英文药名：Opdivo(Nivolumab Injection) 中文药名：纳武单抗注射剂 生产厂家：百时美施贵宝 药品简介 美国FDA批准Opdivo(nivolumab)新适应症,扩展治疗晚期肾细胞癌、转移性黑色素瘤、转移性非小细胞肺癌、霍奇金淋巴瘤的有疗效PD-1药物 OPDIVO（nivolumab）注射剂，用于静脉内使用 最初美国批准：2014年 目前的主要变化 适应证和用法  05/2016 用法与用量  05/2016 警告和注意事项  05/2016 作用机理 结合PD-1的配体PD-L1和PD-L2的，要在T细胞中发现的PD-1受体，抑制T细胞增殖和细胞因子产生。 PD-1配体的上调发生在某些肿瘤，并通过该通路信令可以向抑制肿瘤的活性T细胞免疫监视。 Nivolumab是人免疫球蛋白G4（IgG4的）的单克隆抗体结合至该PD-1受体并阻止其与PD-L1和PD-L2相互作用，释放的免疫反应的PD-1途径介导的抑制，包括抗肿瘤免疫反应。在同系小鼠的肿瘤模型中，阻断PD-1的活性下降导致肿瘤生长。 合并nivolumab（抗PD-1）与易普利姆玛（抗CTLA-4）介导的抑制效果增强的T细胞的功能，比任一抗体的单独的影响更大，并且在转移性黑素瘤改进的抗肿瘤反应的结果。在鼠的同源肿瘤模型，PD-1和CTLA-4的双重阻断导致增加的抗肿瘤活性。 适应症和用法 OPDIVO是一个程序性死亡受体-1（PD-1）的患者治疗表明阻断抗体： •BRAF V600野生型不能切除或转移性黑素瘤，作为单一药剂。 •BRAF V600突变阳性不能切除或转移性黑素瘤，作为单一药剂。这个指示下，基于无进展生存期加速审批核准。这个指示继续批准可不经审核的临床益处描述在验证试验队伍。 •不能手术切除或转移性黑色素瘤，与易普利姆玛组合。这个指示下，基于无进展生存期加速审批核准。这个指示继续批准可不经审核的临床益处描述在验证试验队伍。 •或铂类化疗后转移性非小细胞肺癌和进展。患者的EGFR或ALK基因组肿瘤像差应具有对之前接收OPDIVO这些像差FDA批准的治疗疾病的进展。 •谁已经接受过抗血管生成治疗晚期肾细胞癌。 •已复发或自体造血干细胞移植（HSCT）和移植后期brentuximab vedotin进展后古典霍奇金淋巴瘤。该指示是基于总缓解率下的加速审批核准。这个指示继续批准可不经审核的临床获益描述验证试验队伍。 用法用量 管理作为一个静脉滴注60分钟。 •不能手术切除或转移性黑色素瘤 •OPDIVO 3毫克/公斤，每2个星期。 •OPDIVO与易普利姆玛：OPDIVO 1毫克/千克，接着易普利姆玛在同一天，每3周4次，然后OPDIVO 3毫克/公斤，每2个星期。 •转移性非小细胞肺癌 •OPDIVO 3毫克/公斤，每2个星期。 •晚期肾细胞癌 •OPDIVO 3毫克/公斤，每2个星期。 •经典霍奇金淋巴瘤 •OPDIVO 3毫克/公斤，每2个星期。 剂型和规格 注射：40毫克/ 4毫升和100毫克/在单剂量小瓶10毫升溶液。 禁忌症 没有。 警告和注意事项 •免疫介导性肺炎：暂停对中度和永久停止对严重或危及生命的肺炎。 •免疫介导性结肠炎：当为中度或重度单药给予永久停止对危及生命的结肠炎扣压OPDIVO。当易普利姆玛给予适度和永久停止对严重或危及生命的结肠炎扣压OPDIVO。 •免疫介导性肝炎：监测肝功能变化。扣压中度和永久停止对严重或危及生命的转氨酶或总胆红素升高。 •免疫介导的内分泌疾病：中度或重度和永久性停止对危及生命垂体炎。扣压中度和永久停止对严重或危及生命的肾上腺皮质功能不全。监测甲状腺功能变化。根据需要启动甲状腺激素替代。监测血糖。扣压严重和永久性停止对危及生命的高血糖。 •免疫介导性肾炎和肾功能不全：监测肾功能变化。扣留中度或重度和永久性停止对危及生命的血肌酐升高。 •免疫介导的皮疹：暂停严重和永久性停止对威胁生命的皮疹。 •免疫介导性脑炎：监测在神经功能的变化。扣压新发中度至严重的神经系统体征或症状，并永久停止对免疫介导性脑炎。 •输液反应：请停止OPDIVO严重和危及生命的输液反应。中断或减缓输液患者的比率轻度或中度输液反应。 •OPDIVO后异体移植的并发症：监测超急性移植物抗宿主病（GVHD），3-4级急性GVHD，激素需要发热综合征，肝小静脉闭塞病，和其他免疫介导的不良反应。发生移植相关死亡率。 •胚胎-胎儿毒性：可引起胎儿造成伤害。告知潜在风险胎儿和使用有效的避孕措施。 不良反应 在黑色素瘤患者最常见的不良反应（≥20％），分别为： •OPDIVO单药：乏力，皮疹，肌肉疼痛，皮肤瘙痒，腹泻，恶心。 •OPDIVO与易普利姆玛：乏力，皮疹，腹泻，恶心，发热，呕吐和呼吸困难。 转移性非小细胞肺癌最常见的不良反应（≥20％）为乏力，肌肉疼痛，食欲下降，咳嗽，便秘等。 在晚期肾细胞癌最常见的不良反应（≥20％）分别为：虚寒条件，咳嗽，恶心，皮疹，呼吸困难，腹泻，便秘，食欲减退，腰痛，关节痛。 患者的经典霍奇金淋巴瘤最常见的不良反应（≥20％）为：乏力，上呼吸道感染，发热，腹泻和咳嗽。 特殊人群中使用 哺乳期：哺乳请停止。 包装供应 OPDIVO 10MG/ML 4ML SDV 1/EA NIVOLUMAB  BRISTOL-MYERS SQUIBB COMPANY  00003-3772-11   OPDIVO 10MG/ML 10ML SDV 1/EA  NIVOLUMAB  BRISTOL-MYERS SQUIBB COMPANY  00003-3774-12   Opdivo (Nivolumab Injection) Opdivo (nivolumab) Demonstrates Superior Overall Survival in a Phase 3 Trial Compared to Standard of Care in Patients with Previously Treated Advanced Renal Cell Carcinoma Patients treated with Opdivo achieved a median overall survival of 25 months; greater than 5 month improvement over everolimus, a current standard of care in this patient population PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced results from CheckMate -025, a Phase 3 study comparing Opdivo to everolimus in advanced renal cell carcinoma (RCC) after prior anti-angiogenic treatment, showing a significant overall survival (OS) benefit for Opdivo. In the trial, Opdivo demonstrated a median OS benefit of 25 months compared to 19.6 months for everolimus. Clinical benefit for Opdivo was observed regardless of level of PD-L1 expression. The safety profile shown in CheckMate -025 is consistent with previously reported Opdivo trials. These data will be presented Saturday, September 26, during the 2015 European Cancer Congress (ECC2015) at a Presidential Session from 4:10 - 4:20 PM CEST (Late Breaking Abstract #3). The results were also featured during the ECC2015 press program on September 25 and published in The