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完整的处方信息

1适应症和用途

1.1成人溃疡性结肠炎

ENTYVIO（vedolizumab）用于：

• 诱导并维持临床反应，
• 诱导并维持临床缓解，
• 改善粘膜的内窥镜外观，以及
• 实现无糖皮质激素的缓解

在患有中度至重度活动性溃疡性结肠炎的成年患者中，对肿瘤坏死因子（TNF）阻滞剂或免疫调节剂反应不足，反应迟钝或不耐受；或对皮质类固醇的反应不足，不耐受或表现出依赖性。

1.2成人克罗恩氏病

ENTYVIO（vedolizumab）用于：

• 达到临床反应，
• 实现临床缓解，以及
• 实现无糖皮质激素的缓解

在患有中度至重度活动性克罗恩病的成年患者中，对肿瘤坏死因子（TNF）阻滞剂或免疫调节剂反应不足，反应迟钝或不耐受；或对皮质类固醇的反应不足，不耐受或表现出依赖性。

2用法用量

2.1重要的准备和管理说明

• 在30分钟内以静脉输注的形式施用ENTYVIO。请勿静脉推注或推注。
• 注射前用无菌注射用水将ENTYVIO冻干粉复溶，并在250 mL无菌0.9％氯化钠注射液或无菌林格氏注射液中稀释[参见剂量和用法（2.4） ]。
• 输注完成后，用30 mL无菌0.9％氯化钠注射液或无菌乳酸林格注射液冲洗。
• ENTYVIO应该由医务人员管理，如果发生过敏反应，包括过敏反应，应做好准备[见警告和注意事项（5.1） ]。适当的监测和医疗支持措施应可立即使用。在输液期间以及输液完成之前观察患者。

2.2在管理ENTYVIO之前

• 在开始使用ENTYVIO治疗之前，应根据当前的免疫指南对所有患者进行所有免疫接种。

2.3成人溃疡性结肠炎或克罗恩病的剂量

在患有溃疡性结肠炎或克罗恩病的成人中，ENTYVIO的推荐剂量为300 mg ，分别在第0、2和6周，然后每8周静脉输注。

在第14周仍未显示出治疗效果的患者中止治疗。

2.4稀释说明

配制说明

1. 从单剂量小瓶上取下翻盖，然后用酒精棉签擦拭。使用带有21至25号规格针头的注射器，在室温（20°至25°C [68°至77°F]）下，将装有冻干粉的ENTYVIO小瓶与4.8 mL无菌水重新配制，以进行注射。
2. 通过塞子的中心将注射器针头插入样品瓶，并将无菌注射用水流引导至样品瓶的玻璃壁，以免产生过多的泡沫。
3. 轻轻旋转小瓶至少15秒钟以溶解冻干的粉末。请勿剧烈摇晃或倒置。
4. 让溶液在室温下静置20分钟，以使溶液复原并沉淀任何泡沫；在此期间，可以旋转小瓶并检查其是否溶解。如果20分钟后仍未完全溶解，则再等待10分钟溶解。如果药品在30分钟内未溶解，请勿使用小瓶。
5. 稀释前，目视检查重新配制的ENTYVIO溶液中是否有颗粒物和变色。溶液应为澄清或乳白色，无色至浅棕黄色，无可见颗粒。请勿使用颜色不正常或含有颗粒的重构溶液。
6. 溶解后，将小瓶轻轻倒置3次。
7. 立即用带21至25号针头的注射器取出5 mL（300 mg）重构的ENTYVIO溶液。丢弃小瓶中任何剩余的重构溶液。

稀释说明

将5毫升（300毫克）重构的ENTYVIO溶液添加到250毫升无菌的0.9％氯化钠注射液或乳酸林格氏注射液中，并轻轻混合输液袋。请勿在准备好的输液或静脉输液器中添加其他药品。复原和稀释后，请尽快使用输注溶液。

丢弃输液溶液中任何未使用的部分。

存储

表1列出了小瓶中的重构溶液和输液袋中的稀释溶液的具体存储条件和时间安排。

不要将重新配制的溶液冷冻在小瓶中或将稀释的溶液冷冻在输液袋中。

室温下（20°至25°C [68°至77°F]），用0.9％氯化钠注射液配制的ENTYVIO溶液在小瓶中和稀释液在输液袋中的总存储时间总计为12小时或冷藏24小时（2°至8°C [36°至46°F]）。该合并的存储时间可以包括在2°至8°C的小瓶中多达八小时的重构溶液。

装有乳酸林格氏注射液的小瓶中重构的ENTYVIO溶液和输液袋中的稀释溶液的总存储时间总计为六个小时（2°至8°C [36°至46°F]）。

3剂型和强度

注射用：300 mg维多珠单抗，白色至灰白色冻干饼，装在单剂量小瓶中，以进行重构。

4禁忌症

ENTYVIO禁用于对ENTYVIO或其任何赋形剂有严重或严重过敏反应的患者（例如呼吸困难，支气管痉挛，荨麻疹，潮红，皮疹和心率加快）[请参阅警告和注意事项（5.1）和不良反应（6.1） ]。

5警告和注意事项

5.1输注相关反应和超敏反应

在UC试验I和II和CD试验I和III中，发生超敏反应，包括过敏反应（1434名患者中有1名[0.07％]）[见不良反应（6.1） ]。还观察到了过敏反应，包括呼吸困难，支气管痉挛，荨麻疹，潮红，皮疹以及血压和心率升高。经研究者评估，多数患者轻度至中度。其他生物药物的经验表明，对ENTYVIO的超敏反应和过敏反应的发生时间可能从输注期间或输注后立即变化到输注后长达数小时不等。

如果发生过敏反应或其他严重的过敏反应，请立即中断ENTYVIO的给药并开始适当的治疗（例如，肾上腺素和抗组胺药）。

5.2感染

用ENTYVIO治疗的患者发生感染的风险增加[见不良反应（6.1） ]。临床试验中最常报告的感染发生在ENTYVIO上的发生率高于安慰剂，涉及上呼吸道和鼻粘膜（例如，鼻咽炎，上呼吸道感染）。用ENTYVIO治疗的患者也有严重感染的报道，包括肛门脓肿，败血症（部分致命），肺结核，沙门氏菌败血症，李斯特菌脑膜炎，贾第鞭毛虫病和巨细胞病毒性结肠炎。

在活动性，严重感染的患者中，除非控制感染，否则不建议使用ENTYVIO。对于使用ENTYVIO治疗时发生严重感染的患者，应考虑不予治疗。在有反复严重感染史的患者中考虑使用ENTYVIO时应格外小心。考虑根据当地惯例筛查结核病（TB）。对于进行性多灶性白质脑病（PML），请参阅警告和注意事项（5.3）。

5.3进行性多灶性白质脑病

另一种整联蛋白受体拮抗剂与进行性多灶性白质脑病（PML）有关，后者是中枢神经系统（CNS）的罕见且通常是致命的机会性感染。PML由John Cunningham（JC）病毒引起，通常仅在免疫功能低下的患者中发生。

