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1适应症和用途

PADCEV TM用于治疗局部局部晚期或转移性尿路上皮癌（mUC）的成年患者，这些患者先前已接受程序性死亡受体1（PD-1）或程序​​性死亡配体1（PD-L1）抑制剂，以及新辅助/辅助，局部晚期或转移性环境中的含铂化疗。

该适应症是根据肿瘤反应率在加速批准下批准的[参见临床研究（14.1）]。对于该适应症的持续批准可能取决于验证试验中对临床益处的验证和描述。

2剂量和给药

2.1推荐剂量

PADCEV的推荐剂量为1.25 mg / kg（≥100 kg的患者最多125 mg），在28天周期的第1、8和15天30分钟内静脉输注，直至疾病进展或不可接受毒性。

2.2剂量修改

表1.剂量修改

表2.推荐的减量时间表

2.3准备和管理说明

•辖PADCEV仅作为静脉内输注。

•PADCEV是一种细胞毒性药物。请遵循适用的特殊处理和处置程序。1个

给药前，用无菌注射用水（SWFI）重构PADCEV小瓶。随后将重构的溶液稀释在静脉输液袋中，该输液袋包含5％葡萄糖注射液USP，0.9％氯化钠注射液USP或乳酸林格氏注射液USP。

在单剂量小瓶中重建

1。遵循正确处理和处置抗癌药物的程序。

2。使用适当的无菌技术来重构和制备剂量解决方案。

3。根据患者的体重计算推荐剂量，以确定所需的小瓶数量和强度（20 mg或30 mg）。

4。如下重新配制每个小瓶，如果可能，将SWFI液流沿着小瓶壁引导，而不是直接引导至冻干粉末上：

a。20 mg小瓶：加入2.3 mL SWFI，得到10 mg / mL PADCEV。

b。30 mg小瓶：加入3.3 mL SWFI，得到10 mg / mL PADCEV。

5。缓慢旋转每个小瓶，直到内容物完全溶解。让重构后的小瓶沉降至少1分钟，直到气泡消失。不要摇晃小瓶。不直接暴露在阳光下。

6。只要溶液和容器允许，在给药前应目视检查肠胃外药品中是否有颗粒物和变色。重新配制的溶液应为澄清至微乳白色，无色至浅黄色，无可见颗粒。丢弃所有带有可见颗粒或变色的小瓶。

7。根据计算的剂量，应立即将小瓶中的重构溶液添加到输液袋中。该产品不含防腐剂。如果不立即使用，重构过的样品瓶可在2°C至8°C（36°F至46°F）的冷藏条件下最多保存4小时。不要冻结。超过建议的存储时间，请使用未配制的溶液丢弃未使用的样品瓶。

输液袋稀释

8。从小瓶中取出计算出的配制溶液剂量，然后转移到输液袋中。

9。用5％葡萄糖注射液，0.9％氯化钠注射液或乳酸林格氏注射液稀释PADCEV。输液袋的大小应允许有足够的稀释剂，以使最终浓度达到0.3 mg / mL至4 mg / mL PADCEV。

10。轻轻颠倒混合稀释的溶液。不要摇晃包。不直接暴露在阳光下。

11。使用前，目视检查输液袋是否有任何颗粒物或变色。重新配制的溶液应为澄清至微乳白色，无色至浅黄色，无可见颗粒。如果发现颗粒物或变色，请勿使用输液袋。

12。丢弃单剂量药瓶中任何未使用的部分。

行政

13。通过静脉管线在30分钟内立即给药。

14。如果不立即输注，准备好的输液袋在2°C至8°C（36°F至46°F）下不应存放超过8小时。不要冻结。

请勿以静脉推注或推注的方式给予PADCEV。

请勿将PADCEVEV与其他药品混合或作为输注剂使用。

3剂型和强度

注射用：20毫克和30毫克的enfortumab vedotin-ejfv，白色至灰白色冻干粉末，装在单剂量小瓶中，以进行重构。

4禁忌症

没有。

5警告和注意事项

5.1高血糖

高血糖症发生在接受PADCEV治疗的患者中，包括有和没有糖尿病的患者，包括死亡和糖尿病性酮症酸中毒（DKA）。体重指数较高的患者和基线A1C较高的患者，3-4级高血糖的发生率持续增加。在EV-201中，有8％的患者出现3-4级高血糖。在该试验中，排除了基线血红蛋白A1C≥8％的患者。密切监测患有糖尿病或高血糖症或有此风险的患者的血糖水平。如果血糖升高（> 250 mg / dL），则停用PADCEV [参见剂量和用法（2.2）]。

5.2周围神经病变

临床试验中，接受PADCEV治疗的310例患者中有49％发生了周围神经病变，主要是感觉异常。2％经历了3级反应。

在研究EV-201中，接受PADCEV治疗的患者有或没有既往存在周围神经病变，都会发生周围神经病变。≥2级的中位发作时间为3.8个月（范围：0.6至9.2）。神经病导致6％的患者停药。上一次评估时，有19％的人拥有完整的分辨率，而26％的人有部分改善。

监测患者是否出现新的或恶化的周围神经病症状，并在发生周围神经病时考虑剂量中断或PADCEV剂量减少。永久中止PADCEV在于开发级患者> 3周神经病[见剂量和给药方法（2.2）]。

5.3眼部疾病

在接受PADCEV治疗的310例患者中，有46％发生了眼部疾病。这些事件大多数涉及角膜，包括角膜炎，视力模糊，角膜缘干细胞缺乏症和其他与干眼有关的事件。

在PADCEV治疗期间，有36％的患者出现干眼症状，有14％的患者出现视力模糊。症状性眼病发作的中位时间为1.9个月（范围：0.3至6.2）。

监视患者的眼部疾病。如果眼部症状出现或无法解决，请考虑使用人工泪液预防干眼和眼科评估。如果经过眼科检查后发现有眼科局部类固醇治疗，可以考虑。对于有症状的眼部疾病，考虑中断PADCEV的剂量或降低剂量。

