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完整的处方信息

1适应症和用途

LIBTAYO适用于治疗转移性皮肤鳞状细胞癌（mCSCC）或局部晚期CSCC（laCSCC）的患者，这些患者不适合进行根治性手术或根治性放射治疗。

2剂量和给药

2.1推荐剂量

LIBTAYO的推荐剂量为每3周30分钟静脉输注350 mg，直至疾病进展或出现不可接受的毒性。

2.2不良反应的剂量修改

如表1 所示，停药或停用LIBTAYO以管理不良反应。不建议降低LIBTAYO的剂量。

*毒性根据国家癌症研究所不良事件通用术语标准4.0版进行分级

†糖皮质激素减量后恢复完全或部分消退（0至1级）的患者。

2.3准备和管理

• 给药前目视检查颗粒物和变色。LIBTAYO是一种澄清至微乳白色，无色至浅黄色的溶液，可能包含微量的半透明至白色颗粒。如果溶液浑浊，变色或含有无关的半透明至白色颗粒的异物，请丢弃小瓶。

制备

• 不要摇晃。
• 从小瓶中取出7 mL，并用0.9％USP氯化钠注射液或5％USP葡萄糖注射液稀释至1 mg / mL至20 mg / mL的最终浓度。
• 轻轻颠倒混合稀释的溶液。不要摇晃。
• 丢弃所有未使用的药品或废料。

输注液的储存

• 从制备到输液结束，在室温下最多25°C（77°F）的温度下保存不超过8小时，或者在2°C至8°C（36°F到46°F）的温度下保存。从准备到输液结束不超过24小时。
• 给药前，让稀释后的溶液达到室温。
• 不要冻结。

行政

• 通过30分钟的静脉内输注，通过包含无菌，在线或附加0.2微米至5微米过滤器的静脉内管线进行静脉输注。

3剂型和强度

注射剂：350 mg / 7 mL（50 mg / mL），透明至微乳白色，无色至浅黄色溶液，在单剂量小瓶中可能含有痕量的半透明至白色颗粒。

4禁忌症

没有。

5警告和注意事项

5.1严重和致命的免疫介导的不良反应

LIBTAYO是一种单克隆抗体，属于一类药物，该药物与程序性死亡受体-1（PD-1）结合，阻断PD-1 / PD-L1途径，从而消除对免疫反应的抑制并可能破坏耐受性和免疫介导的不良反应的诱导 警告和注意事项中列出的重要的免疫介导的不良反应可能并不包括所有可能的免疫介导的反应。

免疫介导的不良反应可能是严重的或致命的，可发生在任何器官系统或组织中。虽然免疫介导的不良反应通常在用PD-1 / PD-L1阻断抗体治疗期间出现，但免疫介导的不良反应也可能在PD-1 / PD-L1阻断抗体终止后出现。免疫介导的不良反应会同时影响多个身体系统。

早期识别和管理对于确保安全使用PD-1 / PD-L1阻断抗体至关重要。监测免疫介导的不良反应的症状和体征。在基线和治疗期间定期评估临床化学，包括肝功能检查和甲状腺功能检查。及时进行医学管理，包括适当的专业咨询。

通常，对于3级或4级以及某些2级免疫介导的不良反应，暂不使用LIBTAYO。永久终止LIBTAYO用于4级和某些3级免疫介导的不良反应[参见剂量和给药方法（2.2） ]。对于3级或4级以及某些2级免疫介导的不良反应，给予皮质类固醇（1至2 mg / kg /天泼尼松或同等剂量）或其他适当的疗法，直至改善至1级以下，然后在一个月内逐渐减少皮质类固醇[见剂量和用法（2.2） ]。对于免疫介导的不良反应不受皮质类固醇控制的患者，可考虑服用其他全身性免疫抑制剂。必须进行激素替代疗法治疗内分泌病变。

免疫介导的肺炎

534例接受LIBTAYO的患者中有2.4％发生了免疫介导的肺炎，包括5级（0.2％），3级（0.7％）和2级（1.3％）[请参阅不良反应（6.1） ]。肺炎导致1.3％的患者永久停用LIBTAYO。所有肺炎患者都需要全身性皮质类固醇激素治疗，其中包括每天接受泼尼松≥40 mg或同等剂量的85％的患者。肺炎在62％的患者中得到解决。

免疫介导的结肠炎

534例接受LIBTAYO的患者中有0.9％发生了免疫介导的结肠炎，包括3级（0.4％）和2级（0.6％）[见不良反应（6.1） ]。结肠炎导致0.2％的患者永久停用LIBTAYO。所有结肠炎患者都需要全身性皮质类固醇激素治疗，包括60％每天接受泼尼松≥40 mg或同等剂量的患者。结肠炎在80％的患者中得到解决。

免疫介导的肝炎

534例接受LIBTAYO的患者中有2.1％发生了免疫介导的肝炎，包括5级（0.2％），4级（0.2％）和3级（1.7％）[见不良反应（6.1） ]。肝炎导致0.9％的患者永久停用LIBTAYO。所有肝炎患者都需要全身性皮质类固醇激素治疗，包括91％每天接受泼尼松≥40 mg或同等剂量的患者。肝炎在64％的患者中得到解决。

