英文药名：ONIVYDE(irinotecan liposome injection，MM-398) 中文药名：注射用伊立替康脂质体 生产厂家：Merrimack Pharmaceuticals, Inc 药品介绍 药品名称：Onivyde（irinotecan liposome injection） 通用名称：伊立替康脂质体 以前的名称：MM-398 ONIVYDE™（伊立替康脂质体 irinotecan liposome）注射液，供静脉使用 美国首次批准：1996 警告： 严重中性粒细胞和严重腹泻查看全部处方信息进行完整的黑框警告 致命的中性粒细胞减少败血症的发生率为0.8％，接受ONIVYDE，严重或危及生命的中性粒细胞减少发热或败血症发生在3％和严重或危及生命的中性粒细胞减少发生在接收ONIVYDE与氟尿嘧啶和亚叶酸结合患者的20％。ONIVYDE的绝对中性粒细胞计数低于1500个/mm3或中性粒细胞减少发热。治疗期间定期监测血细胞数。 严重的腹泻发生在接收ONIVYDE与氟尿嘧啶和亚叶酸结合患者的13％。不要给予ONIVYDE给患者肠梗阻。扣压ONIVYDE为2-4级严重腹泻。辖洛哌丁胺任何程度的后期腹泻辖阿托品，如果没有禁忌，任何严重程度的早期腹泻。 作用机制 伊立替康脂质体注射液是一种拓扑异构酶1抑制剂包封在脂质双层囊泡或脂质体中。拓扑异构酶1通过诱导单链断裂减轻在DNA中的扭转变形。伊立替康及其活性代谢物的SN-38结合可逆的拓扑异构酶1-DNA复合体，并防止再结扎的单链断裂，导致曝光时间依赖双链DNA损伤和细胞死亡。在小鼠中携带人肿瘤异种移植物，伊立替康脂质体施用伊立替康盐酸等效剂量5倍低于伊立替康盐酸达到类似SN-38的肿瘤内照射。 适应症和用法 ONIVYDE是拓扑异构酶抑制剂所指出的，在结合氟尿嘧啶和甲酰四氢叶酸，用于治疗患有以下吉西他滨为基础的治疗疾病进展后胰腺的转移性腺癌的治疗： 使用:ONIVYDE限制没有指示为用于治疗患有胰腺转移性腺癌的治疗单一试剂.用法用量 不要代替ONIVYDE含有盐酸伊立替康等药物。 ONIVYDE的推荐剂量是70毫克/米2静脉输注在90分钟内每两个星期。 ONIVYDE的纯合子患者UGT1A1推荐起始剂量*28是50毫克/米2每两个星期。 没有推荐剂量ONIVYDE的患者的血清胆红素以上的正常上限。 Premedicate与前30分钟ONIVYDE皮质类固醇和抗催吐剂。 剂型和规格 注射剂：43毫克/10毫升单剂量小瓶 禁忌 严重过敏反应到ONIVYDE或伊立替康HCl中。 警告和注意事项 间质性肺病（ILD）：致命ILD中已经发生接收伊立替康盐酸请停止ONIVYDE患者如果ILD诊断. 严重的过敏反应：永久停止ONIVYDE严重过敏反应. 胚胎 - 胎儿毒性：可引起胎儿危害提醒女性的潜在风险生殖潜力的一个胎儿，并使用有效的避孕 不良反应 ONIVYDE:腹泻，疲劳/乏力，呕吐，恶心，最常见的不良反应（≥20％），食欲下降，口腔炎和发热最常见的实验室异常（≥10％3或4级）分别为淋巴细胞和中性粒细胞减少。 要报告疑似不良反应，请联系梅里马克制药公司在1-844-441-6225或FDA电话1-800-FDA-1088或www.fda.gov/medwatch。 药物相互作用 强CYP3A4诱导剂:避免使用强CYP3A4诱导剂如可能替代非酶诱导治疗至少2周前ONIVYDE的开始. 强CYP3A4抑制剂：避免使用强CYP3A4或UGT1A1的抑制剂，如果可能的话，在开始治疗前至少1周停止强CYP3A4抑制剂. 特殊人群中使用 哺乳期：不要母乳喂养. 包装规格/储存与处理 供应 ONIVYDE可在含有43毫克伊立替康的游离碱以4.3毫克/ mL的浓度单剂量小瓶 NDC：69171-398-01 存储和处理 商店ONIVYDE在2℃至8ºC（36°F至46°F）。不要冷冻。避光。 ONIVYDE是细胞毒性药。按照适用的特殊处理和处置程序. U.S. FDA Approves Merrimack's ONIVYDE(TM) (irinotecan liposome injection) In Combination with Fluorouracil and Leucovorin for the Treatment of Metastatic Adenocarcinoma of the Pancreas after Disease Progression Following Gemcitabine-Based Therapy U.S. FDA has approved Merrimack's MACK, -9.06% ONIVYDE [TM]  (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin (LV) for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy on October 22. Earlier on the same day, the Taiwan FDA approved ONIVYDE/5-FU/LV for the same indication. ONIVYDE is not indicated for use as a single agent. "ONIVYDE is the first cancer drug to begin its clinical development in Taiwan and go on to receive regulatory approval by the US FDA," said C. Grace Yeh, Ph.D., President and CEO of PharmaEngine. "We applaud Merrimack for achieving this important milestone and we are pleased to have supported Merrimack in completing the final phase of the development for this new drug application (NDA). We believe that ONIVYDE will become an established therapeutic option for the management of metastatic pancreatic cancer in the foreseeable future."  ONIVYDE (formerly known as MM-398, PEP02, or nal-IRI) is a proprietary liposomal encapsulation of irinotecan, a topoisomerase inhibitor. The NDA for ONIVYDE was based on the results of the international Phase 3 study (NAPOLI-1). ONIVYDE plus 5-FU/LV achieved the study's primary endpoint by demonstrating a clinically and statistically significant improvement in overall survival, as well as demonstrating improvement in progression free survival compared to the control group of patients who received 5-FU/LV alone. The ONIVYDE monotherapy arm did not achieve the primary endpoint and, therefore, is not indicated as a single agent. The most common adverse reactions (≥20%) with ONIVYDE were diarrhea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis and pyrexia and the most common severe laboratory abnormalities (≥10% Grade 3 or 4) were lymphopenia and neutropenia. For additional safety information, please see the Important Safety Information below. This was the first global Phase 3 study in a post-gemcitabine setting to demonstrate a survival benefit in this aggressive disease. The marketing authorization application (MAA) submitted to the European Medicines Agency by Baxalta Incorporated is under review and there are plans for submissions to other countries.  