5.4皮肤反应

在临床试验中，接受PADCEV治疗的310名患者中有54％发生皮肤反应。26％（26％）的患者出现了斑丘疹和30％的瘙痒。3-4级皮肤反应发生在10％的患者中，包括对称的药物相关性三叉和弯曲性皮层瘤（SDRIFE），大疱性皮炎，剥脱性皮炎和掌-红斑感觉异常。

在研究EV-201中，发生严重皮肤反应的中位时间为0.8个月（范围：0.2至5.3）。在发生皮疹的患者中，65％的患者可以完全解决，22％的患者可以部分改善。

监视患者的皮肤反应。根据临床指示，考虑采取适当的治疗方法，例如局部皮质类固醇和抗组胺药治疗皮肤反应。对于严重的（第3级）皮肤反应，应暂缓使用PADCEV，直至改善或缓解并进行适当的医学治疗。在出现4级或复发3级皮肤反应的患者中永久停用PADCEV [请参阅剂量和给药方法（2.2）]。

5.5输液部位外渗

给予PADCEV后，观察到了皮肤和软组织的外溢继发反应。在310名患者中，有1.3％的患者出现了皮肤和软组织反应。反应可能会延迟。红斑，肿胀，体温升高和疼痛加剧，直至外渗后2-7天，并在高峰后1-4周内消失。百分之一的患者发生继发性蜂窝织炎，大疱或脱落的渗出反应。在开始使用PADCEV之前，请确保有足够的静脉通路，并在给药期间监测可能的外渗。如果发生渗出，停止输液并监测不良反应。

5.6胚胎-胎儿毒性

根据动物的作用机制和发现，PADCEV对孕妇给药可引起胎儿伤害。在动物生殖研究中，在器官发生期间向孕鼠施用恩诺单抗vedotin导致母体暴露时的母体毒性，胚胎-胎儿致死率，结构畸形和骨骼异常与推荐的人为1.25 mg / kg的人体暴露量大致相似。

告知患者胎儿的潜在危险。劝告有生殖潜力的女性患者在PADCEV治疗期间和最后一次给药后的2个月内使用有效的避孕方法。建议男性患者繁殖潜力的女性伴侣与治疗过程中使用的有效避孕PADCEV和用于在最后一次给药4个月后[见特殊人群中使用（8.1，8.3）和临床药理学（12.1）]。

6不良反应

标签上其他地方描述了以下严重不良反应：

•高血糖[请参阅警告和注意事项（5.1）]

•周围神经病变[请参阅警告和注意事项（5.2）]

•眼部疾病[请参阅警告和注意事项（5.3）]

•皮肤反应[请参阅警告和注意事项（5.4）]

•输液部位外溢[请参阅警告和注意事项（5.5）]

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”部分中的数据反映了EV-201，EV-101（NCT02091999）和EV-102（NCT03219333）的310位患者中以单药1.25 mg / kg 暴露于PADCEV的情况。在接受PADCEV的 310位患者中，有30％暴露> 6个月，而8％暴露≥12个月。

本节中描述的数据反映了EV-201 对PADCEV的暴露，EV-201是一项单臂研究，针对先前接受过PD-1或PD-L1抑制剂和铂治疗的局部晚期或转移性尿路上皮癌患者（n = 125）化疗。患者在28天周期的第1、8和15天接受PADCEV 1.25 mg / kg，直到疾病进展或出现不可接受的毒性。PADCEV的中位暴露时间为4.6个月（范围：0.5-15.6）。

在接受PADCEV治疗的患者中，有46％发生了严重的不良反应。最常见的严重不良反应（≥3％）是尿路感染（6％），蜂窝织炎（5％），高热性中性粒细胞减少症（4％），腹泻（4％），败血症（3％），急性肾损伤（3） ％），呼吸困难（3％）和皮疹（3％）。致命的不良反应发生在3.2％的患者中，包括急性呼吸衰竭，吸入性肺炎，心脏疾病和败血症（每人0.8％）。

导致停药的不良反应发生在16％的患者中；导致停药的最常见不良反应是周围神经病变（6％）。导致剂量中断的不良反应发生在64％的患者中；导致剂量中断的最常见不良反应是周围神经病变（18％），皮疹（9％）和疲劳（6％）。导致剂量降低的不良反应发生在34％的患者中；导致剂量减少的最常见不良反应是周围神经病（12％），皮疹（6％）和疲劳（4％）。

最常见的不良反应（≥20％）为疲劳，周围神经病变，食欲下降，皮疹，脱发，恶心，消化不良，腹泻，干眼症，瘙痒和皮肤干燥。最常见的≥3级不良反应（≥5％）是皮疹，腹泻和疲劳。

表3总结了EV-201患者中报告的所有等级和≥3级不良反应。

表3. 在EV-201中接受PADCEV治疗的患者中≥15％（任何年级）或≥5％（≥3年级）的不良反应报道

其他临床上显着的不良反应（≤15％）包括：带状疱疹（3％）和输注部位外渗（2％）。

表4. 在EV-201中接受PADCEV治疗的患者中≥10％（2-4级）或≥5％（3-4级）报告的某些实验室异常

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，将以下描述的研究中的抗体发生率与其他研究或其他Enfortumab vedotin产品中的抗体发生率进行比较可能会产生误导。

共有365名患者对PADCEV进行了免疫原性检测 ; 确认有4例（1％）的抗治疗性抗体（ATA）暂时呈阳性，而有1例（0.3％）的ATA持续阳性在任何基线后时间点均被确认。没有观察到ATA对功效，安全性和药代动力学的影响。

7药物相互作用

7.1其他药物对PADCEV的影响

强效CYP3A4抑制剂与强效CYP3A4抑制剂同时使用可能会增加MMAE的游离暴露[见临床药理学（12.3）]，这可能会增加PADCEV毒性的发生率或严重性。当PADCEV与强效CYP3A4抑制剂同时给予时，应密切监测患者的毒性迹象。