免疫介导的内分泌病变

肾上腺功能不全

534名接受LIBTAYO的患者中有0.4％发生肾上腺功能不全，包括3级（0.2％）和2级（0.2％）[见不良反应（6.1） ]。

垂体炎

534例接受LIBTAYO的患者中有0.2％发生垂体垂体病，可导致垂体功能低下，其中1例患有3级垂体炎。

甲状腺功能减退

534例接受LIBTAYO的患者发生甲状腺功能减退，包括3级（0.2％）和2级（5.6％）。没有患者停止激素替代治疗。

甲亢

534名接受LIBTAYO的患者中有1.5％发生甲亢，包括3级（0.2％）和2级（0.4％）。甲状腺功能亢进症在38％的患者中得到解决。

1型糖尿病

可以伴有糖尿病性酮症酸中毒的1型糖尿病在534例患者中占0.7％，包括4级（0.4％）和3级（0.4％）。1型糖尿病导致0.2％的患者永久停用LIBTAYO。

肾功能不全的免疫介导性肾炎

534例接受LIBTAYO的患者中有0.6％发生了免疫介导的肾炎，包括3级（0.4％）和2级（0.2％）[见不良反应（6.1） ]。肾炎导致0.2％的患者永久停用LIBTAYO。所有肾炎患者都需要全身性皮质类固醇激素治疗，包括67％每天接受泼尼松≥40 mg或同等剂量的患者。肾炎在所有患者中均得到缓解。

免疫介导的皮肤不良反应

534例接受LIBTAYO的患者中有1.7％发生了免疫介导的皮肤病反应，包括多形红斑和类天疱疮，包括3级（1.1％）和2级（0.6％）[见不良反应（6.1） ]。此外，在LIBTAYO和该类别的其他产品中，已观察到史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死溶解（TEN）。所有有皮肤病反应的患者都需要全身性皮质类固醇激素治疗，包括89％每天接受泼尼松≥40 mg或同等剂量的患者。皮肤病反应在33％的患者中得到解决。重新启动LIBTAYO后，约有22％的患者出现皮肤病反应复发。

其他免疫介导的不良反应

在接受LIBTAYO的 534例患者中，发生以下临床上明显的免疫介导的不良反应，发生率＜1％[见不良反应（6.1） ]，或报道使用其他PD-1 / PD-L1阻断抗体。据报告，其中一些不良反应严重或致命。

神经系统疾病：脑膜炎，脑炎，脊髓炎和脱髓鞘，肌无力综合征/重症肌无力，格林-巴利综合征，神经麻痹，自身免疫性神经病

心血管疾病：心肌炎，心包炎，血管炎

眼睛：葡萄膜炎，虹膜炎和其他眼部炎症毒性。有些情况可能与视网膜脱离有关。可能会出现各种等级的视力障碍，包括失明。如果葡萄膜炎与其他免疫介导的不良反应同时发生，请考虑Vogt-Koyanagi-Harada综合征，因为这可能需要全身性皮质类固醇激素治疗，以减少永久性视力丧失的风险。

胃肠道：胰腺炎包括血清淀粉酶和脂肪酶水平升高，胃炎，十二指肠炎

肌肉骨骼和结缔组织：肌炎，横纹肌溶解症和相关后遗症，包括肾衰竭，关节炎，风湿性多肌痛

血液学和免疫学：溶血性贫血，再生障碍性贫血，吞噬性淋巴细胞组织细胞增生，全身性炎症反应综合征，组织细胞坏死性淋巴结炎（菊池淋巴结腺炎），结节病，免疫性血小板减少性紫癜，实体器官移植排斥

5.2输注相关反应

接受LIBTAYO 的患者中有0.2％发生了严重的输液相关反应（3级）[见不良反应（6.1） ]。监视患者输液相关反应的体征和症状。根据反应的严重程度中断或减慢输注速度或永久终止LIBTAYO [请参阅剂量和给药方法（2.2） ]。

5.3胚胎-胎儿毒性

根据其作用机理，LIBTAYO对孕妇给药可引起胎儿伤害。动物研究表明，对PD-1 / PD-L1途径的抑制会导致免疫介导的发育中胎儿排斥反应的风险增加，从而导致胎儿死亡。建议妇女注意胎儿的潜在危险。繁殖潜力的提醒女治疗过程中使用有效的避孕LIBTAYO和最后一次给药后至少4个月[见特殊人群中使用（8.1，8.3） ]。

6不良反应

标签上其他地方描述了以下严重不良反应。

• 严重和致命的免疫介导不良反应[请参阅警告和注意事项（5.1） ]
• 输注相关反应[请参阅警告和注意事项（5.2） ]

6.1临床试验经验

由于临床试验是在变化很大的条件下进行的，因此不能将在某种药物的临床试验中观察到的不良反应率直接与另一种药物的临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

警告和注意事项中所述的数据反映了两项开放标签，单组，多队列研究（研究1423和研究1540）中534名患者暴露于LIBTAYO的情况，其中包括98名mCSCC（淋巴结或远处），65名laCSCC， 371例其他晚期实体瘤患者。LIBTAYO作为单一药物或与化学疗法或放射疗法联合给药，剂量为每2周1 mg / kg（n = 27），每2周3 mg / kg（n = 446），每3周3 mg / kg周（n = 12），每2周10 mg / kg（n = 6），每2周200 mg（n = 20）或每3周350 mg（n = 23）。在534例患者中，有38％的患者暴露时间≥6个月，有16％的患者暴露时间≥12个月。

下述数据反映了研究1423和研究1540中219位晚期CSCC（转移性或局部晚期疾病）患者的LIBTAYO暴露[参见临床研究（14） ]。在这219例患者中，有131例患有mCSCC（淋巴结或远处），而88例患有laCSCC。患者接受LIBTAYO 1毫克/公斤，每2周（N = 1），3毫克/公斤，每2周（N = 162）或350毫克每3周（N = 56）作为静脉内输注，直至疾病进展，不可接受的毒性，或完成计划的治疗。中位暴露时间为38周（2周至110周）。

安全人群的特征是：中位年龄为72岁（38至96岁），男性为83％，白人为96％，欧洲合作肿瘤小组（ECOG）的绩效评分（PS）分别为0（44％）和1（56％） ）。

