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Tecentriq(atezolizumab)注射液使用说明

2016年第一版

批准治疗：2016年5月18日；

公司：Genentech，Inc.
FDA为批准对膀胱癌新靶向治疗。Tecentriq是FDA批准的第一个PD-L1抑制剂。FDA的药品评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说： “Tecentriq提供这些患者一个新治疗靶向PD-L1通路，” “产品阻断PD-1/PD-L1的机制部分地与机体的免疫系统和它的与癌细胞间相互作用相互关系有关。” 突破性治疗指定，优先审批状态和加速批准
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761034s000lbl.pdf
处方资料重点
这些重点不包括安全和有效使用TECENTRIQ所需所有资料。请参阅TECENTRIQ完整处方资料。
TECENTRIQTM(atezolizumab)注射液，为静脉使用
美国初次批准：2016
适应证和用途
TECENTRIQ是一种程序死亡配体1(PD-L1)阻断抗体适用为有局部晚期或转移尿路上皮癌患者的治疗患者：
⑵ 含铂化疗期间或后有疾病进展(1)
⑵用含铂化疗新辅助或辅助治疗12个月内有疾病进展(1)
这个适应证在加快批准下被根据肿瘤反应率和反应时间批准的。继续批准这个适应证可能取决于在验证性试验临床获益的确证和描述。(1，14)
剂量和给药方法
每3周给予1200 mg作为一次静脉输注历时60分。(2.1)
静脉输注前稀释。(2.3)
剂型和规格
注射液：1200 mg/20 mL(60 mg/mL)溶液在一单剂量小瓶中(3)
禁忌证
无。(4)
警告和注意事项
●免疫相关肺炎：对中度不给和对严重或危及生命肺炎永久地终止。(5.1)
●免疫相关肝炎：监视肝功能变化。对中度不给和对严重或危及生命转氨酶或总胆红素升高永久地终止。(5.2)
●免疫相关结肠炎：对中度不给或严重，和对危及生命结肠炎永久地终止。(5.3)
● 免疫相关内分泌病(5.4)：
o 垂体炎：对中度不给或严重和对危及生命垂体炎永久地终止。
o 甲状腺疾病：监视甲状腺功能。对症状性甲状腺病不给。
o 肾上腺功能不全：对症状性肾上腺功能不全不给。
o 1型糖尿病：对 ≥3级高血糖不给。
● 免疫相关肌无力综合征/重症肌无力，Guillain-Barré或脑膜脑炎：对任何程度永久地终止.(5.5)
●眼炎症毒性：对中度不给和对严重眼炎症毒性永久地终止。(5.5)
●免疫相关胰腺炎：对中度不给或严重，和对危及生命胰腺炎，或任何级别复发性胰腺炎永久地终止。(5.5)
●感染：对严重或危及生命感染不给。(5.6)
●输注反应：对轻度或中度输注反应中断或减慢输注速率和对严重或危及生命输注反应终止。(5.7)
●胚胎-胎儿毒性：TECENTRIQ可能致胎儿危害。忠告生殖潜能女性对胎儿潜在风险和使用有效避孕。(5.8，8.1，8.3)
不良反应
最常见不良反应(≥ 20%的患者)包括：疲乏，食欲减退，恶心，尿路感染，发热，和便秘。(6.1)
报告怀疑不良反应，联系Genentech电话1-888-835-2555或FDA电话1-800-FDA-1088或在特殊人群中使用
哺乳：忠告不要哺乳喂养。(8.2)
完整处方资料
1 适应证和用途
TECENTRIQ(atezolizumab)是适用为有局部晚期或转移尿路上皮癌患者的治疗患者：
● 含铂化疗期间或后有疾病进展
● 用含铂化疗新辅助或辅助治疗12个月内有疾病进展有疾病进展
这个适应证在加快批准下根据肿瘤反应率和反应时间被批准的。继续批准这个适应证可能取决于在验证性试验临床获益的确证和描述。[见临床研究(14.1)].