8在特定人群中的使用

8.1怀孕

风险摘要

根据动物的作用机制和发现，PADCEV对孕妇给药可引起胎儿伤害[见临床药理学（12.1）]。目前尚无有关孕妇使用PADCEV的人类数据来告知与药物相关的风险。在一项动物生殖研究中，在器官形成过程中对怀孕大鼠给予enfortumab vedotin-ejfv导致母体暴露时的母体毒性，胚胎-胎儿致死率，结构畸形和骨骼异常与推荐的人为1.25 mg / kg的人为暴露量相似（参见数据）。告知患者胎儿的潜在危险。

对于所指示的人群，主要出生缺陷和流产的背景风险尚不清楚。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％-4％和15％-20％。

数据

动物资料

在一项大鼠先天胚胎胎儿发育研究中，在器官发生期间的妊娠第6天和第13天服用enfortumab vedotin-ejfv在母体毒性剂量为5 mg / kg（约3倍于建议的人类剂量的暴露量）。2 mg / kg的剂量（大约与建议的人类剂量下的暴露量相似）导致孕产妇毒性，胚胎-胎儿致死率和结构畸形，包括胃痉挛，后肢旋转不良，前爪缺失，内脏器官位置不正确和颈弓融合。此外，观察到骨骼异常（不对称，融合，骨化不完全，胸骨畸形，颈弓畸形和胸椎中央单侧骨化）和胎儿体重减少。

8.2哺乳

风险摘要

没有关于母乳中存在enfortumab vedotin-ejfv，对母乳喂养的孩子的影响或对牛奶产量的影响的数据。由于母乳喂养的孩子可能会出现严重的不良反应，因此建议哺乳期妇女在PADCEV治疗期间以及最后一次给药后至少3周内不要母乳喂养。

8.3生殖潜力的雌雄

验孕

在开始PADCEV治疗之前，验证具有生殖潜能的女性的妊娠状况[请参阅在特定人群中使用（8.1）]。

避孕

女性

对孕妇使用PADCEV可能会造成胎儿伤害[请参阅“在特定人群中使用（8.1）”]。劝告有生殖潜力的女性在使用PADCEV治疗期间以及最后一次用药后2个月内使用有效的避孕方法。

雄性

建议具有生殖潜能的女性伴侣的男性患者在接受PADCEV治疗期间以及最后一次给药后的4个月内使用有效的避孕方法。

不孕症

雄性

根据动物研究的结果，PADCEV可能会损害男性的生育能力[请参见非临床毒理学（13.1）]。

8.4小儿使用

尚未确定PADCEV在儿科患者中的安全性和有效性。

8.5老年用途

在临床研究中接受PADCEV治疗的310名患者中，有187名（60％）为65岁或以上，另有80名（26％）为75岁或以上。在这些患者和年轻患者之间未观察到安全性或有效性的总体差异[见临床药理学（12.3）]。

8.6肝功能不全

在中度或重度肝功能不全的患者中避免使用PADCEV。尚未对中度或重度肝功能不全患者进行PADCEV研究[见临床药理学（12.3）]。在另一个包含MMAE的ADC中，中度（Child-Pugh B）或重度（Child-Pugh C）肝功能不全患者的≥3级不良反应和死亡的频率高于正常肝功能的患者。对轻度肝功能不全的患者给予PADCEV时，无需调整起始剂量。

8.7肾功能不全

轻度（CrCL> 60-90 mL / min），中度（CrCL 30-60 mL / min）或重度（CrCL <30 mL / min）肾功能不全的患者无需调整剂量[参见临床药理学（12.3）]。

11说明

Enfortumab vedotin-ejfv是一种Nectin-4定向抗体-药物偶联物（ADC），由与小分子微管破坏剂单甲基澳他汀E（MMAE）偶联的完全人源抗Nectin-4 IgG1 kappa单克隆抗体（AGS-22C3）组成。 ）可通过蛋白酶裂解的马来酰亚胺基己酰基缬氨酸-瓜氨酸（vc）接头（SGD-1006）。在包含抗体的链间二硫键的半胱氨酸残基上发生缀合，以产生药物/抗体比率约为3.8：1的产物。分子量约为152kDa。

图1.结构式

每个抗体分子连接大约4个MMAE分子。Enfortumab vedotin-ejfv是通过抗体和小分子成分的化学结合而产生的。该抗体是由哺乳动物（中国仓鼠卵巢）细胞产生的，而小分子成分是通过化学合成产生的。

注射用的PADCEV（enfortumab vedotin-ejfv）为无菌，不含防腐剂的白色至灰白色冻干粉剂，用于静脉内单剂量小瓶中。PADCEV以每瓶20 mg和每瓶30 mg的形式提供，并需要用USP无菌注射用水（分别为2.3 mL和3.3 mL）重新配制，以产生澄清至微乳白色，无色至微黄色的溶液，最终浓度为10 mg / mL [请参阅剂量和用法（2.3）]。复溶后，每个小瓶可抽出2 mL（20 mg）和3 mL（30 mg）。每毫升重构溶液包含10毫克的Enfortumab vedotin-ejfv，组氨酸（1.4毫克），组氨酸盐酸盐一水合物（2.31毫克），聚山梨酯20（0.2毫克）和海藻糖二水合物（55毫克），pH值为6.0。

12临床药理学

12.1行动机制

Enfortumab vedotin-ejfv是ADC。该抗体是针对Nectin-4的人IgG1，Nectin-4是一种位于细胞表面的粘附蛋白。小分子MMAE是一种微管破坏剂，通过蛋白酶可裂解的接头与抗体连接。非临床数据表明，enfortumab vedotin-ejfv的抗癌活性是由于ADC与表达Nectin-4的细胞结合，随后ADC-Nectin-4复合物的内在化，以及通过蛋白水解切割释放的MMAE。MMAE的释放破坏了细胞内的微管网络，随后诱导了细胞周期停滞和凋亡性细胞死亡。