在至少20％的患者中，最常见的不良反应是疲劳，皮疹，腹泻，肌肉骨骼疼痛和恶心。最常见的3-4级不良反应（≥2％）是蜂窝织炎，贫血，高血压，肺炎，肌肉骨骼疼痛，疲劳，肺炎，败血症，皮肤感染和高钙血症。锂电8％的患者因不良反应而永久停药；导致永久停药的不良反应是肺炎，咳嗽，肺炎，脑炎，无菌性脑膜炎，肝炎，关节痛，肌无力，颈部疼痛，软组织坏死，复杂的局部疼痛综合征，嗜睡，牛皮癣，斑疹性斑丘疹，直肠炎和混乱状态。35％的患者发生了严重的不良反应。在至少2％的患者中发生的严重不良反应为肺炎，蜂窝织炎，败血症和肺炎。

表2总结了≥10％的患者发生的不良反应，表3总结了接受LIBTAYO的 ≥1％的患者的3或4级实验室异常从基线开始恶化。

根据国家癌症研究所不良事件通用术语标准（NCI CTCAE）v.4.03对毒性进行了分级

*疲劳是一个综合性术语，包括疲劳和虚弱

†皮疹是一个综合性术语，包括皮疹，皮疹，丘疹，红斑，皮炎，大疱性皮炎，全身性皮疹，天疱疮，皮疹，红斑，黄斑，皮疹，瘙痒，药疹，牛皮癣和皮肤反应

‡瘙痒是一个复合词，包括瘙痒和过敏性瘙痒

§腹泻是包括腹泻和结肠炎的复合术语

¶肌肉骨骼疼痛是一个综合术语，包括背痛，四肢疼痛，肌痛，肌肉骨骼疼痛和颈部疼痛

＃咳嗽是一个综合性术语，包括咳嗽和上呼吸道咳嗽综合征

根据NCI CTCAE v.4.03分级的毒性

*百分比基于具有至少一个可用于该参数的基线后值的患者数量。

6.2免疫原性

与所有治疗性蛋白质一样，具有免疫原性的潜力。抗体形成的检测高度依赖于测定的灵敏度和特异性。另外，在测定中观察到的抗体（包括中和抗体）阳性的发生率可能受到多种因素的影响，包括测定方法，样品处理，样品收集的时间，伴随用药和基础疾病。由于这些原因，将下述研究中的塞米普利单抗-rwlc抗体的发生率与其他研究或其他产品中的抗体发生率进行比较可能会产生误导。

在接受LIBTAYO的 467位患者中测试了抗药物抗体（ADA）。使用电致发光（ECL）桥接免疫测定法，出现cemiplimab-rwlc紧急治疗的ADA的发生率为1.1％。0.2％是ADA持续反应。在开发抗西米普利单抗-rwlc抗体的患者中，没有证据显示西米普利单抗-rwlc的药代动力学特征发生了改变。

8在特定人群中的使用

8.1怀孕

风险摘要

基于其作用机理，LIBTAYO应用于孕妇时可能会造成胎儿伤害[参见临床药理学（12.1） ]。没有关于孕妇使用LIBTAYO的可用数据。动物研究表明，对PD-1 / PD-L1途径的抑制会导致免疫介导的发育中胎儿排斥反应而导致胎儿死亡的风险增加（参见数据）。已知人IgG4免疫球蛋白（IgG4）穿过胎盘；因此，LIBTAYO有潜力从母亲传播给发育中的胎儿。建议妇女注意胎儿的潜在危险。

在美国普通人群中，临床公认的怀孕中主要先天缺陷和流产的估计背景风险分别为2％至4％和15％至20％。

数据

动物资料

LIBTAYO尚未进行动物繁殖研究，以评估其对繁殖和胎儿发育的影响。PD-1 / PD-L1途径的主要功能是通过维持母体对胎儿的免疫耐受来保持妊娠。在怀孕的鼠模型中，已证明PD-​​L1信号传导的阻断会破坏对胎儿的耐受力，并导致胎儿流失的增加。因此，管理LIBTAYO的潜在风险怀孕期间流产或死产的发生率增加。如文献报道，在这些动物的后代中，没有与阻断PD-1 / PD-L1信号有关的畸形。但是，免疫介导的疾病发生在PD-1和PD-L1基因敲除小鼠中。根据其作用机理，胎儿暴露于西米单抗-rwlc可能会增加发生免疫介导的疾病或改变正常免疫反应的风险。

8.2哺乳

风险摘要

没有关于人乳中塞米普利单抗的含量及其对母乳喂养的孩子或产奶量的影响的信息。由于母乳喂养的儿童有可能发生严重的不良反应，因此建议女性在治疗期间以及最后一次使用LIBTAYO后至少4个月内不要母乳喂养。

8.3生殖潜力的雌雄

验孕

在开始使用 LIBTAYO 之前，请验证具有生殖潜能的女性的怀孕状况[请参阅在特定人群中使用（8.1） ]。

避孕

向孕妇服用时，LIBTAYO可能会造成胎儿伤害[请参见“ 在特定人群中使用（8.1）” ]。

女性

劝告有生殖潜力的女性在使用LIBTAYO治疗期间以及最后一剂后至少4个月内使用有效的避孕方法。

8.4小儿使用

在小儿患者中，LIBTAYO的安全性和有效性尚未确定。

8.5老年用途

在临床研究中接受LIBTAYO的219名mCSCC或laCSCC患者中，有34％为65岁至75岁，有41％为75岁或以上。在这些受试者和较年轻的受试者之间未观察到安全性或有效性的总体差异。

11说明

Cemiplimab-rwlc是一种人类程序性死亡受体1（PD-1）阻断抗体。Cemiplimab-rwlc是重组人IgG4单克隆抗体，可与PD-1结合并阻断其与PD-L1和PD-L2的相互作用。Cemiplimab-rwlc是通过重组DNA技术在中国仓鼠卵巢（CHO）细胞悬浮培养物中生产的。Cemiplimab-rwlc的分子量约为146 kDa。

静脉内使用的LIBTAYO（cemiplimab-rwlc）注射剂是无菌，不含防腐剂，澄清至微乳白色，无色至浅黄色的pH值为6的溶液。溶液中可能含有微量的半透明至白色颗粒。