ONIVYDE has orphan drug designation in the US, EU and elsewhere. About Pancreatic Cancer According to the most recent information from World Health Organization (WHO), 330,000 people die of pancreatic cancer per year and pancreatic cancer is the seventh-leading cause of cancer-related death in the world. Metastatic pancreatic cancer is almost uniformly fatal, with an overall survival rate of approximately 6 percent at 5 years worldwide. Currently, patients with metastatic pancreatic cancer who progress after gemcitabine treatment have no set standard of care. About ONIVYDE (MM-398, PEP02, nal-IRI) PharmaEngine licensed the Asian (2003) and European (2005) development, manufacturing and commercialization rights for ONIVYDE from Hermes BioSciences, Inc., South San Francisco, CA. Hermes was acquired by Merrimack Pharmaceuticals, Inc., Cambridge, MA in 2009. After completed preclinical, Phase 1 and 2 clinical studies, PharmaEngine licensed its Asian and European rights, except Taiwan, back to Merrimack in 2011. From 2012 to 2014, Merrimack sponsored the global Phase 3 study in metastatic pancreatic cancer patients who progressed after receiving a gemcitabine-containing regimen. In September 2014, Merrimack licensed ONIVYDE outside of the U.S. and Taiwan to Baxalta Incorporated BXLT, -1.98% formerly Baxter International's BioScience business. IMPORTANT SAFETY INFORMATION INDICATION ONIVYDE™ (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas. WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity. CONTRAINDICATION ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl. WARNING AND PRECAUTIONS Severe Neutropenia ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in one of 117 patients in the ONIVYDE plus fluorouracil/leucovorin (ONIVYDE/5-FU/LV) arm and one of 147 patients receiving ONIVYDE as a single agent.  Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV. In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian [18/33 (55%)] vs White patients [13/73 (18%)]. Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients. Severe Diarrhea ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset >24 hours after chemotherapy) and early-onset diarrhea (onset ≤24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea. In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 late-onset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea. Interstitial Lung Disease (ILD) Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD. Severe Hypersensitivity Reactions Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction. Embryo-Fetal Toxicity Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for one month after ONIVYDE treatment. ADVERSE REACTIONS •The most common (≥20%) adverse reactions in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%, severe 13%, 4 %) [early diarrhea (any 30%, 15%; severe 3%, 0%), late diarrhea (any 43%, 17%; severe 9%, 4%)], fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%). •Of less common (<20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a ≥2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%). •The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%; 0%). •ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early onset diarrhea. Grade 1 or 2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients. •Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV. •The most common serious adverse reactions (≥2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. DRUG INTERACTIONS Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy. USE IN SPECIFIC POPULATIONS Pregnancy and Reproductive Potential Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment. Lactation Advise nursing women not to breastfeed during and for one month after ONIVYDE treatment. Pediatric Safety and effectiveness of ONIVYDE have not been established in pediatric patients. DOSAGE AND ADMINISTRATION The recommended dose of ONIVYDE is 70 mg/m [2] based on irinotecan free base (equivalent to 80 mg/m [2] of irinotecan as the hydrochloride trihydrate) intravenous infusion over 90 minutes every two weeks, administered prior to leucovorin and fluorouracil. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m [2] based on irinotecan free base (equivalent to 60 mg/m [2] of irinotecan as the hydrochloride trihydrate) administered by intravenous infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal.  Pre-medicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3 or 4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to ≤Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of interstitial lung disease. Do not substitute ONIVYDE for other drugs containing irinotecan HCl. Please see full US Prescribing Information for ONIVYDE. 伊立替康脂质体注射液Onivyde(irinotecan liposome injection) 被美国FDA批准用于治疗转移性胰腺癌 Onivyde（伊立替康脂质体注射液）是拓扑异构酶I抑制剂伊立替康表示为胰腺后吉西他滨转移性腺癌的治疗的脂质体制剂。 FDA批准Onivyde的有效性表现在对417例转移性胰腺癌的癌下面吉西他滨为基础的治疗取得了进展的研究。与Onivyde加氟尿嘧啶/亚叶酸钙治疗的患者平均6.1个月住了，相比4.2个月，那些只有氟尿嘧啶/亚叶酸钙治疗。 Onivyde是伊立替康在脂质体制剂的新型封装。 SN-38，伊立替康的活性代谢物，具有抑制拓扑异构酶I（参与DNA转录和复制必需酶）和促进细胞死亡。