12.2药效学

在暴露-反应分析中，较高的enfortumab vedotin暴露与某些不良反应的发生率较高（例如，≥2级周围神经病，≥3级高血糖）和较低的暴露与较低的疗效相关。

心脏电生理学

在推荐剂量下，PADCEV的 QTc延长时间不大（> 20毫秒）。

12.3药代动力学

人群药代动力学分析包括基于三项1期研究和一项2期研究的369位患者的数据。在患有局部晚期或转移性尿路上皮癌和其他实体瘤的患者中，单次和多次给药后表征Enfortumab vedotin-ejfv的药代动力学。

ADC和未缀合的MMAE（enfortumab vedotin-ejfv的细胞毒性成分）的暴露参数总结在下表5中。在enfortumab vedotin-ejfv给药后约2天，在静脉输注即将结束时观察到了ADC峰浓度，而在MMAE峰中观察到了浓度。在患者中重复施用enfortumab vedotin-ejfv后，观察到ADC和MMAE的累积最少。1个治疗周期后达到ADC和MMAE的稳态浓度。

表5.第1、8和15天的Enfortumab vedotin-ejfv剂量第一个治疗周期1.25 mg / kg的ADC和未结合的MMAE的暴露参数

分配

服用enfortumab vedotin-ejfv后，ADC的估计平均稳态分布体积为11升。在体外，MMAE的血浆蛋白结合率为68％至82％。

消除

ADC和MMAE表现出多指数下降，消除半衰期分别为3.4天和2.4天。患者中enfortumab vedotin-ejfv和游离MMAE的平均清除率（CL）分别为0.10 L / h和2.7 L / h。MMAE的消除似乎受到其从enfortumab vedotin-ejfv释放的速率的限制。

代谢

Enfortumab vedotin-ejfv分解代谢尚未在人类中进行研究；但是，它预期会分解为小肽，氨基酸，未结合的MMAE和未结合的MMAE相关分解代谢产物。Enfortumab vedotin-ejfv通过蛋白水解裂解释放MMAE，MMAE在体外主要通过CYP3A4代谢。

排泄

Enfortumab vedotin-ejfv的排泄尚未完全表征。在单剂量的另一个包含MMAE的ADC之后，在1周的时间内，粪便中回收的MMAE总量为17％，尿液中回收的MMAE为6％，主要是作为未改变的药物。服用enfortumab vedotin-ejfv后，预计MMAE的排泄情况类似。

特定人群

根据人群药代动力学分析，enfortumab vedotin-ejfv的药代动力学在临床上没有发现显着差异，这是基于年龄（24至87岁），性别或种族/民族（高加索人，亚洲人，黑人或其他人）的。

肝功能不全

根据人群药代动力学分析，轻度肝功能不全（胆红素为1至1.5×ULN和AST ULN，n = 31）的患者在未结合的MMAE暴露中观察到的AUC升高了48％与正常肝功能相比。尚不清楚中度或重度肝功能损害（AST或ALT> 2.5 x ULN或总胆红素> 1.5 x ULN）或肝移植对ADC或未结合的MMAE药代动力学的影响。

肾功能不全

在轻度（肌酐清除率； CrCL> 60–90 mL / min； n = 135），中度（CrCL 30）患者中，给予1.25 mg / kg的enfortumab vedotin-ejfv后，评估enfortumab vedotin-ejfv和MMAE的药代动力学–60 mL / min； n = 147）和严重（CrCL <30 mL / min； n = 8）肾功能不全。与轻度，中度或重度肾功能不全患者相比，肾功能正常的患者ADC和MMAE的暴露量（AUC）无明显差异。尚无透析的终末期肾脏疾病对ADC或未结合的MMAE药代动力学的影响尚不清楚。

药物相互作用研究

临床研究

尚未进行评估enfortumab vedotin-ejfv的药物相互作用的临床研究。为了表征游离MMAE的药物相互作用的潜力，下面介绍了使用另一个包含MMAE的ADC进行的临床研究。

强效CYP3A4抑制剂：另一个含有MMAE与酮康唑（一种强效CYP3A4抑制剂）共同给药的ADC将MMAE C max升高25％，AUC 升高34％，而ADC暴露无变化。CYP3A4的强抑制剂与PADCEV的同时使用可能会对游离MMAE和ADC产生相似的作用。

强效CYP3A4诱导剂：另一种包含MMAE与利福平（一种强效CYP3A4诱导剂）共同给药的ADC使MMAE max降低44％，AUC降低46％，而ADC暴露无变化。CYP3A4的强诱导剂与PADCEV的同时使用可能会对游离MMAE和ADC产生相似的作用。

敏感的CYP3A4底物：另一个含有MMAE与咪达唑仑共同给药的ADC（敏感的CYP3A4底物）不影响咪达唑仑的暴露。同样，PADCEV不会改变被CYP3A4酶代谢的药物的暴露。

体外研究

转运系统： MMAE是P-糖蛋白（P-gp）的底物，但不是P-gp的抑制剂。

13毒理学

13.1致癌，诱变，生育力受损

尚未进行使用enfortumab vedotin-ejfv或小分子细胞毒剂（MMAE）的致癌性研究。

MMAE在大鼠骨髓微核中通过一种成气机制具有遗传毒性。该作用与MMAE作为微管破坏剂的药理作用一致。在细菌反向突变测定（Ames试验）或L5178Y小鼠淋巴瘤正向突变测定中，MMAE不致突变。

尚未进行enfortumab vedotin-ejfv或MMAE的生育力研究。但是，大鼠重复剂量毒性研究的结果表明，enfortumab vedotin-ejfv可能损害男性生殖功能和生育能力。

在长达13周的大鼠重复剂量毒理学研究中，剂量≥2 mg / kg的enfortumab vedotin-ejfv（与推荐的人类剂量下的暴露量相似）导致睾丸和附睾重量减少，生精小管变性，睾丸中精子/精细胞的消耗以及附睾中的细胞碎片，精子肉芽肿和精子过多/精子异常。在恢复期结束时，睾丸和附睾中的发现并未逆转。