2 剂量和给药方法
2.1 推荐给药
TECENTRIQ的推荐剂量是1200 mg给药作为一个静脉输注历时60分每3周直至疾病进展或不可接受毒性。如首次输注被耐受，所有随后输注可能被历时30分输送。不要作为一个静脉推注或丸注给予TECENTRIQ。
2.2 剂量调整
推荐无TECENTRIQ剂量减低。
对以下任何不给TECENTRIQ：
● 2级肺炎[见警告和注意事项(5.1)]
● 谷草转氨酶(AST)或谷丙转氨酶(ALT)大于3和至5倍正常上限(ULN)或总胆红素大于1.5和至3倍ULN[见警告和注意事项(5.2)]
● 2或3级腹泻或结肠炎[见警告和注意事项(5.3)]
● 症状性垂体炎，肾上腺功能不全，甲状腺功能减退症，甲状腺功能亢进症，或3或4级高血糖[见警告和注意事项(5.4)]
● 2级眼炎症毒性[见警告和注意事项(5.5)]
● 2或3级胰腺炎，或淀粉或脂肪酶水平3或4级增加(大于2.0倍ULN)[见警告和注意事项(5.5)]
● 3或4级感染[见警告和注意事项(5.6)]
● 2级输注相关反应[见警告和注意事项(5.7)]
● 3级皮疹
在患者其不良反应恢复至0–1级TECENTRIQ可能被恢复。
对任何以下永久地终止TECENTRIQ：
● 3或4级肺炎[见警告和注意事项(5.1)]
● AST或ALT大于5倍ULN或总胆红素大于3倍ULN[见警告和注意事项(5.2)]
● 4级腹泻或结肠炎[见警告和注意事项(5.3)]
● 4级垂体炎
● 肌无力综合征/重症肌无力，Guillain-Barré或脑膜脑炎(所以级别)[见警告和注意事项(5.5)]
● 3或4级眼炎症毒性[见警告和注意事项(5.5)]
● 4级或任何级别复发性胰腺炎[见警告和注意事项(5.5)]
● 3或4级输注相关反应[见警告和注意事项(5.7)]
● 4级皮疹
2.3 制备和给药
制备
任何时候溶液和容器允许给药前视力观察药品颗粒物质和变色。TECENTRIQ是一个无色至浅黄色溶液。如溶液是云雾状，变色，或观察到可见颗粒遗弃小瓶。不要摇晃小瓶。
制备为输注溶液如下：
● 从小瓶抽吸20 mL的TECENTRIQ。
● 稀释至一个含0.9%氯化钠注射液，USP的250 mL聚氯乙烯(PVC)，聚乙烯(PE)，或聚烯烃(PO)输注袋。
● 仅用0.9%氯化钠注射液稀释。
● 通过轻轻倒置混合稀释溶液，不要摇晃。
● 遗弃部分地使用或空TECENTRIQ小瓶。
输注溶液的贮存
本产品不含防腐剂。一旦制备好立即给药。如稀释好TECENTRIQ输注溶液不立即使用，它可如下任一贮存：
● 在室温从制备时间共不超过6小时。这包括室温贮存输注袋和为输注给药时间。.
● 在冰箱2°C–8°C(36°F–46°F)共不超过24小时。不要冻结。不要摇晃。
给药
通过一个静脉线有或无一个无菌，无-热原，低-蛋白结合在线过滤器(孔大小0.2–0.22微米)历时60分给予初始输注。如首次输注被耐受，所有随后输注可历时30分输送。不要与其他药物通过相同静脉线共同给予。
3 剂型和规格
注射液：1200 mg/20 mL(60 mg/mL)无色至浅黄色溶液在一单剂量小瓶中。
4 禁忌证
无。
5 警告和注意事项
5.1 免疫相关肺炎
免疫介导肺炎或间质性肺病，被定义为需要使用皮质激素和与无明确另外病因，发生在接受TECENTRIQ患者。跨越临床试验，2.6%(51/1978)患者发生肺炎。致命性肺炎发生在两例患者。在523例有尿路上皮癌患者接受TECENTRIQ，肺炎发生在6例(1.1%)患者。这些患者中，有一例患者有致命性肺炎，一例患者有3级，三例患者有2级，和一例患者有1级肺炎。在所有病例不给TECENTRIQ和五例患者被用皮质激素治疗。在3例患者肺炎解决。中位发病时间为2.6个月(范围：15天至4.2个月)。中位时间为15天(范围：6天至3.1+个月)。