在ENTYVIO临床试验中，通过频繁和定期的筛查积极监测患者的PML，并根据需要评估任何新的，无法解释的神经系统症状。虽然在暴露至少24个月的患者中发现了零例PML，但不能排除PML的风险。基于此数据，无法声称与其他整联蛋白受体拮抗剂具有相对的安全性。

监测ENTYVIO上的患者是否出现新的或恶化的神经系统症状和体征。与PML相关的典型体征和症状是多种多样的，会持续数天至数周不等，包括身体一侧的进行性无力或四肢笨拙，视力障碍以及思维，记忆力和方向改变，从而导致混乱和性格改变。缺陷的发展通常导致数周或数月的死亡或严重残疾。如果怀疑存在PML ，请停止服用ENTYVIO并咨询神经科医师；如果确认，请永久停止给药。

5.4肝损伤

有报道称接受ENTYVIO的患者转氨酶和/或胆红素升高。通常，转氨酶升高和胆红素升高而无阻塞的结合通常被认为是严重肝损伤的重要预测指标，在某些患者中可能导致死亡或需要肝移植。黄疸病或其他有明显肝损伤迹象的患者应停止使用ENTYVIO [见不良反应（6.1） ]。

5.5活疫苗和口服疫苗

在开始使用ENTYVIO治疗之前，应根据当前的免疫指南对所有患者进行所有免疫接种[见剂量和给药方法（2.2） ]。接受ENTYVIO的患者可以接受非活疫苗（例如流感疫苗注射），并且如果获益大于风险，则可以接受活疫苗。没有关于接受ENTYVIO的 患者通过活疫苗进行二次感染传播的数据[见不良反应（6.1） ]。

6不良反应

以下主题在“警告和注意事项”部分中也进行了详细讨论：

• 输注相关反应和超敏反应[请参阅警告和注意事项（5.1） ]
• 感染[请参阅警告和注意事项（5.2） ]
• 进行性多灶性白质脑病[请参阅警告和注意事项（5.3） ]
• 肝损伤[请参阅警告和注意事项（5.4） ]

6.1临床试验经验

由于临床试验是在广泛不同的条件下进行的，因此无法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。

下述数据反映了3326例患者和健康志愿者在临床试验中接触ENTYVIO的情况，其中1,396例接触了一年以上，835例接触了两年以上。

表2中描述的安全性数据来自四个受控的3期试验（UC试验I和II，以及CD试验I和III）；来自第0和第2周（在进入UC试验II和CD试验III之前）和第6至52周（在UC试验I和CD试验I第6周无反应）接受开放性ENTYVIO治疗的患者的数据包括[见临床研究（14.1和14.2） ]。

在这些试验中，1,434例患者接受ENTYVIO 300 mg治疗长达52周，而297例患者接受安慰剂治疗长达52周。其中，769例患有溃疡性结肠炎，962例患有克罗恩氏病。患者的平均暴露时间为259天（UC试验I和II）和247天（CD试验I和III）。

据报道52％的ENTYVIO患者和45％的安慰剂患者发生了不良反应（UC试验I和II：ENTYVIO为 49 ％，安慰剂为37％; CD试验I和III：ENTYVIO为 55％和47％与安慰剂）。据报道，用ENTYVIO治疗的患者中有7％出现严重不良反应，而用安慰剂治疗的患者为4％（UC试验I和II：ENTYVIO为 8％，安慰剂为7％； CD试验I和III：使用ENTYVIO和安慰剂为12％9％，含安慰剂）。

最常见的不良反应是鼻咽炎，头痛，关节痛，恶心（在UC试验I和II和CD试验I和III联合治疗组中，接受ENTYVIO治疗的患者≥3％，比安慰剂联合治疗组高≥1％）。 ，发热，上呼吸道感染，疲劳，咳嗽，支气管炎，流行性感冒，背痛，皮疹，瘙痒，鼻窦炎，口咽痛和四肢疼痛（表2）。

UC试验I和II和CD试验I和III中在第0和2周接受ENTYVIO，然后在第6周随机分配至安慰剂的患者（n = 279），长达52周，以及患者（n = CD试验II（为期10周的克罗恩病试验）中的416）与表2中列出的相似。

输注相关反应和超敏反应

在临床试验中，服用ENTYVIO后已报道了严重的与输液有关的反应和过敏反应，包括过敏反应[见警告和注意事项（5.1） ]。在UC试验I和II和克罗恩试验I和III中，克罗恩病患者在第二次输注过程中报告了1例过敏反应[在1434例接受ENTYVIO治疗的患者中占10.0％（0.07％）]（报告的症状为呼吸困难，支气管痉挛，荨麻疹，潮红，皮疹，血压和心率增高），并通过中止输注以及使用抗组胺药和静脉注射氢化可的松进行治疗。

在UC试验I和II和CD试验I和III中，接受ENTYVIO治疗的患者中有4％和接受安慰剂治疗的患者中有3％经历了输注相关反应（IRR）。在使用ENTYVIO治疗的患者中，最常见的IRR （报告超过两次）是恶心，头痛，瘙痒，头晕，疲劳，输液相关反应，发热，荨麻疹和呕吐（这些不良反应中的每一种发生率均低于<1％）。所有接受ENTYVIO治疗的患者，均未发生任何不良反应，发生率超过1％。这些反应通常在输注后的前两个小时内发生，并且未经治疗或在接受抗组胺药和/或静脉注射氢化可的松治疗后即可缓解。不到1％的患者接受过ENTYVIO的研究人员认为IRR严重，需要中断研究治疗的IRR发生率不到 1％。

在临床试验中，对于轻度IRR或超敏反应的患者，在下一次输注之前，允许医生进行标准药物治疗（例如，抗组胺药，氢化可的松和/或对乙酰氨基酚）。

传染病

在UC试验I和II和CD试验I和III中，接受ENTYVIO治疗的患者的感染率是每患者年0.85 ，而接受安慰剂治疗的患者的感染率是每患者年0.7 [请参阅警告和注意事项（5.2） ]。。感染主要包括鼻咽炎，上呼吸道感染，鼻窦炎和泌尿道感染。2％的患者由于感染而停用了ENTYVIO。

在UC试验I和II和CD试验I和III中，接受ENTYVIO治疗的患者的严重感染率为每患者每年0.07，而接受安慰剂治疗的患者的严重感染率为每患者每年0.06。在克罗恩病患者中，严重感染比溃疡性结肠炎患者更常见，肛门脓肿是在克罗恩病患者中最常报告的严重不良反应。在48个月内，严重感染率没有增加。

在接受ENTYVIO治疗的成年人的对照和开放标签的长期延伸试验中，已经报道了严重的感染，包括肛门脓肿，败血症（某些致命），肺结核，沙门氏菌败血症，李斯特菌脑膜炎，贾第鞭毛虫病和巨细胞病毒性结肠炎。