New England Journal of Medicine (NEJM), representing the ninth publication in the NEJM for Opdivo. “Patients with advanced renal cell carcinoma are in need of new treatment approaches that provide improved survival, safety and tolerability,” said Robert J. Motzer, M.D., medical oncologist, Memorial Sloan Kettering Cancer Center and lead author of the NEJM publication. “This is the first Phase 3 study to demonstrate the efficacy of an immune checkpoint inhibitor in advanced renal cell carcinoma. The results show meaningful clinical benefit with Opdivo treatment, producing a significant overall survival advantage and greater number of objective responses compared to everolimus, a current standard of care in the treatment of advanced kidney cancer.” Approximately 30% of patients with RCC, a common type of kidney cancer in adults, present with metastatic or advanced disease at diagnosis. Despite multiple available treatment approaches for advanced RCC, available second-line therapies are associated with limited OS, and significant toxicities and limitations in tolerability, with the majority of current treatment options providing modest progression-free survival benefit. “We continue to see the potential of our Immuno-Oncology agent, Opdivo, to provide meaningful improvement in multiple tumor types over current standards of care in terms of overall survival,” said Michael Giordano, senior vice president, head of Development, Oncology. “Results of CheckMate -025 show that Opdivo has a significant survival advantage over standard of care in patients with advanced kidney cancer who have progressed following prior treatment. These data also reinforce our Immuno-Oncology research goal to provide patients with long-term survival, and brings further confidence to the approach taken in our broader RCC development program, including the combination of Immuno-Oncology agents.” CheckMate -025 was stopped in July because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its primary endpoint, demonstrating superior OS in patients receiving Opdivo compared to the control arm. Opdivo was granted Breakthrough Therapy Designation for advanced RCC by the U.S. Food and Drug Administration based on results from this trial and the clinical need for additional treatment approaches for RCC. About CheckMate -025 CheckMate -025 is a Phase 3 randomized, open-label study of Opdivo versus everolimus in previously treated patients with advanced clear-cell RCC after prior anti-angiogenic treatment. Patients were randomized to receive Opdivo (n=410) 3 mg/kg intravenously every two weeks or everolimus (n=411) 10 mg orally once daily. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), OS by PD-L1 expression, and incidence of adverse events (AEs). Results from CheckMate -025 mark the first and only Phase 3 study to demonstrate a significant survival advantage in previously treated patients with advanced RCC versus standard of care. Patients treated with Opdivo in this study achieved a median OS of 25 months for Opdivo and 19.6 months for everolimus (hazard ratio: 0.73; [98.5% CI, 0.57-0.93; p=0.0018]), with comparable OS benefit seen across PD-L1 expression levels. In addition to improving overall survival, Opdivo demonstrated a superior ORR of 25% versus 5% for everolimus (p<0.0001), with one out of four patients experiencing a response. Seventeen percent of Opdivo and 7% of everolimus patients remain on treatment with a minimum follow-up of 14 months. The safety profile of Opdivo in CheckMate -025 was consistent with prior