14临床研究

14.1转移性尿路上皮癌

PADCEV的疗效在EV-201（NCT03219333）单臂多中心试验中进行了评估，该试验招募了125名接受PD-1或PD-L1抑制剂和铂类化学疗法治疗的局部晚期或转移性尿路上皮癌患者。如果患者患有活跃的中枢神经系统转移，进行中的感觉或运动神经病≥2级或不受控制的糖尿病（定义为血红蛋白A1C（HbA1c）≥8％或HbA1c≥7％，伴有相关糖尿病症状），则排除在外。

中位年龄为69岁（范围：40至84岁），男性占70％，白种人占85％。所有患者的东部协作肿瘤学组（ECOG）基线表现状态为0（32％）或1（68％）。90％的患者发生内脏转移，包括40％的肝转移。三分之二的患者患有单纯性移行细胞癌（TCC）组织学；33％的患者具有其他组织学变异的TCC。免疫组织化学临床试验测定法用于评估可利用肿瘤组织的患者，并在所有接受测试的患者中检测Nectin-4表达（n = 120）。先前全身治疗的中位数为3（范围：1至6）。46％的患者接受过PD-1抑制剂治疗，42％接受了PD-L1抑制剂治疗，另有13％的患者接受了PD-1和PD-L1抑制剂治疗。

主要疗效结局指标是使用RECIST v1.1通过盲目的独立中心评估（BICR）评估的客观缓解率（ORR）和缓解持续时间（DOR）。

功效结果列于表6。

表6. EV201的疗效结果（BICR评估）

15参考

1。“ OSHA危险药物”。OSHA。http://www.osha.gov/SLTC/hazardousdrugs/index.html

16供应/存储和处理方式

16.1供应方式

PADCEV（enfortumab vedotin-ejfv）20 mg和30 mg以无菌，不含防腐剂的白色至灰白色冻干粉末形式提供在单剂量小瓶中。PADCEV小瓶有以下包装：

•一箱20毫克单剂量小瓶（NDC 51144-020-01）

•一箱30 mg单剂量小瓶（NDC 51144-030-01）

16.2储存

将PADCEV样品瓶冷藏在2ºC至8ºC（36ºF至46ºF）的原始纸箱中。不要冻结。不要摇晃。

16.3特殊处理

PADCEV是一种细胞毒性药物。请遵循适用的特殊处理和处置程序。1个

17患者咨询信息

建议患者阅读FDA批准的患者标签（患者信息）。

高血糖症

告知患者高血糖的风险以及如何识别相关症状[参见警告和注意事项（5.1）]。

周围神经病变

通知患者向其医护人员报告手脚或脚部麻木和刺痛或肌肉无力[请参阅警告和注意事项（5.2）]。

眼部疾病：

如果患者出现任何视觉变化，建议他们与他们的医疗保健提供者联系[请参阅警告和注意事项（5.3）]。为了预防或治疗干眼症，建议患者使用人工泪液替代品。

皮肤反应

告知患者服用PADCEV后出现皮疹和严重的皮肤反应。建议患者就其进行性或不可忍受的皮肤反应的体征和症状联系其医疗保健提供者[请参阅警告和注意事项（5.4）]。

输液部位外渗

告知患者输注PADCEV后发生了输液部位反应。这些反应通常在给药后立即发生，但在某些情况下起病延迟（例如24小时）。指示患者如果遇到输液部位反应，请立即与他们的医疗服务提供者联系[请参阅警告和注意事项（5.5）]。

胚胎-胎儿毒性

建议孕妇和女性生殖潜力对胎儿的潜在危险。劝告女性告知其已知或怀疑怀孕的医疗保健提供者[请参阅警告和注意事项（5.6）和特定人群的使用（8.1）]。

生殖潜力的男性和女性

劝告有生殖潜力的女性患者在PADCEV治疗期间和最后一次给药后的2个月内使用有效的避孕方法。建议具有生殖潜力的女性伴侣的男性患者在接受PADCEV治疗期间以及最后一次给药后的4个月内使用有效的避孕药[请参见在特定人群中使用（8.3）]。

哺乳期

劝告妇女在PADCEV治疗期间以及末次给药后3周内不要母乳喂养[见在特定人群中使用（8.2）]。

不孕症

向有生殖能力的男性建议PADCEV可能会损害生育能力[请参见在特定人群中使用（8.3）]。

生产和销售：
Astellas Pharma US，Inc
.伊利诺斯州诺斯布鲁克，60062

发行和销售：
西雅图遗传公司，博塞尔，华盛顿州98021 1-855-4SEAGEN

美国许可证2124
PADCEV TM是Agensys，Inc.和Seattle Genetics，Inc.共同拥有的商标。
©2019 Agensys，Inc.和Seattle Genetics，Inc.。

该患者信息已获得美国食品和药物管理局的批准。发行日期：2019年12月

包装/标签主要显示面板

NDC 51144-020-01

PADCEV TM

恩诺单抗vedotin-ejfv

注射

20毫克/小瓶

注意：细胞毒剂

仅用于静脉输液

使用前必须重新配制并稀释

单剂量小瓶。丢弃未使用的部分

仅接收

包装/标签主要显示面板

NDC 51144-030-01

PADCEV TM

恩诺单抗vedotin-ejfv

注射

30 mg /小瓶

注意：细胞毒剂

仅用于静脉输液

使用前必须重新配制并稀释

单剂量小瓶。丢弃未使用的部分

仅接收

【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网站

https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/b5631d3e-4604-4363-8f20-11dfc5a4a8ed/spl-doc?hl=Padcev

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。

1 INDICATIONS AND USAGE

PADCEVTM is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting.