在UC试验I和II和CD试验I和III中，在接受ENTYVIO治疗的1434名患者中有4名（0.3％）和接受安慰剂治疗的297名患者中有2名（0.7％）报告了败血症，包括细菌性败血症和败血性休克。在这些试验中，有两名接受ENTYVIO治疗的克罗恩病患者死于所报告的败血症或败血性休克。这些患者均患有严重的合并症和复杂的住院过程，导致死亡。在一项开放标签的长期扩展试验中，报告了败血症（某些致命）的其他病例，包括细菌性败血症和败血性休克。接受ENTYVIO治疗的溃疡性结肠炎或克罗恩病患者的败血症发生率为每1000患者年2次。

在临床试验中，对所有患者进行了结核病筛查。在ENTYVIO的对照试验中，诊断出1例潜伏性肺结核。在开放标签试验期间，诊断出了其他肺结核病例。所有这些观察到的病例都发生在美国以外，并且没有患者有肺外表现。

肝损伤

有报道称接受ENTYVIO的 患者转氨酶和/或胆红素升高[见警告和注意事项（5.4） ]。在UC试验I和II和CD试验I和III中，三名患者报告了严重的肝炎不良反应，表现为转氨酶升高或胆红素升高或与肝炎一致的症状（例如不适，恶心，呕吐，腹痛，厌食） 。这些不良反应发生在2至5次ENTYVIO之后剂量 然而，根据病例报告信息，尚不清楚该反应是否表明药物诱发或自身免疫病因。所有患者在停止治疗后恢复，其中一些需要皮质类固醇治疗。在对照试验中，接受ENTYVIO治疗的患者和接受安慰剂治疗的患者ALT和AST升高≥3×ULN的发生率＜2％。在开放标签试验中，观察到另一例严重肝炎。

恶性肿瘤

在UC试验I和II和CD试验I和III中，在1434例接受ENTYVIO治疗的患者中，有6例（0.4％）发生了恶性肿瘤（不典型增生和基底细胞癌），其中包括结肠癌（n = 2），移行细胞癌（ n = 1），乳腺癌（n = 1），阑尾类癌（n = 1）和鳞状细胞癌（n = 1）。据报道，在接受安慰剂（鳞状细胞癌）治疗的297名患者中，有一名（0.3％）发生了恶性肿瘤。

在正在进行的开放标签长期扩展试验中观察到的恶性肿瘤（不典型增生和基底细胞癌除外）包括B细胞淋巴瘤，乳腺癌，结肠癌，恶性肝肿瘤，恶性肺肿瘤，恶性黑色素瘤，原发性神经内分泌癌的肺癌，肾癌和鳞状细胞癌。总体而言，临床试验中的恶性肿瘤数量很少。但是，长期接触是有限的。

活疫苗和口服疫苗

没有关于接受ENTYVIO的患者通过活疫苗继发感染的数据。

在对健康志愿者进行的安慰剂对照研究中，对61位受试者进行了750 mg 单次ENTYVIO剂量（推荐剂量的2.5倍）的治疗，对62位受试者进行了安慰剂的接种，然后进行了乙肝表面抗原和口服霍乱疫苗的肌肉注射。用三剂重组乙型肝炎表面抗原进行肌内疫苗接种后，用ENTYVIO治疗的患者对乙型肝炎病毒的保护性免疫率较低。但是，在接受两剂灭活的口服霍乱疫苗后，与安慰剂相比，接触ENTYVIO的患者确实具有较低的血清转化率和抗霍乱滴度。尚不清楚患者对其他口服疫苗和鼻疫苗的影响。

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几个因素的影响，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，将下述研究中的维多珠单抗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ENTYVIO的 UC试验I和II和CD试验I和III中，在最后一剂研究药物后24周，患者中检测到的抗体频率为13％（大于最后一剂的五个半衰期） 。在治疗期间，接受ENTYVIO治疗的1434名患者中有56名（4％）在连续治疗的52周中的任何时间都有可检测的抗维多珠单抗抗体。56名患者中有9名（在两次或两次以上的研究访问中）抗维多珠单抗持续呈阳性（56名患者），其中56名患者中的33名开发了针对维多珠单抗的中和抗体。在这9名抗-维多珠单抗抗体持续阳性且有可用维多珠单抗浓度数据的受试者中，有8名中有6名检测不到，而2名降低了维多珠单抗浓度[参见临床药理学（12.3） ]。在对照试验中，在第6周或第52周，抗vedolizumab抗体持续阳性的9名受试者均未达到临床缓解。

7药物相互作用

7.1纳他珠单抗

由于可能增加PML和其他感染的风险，因此应避免将ENTYVIO与那他珠单抗同时使用。

7.2 TNF阻滞剂

由于可能增加感染的风险，因此请避免将ENTYVIO与TNF阻滞剂同时使用。

7.3活疫苗

只有在收益大于风险的情况下，才可以将活疫苗与ENTYVIO并用[见警告和注意事项（5.5） ]。

8在特定人群中的使用

8.1怀孕

怀孕暴露登记

有一个怀孕暴露注册表，可以监控怀孕期间接触ENTYVIO的妇女的怀孕结局。可以通过致电1-877-TAKEDA7（1-877-825-3327）获得有关注册表的信息。

风险摘要

现有的药物警戒性数据，正在进行的妊娠登记中的数据以及已发表的孕妇案例研究和队列研究中的数据尚未发现与ENTYVIO相关的重大先天缺陷，流产或不利的母婴结果的风险。妊娠期炎症性肠病会给母亲和胎儿带来风险（请参阅临床注意事项）。在动物繁殖研究中，未向兔子和猴子静脉内注射维多珠单抗，剂量为建议人类剂量的20倍，未观察到胎儿危害（见数据）。

对于指定人群，估计的主要先天缺陷和流产的背景风险尚不清楚。所有怀孕都有出生缺陷，流产或其他不良后果的背景风险。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％和流产15％至20％。

临床注意事项

与疾病相关的孕产妇和胚胎/胎儿风险

已发表的数据表明，炎症性肠病（IBD）妇女的不良妊娠结局风险与疾病活动增加有关。不良妊娠结局包括早产（妊娠37周之前），低出生体重（小于2500 g）的婴儿，以及出生时胎龄小的婴儿。

胎儿/新生儿不良反应

怀孕期间服用ENTYVIO可能会影响子宫内暴露的新生儿和婴儿的免疫反应。子宫内暴露的婴儿中低水平的ENTYVIO的临床意义尚不清楚。在暴露的婴儿中接种活疫苗或减毒活疫苗的安全性尚不清楚。

数据

动物资料

已在妊娠第7天以最高100 mg / kg的单次静脉内剂量（约为人体推荐剂量的20倍）对怀孕的兔子进行了生殖研究，但未发现由于维多珠单抗导致生育力受损或对胎儿造成伤害的证据。猴子的产前和产后发育研究表明，在静脉内剂量最高100 mg / kg（约为人体推荐剂量的20倍）时，没有证据表明对产前和产后发育有任何不利影响。

