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注射用KEYTRUDA®(pembrolizumab)为静脉注射用获美国食品和药品监管局(FDA)授权加快批准为Keytruda(pembrolizumab)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。”
批准日期：2014年9月4日；公司：Merck & Co.，Inc
注射用KEYTRUDA®(pembrolizumab)，为静脉注射用
美国初次批准：2014
最近重大修改-红色为重大修改部分
适应证和用途 10/2015
剂量和给药方法 10/2015
剂量和给药方法 01/2015
警告和注意事项 10/2015
警告和注意事项 06/2015
适应证和用途
1 黑色素瘤
KEYTRUDA®(pembrolizumab)适用为有不可切除的或转移黑色素瘤和普利姆玛后疾病进展和，如BRAF V600突变阳性，一个BRAF抑制剂患者的治疗[见临床研究(14)]。
在加速批准下根据肿瘤反应率和反应的持久性批准这个适应证。尚未确定An在生存或疾病相关症状改善。对这个适应证的继续批准可能取决于在验证性试验中临床获益验证和描述。
2 非-小细胞肺癌
KEYTRUDA适用为有转移非-小细胞肺癌(NSCLC)其肿瘤表达PD-L1被FDA批准的测试确定有疾病进展用或含铂化疗后患者的治疗。患者接受KEYTRUDA前有EGFR或ALK基因组肿瘤畸变应有疾病进展用FDA-批准的治疗对这些畸变[见临床研究(14.2)].
这个适应证是根据肿瘤反应率和反应持久性在加快批准下被批准的。尚未确定在生存率或疾病相关症状这改善。继续批准这个适应证可能取决于在验证试验这临床获益验证和描述。
剂量和给药方法
1 患者选择
根据阳性PD-L1表达的存在选择患者为二线或转移NSCLC用KEYTRUDA更大治疗[见临床研究]。在: http://www.fda.gov/CompanionDiagnostics可得到关于FDA-批准为检测在NSCLC中PD-L1表达测试的资料。
2推荐给药
KEYTRUDA的推荐剂量是2 mg/kg给药作为历时30分钟静脉输注每3周给予直至疾病进展或不可接受毒性。
3 剂量调整
对以下任何不给KEYTRUDA：
● 2级肺炎[见警告和注意事项]
● 2或3级结肠炎[见警告和注意事项]
● 3或4级内分泌病[见警告和注意事项]
● 2级肾炎[见警告和注意事项]
● 谷草转氨酶(AST)或谷丙转氨酶(ALT)大于3和直至正常上限(ULN)5倍或总胆红素大于1.5和直至ULN 3倍。
● 任何其他严重或3级治疗-相关不良反应[见警告和注意事项]
在患者其不良反应恢复至0-1级恢复KEYTRUDA。
对以下任何永远终止KEYTRUDA：
●任何危及生命不良反应(除外内分泌病用激素替代治疗控制)
● 3或4级肺炎或2级严重程度的复发肺炎[见警告和注意事项]
●3或4级肾炎[见警告和注意事项]
● AST或ALT大于5倍ULN或总胆红素大于3倍ULN
○ 对有肝转移患者开始治疗有2级AST或ALT，如AST或ALT增加相对于基线大于或等于50%和持续共至少1周
● 3或4级输注相关反应[见警告和注意事项]
● 12 周内不能减低皮质激素剂量至10mg或低于泼尼松[prednisone]或等价物每天
● 持续2或3级不良反应KEYTRUDA末次剂量后12周内不恢复至0-1级
● 任何在发生严重或3级治疗-相关不良反应[见警告和注意事项]
4 制备和给药
注射用KEYTRUDA的重建(冻干粉)
●通过沿小瓶壁注射水加入2.3mL的注射用无菌水，USP和不要直接在冰冻干燥粉上(造成浓度25 mg/mL)。
● 缓慢旋转小瓶。允许至5分钟让泡沫被清除。不要摇晃小瓶。
为静脉输注制备
● 给药前肉眼观察颗粒物质和变色。溶液是清澈至轻微乳白色，无色至浅黄色。如观察到可见颗粒遗弃小瓶。
● 静脉给药前稀释KEYTRUDA注射液或重建冰冻干燥粉。
●从KEYTRUDA小瓶抽吸需要容积和转移至含0.9%氯化钠注射液，USP或5% 葡萄糖注射液，USP静脉袋。通过轻轻倒置混合稀释溶液。被稀释溶液最终浓度应是1 mg/mL至10 mg/mL间。
● 遗弃留在小瓶中任何未使用部分。
重建和已稀释溶液的贮存
产品不含防腐剂。
贮存重建和已稀释溶液从KEYTRUDA 50 mg小瓶或:
● 在室温从重建时间共不超过6小时。这包括重建小瓶室温贮存，在IV袋输注溶液的贮存，和输注时间。
● 冰箱在2°C至8°C(36°F至46°F)从重建时间共不超过24小时。如冰箱，给药前允许稀释拽至室温。
从KEYTRUDA 100 mg/4 mL小瓶被稀释溶液贮存或:
● 在室温从稀释时间共不超过6小时。这包括IV袋输注溶液在室温贮存，和输注时间。
●在冰箱在2°C至8°C(36°F至46°F)从稀释时间共不超过24小时。如冰箱。在给药前允许已稀释溶液至室温。
不要冻结。
给药
● 通过一个输注线历时30分钟静脉给予含无菌，无-热原，低-蛋白结合0.2µm至5 µm在-线或附加的过滤器的输注溶液。
● 不要通过相同输注线共-给予其他药物。
禁忌证
无。
警告和注意事项
⑴免疫-介导肺炎:对中度不给，和永远终止对严重，危及生命或复发中度肺炎。
⑵免疫-介导结肠炎:对中度或严重不给，和对危及生命结肠炎永远终止。
⑶免疫-介导肝炎: 监视肝功能中变化。根据肝酶升高严重程度，不给或终止。
⑷ 免疫-介导内分泌病:
① 垂体炎:对中度不给和对严重或危及生命垂体炎不给或永久终止。
②甲状腺疾病: 监视甲状腺功能。对严重或危及生命甲状腺功能亢进不给或永远终止。
③1型糖尿病: 监视高血糖。在严重高血糖病例不给 KEYTRUDA。
⑸ 免疫-介导肾炎: 监视肾功能变化。对中度不给，和对严重或危及生命肾炎永远终止。
⑹ 输注-相关反应: 停止输注和对严重或危及生命 输注反应永远终止KEYTRUDA。(5.7)
⑺ 胚胎胎儿毒性: KEYTRUDA可致胎儿危害。忠告生殖潜能女性对胎儿潜在风险。(5.8)
不良反应
最常见不良反应(报告在≥20%患者)有：
⑴黑色素瘤包括疲劳，咳嗽，恶心，瘙痒，皮疹，食欲减低, 便秘，关节痛，和腹泻。
⑵NSCLC 包括疲乏，食欲减退，呼吸困难和咳嗽。
特殊人群中使用
哺乳母亲：终止哺乳或终止KEYTRUDA。
Keytruda(pembrolizumab (MK-3475))
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. 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.
PD-L1 = programmed death ligand 1; EGFR = epidermal growth factor receptor; ALK = anaplastic lymphoma kinase.
SELECTED SAFETY INFORMATION FOR MELANOMA
Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. 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 patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). 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.
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® (pembrolizumab) for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia.
Nephritis occurred in 3 (0.7%) patients, 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.
Other clinically important immune-mediated adverse reactions can occur. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, 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.
Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.
Based on its mechanism of action, KEYTRUDA can 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.
KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.
The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).
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.
SELECTED SAFETY INFORMATION FOR NSCLC
Pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients receiving KEYTRUDA. 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 or recurrent Grade 2 pneumonitis.
Colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients 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 occurred in patients receiving KEYTRUDA® (pembrolizumab). 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 1 (0.2 %) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.
Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%). 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 replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.
Nephritis occurred in patients receiving KEYTRUDA. 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.
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. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
The following clinically significant, immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, myasthenia gravis, bullous pemphigoid, and Guillain-Barré syndrome.
Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.
Based on its mechanism of action, KEYTRUDA can 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.
KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis.
The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), decreased appetite (25%), dyspnea (23%), and cough (29%).
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 and for 4 months after the final dose.
Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.
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产地国家：美国
原产地英文商品名:
KEYTRUDA Injection 50mg/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/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 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 Injection 50mg/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/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
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