Keytruda(pembrolizumab，(MK-3475)中文药名：派姆单抗注射冻干粉)被欧洲及美国(FDA)批准的首例PD-1单抗，为治疗不可切除的或转移性黑色素瘤和晚期非小细胞肺癌 第一个PD-1阻断药接受监管局批准,授权加速批准。 转移性黑色素瘤批准日期：2014年9月4日；非小细胞肺癌批准日期：2015年10月2日 公司：Merck & Co.，Inc. 注射用KEYTRUDA®(pembrolizumab)为静脉注射用 美国初次批准：2014 KEYTRUDA®（pembrolizumab）用于注射，用于静脉内使用 KEYTRUDA®（pembrolizumab）注射，静脉使用 美国首次批准：2014年 目前的主要变化 剂量和给药方法 01/2015 警告和注意事项 06/2015 作用机制 PD-1配体，PD-L1和PD-L2，与T细胞上发现的PD-1受体的结合，抑制T细胞增殖和细胞因子的产生。在某些肿瘤中发生PD-1配体的上调和通过这个途径信号对肿瘤活性的T-细胞免疫监视抑制作用可能有贡献。 Pembrolizumab是一个单克隆抗体结合至PD-1受体和阻断其与PD-L1和PD-L2相互作用，释放免疫反应的PD-1通路-介导抑制作用，包括抗-肿瘤免疫反应。在同基因小鼠肿瘤模型中，阻断PD-1活性导致肿瘤生长的减低 适应症和用法 KEYTRUDA是人程序性死亡受体-1（PD-1）-blocking以下易普利姆玛和，如果BRAF V600突变阳性，一个BRAF抑制剂指示用于治疗不能切除或转移性黑素瘤和疾病进展的治疗抗体。 这个指示下，根据肿瘤的响应率和响应的耐久性加速审批核准。在存活或与疾病相关的症状的改善尚未确立。继续批准该适应症可能是在验证和临床获益说明在验证试验队伍。 用法用量 2毫克/公斤作为静脉内输注在30分钟内，每3周。 稀释前静脉滴注。 剂型和规格 注射：50mg的冻干粉末在单次使用的小瓶用于重建。 注射：在单次使用的小瓶100毫克/ 4毫升（25毫克/毫升）溶液。 禁忌 无。 警告和注意事项 免疫介导的不良反应：管理基于反应的严重程度皮质类固醇。 免疫介导性肺炎：暂停对中度，并永久停止对严重或危及生命的肺炎。 免疫介导的结肠炎：暂停为中度或重度，并永久终止危及生命的结肠炎。 免疫介导的肝炎：监测的变化肝功能。基于对肝酶升高的严重程度，将暂停或终止。 免疫介导的内分泌疾病： 垂体：暂停对中度，扣留或停止严重，并永久地停止了生命危险垂体炎。 甲状腺疾病：监视的变化甲状腺功能。扣压严重和永久性停止对危及生命的甲状腺功能亢进症。 1型糖尿病：监视高血糖。注射胰岛素的1型糖尿病和扣留KEYTRUDA在严重的高血糖的情况下，直到代谢控制的实现。 免疫介导的肾炎：监视对肾功能的变化。扣压中度，并永久停止对严重或危及生命的肾炎。 输液相关反应：停止输液，并永久停止KEYTRUDA严重或危及生命的输液反应。 胚胎 - 胎仔毒性：KEYTRUDA可能对胎儿造成伤害。奉劝女性的潜在危险胎儿生殖潜力的。 不良反应 最常见的不良反应（报道的患者≥20％）包括乏力，咳嗽，恶心，皮肤瘙痒，皮疹，食欲减退，便秘，关节痛，腹泻等。 特殊人群中使用 哺乳母亲：终止哺乳或终止KEYTRUDA。 HOW SUPPLIED/STORAGE AND HANDLING KEYTRUDA for injection (lyophilized powder): carton containing one 50mg single-use vial (NDC 0006-3029-02). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). KEYTRUDA injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), single-use vial (NDC 0006-3026-02) Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake. KEYTRUDA® (pembrolizumab) is First Medicine to be Made Available to Patients Through U.K. Early Access to Medicines Scheme (EAMS) for Advanced Melanoma EAMS Aims to Give U.K. Patients Access to Promising, Innovative Treatments Prior to European License Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the company’s anti-PD-1 therapy, pembrolizumab, which is marketed in the U.S. under the name KEYTRUDA®, is the first treatment to be accepted under the U.K.’s new Early Access to Medicines Scheme (EAMS). Pembrolizumab was accepted under the scheme for the treatment of advanced melanoma based on the significance of the early study findings and unmet medical need. Pembrolizumab received the Promising Innovative Medicine (PIM) designation in the U.K., on Oct. 10, 2014. In 2014, the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) introduced the EAMS to help patients benefit from promising, innovative treatments before a European license has been granted. The European Marketing Authorization for pembrolizumab for the treatment of advanced melanoma is currently under review. “Merck has charted a path to accelerate the development of pembrolizumab, and is collaborating with governments around the world to bring our anti-PD-1 therapy to cancer patients,” said Dr. Roger Perlmutter, president, Merck