8.2哺乳

风险摘要

现有的公开文献表明人乳中存在维多珠单抗。对于母乳喂养的婴儿，局部胃肠道暴露和对维多珠单抗预期的低全身暴露的影响尚不清楚。没有关于维多珠单抗对母乳喂养婴儿的影响或对产奶量的影响的数据。应当考虑母乳喂养对发育和健康的好处，以及母亲对ENTYVIO的临床需求以及ENTYVIO或潜在母体状况对母乳喂养婴儿的任何潜在不利影响。

8.4小儿使用

尚未确定ENTYVIO在儿科患者中的安全性和有效性。

8.5老年人使用

ENTYVIO的临床试验未包括足够多的65岁及以上的受试者（在对照的3期临床试验中，对46名65岁及65岁以上的克罗恩氏和溃疡性结肠炎患者进行了ENTYVIO的治疗），以确定他们对年轻受试者的反应是否不同。但是，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，其他报告的临床经验也未发现老年患者和年轻患者的反应差异。

11说明

Vedolizumab是一种整合素受体拮抗剂，是在中国仓鼠卵巢细胞中产生的人源化IgG 1单克隆抗体，可与人α4β7整合素结合。ENTYVIO的分子量约为147道尔顿。

注射用恩替威（维多珠单抗）为无菌，白色至灰白色，不含防腐剂的冻干饼，用于静脉输注。用4.8 mL无菌注射用水（USP）复溶后，最终浓度为60 mg / mL，可输送体积为5 mL（300 mg），pH约为6.3。

每个单剂量小瓶包含300 mg vedolizumab，L-精氨酸盐酸盐（131.7 mg），L-组氨酸（23 mg），L-组氨酸一盐酸盐（21.4 mg），聚山梨酸酯80（3 mg）和蔗糖（500 mg）。

12临床药理学

12.1行动机制

Vedolizumab是一种人源化单克隆抗体，可特异性结合α4β7整联蛋白并阻断α4β7整联蛋白与粘膜寻址蛋白细胞粘附分子-1（MAdCAM-1）的相互作用，并抑制记忆性T淋巴细胞通过内皮迁移至发炎的胃肠道实质组织。维多珠单抗不结合或抑制α4β1和αEβ7整联蛋白的功能，并且不拮抗α4整联蛋白与血管细胞粘附分子-1（VCAM-1）的相互作用。

α4β7整联蛋白在记忆性T淋巴细胞的一个离散子集的表面表达，该子集优先迁移到胃肠道中。MAdCAM-1主要在肠内皮细胞上表达，在T淋巴细胞归巢到肠淋巴组织中起关键作用。已经暗示α4β7整联蛋白与MAdCAM-1的相互作用是导致溃疡性结肠炎和克罗恩氏病的特征的慢性炎症的重要因素。

12.2药效学

在ENTYVIO剂量范围为0.2至10 mg / kg（包括超出推荐剂量的剂量）的临床试验中，观察到参与肠道免疫监控的循环淋巴细胞亚群上的α4β7受体饱和。

在健康受试者和溃疡性结肠炎或克罗恩氏病患者中，使用ENTYVIO的剂量介于0.2至10 mg / kg和180至750 mg（包括建议剂量以外的剂量）的临床试验中，维多珠单抗不会升高中性粒细胞，嗜碱性粒细胞，嗜酸性粒细胞，B辅助和细胞毒性T淋巴细胞，总记忆辅助T淋巴细胞，单核细胞或自然杀伤细胞。

通过组织病理学评估，与安慰剂对照相比，在接受ENTYVIO治疗4或6周的2期溃疡性结肠炎患者的直肠活检标本中，胃肠道炎症的减少。

在一项针对14位健康受试者的研究中，ENTYVIO并未影响CSF中CD4 +淋巴细胞的细胞计数，CD8 +淋巴细胞的细胞计数或CD4 +：CD8 +的比例[请参见临床药理学（12.3） ]。

12.3药代动力学

在溃疡性结肠炎和克罗恩病患者中，在第0周和第2周以30分钟静脉输注300 mg ENTYVIO的形式观察到相似的药代动力学，随后从第6周开始每8周施用 300 mg ENTYVIO （表3）。

在第6周和第52周，观察到持续存在的抗维多珠单抗抗体可将维多单抗的血清浓度显着降低至不可检测或可忽略的水平（n = 8）。

Vedolizumab清除率取决于线性和非线性途径。非线性清除率随浓度增加而降低。群体药代动力学分析表明，在300 mg剂量下，线性清除率约为0.157 L /天，血清半衰期约为25天，分布体积约为5L。

单次静脉内注射450 mg ENTYVIO（建议剂量的1.5倍）后五周，在14位健康受试者的脑脊液（CSF）中未检测到维多珠单抗。

特殊人群

人群药代动力学分析表明，疾病的严重程度，体重，使用TNF受体阻滞剂治疗的先前治疗，年龄（18至78岁），血清白蛋白，并用免疫调节剂（包括硫唑嘌呤，6-巯基嘌呤，甲氨蝶呤）和给予氨基水杨酸酯对ENTYVIO的药代动力学没有临床意义。

尚未对维多珠单抗在肾或肝功能不全患者中的药代动力学进行研究。

13毒理学

13.1致癌，诱变，生育力受损

尚未进行动物长期研究来评估维多珠单抗的致癌潜力。尚未进行评估维多珠单抗的生育力或致突变性潜在损害的研究。

14临床研究

14.1溃疡性结肠炎的临床研究

ENTYVIO的安全性和有效性在两项中度至重度活动性溃疡性结肠炎（UC）成年患者中的两项随机，双盲，安慰剂对照试验（UC试验I和II）中进行了评估，内镜下Mayo评分为6至12分数为二或三。Mayo评分的范围从零到12，并且有四个分量表，每个分量表的得分从零（正常）到三个（最严重）：大便频率，直肠出血，内窥镜检查结果和医师总体评估。内窥镜检查评分为2分是由明显的红斑，缺乏血管模式，易碎性和糜烂所决定。内窥镜检查评分为三分是自发性出血和溃疡。

在美国（美国）登记的患者在过去的五年中对免疫调节剂疗法（例如，硫唑嘌呤或6-巯基嘌呤）的反应或耐受性不足，和/或对TNF的反应不足，反应丧失或不耐受阻止者。在美国境外，如果在过去五年中患者是皮质类固醇依赖者（即无法成功缓解皮质类固醇激素而又未出现UC症状）或对药物的反应或耐受不良，则事先接受皮质类固醇激素治疗即可进入治疗皮质类固醇。