每个小瓶包含350 mg西米单抗-rwlc。每毫升含西米普单抗50毫克，左旋组氨酸（0.74毫克），左旋组氨酸一盐酸盐一水合物（1.1毫克），蔗糖（50毫克），左旋脯氨酸（15毫克），聚山梨酯80（2毫克）和水USP注射剂。

12临床药理学

12.1行动机制

PD-1配体PD-L1和PD-L2与T细胞上的PD-1受体的结合抑制了T细胞增殖和细胞因子的产生。PD-1配体的上调发生在某些肿瘤中，通过该途径的信号传导可能有助于抑制肿瘤的主动T细胞免疫监视。

Cemiplimab-rwlc是重组人免疫球蛋白G4（IgG4）单克隆抗体，可与PD-1结合并阻断其与PD-L1和PD-L2的相互作用，从而释放PD-1途径介导的免疫应答抑制作用，包括抗肿瘤免疫反应。在同系小鼠肿瘤模型中，阻断PD-1活性导致肿瘤生长减少。

12.3药代动力学

在548例患有各种实体瘤的患者（包括178例CSCC患者）中收集了Cemiplimab-rwlc的药代动力学数据。Cemiplimab-rwlc的药代动力学是线性的，剂量成比例，每2周静脉内给药1 mg / kg至10 mg / kg LIBTAYO。

在CSCC患者中，每3周接受cemiplimab-rwlc稳态暴露的剂量为每3周3 mg / kg的暴露剂量为350 mg。每3周350 mg的稳态稳态平均塞米普单抗-rwlc浓度（变异系数，CV％）介于最小浓度63 mg / L（45％）和最大浓度151 mg / L之间（31 ％）。治疗4个月后达到稳态暴露。

分配

稳定状态下塞米普利单抗的分布体积为5.2 L（24％）。

消除

首次剂量后的Cemiplimab-rwlc清除率（CV％）为0.33 L /天（39％），并随时间减少36％，从而导致稳态清除率（CL ss）（CV％）为0.21 L /天（ 39％）。稳态下的消除半衰期（CV％）为19天（38％）。

特定人群

以下因素对Cemiplimab-rwlc的暴露无临床重要影响：年龄（27至96岁），性别，体重（31至172 kg），种族（白人，黑人，亚裔和其他），癌症类型，白蛋白水平（22至48 g / L），肾功能（肌酐清除率由Cockcroft-Gault确定为25 mL / min或更高）和肝功能（总胆红素为0.35至45 µmol / L）。LIBTAYO尚未在中度或重度肝功能不全患者中进行过研究。

13毒理学

13.1致癌，诱变，生育力受损

尚未进行评估塞米普利单抗的致癌性或遗传毒性的研究。

在对性成熟食蟹猴进行的为期3个月的重复剂量毒理学研究中，剂量不超过ceemiplimab-rwlc的相关性对生育参数（月经周期，精液分析或睾丸测量）或雄性或雌性生殖器官没有影响测试的最高剂量为50 mg / kg /周（基于每3周一次350 mg的临床剂量的AUC，约为人类暴露量的5.5至25.5倍）。

13.2动物毒理学和/或药理学

在动物模型中，对PD-L1 / PD-1信号的抑制会增加某些感染的严重程度并增强炎症反应。与野生型对照相比，感染了结核分枝杆菌的PD-1基因敲除小鼠的存活率明显降低，这与这些动物的细菌增殖和炎症反应增加有关。PD-L1和PD-1基因敲除小鼠以及接受PD-L1阻断抗体的小鼠也显示出感染了淋巴细胞性脉络膜脑膜炎病毒后存活率下降。

14临床研究

功效LIBTAYO在219例转移性（淋巴结或远处）皮肤鳞状细胞癌（mCSCC）或局部晚期CSCC（laCSCC）谁是不是根治性手术或治疗辐射候选人在两个开放标签进行了评价，多中心，非随机多队列研究：研究1423（NCT02383212）和研究1540（NCT02760498）。两项研究均排除了需要在5年内使用免疫抑制剂进行全身治疗的自身免疫疾病患者。实体器官移植史；预先使用抗PD-1 / PD-L1阻断抗体或其他免疫检查点抑制剂治疗；感染艾滋病毒，乙型肝炎或丙型肝炎；或ECOG PS≥2。

患者接受LIBTAYO在研究1423中，每2周静脉注射3 mg / kg，最长48周；在研究1540中，静脉注射最高96周。另外一组研究1540的患者每3周接受350 mg，持续54周。继续治疗直至疾病进展，不可接受的毒性或完成计划的治疗。每8或9周进行一次肿瘤反应评估。主要疗效结局指标为确认的客观缓解率（ORR），定义为完全缓解（CR）加部分缓解（PR）（由独立的中央评价（ICR）评估）和ICR评估的缓解持续时间（DOR）。对于没有外部可见目标病变的mCSCC患者，通过实体瘤反应评估标准（RECIST 1.1）确定ORR。对于具有外部可见目标病变（laCSCC和mCSCC）的患者，

研究1540

其中193例晚期CSCC参加研究1540谁收到LIBTAYO在任3毫克/公斤，每2周或350mg的每三周，115有mCSCC和78有laCSCC。中位年龄为72岁（38至96岁）；83％是男性；97％是白人；ECOG PS 0为45％，ECOG PS 1为55％；34％的患者至少接受过一种抗癌全身治疗；90％的人曾接受过癌症相关的手术；68％的患者接受过放疗。在mCSCC患者中，有77％有远处转移，只有23％有淋巴结转移。