This indication is approved under accelerated approval based on tumor response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of PADCEV is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

2.2 Dose Modifications

Table 1. Dose Modifications

Table 2. Recommended Dose Reduction Schedule

2.3 Instructions for Preparation and Administration

•Administer PADCEV as an intravenous infusion only.

•PADCEV is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Prior to administration, the PADCEV vial is reconstituted with Sterile Water for Injection (SWFI). The reconstituted solution is subsequently diluted in an intravenous infusion bag containing either 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.

Reconstitution in single-dose vial

1.Follow procedures for proper handling and disposal of anticancer drugs.

2.Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.

3.Calculate the recommended dose based on the patient’s weight to determine the number and strength (20 mg or 30 mg) of vials needed.

4.Reconstitute each vial as follows and, if possible, direct the stream of SWFI along the walls of the vial and not directly onto the lyophilized powder:

a.20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL PADCEV.

b.30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL PADCEV.

5.Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least 1 minute until the bubbles are gone. DO NOT SHAKE THE VIAL. Do not expose to direct sunlight.

6.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. Discard any vial with visible particles or discoloration.

7.

Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 4 hours in refrigeration at 2°C to 8°C (36 °F to 46 °F). DO NOT FREEZE. Discard unused vials with reconstituted solution beyond the recommended storage time.

Dilution in infusion bag

8.Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.

9.Dilute PADCEV with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection. The infusion bag size should allow enough diluent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL PADCEV.

10.Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG. Do not expose to direct sunlight.

11.Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. DO NOT USE the infusion bag if particulate matter or discoloration is observed.

12.Discard any unused portion left in the single-dose vials.

Administration

13.Immediately administer the infusion over 30 minutes through an intravenous line.

14.If the infusion is not administered immediately, the prepared infusion bag should not be stored longer than 8 hours at 2°C to 8°C (36 °F to 46 °F). DO NOT FREEZE.

DO NOT administer PADCEV as an intravenous push or bolus.

DO NOT mix PADCEV with, or administer as an infusion with, other medicinal products.

3 DOSAGE FORMS AND STRENGTHS

For Injection: 20 mg and 30 mg of enfortumab vedotin-ejfv as a white to off-white lyophilized powder in a single-dose vial for reconstitution.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hyperglycemia

Hyperglycemia occurred in patients treated with PADCEV, including death, and diabetic ketoacidosis (DKA) in those with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In EV-201, 8% of patients developed Grade 3-4 hyperglycemia. In this trial, patients with baseline hemoglobin A1C ≥8% were excluded. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV [see Dosage and Administration (2.2)].

5.2 Peripheral Neuropathy

Peripheral neuropathy, predominantly sensory, occurred in 49% of the 310 patients treated with PADCEV in clinical trials; 2% experienced Grade 3 reactions.

In study EV-201, peripheral neuropathy occurred in patients treated with PADCEV with or without preexisting peripheral neuropathy. The median time to onset of Grade ≥2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement.

Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when peripheral neuropathy occurs. Permanently discontinue PADCEV in patients that develop Grade >3 peripheral neuropathy [see Dosage and Administration (2.2)].

5.3 Ocular Disorders

Ocular disorders occurred in 46% of the 310 patients treated with PADCEV. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes.

Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2).

Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

5.4 Skin Reactions

Skin reactions occurred in 54% of the 310 patients treated with PADCEV in clinical trials. Twenty-six percent (26%) of patients had maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia.

In study EV-201, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3). Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement.

Monitor patients for skin reactions. Consider appropriate treatment, such as topical corticosteroids and antihistamines for skin reactions, as clinically indicated. For severe (Grade 3) skin reactions, withhold PADCEV until improvement or resolution and administer appropriate medical treatment. Permanently discontinue PADCEV in patients that develop Grade 4 or recurrent Grade 3 skin reactions [see Dosage and Administration (2.2)].

5.5 Infusion Site Extravasation

Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

5.6 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of enfortumab vedotin to pregnant rats during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures approximately similar to the clinical exposures at the recommended human dose of 1.25 mg/kg.

Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

6 ADVERSE REACTIONS

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

•Hyperglycemia [see Warnings and Precautions (5.1)]

•Peripheral Neuropathy [see Warnings and Precautions (5.2)]

•Ocular Disorders [see Warnings and Precautions (5.3)]

•Skin Reactions [see Warnings and Precautions (5.4)]

•Infusion Site Extravasation [see Warnings and Precautions (5.5)]

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 in the WARNINGS AND PRECAUTIONS section reflect exposure to PADCEV as a single agent at 1.25 mg/kg in 310 patients in EV-201, EV-101 (NCT02091999), and EV-102 (NCT03219333). Among 310 patients receiving PADCEV, 30% were exposed for > 6 months and 8% were exposed for ≥12 months.

The data described in this section reflect exposure to PADCEV from EV-201, a single arm study in patients (n=125) with locally advanced or metastatic urothelial cancer who had received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients received PADCEV 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. The median duration of exposure to PADCEV was 4.6 months (range: 0.5-15.6).

Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (≥20%) were fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, dysgeusia, diarrhea, dry eye, pruritus and dry skin. The most common Grade ≥3 adverse reaction (≥5%) were rash, diarrhea, and fatigue.

Table 3 summarizes the all grade and Grade ≥3 adverse reactions reported in patients in EV-201.

Table 3. Adverse Reactions Reported in ≥15% (Any Grade) or ≥5% (Grade ≥3) of Patients Treated with PADCEV in EV-201

Other clinically significant adverse reactions (≤15%) include: herpes zoster (3%) and infusion site extravasation (2%).

Table 4. Selected Laboratory Abnormalities Reported in ≥ 10% (Grades 2-4) or ≥ 5% (Grade 3-4) of Patients Treated with PADCEV in EV-201

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 in the studies described below with the incidence of antibodies in other studies or other enfortumab vedotin products may be misleading.