过去曾接受那他珠单抗治疗的患者以及过去60天内曾接受TNF阻断剂的患者被排除在研究范围之外。不允许同时使用那他珠单抗或TNF阻滞剂。

UC审判I

在UC试验I中，以双盲方式（3：2）将374例患者随机分配在第0周和第2周通过静脉输注ENTYVIO 300 mg或安慰剂。在第6周进行疗效评估。同时给予稳定的氨基水杨酸盐​​剂量，在第6周内允许使用皮质类固醇（泼尼松剂量≤30 mg /天或同等剂量）和免疫调节剂（硫唑嘌呤或6-巯基嘌呤）。

在基线时，患者接受皮质类固醇（54％），免疫调节剂（硫唑嘌呤或6-巯基嘌呤）（30％）和/或氨基水杨酸酯（74％）。39％的患者对TNF阻断剂治疗的反应不足，反应丧失或不耐受。18％的患者仅对先前的皮质类固醇激素治疗反应不足，不能逐渐减量或不能耐受（即未接受先前的免疫调节剂或TNF阻断剂）。ENTYVIO组的基线Mayo评分中位数为9，安慰剂组为8。

在UC试验I中，与接受安慰剂治疗的患者相比，接受ENTYVIO治疗的患者在第6周获得了临床缓解（表4中定义）。与接受安慰剂治疗的患者相比，接受ENTYVIO治疗的患者在第六周也达到了临床缓解（表4中定义）。此外，在第6周，接受ENTYVIO治疗的患者内镜下粘膜外观改善的比例更高（见表4）。

UC审判II

为了随机接受UC Trial II的治疗，患者必须已接受ENTYVIO并在第6周处于临床反应。患者可能来自UC Trial I或接受ENTYVIO开放标签的一组。

（1：1）在UC试验II，373例在双盲的方式随机分为以下方案之一在第6周开始：ENTYVIO 300毫克每八周，ENTYVIO 300毫克每四个星期或安慰剂每四个周。在第52周进行疗效评估。在第52周允许同时使用氨基水杨酸酯和皮质类固醇。在美国境外允许使用伴随的免疫调节剂（硫唑嘌呤或6-巯基嘌呤），但在美国第六周以后不允许使用。

在第6周时，患者接受皮质类固醇（61％），免疫调节剂（硫唑嘌呤或6-巯基嘌呤）（32％）和氨基水杨酸酯（75％）。32％的患者对TNF阻断剂疗法的反应不足，反应丧失或不耐受。在第6周，ENTYVIO每8周组，ENTYVIO每4周组和安慰剂组的Mayo得分中位数为8 。在第6周已达到临床反应并接受糖皮质激素治疗的患者，必须在第6周开始进行糖皮质激素逐渐减量治疗。

在UC Trial II中，与安慰剂相比，接受ENTYVIO治疗的组中有更大比例的患者在52周时达到临床缓解，并维持了临床反应（在第6周和第52周均出现临床反应）（表5）。另外，与安慰剂相比，在接受ENTYVIO治疗的组中，在第6周和第52周均有更多的患者处于临床缓解期，并且在第52周时内镜下粘膜的外观有所改善（表5）。在第6周获得临床反应并在基线时接受皮质类固醇药物治疗的患者亚组中，接受ENTYVIO治疗的组中有更大比例的患者与安慰剂停用的皮质类固醇相比，在第52周时处于临床缓解状态（表5）。

该ENTYVIO每四个星期给药方案并没有表现出在每八次给药方案的附加临床益处。每四周一次的给药方案不是推荐的给药方案[参见剂量和给药方法（2.3） ]。

14.2克罗恩氏病的临床研究

在三项随机，双盲，安慰剂对照的临床试验（CD试验I，II和III）中，对中度至重度活动性克罗恩病（CD）的成年患者评估了ENTYVIO的安全性和有效性（克罗恩病活性指数[ CDAI]分数为220到450）。1

在美国（美国）登记的患者在过去五年中对免疫调节剂疗法（例如，硫唑嘌呤，6-巯基嘌呤或甲氨蝶呤）的反应或耐受性不足，和/或反应，耐受性丧失或耐受性不足一种或多种TNF阻断剂。在美国以外的地区，如果在过去五年中患者是皮质类固醇依赖者（即无法成功缓解皮质类固醇的症状而又未出现CD症状）或对药物的反应不足或不耐受，则先前接受皮质类固醇治疗就足以进入皮质类固醇。

过去曾接受那他珠单抗的患者以及过去30至60天曾接受TNF阻滞剂的患者被排除在研究范围之外。不允许同时使用那他珠单抗或TNF阻滞剂。

CD试验I

在CD试验I中，以双盲方式（3：2）将368例患者随机分配到第0周和第2周通过静脉输注ENTYVIO 300 mg或安慰剂。在第6周进行疗效评估。同时测定稳定的氨基水杨酸盐​​剂量，在第6周内允许使用皮质类固醇（泼尼松剂量≤30mg /天或同等剂量）和免疫调节剂（硫唑嘌呤，6-巯基嘌呤或氨甲蝶呤）。

在基线时，患者正在接受皮质类固醇（49％），免疫调节剂（硫唑嘌呤，6-巯基嘌呤或甲氨蝶呤）（35％）和/或氨基水杨酸酯（46％）。48％的患者对TNF阻断剂治疗的反应不足，反应丧失或不耐受。17％的患者仅对既往的皮质类固醇激素治疗没有足够的应答，不能逐渐变细或不能耐受（即，以前没有接受过免疫调节剂或TNF阻断剂）。ENTYVIO组的基线CDAI得分中位数为324，安慰剂组为319。

在CD试验I中，与安慰剂相比，在第6周时，接受ENTYVIO治疗的患者达到临床缓解（定义为CDAI≤150）的统计学百分比显着更高（表6）。在第6周，表现出临床反应的患者百分比差异（定义为CDAI得分比基线降低≥100分）在统计学上无统计学意义。

CD试验II

与CD试验I相比，CD试验II招募了更多的患者，这些患者在过去五年中对一种或多种TNF阻滞剂的反应不足，反应丧失或不耐受（76％）；这是主要的分析人群。在CD试验II中，以双盲方式（1：1）将416例患者随机分配在第0、2和6周接受ENTYVIO 300 mg或安慰剂。在第6和10周进行疗效评估。同时进行氨基水杨酸酯，皮质类固醇，并在第10周内允许使用免疫调节剂（硫唑嘌呤，6-巯基嘌呤或甲氨蝶呤）。

在基线时，患者正在接受皮质类固醇（54％），免疫调节剂（硫唑嘌呤，6-巯基嘌呤或甲氨蝶呤）（34％）和氨基水杨酸酯（31％）。ENTYVIO组的基线CDAI评分中位数为317，安慰剂组为301。

对于主要终点（第6周临床缓解），使用ENTYVIO治疗并未比安慰剂产生统计学上的显着改善（表6）。由于主要终点没有统计学意义，因此未测试包括第10周评估在内的次要终点。

CD试验III

为了随机接受CD试验III的治疗，患者必须在第6周接受ENTYVIO且临床反应（定义为CDAI得分比基线降低70分以上）。患者可能来自任何CD试验我或来自接受ENTYVIO开放标签的小组。