Research Laboratories. “This acceptance of pembrolizumab into the Scheme will enable many patients in the U.K. with advanced melanoma to gain earlier access to pembrolizumab, and underscores the importance of creating new mechanisms to bring promising medicines to patients for whom there are limited options.” Pembrolizumab is one of the first of a new generation of immuno-oncology therapies called anti-PD-1s (programmed death receptor-1). The EAMS acceptance was based on review of data for pembrolizumab from KEYNOTE-001, the largest Phase 1b study of an anti-PD-1 therapy in patients with advanced melanoma. Pembrolizumab was previously granted Breakthrough Therapy Designation for advanced melanoma by the U.S. Food and Drug Administration based on these data, and approved in September of 2014. “This news will be greatly received by the melanoma community in the U.K. At the moment, there are limited options for advanced melanoma patients, the majority of whom are in difficult positions which simply means they cannot afford to play any kind of waiting game,” said Gillian Nuttall, Melanoma UK. “We welcome early access to this treatment for advanced patients made possible through this new scheme. There is clearly an unmet need and we are delighted such progress is being made.” “We welcome the Government’s proactive approach in facilitating early access to medicines for critically ill patients and are delighted that pembrolizumab will be the first innovative medicine to be available to patients through the Early Access to Medicines Scheme,” said Mike Nally, managing director for MSD UK and Ireland. To date, more than 3,500 patients in over 40 countries have received early access to pembrolizumab for the treatment of advanced melanoma through the company’s global expanded access program. Today, Merck is advancing a broad and fast-growing clinical development program for pembrolizumab with more than 70 clinical trials – across more than 30 tumor types and over 8,000 patients – both as a monotherapy and in combination with other therapies. About U.K. Early Access to Medicines Scheme The U.K. EAMS aims to give patients with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorization when there is a clear unmet medical need. Under the scheme, the MHRA will give a scientific opinion on the benefit/risk balance of the medicine, based on the data available when the EAMS submission was made. The opinion lasts for a year and can be renewed. The scheme is voluntary and the opinion from MHRA does not replace the normal licensing procedures for medicines. More information is available on the MHRA website at https://www.gov.uk/apply-for-the-early-access-to-medicines-scheme-eams. About KEYTRUDA® (pembrolizumab) KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following 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. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Selected Important Safety Information for KEYTRUDA® Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis. Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis. Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis. Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA. For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%). The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287 http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s005lbl.pdf 美国FDA批准Keytruda扩展治疗晚期非小细胞肺癌 2015年10月2日，美国食品和药品监管局(FDA)授权加快批准为Keytruda(pembrolizumab/MK-3475)治疗患者有晚期(转移)非-小细胞肺癌(NSCLC)其疾病在其它治疗和有表达蛋白被称为PD-L1的肿瘤。Keytruda是与批准使用一种协同诊断， PD-L1 IHC 22C3 pharmDx测试，第一个测试被设计检测在非-小细胞肺肿瘤表达PD-L1。 根据美国国家癌症研究所肺癌是美国癌症死亡的首要原因，在2015年有一个估算的221,200 新诊断和158,040例死亡。NSCLC是肺癌最常见类型。 FDA的药品评价和研究中心中血液学和肿瘤室主任Richard Pazdur，M.D.说：“我们对潜在的分子途径和我们的免疫系统如何与癌症的交互作用了解的日益增长导致医疗中重要的进展。” “今天Keytruda的批准给予医生靶向最可能从药物获益的特异性患者的能力。” Keytruda通过靶向细胞通路被称为(机体的免疫细胞和某些癌症细胞上发现的蛋白)起作用。通过阻断这个通路，Keytruda可能有助于机体免疫系统与癌症细胞斗争。在2014年，Keytruda 被批准治疗用普利姆玛[ipilimumab]，免疫治疗的一种类型治疗后有晚期患。在2015年另一种药物，Opdivo (nivolumab)，由Bristol-Meyers Squibb公司制造，也靶向PD-1/PD-L1通路和被批准治疗鳞状上皮非-小细胞肺癌(NSCLC的某种类型)。 在550例有晚期NSCLC患者中研究Keytruda的安全性。Keytruda的最常见副作用包括疲乏，食欲减退，气短或受损的呼吸(呼吸困难)和咳嗽。Keytruda还有潜能致来自Keytruda的免疫系统结果(被称为 “免疫-介导副作用”)严重副作用。 在一项较大多中心，开放，多-部分研究内纳入一个61例患者亚组证实对这个使用Keytruda的有效性。这个亚组由有晚期NSCLC在基于铂化疗后进展或，如适当，对某些遗传突变(ALK或EGFR)靶向治疗患者组成。这个亚组还有PD-L1根据22C3 pharmDx诊断测试阳性肿瘤的结果。研究参加者接受10 mg/kg的Keytruda每2或2周。主要结局测量是总体反应率(患者经历他们的肿瘤完全和部分缩小患者的百分率)。用Keytruda治疗患者41%肿瘤缩小和效应持续2.1和9.1 个月间。                                       在550例有晚期NSCLC研究参加者，严重免疫-介导副作用发生涉及肺，结肠和激素-产生腺。其他不常见免疫-介导副作用为皮疹和血管炎症(血管炎)。妊娠或哺乳喂养妇女不应用 Keytruda因为它可能危害发育中胎儿或新生儿。跨越临床研究，还发生一种疾病其中机体的免疫系统攻击的周围神经系统的一部分(Guillain-Barre综合证)。 FDA授权Keytruda对这个适应证突破性治疗指定因为Merck证实通过初步临床证据药物可能提供超过可得到治疗的一种实质上改进。药物还接受优先审评状态，它被授权于药物在这个时间申请被递交，有将是在一种严重情况治疗中在安全性或有效性显著改进的潜能。 Keytruda是在监管局加快批准程序下被批准，这个程序允许根据临床数据显示该药物对一个替代性终点可能合理地预测对患者临床获益批准一个药物治疗一个严重或危及生命疾病。这个程序提供This program provides earlier 患者较早得到鼓舞人有前途新药而公司进行验证性临床试验。未曽确定用Keytruda 治疗在正在被治疗患者中生存或疾病相关症状改善。 Keytruda由总部设在新泽西白宫站默克公司上市和PD-L1 IHC 22C3 pharmDx诊断测试由加州 Carpinteria的Dako North America公司上市。 --------------------------------------- 产地国家：美国 原产地英文商品名: KEYTRUDA 100mg/4ml（25mg/ml）/vial 1vial 原产地英文药品名: pembrolizumab 中文参考商品译名: KEYTRUDA注射液  100毫克/4毫升(25毫克/毫升)/瓶 1瓶 中文参考药品译名: 派姆单抗 生产厂家中文参考译名: 默克 生产厂家英文名: Merck  --------------------------------------- 产地国家：美国 原产地英文商品名: KEYTRUDA 50MG SINGLE USE VIAL 原产地英文药品名: pembrolizumab 中文参考商品译名: KEYTRUDA注射液  50毫克/毫升瓶 中文参考药品译名: 派姆单抗 生产厂家中文参考译名: 默克 生产厂家英文名: Merck  --------------------------------------- 产地国家：香港 原产地英文商品名: KEYTRUDA Injection 100mg/4ml（25mg/ml）/Vial 原产地英文药品名: pembrolizumab 中文参考商品译名: KEYTRUDA注射液  100毫克/4毫升(25毫克/毫升)/瓶 中文参考药品译名: 派姆单抗 生产厂家中文参考译名: 默克 生产厂家英文名: Merck  --------------------------------------- 产地国家：德国 原产地英文商品名: KEYTRUDA 100mg/4ml（25mg/ml）/vial 1vial 原产地英文药品名: pembrolizumab 中文参考商品译名: KEYTRUDA注射液  100毫克/4毫升(25毫克/毫升)/瓶 1瓶 中文参考药品译名: 派姆单抗 生产厂家中文参考译名: 默克 生产厂家英文名: Merck  --------------------------------------- 产地国家：德国 原产地英文商品名: KEYTRUDA 50MG SINGLE USE VIAL 原产地英文药品名: pembrolizumab 中文参考商品译名: KEYTRUDA注射液  50毫克/毫升/瓶 中文参考药品译名: 派姆单抗 生产厂家中文参考译名: 默克 生产厂家英文名: Merck