对于下表4中列出的有反应的患者，中位反应时间为1.9个月（范围：1.7到9.1个月）。

表4列出了每2周接受3 mg / kg的患者的疗效结果。

CI：置信区间；NR：未达到；+：表示上次评估正在进行

*随访中位数：mCSCC：16.5个月；laCSCC：9.3个月；综合CSCC：11.1个月

†仅包括先前皮肤受累完全治愈的患者；研究1540中的laCSCC患者需要进行活检以确认CR。

‡分子包括观察到的DOR至少达到指定的6或12个月的时间的患者人数。没有机会达到指定时间点的患者仅包括在分母中。

研究1540：每3周350毫克

在研究1540中的另一个队列中，有56名患者每3周静脉内接受350 mg剂量的塞米普利单抗，直至54周。中位随访时间为8.0个月，确诊的ORR为41％（95％CI：28、55），有65％的应答者DOR≥6个月。

研究1423

在研究1423中的26位CSCC患者中，有16位患有mCSCC，而10位患有laCSCC。中位年龄为73岁（52至88岁）；81％的患者为男性；92％的患者为白人；ECOG PS为0（38％）和1（62％）；58％的患者先前至少接受过1次抗癌全身治疗；92％的患者曾接受过与癌症相关的手术，而81％的患者曾接受过放疗。mCSCC组的一名患者剂量为1 mg / kg。其余每2周接受3 mg / kg。

中位随访时间为13.3个月，确认的ORR为50％（95％CI：30、70）；所有回应均为PR。中位反应时间为1.9个月（范围为1.7至7.3个月），有85％的反应者DOR≥6个月。

16供应/存储和处理方式

LIBTAYO（cemiplimab-rwlc）注射液为澄清至微乳白色，无色至浅黄色溶液，其中可能含有微量的半透明至白色颗粒。它装在一个纸箱中，该纸箱包含1个单剂量的小瓶：

• 350 mg / 7 mL（50 mg / mL）（NDC 61755-008-01）

将原始纸箱存放在2°C至8°C（36°F至46°F）的冰箱中。避光。请勿冻结或摇动。

17患者咨询信息

建议患者阅读FDA批准的患者标签（用药指南）。

免疫介导的不良反应

告知患者LIBTAYO可能引起免疫介导的不良反应，包括以下[参见警告和注意事项（5.1） ]：

• 肺炎：建议患者就肺炎的体征或症状，包括新的或恶化的咳嗽，胸痛或呼吸急促症状，立即联系其医疗保健提供者。
• 结肠炎：建议患者就结肠炎的体征或症状（包括腹泻，便血或粘液或严重的腹痛）立即联系其医疗保健提供者。
• 肝炎：建议患者就肝炎的体征或症状立即与他们的医疗保健提供者联系。
• 内分泌疾病：建议患者立即就其甲状腺功能减退，甲状腺功能亢进，肾上腺皮质功能不全，垂体炎或1型糖尿病的体征或症状与医生联系。
• 肾炎：建议患者立即就其肾炎的体征或症状与医疗保健提供者联系。
• 皮肤不良反应：建议患者如果出现新的皮疹，请立即与医疗人员联系。

输注相关反应

建议患者立即就其输液相关反应的体征或症状与他们的医护人员联系[请参阅警告和注意事项（5.2） ]。

胚胎-胎儿毒性

有生育能力的女性提供咨询该LIBTAYO会损害胎儿和通知已知或可疑的妊娠他们的医疗保健提供者[见警告和注意事项（5.3）和特殊人群中使用（8.1，8.3） ]。

劝告有生殖潜力的女性在治疗期间以及最后一次使用 LIBTAYO 后至少4个月内使用有效避孕方法（请参阅“ 在特定人群中使用（8.3） ”）。

哺乳期

劝告女性患者在服用LIBTAYO时以及最后一次服药后至少4个月内不要母乳喂养[请参见在特定人群中使用（8.2） ]。

制造商：
Regeneron Pharmaceuticals，Inc. 塔里敦，纽约州
777 Old Saw Mill River Road，
塔里敦，美国10591-6707
美国牌照编号1760

销售方：
Regeneron Pharmaceuticals，Inc.（纽约州塔里敦10591）和
sanofi-aventis US LLC（Bridgewater，新泽西州08807）
©2020 Regeneron Pharmaceuticals，Inc./ sanofi-aventis US LLC。
版权所有。

主要显示屏-350毫克/ 7毫升瓶装纸箱

仅NDC 61755- 008 -01
Rx

LIBTAYO ®
（cemiplimab-rwlc）
注射液

350 mg / 7毫升（50 mg / mL）

稀释
单剂量小瓶后静脉输注

丢弃未使用的部分。

如果密封件破裂或丢失，请勿使用小瓶。
将随附的用药指南分配给每位患者。

REGENERON ∣萨诺菲基因

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。

本说明书来源于：美国FDA

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/4347ae1f-d397-4f18-8b70-03897e1c054a/spl-doc?hl=LIBTAYO#section-13

温馨提醒：

①建议您用 谷歌浏览器  在电脑上或手机  打开以上链接，就可以自动翻译成简体中文，而且翻译的还比较准确。

②本说明书仅供参考，最新的说明书详见药品附带的说明书。

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

LIBTAYO is indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

2.2 Dosage Modifications for Adverse Reactions

Withhold or discontinue LIBTAYO to manage adverse reactions as described in Table 1. No dose reduction of LIBTAYO is recommended.

*Toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0

†Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper.

2.3 Preparation and Administration

• Visually inspect for particulate matter and discoloration prior to administration. LIBTAYO is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. Discard the vial if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of translucent to white particles.

Preparation

• Do not shake.
• Withdraw 7 mL from a vial and dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 1 mg/mL to 20 mg/mL.
• Mix diluted solution by gentle inversion. Do not shake.
• Discard any unused medicinal product or waste material.

Storage of Infusion Solution

• Store at room temperature up to 25°C (77°F) for no more than 8 hours from the time of preparation to the end of the infusion or at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of infusion.
• Allow the diluted solution to come to room temperature prior to administration.
• Do not freeze.