（1：1）在CD试验III，461例患者的双盲，随机分为以下方案之一在第6周开始：ENTYVIO 300毫克每八周，ENTYVIO 300毫克每四个星期或安慰剂每四个周。功效评估在第52周进行。在第52周允许同时使用氨基水杨酸酯和皮质类固醇。在美国以外允许使用伴随的免疫调节剂（硫唑嘌呤，6-巯基嘌呤或甲氨蝶呤），但在美国第6周之后不允许使用。

在第6周，患者接受皮质类固醇（59％），免疫调节剂（硫唑嘌呤，6-巯基嘌呤或甲氨蝶呤）（31％）和氨基水杨酸酯（41％）。51％的患者对TNF阻断剂治疗的反应不足，反应丧失或不耐受。在第6周，每8周一次ENTYVIO组的CDAI得分中位数为322，每4周一次ENTYVIO组为316 ，而安慰剂组为315。在第6周已达到临床反应（CDAI得分比基线降低≥70）并接受皮质类固醇的患者必须在第6周开始进行皮质类固醇药物治疗。

在CD试验III的患者在用治疗组的更大百分比ENTYVIO与安慰剂相比，均临床缓解在患者与治疗组周52具有更大的百分比（定义为CDAI评分≤150）ENTYVIO与安慰剂相比，有第52周的临床反应（定义为CDAI得分比基线降低≥100）（表7）。在基线时接受皮质类固醇且在第6周开始临床缓解的患者亚组（定义为CDAI得分比基线降低≥70），与安慰剂停药的皮质类固醇相比，接受ENTYVIO治疗的患者比例更高在第52周并且在第52周处于临床缓解中（表7）。

该ENTYVIO每四个星期给药方案并没有表现出在每八次给药方案的附加临床益处。每四周一次的给药方案不是推荐的给药方案[参见剂量和给药方法（2.3） ]。

15参考

1. 最佳WR，Becktel JM，Singleton JW，Kern F：克罗恩病活动指数的发展，国家合作式克罗恩病研究。胃肠病学1976；70（3）：439-444

16供应/存储和处理方式

注射用ENTYVIO（维多珠单抗）装在无菌的20 mL单剂量玻璃小瓶中，其中包含300 mg维多珠单抗，为白色至灰白色冻干饼。

将未打开的样品瓶冷藏在2º至8ºC（36º至46ºF）的温度下。保留在原包装中以避光。

17患者咨询信息

请参阅FDA批准的患者标签（用药指南）。

过敏反应

指导患者如果在输注ENTYVIO 期间或之后出现与超敏反应一致的症状，请立即报告[见警告和注意事项（5.1） ]。

传染病

告知患者服用ENTYVIO时更可能感染。指示患者告知其医疗服务提供者是否出现感染的任何体征或症状[请参阅警告和注意事项（5.2） ]。

进行性多灶性白质脑病

告知患者接受不同整联蛋白受体拮抗剂产品的患者已发生进行性多灶性白质脑病（PML）。指导患者立即报告是否有任何新的发作或神经系统症状和体征恶化，因为它们可能是PML的征兆[见警告和注意事项（5.3） ]。

肝损伤

告知患者接受ENTYVIO的患者转氨酶水平升高或胆红素水平升高。指导患者及时报告可能表明肝损伤的任何症状，包括疲劳，厌食，右上腹部不适，尿色或黄疸[见警告和注意事项（5.4） ]。

怀孕

告知患者有一个怀孕登记簿， 以监测已暴露于ENTYVIO的孕妇或已怀孕的妇女的妊娠结局[见特定人群的使用（8.1） ]。

制造商：
Takeda Pharmaceuticals America，Inc.
Deerfield，IL 60015

美国许可证号1898

主要显示屏-300毫克瓶装纸箱

NDC 64764-300-20

仅Rx

Entyvio
vedolizumab
注射液
300 mg /小瓶*

注意：每位患者均需
接受随附的用药指南。

仅限静脉使用

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

【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/6e94621c-1a95-4af9-98d1-52b9e6f1949c/spl-doc?hl=ENTYVIO

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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

1.1 Adult Ulcerative Colitis

ENTYVIO (vedolizumab) is indicated for:

• inducing and maintaining clinical response,
• inducing and maintaining clinical remission,
• improving the endoscopic appearance of the mucosa, and
• achieving corticosteroid-free remission

in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

1.2 Adult Crohn's Disease

ENTYVIO (vedolizumab) is indicated for:

• achieving clinical response,
• achieving clinical remission, and
• achieving corticosteroid-free remission

in adult patients with moderately to severely active Crohn's disease who have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

2 DOSAGE AND ADMINISTRATION

2.1 Important Preparation and Administration Instructions

• Administer ENTYVIO as an intravenous infusion over 30 minutes. Do not administer as an intravenous push or bolus.
• Reconstitute ENTYVIO lyophilized powder with Sterile Water for Injection and dilute in 250 mL of sterile 0.9% Sodium Chloride Injection or sterile Lactated Ringer's Injection prior to administration [see Dosage and Administration (2.4)].
• After the infusion is complete, flush with 30 mL of sterile 0.9% Sodium Chloride Injection or sterile Lactated Ringer's Injection.
• ENTYVIO should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur [see Warnings and Precautions (5.1)]. Appropriate monitoring and medical support measures should be available for immediate use. Observe patients during infusion and until the infusion is complete.

2.2 Prior to Administration of ENTYVIO

• Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines.

2.3 Dosage in Adults with Ulcerative Colitis or Crohn's Disease

The recommended dosage of ENTYVIO in adults with ulcerative colitis or Crohn's disease is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.

Discontinue therapy in patients who show no evidence of therapeutic benefit by Week 14.

2.4 Reconstitution and Dilution Instructions

Reconstitution Instructions

1. Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. Reconstitute ENTYVIO vial containing lyophilized powder with 4.8 mL of Sterile Water for injection at room temperature (20° to 25°C [68º to 77ºF]), using a syringe with a 21- to 25- gauge needle.
2. Insert the syringe needle into the vial through the center of the stopper and direct the stream of Sterile Water for Injection to the glass wall of the vial to avoid excessive foaming.
3. Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not vigorously shake or invert.
4. Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes.
5. Visually inspect the reconstituted ENTYVIO solution for particulate matter and discoloration prior to dilution. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates.
6. Once dissolved, gently invert vial three times.
7. Immediately, withdraw 5 mL (300 mg) of reconstituted ENTYVIO solution using a syringe with a 21- to 25- gauge needle. Discard any remaining portion of the reconstituted solution in the vial.

Dilution Instructions

Add the 5 mL (300 mg) of reconstituted ENTYVIO solution to 250 mL of sterile 0.9% Sodium Chloride Injection or Lactated Ringer's Injection and gently mix the infusion bag. Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Once reconstituted and diluted, use the infusion solution as soon as possible.

Discard any unused portion of the infusion solution.

Storage

Specific storage conditions and timing for the reconstituted solution in vial and diluted solution in the infusion bag are outlined in Table 1.

Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag.

The combined storage time of reconstituted ENTYVIO solution in the vial and the diluted solution in the infusion bag with 0.9% Sodium Chloride Injection is a total of 12 hours at room temperature (20° to 25°C [68° to 77°F]) or 24 hours refrigerated (2° to 8°C [36º to 46ºF]). This combined storage time may include up to eight hours of the reconstituted solution in the vial at 2° to 8°C.

The combined storage time of reconstituted ENTYVIO solution in the vial and the diluted solution in the infusion bag with Lactated Ringer's Injection is a total of six hours refrigerated (2° to 8°C [36º to 46ºF]).

3 DOSAGE FORMS AND STRENGTHS

For injection: 300 mg of vedolizumab as a white to off-white lyophilized cake in a single-dose vial for reconstitution.

4 CONTRAINDICATIONS

ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Infusion-Related Reactions and Hypersensitivity Reactions

In UC Trials I and II and CD Trials I and III, hypersensitivity reactions occurred including a case of anaphylaxis (one out of 1434 patients [0.07%]) [see Adverse Reactions (6.1)]. Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed. The majority were mild to moderate in severity as assessed by the investigator. Experience with other biologic medications suggests that hypersensitivity reactions and anaphylaxis to ENTYVIO may vary in their time of onset from during infusion or immediately post-infusion to occurring up to several hours post-infusion.

If anaphylaxis or other serious allergic reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment (e.g., epinephrine and antihistamines).

5.2 Infections

Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions (6.1)]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.

ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions (5.3).

5.3 Progressive Multifocal Leukoencephalopathy

Another integrin receptor antagonist has been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system (CNS). PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised.

In ENTYVIO clinical trials, patients were actively monitored for PML with frequent and regular screenings, and evaluations of any new, unexplained neurological symptoms, as necessary. While zero cases of PML were identified among patients with at least 24 months of exposure, a risk of PML cannot be ruled out. No claims of comparative safety to other integrin receptor antagonists can be made based on this data.

Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently.

5.4 Liver Injury

There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions (6.1)].

5.5 Live and Oral Vaccines

Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines [see Dosage and Administration (2.2)]. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions (6.1)].

6 ADVERSE REACTIONS

The following topics are also discussed in detail in the Warnings and Precautions section:

• Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Infections [see Warnings and Precautions (5.2)]
• Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)]
• Liver Injury [see Warnings and Precautions (5.4)]

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 below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.

The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included [see Clinical Studies (14.1 and 14.2)].

In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn's disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).

Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9%, with placebo).

The most common adverse reactions (reported by ≥3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and ≥1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2).

Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn's disease trial, are similar to those listed in Table 2.

Infusion-Related Reactions and Hypersensitivity Reactions

Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions (5.1)]. In UC Trials I and II and Crohn's Trials I and III, one case of anaphylaxis [one out of 1434 patients treated with ENTYVIO (0.07%)] was reported by a Crohn's disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.

In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.

In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion.

Infections

In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions (5.2)]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections.

In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohn's disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohn's disease patients. Over 48 months, there was no increase in the rate of serious infections.

In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.

In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohn's disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both of these patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohn's disease receiving ENTYVIO was two per 1000 patient-years.

In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.

Liver Injury

There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions (5.4)]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations ≥3 × ULN was <2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.

Malignancies

In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1), breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma).

Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited.

Live and Oral Vaccines

There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO.

In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.

6.2 Immunogenicity

As with all therapeutic proteins, there is 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 vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations [see Clinical Pharmacology (12.3)]. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.

7 DRUG INTERACTIONS

7.1 Natalizumab

Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab.

7.2 TNF Blockers

Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers.

7.3 Live Vaccines

Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions (5.5)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327).

Risk Summary

Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations). No fetal harm was observed in animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 miscarriage is 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal adverse reactions

ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

Data

Animal Data

A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).

8.2 Lactation

Risk Summary

Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition.

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohn's and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

11 DESCRIPTION

Vedolizumab, an integrin receptor antagonist, is a humanized IgG1 monoclonal antibody produced in Chinese hamster ovary cells that binds to the human α4β7 integrin. ENTYVIO has an approximate molecular weight of 147 kilodaltons.

ENTYVIO (vedolizumab) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized cake for intravenous infusion. After reconstitution with 4.8 mL Sterile Water for Injection, USP, the final concentration is 60 mg/mL with a deliverable volume of 5 mL (300 mg) and the resulting pH is approximately 6.3.

Each single-dose vial contains 300 mg vedolizumab, L-arginine hydrochloride (131.7 mg), L-histidine (23 mg), L-histidine monohydrochloride (21.4 mg), polysorbate 80 (3 mg), and sucrose (500 mg).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).

The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn's disease.

12.2 Pharmacodynamics

In clinical trials with ENTYVIO at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed.

In clinical trials with ENTYVIO at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn's disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells.

A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to ENTYVIO for four or six weeks compared to placebo control as assessed by histopathology.

In a study of 14 healthy subjects, ENTYVIO did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF [see Clinical Pharmacology (12.3)].

12.3 Pharmacokinetics

Similar pharmacokinetics were observed in ulcerative colitis and Crohn's disease patients administered 300 mg ENTYVIO as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg ENTYVIO every eight weeks starting from Week 6 (Table 3).

The presence of persistent anti-vedolizumab antibody was observed to substantially reduce serum concentrations of vedolizumab, either to undetectable or negligible levels at Weeks 6 and 52 (n=8).

Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L.

Vedolizumab was not detected in the cerebrospinal fluid (CSF) of 14 healthy subjects at five weeks after a single intravenous administration of 450 mg ENTYVIO (1.5 times the recommended dosage).

Special Populations

Population pharmacokinetic analysis showed that the severity of disease state, body weight, prior treatment with TNF blocker therapy, age (18 to 78 years), serum albumin, co-administered immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and co-administered aminosalicylates did not have a clinically meaningful effect on the pharmacokinetics of ENTYVIO.

Pharmacokinetics of vedolizumab in patients with renal or hepatic insufficiency have not been studied.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of vedolizumab. Studies to evaluate the possible impairment of fertility or mutagenic potential of vedolizumab have not been performed.

14 CLINICAL STUDIES

14.1 Clinical Studies in Ulcerative Colitis

The safety and efficacy of ENTYVIO were evaluated in two randomized, double-blind, placebo-controlled trials (UC Trials I and II) in adult patients with moderately to severely active ulcerative colitis (UC) defined as Mayo score of six to 12 with endoscopy subscore of two or three. The Mayo score ranges from zero to 12 and has four subscales that are each scored from zero (normal) to three (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of two is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of three is defined by spontaneous bleeding and ulceration.

Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine or 6-mercaptopurine) and/or an inadequate response, loss of response, or intolerance to a TNF blocker. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response or intolerance to corticosteroids.

Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.