A total of 365 patients were tested for immunogenicity to PADCEV; 4 patients (1%) were confirmed to be transiently positive for anti-therapeutic antibody (ATA), and 1 patient (0.3%) was confirmed to be persistently positive for ATA at any post-baseline time point. No impact of ATA on efficacy, safety and pharmacokinetics was observed.

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on PADCEV

Strong CYP3A4 Inhibitors
Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure [see Clinical Pharmacology (12.3)], which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with strong CYP3A4 inhibitors.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on the mechanism of action and findings in animals, PADCEV can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on PADCEV use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration ofenfortumab vedotin-ejfv to pregnant rats during organogenesis caused maternal toxicity, embryo-fetal lethality, structural malformations and skeletal anomalies at maternal exposures approximately similar to the exposures at the recommended human dose of 1.25 mg/kg (see Data). Advise patients of the potential risk to the fetus.

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

Data

Animal Data

In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg (approximately 3 times the exposure at the recommended human dose). A dose of 2 mg/kg (approximately similar to the exposure at the recommended human dose) resulted in maternal toxicity, embryo-fetal lethality and structural malformations that included gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs and fused cervical arch. Additionally, skeletal anomalies (asymmetric, fused, incompletely ossified, and misshapen sternebrae, misshapen cervical arch, and unilateral ossification of the thoracic centra) and decreased fetal weight were observed.

8.2 Lactation

Risk Summary

There are no data on the presence of enfortumab vedotin-ejfv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy testing

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

Contraception

Females

PADCEV can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

Infertility

Males

Based on findings from animal studies, PADCEV may impair male fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of PADCEV in pediatric patients have not been established.

8.5 Geriatric Use

Of the 310 patients treated with PADCEV in clinical studies, 187 (60%) were 65 years or older and 80 (26%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Avoid the use of PADCEV in patients with moderate or severe hepatic impairment. PADCEV has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. In another ADC that contains MMAE, the frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment compared to patients with normal hepatic function. No adjustment in the starting dose is required when administering PADCEV to patients with mild hepatic impairment.

8.7 Renal Impairment

No dose adjustment is required in patients with mild (CrCL >60-90 mL/min), moderate (CrCL 30-60 mL/min) or severe (CrCL <30 mL/min) renal impairment [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3) conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.

Figure 1. Structural Formula

Approximately 4 molecules of MMAE are attached to each antibody molecule. Enfortumab vedotin-ejfv is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells and the small molecule components are produced by chemical synthesis.

PADCEV (enfortumab vedotin-ejfv) for injection is provided as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials for intravenous use. PADCEV is supplied as a 20 mg per vial and a 30 mg per vial and requires reconstitution with Sterile Water for Injection, USP, (2.3 mL and 3.3 mL, respectively) resulting in a clear to slightly opalescent, colorless to slightly yellow solution with a final concentration of 10 mg/mL [see Dosage and Administration (2.3)]. After reconstitution, each vial allows the withdrawal of 2 mL (20 mg) and 3 mL (30 mg). Each mL of reconstituted solution contains 10 mg of enfortumab vedotin-ejfv, histidine (1.4 mg), histidine hydrochloride monohydrate (2.31 mg), polysorbate 20 (0.2 mg) and trehalose dihydrate (55 mg) with a pH of 6.0.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Enfortumab vedotin-ejfv is an ADC. The antibody is a human IgG1 directed against Nectin-4, an adhesion protein located on the surface of cells. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death.

12.2 Pharmacodynamics

In an exposure-response analysis, higher enfortumab vedotin exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥2 peripheral neuropathy, Grade ≥3 hyperglycemia) and a lower exposure was associated with lower efficacy.

Cardiac Electrophysiology

At the recommended dose, PADCEV had no large QTc prolongation (>20 msec).

12.3 Pharmacokinetics

Population pharmacokinetic analysis included data from 369 patients based on three Phase 1 studies and one Phase 2 study. Enfortumab vedotin-ejfv pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors.

The exposure parameters of ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table 5 below. Peak ADC concentrations were observed near the end of intravenous infusion while peak MMAE concentrations were observed approximately 2 days after enfortumab vedotin-ejfv dosing. Minimal accumulation of the ADC and MMAE was observed following repeat administration of enfortumab vedotin-ejfv in patients. Steady-state concentrations of ADC and MMAE were reached after 1 treatment cycle.

Table 5. Exposure parameters of ADC and unconjugated MMAE after first treatment cycle of 1.25 mg/kg of enfortumab vedotin-ejfv dose of Days 1, 8 and 15

Distribution

The estimated mean steady-state volume of distribution of ADC was 11 liters following administration of enfortumab vedotin-ejfv. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.

Elimination

ADC and MMAE exhibited multi-exponential declines with an elimination half-life of 3.4 days and 2.4 days, respectively. The mean clearance (CL) of enfortumab vedotin-ejfv and free MMAE in patients was 0.10 L/h and 2.7 L/h, respectively, in patients. Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin-ejfv.

Metabolism

Enfortumab vedotin-ejfv catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Enfortumab vedotin-ejfv releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion

The excretion of enfortumab vedotin-ejfv is not fully characterized. Following a single-dose of another ADC that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after enfortumab vedotin-ejfv administration.

Specific Populations

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin-ejfv were observed based on age (24 to 87 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).

Hepatic Impairment

Based on population pharmacokinetics analysis, there was a 48% AUC increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (bilirubin of 1 to 1.5 × ULN and AST ULN, n=31) compared to normal hepatic function. The effect of moderate or severe hepatic impairment (AST or ALT >2.5 x ULN or total bilirubin >1.5 x ULN) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Renal Impairment

The pharmacokinetics of enfortumab vedotin-ejfv and MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin-ejfv to patients with mild (creatinine clearance; CrCL >60–90 mL/min; n=135), moderate (CrCL 30–60 mL/min; n=147) and severe (CrCL <30 mL/min; n=8) renal impairment. No significant differences in exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Drug Interaction Studies

Clinical Studies

No clinical studies evaluating the drug-drug interaction potential of enfortumab vedotin-ejfv have been conducted. To characterize the drug-drug interaction potential of free MMAE, clinical studies with another ADC that contains MMAE are described below.