studies and favorable versus everolimus. Fewer grade 3-4 treatment-related AEs occurred with Opdivo (19%) compared to everolimus (37%). Any grade treatment-related AEs occurred in 79% of patients treated with Opdivo and 88% of patients treated with everolimus. The most frequent treatment-related AEs were fatigue (33%), pruritus (14%), and nausea (14%) in the Opdivo arm and fatigue (34%) and stomatitis (30%) in the everolimus arm. About Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. RCC is approximately twice as common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally, the five-year survival rate for those diagnosed with advanced kidney cancer is 12.1%. About Opdivo Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide. Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the FDA as a monotherapy in two cancer indications. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous (SQ) non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. On July 20, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic SQ NSCLC after prior chemotherapy. IMPORTANT SAFETY INFORMATION Immune-Mediated Pneumonitis •Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2. Immune-Mediated Colitis •In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated Hepatitis •In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction •In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO. Immune-Mediated Hypothyroidism and Hyperthyroidism •In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Other Immune-Mediated Adverse Reactions •In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone replacement therapy. Embryofetal Toxicity •Based on its mechanism of action, OPDIVO 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 treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO. Lactation •It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment. Serious Adverse Reactions •In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. •In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Common Adverse Reactions •The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%). Please see U.S. Full Prescribing Information for OPDIVO. Immuno-Oncology at Bristol-Myers Squibb Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease. To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as Immuno-Oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining Immuno-Oncology agents that target different pathways in the treatment of cancer. Bristol-Myers Squibb is committed to advancing the science of Immuno-Oncology, with the goal of changing survival expectations and the way patients live with cancer. About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration In 2011, through a collaboration with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono Pharmaceutical further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394 PD-1抑制剂OPDIVO(nivolumab)injection已获批扩展治疗晚期肾细胞癌 2015年11月23日，美国食品和药物监管局（FDA）批准了Nivolumab（商品名Opdivo，美国施贵宝公司生产），用于治疗晚期肾细胞癌。这些患者先前接受过抗 血管生成药物治疗，但病情仍有恶化。 Nivolumab是一种结合于PD-1受体的单克隆抗体，通过阻断PD-1和PD-L1及PD-L2间的相互作用， 从而阻断PD-1通路介导的免疫抑制反应，包括抗肿瘤免疫反应。 该批准是基于一项随机临床试验的有效结果。晚期肾细胞癌患者被随机分配到Nivolumab组或依维莫司（Everolimus）组。 试验结果显示，Nivolumab优于依维莫司。Nivolumab组的平均总生存期为25个月，而依维莫司组的则为19.6个月。Nivolumab组的有效率为21.5%，而依维莫司组的则为3.9%。Nivolumab组的平均有效期为23个月，而依维莫司组的则为13.7个月。 Nivolumab最常见的副作用（发生率大于或等于20%）为虚弱、咳嗽、恶心、皮疹、呼吸困难、腹泻、便秘、食欲下降、背和关节疼痛。 最常见的化验异常（发生率大于或等于30％）为肌酐升高、淋巴细胞减少、贫血、肝功能异常、低钠、甘油三酯增高和高钾。47%的患者发生严重副作用，最常见的严重副作用（发生率大于或等于2％）包括急性肾功能损伤、胸腔积液、肺炎、腹泻和高血钙。免疫介导的副作用包括肺炎、肠炎、肝炎、肾炎、内分泌病和脑炎。 Nivolumab的推荐剂量为3毫克/每公斤体重，60分钟静脉点滴，每两周一次。