Administration

• Administer by intravenous infusion over 30 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter.

3 DOSAGE FORMS AND STRENGTHS

Injection: 350 mg/7 mL (50 mg/mL), clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

LIBTAYO is a monoclonal antibody that belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not be inclusive of all possible immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

Early identification and management are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor for symptoms and signs of immune-mediated adverse reactions. Evaluate clinical chemistries, including liver tests and thyroid function tests, at baseline and periodically during treatment. Institute medical management promptly to include specialty consultation as appropriate.

In general, withhold LIBTAYO for Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions. Permanently discontinue LIBTAYO for Grade 4 and certain Grade 3 immune-mediated adverse reactions [see Dosage and Administration (2.2)]. For Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions, administer corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy until improvement to Grade 1 or less followed by a corticosteroid taper over one month [see Dosage and Administration (2.2)]. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroids. Institute hormone replacement therapy for endocrinopathies as warranted.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis occurred in 2.4% of 534 patients receiving LIBTAYO, including Grade 5 (0.2%), Grade 3 (0.7%) and Grade 2 (1.3%) [see Adverse Reactions (6.1)]. Pneumonitis led to permanent discontinuation of LIBTAYO in 1.3% of patients. Systemic corticosteroids were required in all patients with pneumonitis, including 85% who received prednisone ≥ 40 mg per day or equivalent. Pneumonitis resolved in 62% of patients.

Immune-Mediated Colitis

Immune-mediated colitis occurred in 0.9% of 534 patients receiving LIBTAYO, including Grade 3 (0.4%) and Grade 2 (0.6%) [see Adverse Reactions (6.1)]. Colitis led to permanent discontinuation of LIBTAYO in 0.2% of patients. Systemic corticosteroids were required in all patients with colitis, including 60% who received prednisone ≥ 40 mg per day or equivalent. Colitis resolved in 80% of patients.

Immune-Mediated Hepatitis

Immune-mediated hepatitis occurred in 2.1% of 534 patients receiving LIBTAYO, including Grade 5 (0.2%), Grade 4 (0.2%), and Grade 3 (1.7%) [see Adverse Reactions (6.1)]. Hepatitis led to permanent discontinuation of LIBTAYO in 0.9% of patients. Systemic corticosteroids were required in all patients with hepatitis, including 91% who received prednisone ≥ 40 mg per day or equivalent. Hepatitis resolved in 64% of patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

Adrenal insufficiency occurred in 0.4% of 534 patients receiving LIBTAYO, including Grade 3 (0.2%), and Grade 2 (0.2%) [see Adverse Reactions (6.1)].

Hypophysitis

Hypophysitis, which can result in hypopituitarism, occurred in 0.2% of 534 patients receiving LIBTAYO, which consisted of one patient with Grade 3 hypophysitis.

Hypothyroidism

Hypothyroidism occurred in 6% of 534 patients receiving LIBTAYO, including Grade 3 (0.2%) and Grade 2 (5.6%). No patients discontinued hormone replacement therapy.

Hyperthyroidism

Hyperthyroidism occurred in 1.5% of 534 patients receiving LIBTAYO, including Grade 3 (0.2%) and Grade 2 (0.4%). Hyperthyroidism resolved in 38% of patients.

Type 1 Diabetes Mellitus

Type 1 diabetes mellitus, which can present with diabetic ketoacidosis, occurred in 0.7% of 534 patients, including Grade 4 (0.4%) and Grade 3 (0.4%). Type 1 diabetes mellitus led to permanent discontinuation of LIBTAYO in 0.2% of patients.

Immune-Mediated Nephritis with Renal Dysfunction

Immune-mediated nephritis occurred in 0.6% of 534 patients receiving LIBTAYO, including Grade 3 (0.4%) and Grade 2 (0.2%) [see Adverse Reactions (6.1)]. Nephritis led to permanent discontinuation of LIBTAYO in 0.2% of patients. Systemic corticosteroids were required in all patients with nephritis, including 67% who received prednisone ≥ 40 mg per day or equivalent. Nephritis resolved in all patients.

Immune-Mediated Dermatologic Adverse Reactions

Immune-mediated dermatologic reactions, including erythema multiforme and pemphigoid, occurred in 1.7% of 534 patients receiving LIBTAYO, including Grade 3 (1.1%) and Grade 2 (0.6%) [see Adverse Reactions (6.1)]. In addition, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been observed with LIBTAYO and with other products in this class. Systemic corticosteroids were required in all patients with dermatologic reactions, including 89% who received prednisone ≥ 40 mg per day or equivalent. Dermatologic reactions resolved in 33% of patients. Approximately 22% of patients had recurrence of dermatologic reactions after re-initiation of LIBTAYO.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 534 patients who received LIBTAYO [see Adverse Reactions (6.1)] or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Neurological: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome / myasthenia gravis, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy

Cardiovascular: Myocarditis, pericarditis, vasculitides

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal and Connective Tissue: Myositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica

Hematological and Immunological: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

5.2 Infusion-Related Reactions

Severe infusion-related reactions (Grade 3) occurred in 0.2% of patients receiving LIBTAYO [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue LIBTAYO based on severity of reaction [see Dosage and Administration (2.2)].

5.3 Embryo-Fetal Toxicity

Based on its mechanism of action, LIBTAYO can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling.

• Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
• Infusion-Related Reactions [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Warnings and Precautions reflect exposure to LIBTAYO in 534 patients in two open-label, single-arm, multicohort studies (Study 1423 and Study 1540), including 98 patients with mCSCC (nodal or distant), 65 patients with laCSCC, and 371 patients with other advanced solid tumors. LIBTAYO as a single agent or in combination with chemotherapy or radiation was administered intravenously at doses of 1 mg/kg every 2 weeks (n=27), 3 mg/kg every 2 weeks (n=446), 3 mg/kg every 3 weeks (n=12), 10 mg/kg every 2 weeks (n=6), 200 mg every 2 weeks (n=20) or 350 mg every 3 weeks (n=23). Among the 534 patients, 38% were exposed for ≥ 6 months and 16% were exposed for ≥ 12 months.