Strong CYP3A4 Inhibitors: Another ADC that contains MMAE co-administered with ketoconazole (a strong CYP3A4 inhibitor) increased MMAE Cmax by 25% and AUC by 34%, with no change in ADC exposure. The concomitant use of strong inhibitors of CYP3A4 with PADCEV would likely result in similar effects on free MMAE and ADC.

Strong CYP3A4 Inducers: Another ADC that contains MMAE co-administered with rifampin (a strong CYP3A4 inducer) decreased MMAE Cmax by 44% and AUC by 46%, with no change in ADC exposure. The concomitant use of strong inducers of CYP3A4 with PADCEV would likely result in similar effects on free MMAE and ADC.

Sensitive CYP3A4 Substrates: Another ADC that contains MMAE co-administered with midazolam (a sensitive CYP3A4 substrate) did not affect the exposure of midazolam. Similarly, PADCEV is not expected to alter the exposure of drugs that are metabolized by CYP3A4 enzymes.

In Vitro Studies

Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp), but not an inhibitor of P-gp.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with enfortumab vedotin-ejfv or the small molecule cytotoxic agent (MMAE) have not been conducted.

MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies with enfortumab vedotin-ejfv or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats indicate the potential for enfortumab vedotin-ejfv to impair male reproductive function and fertility.

In repeat-dose toxicology studies conducted in rats for up to 13 weeks, doses ≥2 mg/kg enfortumab vedotin-ejfv (at exposures similar to the exposures at the recommended human dose) resulted in decreases in testes and epididymis weights, seminiferous tubule degeneration, spermatid/spermatocyte depletion in the testes and cell debris, sperm granuloma and hypospermia/abnormal spermatids in the epididymis. Findings in the testes and epididymis did not reverse by the end of the recovery period.

14 CLINICAL STUDIES

14.1 Metastatic Urothelial Cancer

The efficacy of PADCEV was evaluated in EV-201 (NCT03219333), single-arm, multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy ≥ Grade 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms.

The median age was 69 years (range: 40 to 84 years), 70% were male, and 85% were Caucasian. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%). Ninety percent of patients had visceral metastases including 40% with liver metastases. Two-thirds of patients had pure transitional cell carcinoma (TCC) histology; 33% had TCC with other histologic variants. An immunohistochemistry clinical trial assay was used to assess patients with tumor tissue available, and detected Nectin-4 expression in all patients tested (n=120). The median number of prior systemic therapies was 3 (range: 1 to 6). Forty-six percent of patients received prior PD-1 inhibitor, 42% received prior PD-L1 inhibitor, and an additional 13% received both PD-1 and PD-L1 inhibitors. Sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 8% received both cisplatin and carboplatin-based regimens.

The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) assessed by blinded independent central review (BICR) using RECIST v1.1.

Efficacy results are presented in Table 6.

Table 6. Efficacy Results in EV201 (BICR Assessment)

15 REFERENCES

1."OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

PADCEV (enfortumab vedotin-ejfv) 20 mg and 30 mg are supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials. PADCEV vials are available in the following packages:

•Carton of one 20 mg single-dose vial (NDC 51144-020-01)

•Carton of one 30 mg single-dose vial (NDC 51144-030-01)

16.2 Storage

Store PADCEV vials refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton. Do not freeze. Do not shake.

16.3 Special Handling

PADCEV is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hyperglycemia

Inform patients about the risk of hyperglycemia and how to recognize associated symptoms [see Warnings and Precautions (5.1)].

Peripheral Neuropathy

Inform patients to report to their healthcare provider any numbness and tingling of the hands or feet or muscle weakness [see Warnings and Precautions (5.2)].

Ocular disorders:

Advise patients to contact their healthcare provider if they experience any visual changes [see Warnings and Precautions (5.3)]. In order to prevent or treat dry eyes, advise patients to use artificial tear substitutes.

Skin Reactions

Inform patients that rashes and severe skin reactions have occurred after administration of PADCEV. Advise patients to contact their healthcare provider for signs and symptoms of progressive or intolerable skin reactions [see Warnings and Precautions (5.4)].

Infusion Site Extravasation

Inform patients that infusion site reactions have occurred after administration of PADCEV. These reactions generally occurred immediately after administration but, in some instances, had a delayed onset (e.g., 24 hours). Instruct patients to contact their healthcare provider immediately if they experience an infusion site reaction [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females to inform their healthcare providers of a known or suspected pregnancy [see Warning and Precautions (5.6) and Use in Specific Population (8.1)].

Females and Males of Reproductive Potential

Advise female patients of reproductive potential to use effective contraception during treatment with PADCEV and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males of reproductive potential that PADCEV may impair fertility [see Use in Specific Populations (8.3)].

Manufactured and Marketed by:
Astellas Pharma US, Inc.
Northbrook, Illinois 60062

Distributed and Marketed by:
Seattle Genetics, Inc.
Bothell, WA 98021
1-855-4SEAGEN

U.S. License 2124
PADCEVTM is a trademark jointly owned by Agensys, Inc. and Seattle Genetics, Inc.
©2019 Agensys, Inc. and Seattle Genetics, Inc.

This Patient Information has been approved by the U.S. Food and Drug Administration.       Issued: December 2019

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 51144-020-01

PADCEVTM

enfortumab vedotin-ejfv

FOR INJECTION

20 mg/vial

CAUTION: Cytotoxic Agent

For intravenous infusion use only

Must reconstitute and dilute before use

Single-dose vial. Discard unused portion

Rx Only

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 51144-030-01

PADCEVTM

enfortumab vedotin-ejfv

FOR INJECTION

30 mg/vial

CAUTION: Cytotoxic Agent

For intravenous infusion use only

Must reconstitute and dilute before use

Single-dose vial. Discard unused portion

Rx Only

【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。