UC Trial I

In UC Trial I, 374 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine or 6-mercaptopurine) were permitted through Week 6.

At baseline, patients received corticosteroids (54%), immunomodulators (azathioprine or 6-mercaptopurine) (30%), and/or aminosalicylates (74%). Thirty-nine percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Eighteen percent of patients had an inadequate response, inability to taper or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline Mayo score was nine in the ENTYVIO group and eight in the placebo group.

In UC Trial I, a greater percentage of patients treated with ENTYVIO compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 4). A greater percentage of patients treated with ENTYVIO compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 4). In addition, a greater percentage of patients treated with ENTYVIO had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 4).

UC Trial II

In order to be randomized to treatment in UC Trial II, patients had to have received ENTYVIO and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received ENTYVIO open-label.

In UC Trial II, 373 patients were randomized in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: ENTYVIO 300 mg every eight weeks, ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the US but were not permitted beyond Week 6 in the US.

At Week 6, patients were receiving corticosteroids (61%), immunomodulators (azathioprine or 6-mercaptopurine) (32%) and aminosalicylates (75%). Thirty-two percent of patients had an inadequate response, loss of response or intolerance to a TNF blocker therapy. At Week 6, the median Mayo score was eight in the ENTYVIO every eight week group, the ENTYVIO every four week group, and the placebo group. Patients who had achieved clinical response at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.

In UC Trial II, a greater percentage of patients in groups treated with ENTYVIO as compared to placebo achieved clinical remission at Week 52, and maintained clinical response (clinical response at both Weeks 6 and 52) (Table 5). In addition, a greater percentage of patients in groups treated with ENTYVIO as compared to placebo were in clinical remission at both Weeks 6 and 52, and had improvement of endoscopic appearance of the mucosa at Week 52 (Table 5). In the subgroup of patients who achieved clinical response at Week 6 and were receiving corticosteroid medication at baseline, a greater proportion of patients in groups treated with ENTYVIO as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 5).

The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see Dosage and Administration (2.3)].

14.2 Clinical Studies in Crohn's Disease

The safety and efficacy of ENTYVIO were evaluated in three randomized, double-blind, placebo-controlled clinical trials (CD Trials I, II, and III) in adult patients with moderately to severely active Crohn's disease (CD) (Crohn's Disease Activity Index [CDAI] score of 220 to 450).1

Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine, 6-mercaptopurine, or methotrexate) and/or an inadequate response, loss of response, or intolerance to one or more TNF blockers. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of CD) or had an inadequate response or intolerance to corticosteroids.

Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 30 to 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.

CD Trial I

In CD Trial I, 368 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤30 mg/day or equivalent), and immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) were permitted through Week 6.

At baseline, patients were receiving corticosteroids (49%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (35%), and/or aminosalicylates (46%). Forty-eight percent of the patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Seventeen percent of patients had inadequate response, inability to taper, or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline CDAI score was 324 in the ENTYVIO group and 319 in the placebo group.

In CD Trial I, a statistically significantly higher percentage of patients treated with ENTYVIO achieved clinical remission (defined as CDAI ≤150) as compared to placebo at Week 6 (Table 6). The difference in the percentage of patients who demonstrated clinical response (defined as a ≥100-point decrease in CDAI score from baseline), was however, not statistically significant at Week 6.

CD Trial II

Compared to CD Trial I, CD Trial II enrolled a higher number of patients who had over the previous five-year period had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76%); this was the primary analysis population. In CD Trial II, 416 patients were randomized in a double-blind fashion (1:1) to receive either ENTYVIO 300 mg or placebo at Weeks 0, 2 and 6. Efficacy assessments were at Weeks 6 and 10. Concomitant aminosalicylates, corticosteroids, and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted through Week 10.

At baseline, patients were receiving corticosteroids (54%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (34%), and aminosalicylates (31%). The median baseline CDAI score was 317 in the ENTYVIO group and 301 in the placebo group.

For the primary endpoint (clinical remission at Week 6), treatment with ENTYVIO did not result in statistically significant improvement over placebo (Table 6). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant.

CD Trial III

In order to be randomized to treatment in CD Trial III, patients had to have received ENTYVIO and be in clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at Week 6. Patients could have come from either CD Trial I or from a group who received ENTYVIO open-label.

In CD Trial III, 461 patients were randomized in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: ENTYVIO 300 mg every eight weeks, ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted outside the US but were not permitted beyond Week 6 in the US.

At Week 6, patients were receiving corticosteroids (59%), immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) (31%), and aminosalicylates (41%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. At Week 6, the median CDAI score was 322 in the ENTYVIO every eight week group, 316 in the ENTYVIO every four week group, and 315 in the placebo group. Patients who had achieved clinical response (≥70 decrease in CDAI score from baseline) at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.

In CD Trial III a greater percentage of patients in groups treated with ENTYVIO as compared to placebo were in clinical remission (defined as CDAI score ≤150) at Week 52. A greater percentage of patients in groups treated with ENTYVIO as compared to placebo had a clinical response (defined as ≥100 decrease in CDAI score from baseline) at Week 52 (Table 7). In the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (defined as ≥70 decrease in CDAI score from baseline), a greater proportion of patients in groups treated with ENTYVIO as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 7).

The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see Dosage and Administration (2.3)].

15 REFERENCES

1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn's Disease Activity Index, National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 439-444

16 HOW SUPPLIED/STORAGE AND HANDLING

ENTYVIO (vedolizumab) for injection is supplied in sterile 20 mL single-dose glass vials, containing 300 mg of vedolizumab as a white to off-white lyophilized cake.

Refrigerate unopened vials at 2º to 8ºC (36º to 46ºF). Retain in original package to protect from light.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Hypersensitivity Reactions

Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction during or following an infusion of ENTYVIO [see Warnings and Precautions (5.1)].

Infections

Inform patients that they may be more likely to develop infections when taking ENTYVIO. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection [see Warnings and Precautions (5.2)].

Progressive Multifocal Leukoencephalopathy

Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received a different integrin receptor antagonist product. Instruct patients to report if they experience any new onset or worsening of neurological signs and symptoms immediately, as these could be indicative of PML [see Warnings and Precautions (5.3)].

Liver Injury

Inform patients that elevated transaminase levels with or without elevated bilirubin has occurred in patients who received ENTYVIO. Instruct patients to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.4)].

Pregnancy

Inform patients that there is a pregnancy registry to monitor pregnancy outcomes of women who are pregnant or become pregnant while exposed to ENTYVIO [see Use in Specific Populations (8.1)].

Manufactured by:
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015

U.S. License No. 1898

PRINCIPAL DISPLAY PANEL - 300 mg Vial Carton

NDC 64764-300-20

Rx only

Entyvio
vedolizumab
for injection
300 mg per vial*

ATTENTION: Each patient is required to
receive the enclosed Medication Guide.

For Intravenous Use Only

Must be reconstituted and diluted prior
to use

Single-Dose Vial - Discard Unused Portion

【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。