The data described below reflect exposure to LIBTAYO in 219 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1423 and Study 1540 [see Clinical Studies (14)]. Of these 219 patients, 131 had mCSCC (nodal or distant) and 88 had laCSCC. Patients received LIBTAYO 1 mg/kg every 2 weeks (n=1), 3 mg/kg every 2 weeks (n=162) or 350 mg every 3 weeks (n=56) as an intravenous infusion until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 38 weeks (2 weeks to 110 weeks).

The safety population characteristics were: median age of 72 years (38 to 96 years), 83% male, 96% white, and European Cooperative Oncology Group (ECOG) performance score (PS) of 0 (44%) and 1 (56%).

The most common adverse reactions reported in at least 20% of patients were fatigue, rash, diarrhea, musculoskeletal pain, and nausea. The most common Grade 3-4 adverse reactions (≥ 2%) were cellulitis, anemia, hypertension, pneumonia, musculoskeletal pain, fatigue, pneumonitis, sepsis, skin infection, and hypercalcemia. LIBTAYO was permanently discontinued due to adverse reactions in 8% of patients; adverse reactions resulting in permanent discontinuation were pneumonitis, cough, pneumonia, encephalitis, aseptic meningitis, hepatitis, arthralgia, muscular weakness, neck pain, soft tissue necrosis, complex regional pain syndrome, lethargy, psoriasis, rash maculopapular, proctitis, and confusional state. Serious adverse reactions occurred in 35% of patients. Serious adverse reactions that occurred in at least 2% of patients were pneumonitis, cellulitis, sepsis, and pneumonia.

Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 3 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving LIBTAYO.

*Fatigue is a composite term that includes fatigue and asthenia

†Rash is a composite term that includes rash, rash maculopapular, erythema, dermatitis, dermatitis bullous, rash generalized, pemphigoid, rash erythematous, rash macular, rash pruritic, drug eruption, psoriasis, and skin reaction

‡Pruritus is a composite term that includes pruritus and pruritus allergic

§Diarrhea is a composite term that includes diarrhea and colitis

¶Musculoskeletal pain is a composite term that includes back pain, pain in extremity, myalgia, musculoskeletal pain, and neck pain

#Cough is a composite term that includes cough and upper airway cough syndrome

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cemiplimab-rwlc in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Anti-drug antibodies (ADA) were tested in 467 patients who received LIBTAYO. The incidence of cemiplimab-rwlc treatment-emergent ADAs was 1.1% using an electrochemiluminescent (ECL) bridging immunoassay; 0.2% were persistent ADA responses. In the patients who developed anti-cemiplimab-rwlc antibodies, there was no evidence of an altered pharmacokinetic profile of cemiplimab-rwlc.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, LIBTAYO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of LIBTAYO in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data). Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, LIBTAYO has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with LIBTAYO to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering LIBTAYO during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to cemiplimab-rwlc may increase the risk of developing immune-mediated disorders or altering the normal immune response.

8.2 Lactation

Risk Summary

There is no information regarding the presence of cemiplimab-rwlc in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for at least 4 months after the last dose of LIBTAYO.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating LIBTAYO [see Use in Specific Populations (8.1)].

Contraception

LIBTAYO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose.

8.4 Pediatric Use

The safety and effectiveness of LIBTAYO have not been established in pediatric patients.

8.5 Geriatric Use

Of the 219 mCSCC or laCSCC patients who received LIBTAYO in clinical studies, 34% were 65 years up to 75 years and 41% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

11 DESCRIPTION

Cemiplimab-rwlc is a human programmed death receptor-1 (PD-1) blocking antibody. Cemiplimab-rwlc is a recombinant human IgG4 monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2. Cemiplimab-rwlc is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. Cemiplimab-rwlc has an approximate molecular weight of 146 kDa.

LIBTAYO (cemiplimab-rwlc) injection for intravenous use is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution with a pH of 6. The solution may contain trace amounts of translucent to white particles.

Each vial contains 350 mg of cemiplimab-rwlc. Each mL contains cemiplimab-rwlc 50 mg, L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.1 mg), sucrose (50 mg), L-proline (15 mg), Polysorbate 80 (2 mg), and Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.

Cemiplimab-rwlc is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

12.3 Pharmacokinetics

Cemiplimab-rwlc pharmacokinetic data were collected in 548 patients with various solid tumors, including 178 patients with CSCC. The pharmacokinetics of cemiplimab-rwlc was linear and dose proportional in the dose range of 1 mg/kg to 10 mg/kg LIBTAYO administered intravenously every 2 weeks.

In patients with CSCC, cemiplimab-rwlc steady-state exposure at 350 mg every 3 weeks is comparable to the exposure at 3 mg/kg every 2 weeks. At 350 mg every 3 weeks, the mean cemiplimab-rwlc concentrations (coefficient of variation, CV%) at steady-state ranged between a minimum concentration of 63 mg/L (45%) and a maximum concentration of 151 mg/L (31%). Steady-state exposure is achieved after 4 months of treatment.

Distribution

The volume of distribution of cemiplimab-rwlc at steady state is 5.2 L (24%).

Elimination

Cemiplimab-rwlc clearance (CV%) after the first dose is 0.33 L/day (39%) and decreases over time by 36%, resulting in a steady-state clearance (CLss) (CV%) of 0.21 L/day (39%). The elimination half-life (CV%) at steady state is 19 days (38%).

Specific Populations

The following factors have no clinically important effect on the exposure of cemiplimab-rwlc: age (27 to 96 years), sex, body weight (31 to 172 kg), race (White, Black, Asian and other), cancer type, albumin level (22 to 48 g/L), renal function (creatinine clearance determined by Cockcroft-Gault 25 mL/min or greater) and hepatic function (total bilirubin 0.35 to 45 µmol/L). LIBTAYO has not been studied in patients with moderate or severe hepatic impairment.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of cemiplimab-rwlc for carcinogenicity or genotoxicity.

