect of Cytochrome CYP3A Inhibitors — Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS®. Avoid taking grapefruit or grapefruit juice. If a strong CYP3A inhibitor for short‐ erm use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS® infusion, and discontinue it the day prior to the next YONDELIS® infusion. Effect of Cytochrome CYP3A Inducers — Avoid using strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) in patients taking YONDELIS®. 056980-160722