2015年10月23日，美国食品药品监督管理局（以下简称FDA）批准化疗药Yondelis（trabectedin）用于治疗不可切除的或晚期（转移性）脂肪肉瘤和平滑肌肉瘤，其适应人群是既往接受过蒽环类化疗药物治疗的患者。
据美国国家癌症研究所的报道，软组织肉瘤是癌细胞形成于人体软组织的疾病，人体软组织包括肌肉、肌腱、脂肪、血管、淋巴管、神经、关节周围组织等。软组织肉瘤几乎可形成于人体的任何部位，但最常见于头部、颈部、四肢、躯干和腹部。脂肪肉瘤和平滑肌肉瘤是软组织肉瘤的两种具体类型，前者形成于脂肪细胞，后者形成于平滑肌细胞。
据估计，2014年美国有12,000名软组织肉瘤新增病例
“治疗晚期或转移性软组织肉瘤的难题是患者可得到的有效治疗选择少之又少，”FDA药品评价与研究中心的血液与肿瘤药品办公室主任Richard Pazdur博士说。“化疗药Yondelis的获批为晚期或转移性脂肪肉瘤和平滑肌肉瘤患者提供了一种治疗选择。”
批准日期：2015年10月  公司：Janssen Products, LP
YONDELIS（曲贝替 trabectedin）无菌冻干粉末注射剂，供用于静脉内使用
最初美国批准：2015年
作用机理
曲贝是烷基化药物结合在DNA的小沟鸟嘌呤残基，形成加合物，并导致朝大沟DNA螺旋的弯曲。加合物的形成触发会影响DNA结合蛋白，包括一些转录因子，和DNA修复途径的随后的活性，从而导致细胞周期和最终的细胞死亡的扰动事件的级联。
适应症和用法
YONDELIS是用于治疗晚期或转移性脂肪肉瘤或平滑肌肉瘤谁收到了事先含蒽环类方案治疗表明烷基化药物.
用法用量
在1.5毫克/m2体表面积通过中央静脉行管理作为一个24小时静脉滴注，每3周.
术前用药：地塞米松20毫克静脉，每次输液前30分钟.
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：严重和严重，中性粒细胞减少败血症发生。治疗期间监测中性粒细胞计数。YONDELIS 2级或更高的中性粒细胞减少.
横纹肌溶解症：可能出现横纹肌溶解症;扣压YONDELIS在肌酸磷酸激酶水平严重或危及生命的增加.
肝毒性：可能出现肝毒性。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。扣压YONDELIS患者的左心功能不全.
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，食欲不振，腹泻，血管神经性水肿，呼吸困难，头痛下降。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，AST升高，并增加肌酸磷酸激酶.
要报告疑似不良反应，请联系扬森生物技术公司在1-800-526-7736（1-800-JANSSEN）或FDA电话1-800-FDA-1088或www.fda.gov/medwatch。
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：避免随之而来的强CYP3A诱导.
特殊人群中使用
哺乳期：哺乳期不建议.
包装规格/储存与处理
如何SuppliedYONDELIS在含有1mg曲贝替玻璃小瓶被提供。每个纸箱包含一个小瓶（NDC：59676-610-01）。
储存和HandlingStore YONDELIS瓶在2℃（36ºF至46ºF）冰箱以8℃。
YONDELIS是细胞毒性药。按照适用的特殊处理和处置procedures.1
修订：10/2015
Yondelis(ET-743,Trabectedin for Injection)
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®. 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%), 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 use of 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 administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS®.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472bd78e-be17-4b9d-90f4-9482c3aec9ff