In a 3-month repeat-dose toxicology study in sexually mature cynomolgus monkeys, there were no cemiplimab-rwlc-related effects on fertility parameters (menstrual cycle, semen analysis, or testicular measurements) or in male or female reproductive organs at doses up to the highest dose tested, 50 mg/kg/week (approximately 5.5 to 25.5 times the human exposure based on AUC at the clinical dose of 350 mg once every 3 weeks).

13.2 Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.

14 CLINICAL STUDIES

The efficacy of LIBTAYO in 219 patients with metastatic (nodal or distant) cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who were not candidates for curative surgery or curative radiation was evaluated in two open-label, multi-center, non-randomized, multicohort studies: Study 1423 (NCT02383212) and Study 1540 (NCT02760498). Both studies excluded patients with autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; prior treatment with anti–PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitor therapy; infection with HIV, hepatitis B or hepatitis C; or ECOG PS ≥ 2.

Patients received LIBTAYO 3 mg/kg intravenously every 2 weeks for up to 48 weeks in Study 1423 or up to 96 weeks in Study 1540. An additional cohort of patients in Study 1540 received 350 mg every 3 weeks for up to 54 weeks. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment. Tumor response assessments were performed every 8 or 9 weeks. The major efficacy outcome measures were confirmed objective response rate (ORR), defined as complete response (CR) plus partial response (PR) as assessed by independent central review (ICR), and ICR-assessed duration of response (DOR). For patients with mCSCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). For patients with externally visible target lesions (laCSCC and mCSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria).

Study 1540

Among the 193 patients with advanced CSCC enrolled in Study 1540 who received LIBTAYO at either 3 mg/kg every 2 weeks or 350 mg every three weeks, 115 had mCSCC and 78 had laCSCC. The median age was 72 years (38 to 96 years); 83% were male; 97% were White; 45% had ECOG PS 0 and 55% had ECOG PS 1; 34% received at least one prior anti-cancer systemic therapy; 90% received prior cancer-related surgery; and 68% received prior radiotherapy. Among patients with mCSCC, 77% had distant metastases and 23% had only nodal metastases.

For the responding patients presented in Table 4 below, the median time to response was 1.9 months (range: 1.7 to 9.1 months).

Efficacy results in patients who received 3 mg/kg every 2 weeks are presented in Table 4.

CI: confidence interval; NR: Not reached; +: Denotes ongoing at last assessment

*Median duration of follow up: mCSCC: 16.5 months; laCSCC: 9.3 months; combined CSCC: 11.1 months

†Only includes patients with complete healing of prior cutaneous involvement; laCSCC patients in Study 1540 required biopsy to confirm CR.

‡The numerator includes the number of patients whose observed DOR reached at least the specified times of 6 or 12 months. Patients who did not have the opportunity to reach the specified timepoint were included in the denominator only.

Study 1540: 350 mg every 3 weeks

In an additional cohort in Study 1540, 56 patients received cemiplimab-rwlc at a dose of 350 mg intravenously every 3 weeks for up to 54 weeks. With a median duration of follow-up of 8.0 months, the confirmed ORR was 41% (95% CI: 28, 55), and 65% of responders had a DOR ≥ 6 months.

Study 1423

Among 26 CSCC patients in Study 1423, 16 had mCSCC and 10 had laCSCC. The median age was 73 years (52 to 88 years); 81% of patients were male; 92% of patients were White; the ECOG PS was 0 (38%) and 1 (62%); 58% of patients had received at least 1 prior anti-cancer systemic therapy; 92% of patients had received prior cancer-related surgery and 81% had received prior radiotherapy. One patient in the mCSCC group was dosed at 1 mg/kg. The rest received 3 mg/kg every 2 weeks.

With a median duration of follow-up of 13.3 months, the confirmed ORR was 50% (95% CI: 30, 70); all responses were PRs. The median time to response was 1.9 months (range: 1.7 to 7.3 months) and 85% of responders had a DOR ≥ 6 months.

16 HOW SUPPLIED/STORAGE AND HANDLING

LIBTAYO (cemiplimab-rwlc) injection is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. It is supplied in a carton containing 1 single-dose vial of:

• 350 mg/7 mL (50 mg/mL) (NDC 61755-008-01)

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Protect from light. Do not freeze or shake.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Advise patients that LIBTAYO can cause immune-mediated adverse reactions including the following [see Warnings and Precautions (5.1)]:

• Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of cough, chest pain, or shortness of breath.
• Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of colitis, including diarrhea, blood or mucus in stools, or severe abdominal pain.
• Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.
• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus.
• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
• Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash.

Infusion-Related Reactions

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].

Embryo-Fetal Toxicity

Advise females of reproductive potential that LIBTAYO can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose of LIBTAYO [see Use in Specific Populations (8.3)].

Lactation

Advise female patients not to breastfeed while taking LIBTAYO and for at least 4 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by:
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown, NY 10591-6707
U.S. License No. 1760

Marketed by:
Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) and
sanofi-aventis U.S. LLC (Bridgewater, NJ 08807)
©2020 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC.
All rights reserved.

PRINCIPAL DISPLAY PANEL - 350 mg/7 mL Vial Carton

NDC 61755-008-01
Rx only

LIBTAYO®
(cemiplimab-rwlc)
Injection

350 mg/7 mL (50 mg/mL)

For Intravenous Infusion After Dilution
Single-Dose Vial

Discard unused portion.

Do not use vial if seal is broken or missing.
Dispense the enclosed Medication Guide to each patient.

REGENERON ∣ SANOFI GENZYME

【备注】以上内容仅供参考，不作为用药依据，详情请参照药品附带说明书。