用放射影像监视患者肺炎的体征和症状。对2级或较大肺炎给予甾体在剂量1至2 mg/kg/day泼尼松[prednisone]等价物，接着通过皮质激素锥形减小。不给TECENTRIQ直至对2级肺炎解决。对3或4级肺炎永久地终止TECENTRIQ [见剂量和给药方法(2.2)]。
5.2 免疫相关肝炎
免疫介导肝炎，被定义为需要使用皮质激素和与无明确另外病因，发生在接受TECENTRIQ患者。接受TECENTRIQ患者中发生肝测试异常。跨越临床试验(n=1978)，3或4级升高发生在ALT(2.5%)，AST(2.3%)，和总胆红素(1.6%)。在有尿路上皮癌患者(n=523)中3或4级升高发生在ALT(2.5%)，AST(2.5%)，和总胆红素(2.1%)。免疫介导肝炎发生在1.3%患者。这些病例中，一例患者死于肝炎，五例患者有3级，和一例患者有2级肝炎。发病中位时间为1.1个月(范围：0.4至7.7个月)。七例有免疫介导肝炎患者中，在四例患者中暂时地中断TECENTRIQ；这些患者没有人恢复TECENTRIQ发生肝炎复发。
监视患者肝炎体征和症状。用TECENTRIQ治疗前和期间定期监视AST，ALT，和胆红素。给予皮质激素在剂量1-2 mg/kg/day泼尼松等价物对2级或更大转氨酶升高，有或无同时总胆红素升高，接着被皮质激素锥形减小。对2级不给TECENTRIQ和对3或4级免疫介导肝炎永久地终止TECENTRIQ[见剂量和给药方法(2.2)和不良反应(6.1)]。
5.3 免疫相关结肠炎
免疫介导结肠炎或腹泻，被定义为需要使用皮质激素和与无明确另外病因，发生在接受TECENTRIQ患者。跨越临床试验，所有患者的19.7%(389/1978)发生结肠炎或腹泻和有尿路上皮癌患者中的18.7%(98/523)。10例患者(1.9%)发生3或4级腹泻。四例患者(0.8%)有免疫介导结肠炎或腹泻有发病中位时间1.7个月(范围：1.1至3.1个月)。这些患者的三例用皮质激素给药解决免疫介导结肠炎，而其他患者腹泻-关联肾衰竭情况中结肠炎未解决死亡。
监视患者腹泻或结肠炎的体征和症状。对2级腹泻或结肠炎不给TECENTRIQ治疗，如症状持续共长于5天或复发，给予1–2 mg/kg泼尼松或等价物每天。对3级腹泻或结肠炎不给TECENTRIQ治疗。用IV 甲泼尼龙[methylprednisolone]治疗1–2 mg/kg每天和转用至口服甾体一旦患者已改善。对2和3级两者腹泻或结肠炎，当症状改善至0或1级，跨越≥ 1个月逐渐减小甾体。如事件12周内改进至0或1级和皮质激素已被减低至等同于 ≤ 10 mg口服泼尼松每天恢复治疗用TECENTRIQ治疗。对4级腹泻或结肠炎永久地终止TECENTRIQ[见剂量和给药方法(2.2)和不良反应(6.1)]。
5.4 免疫相关内分泌病
接受TECENTRIQ患者增发生免疫相关甲状腺疾病，肾上腺功能不全，垂体炎，和1型糖尿病，包括糖尿病酮症酸中毒，监视患者内分泌疾病临床的体征和症状。
垂体炎
有尿路上皮癌患者接受TECENTRIQ中0.2%(1/523)发生垂体炎，监视垂体炎的体征和症状。如临床指示给予皮质激素和激素替代。对2或3级不给TECENTRIQ和对4级垂体炎永久地终止[见剂量和给药方法(2.2)和不良反应(6.1)]。
甲状腺疾病
仅在基线和研究结束时常规地评估甲状腺功能。跨越临床试验，3.9%(77/1978)患者发生甲状腺功能减退和有尿路上皮癌患者中2.5%(13/523)。一例患者有3级和12例患者有1–2级甲状腺功能减退症，至首次发病中位时间为5.4个月(范围：21天至11.3个月)。甲状腺刺激激素(TSH) 升高和有随访测量患者的16%(21/131)高于患者的基线。
跨越临床试验在1.0%(20/1978)患者发生甲状腺功能亢进症和有尿路上皮癌患者中0.6%(3/523)。三例尿路上皮癌患者中，一例患者有2级和两例患者有1级甲状腺功能亢进症。至发病中位时间为3.2个月(范围：1.4至5.8个月)。在3.8%(5/131)有一个随访测量TSH患者减低和低于患者的基线。
用TECENTRIQ治疗前和期间定期地监视甲状腺功能。无症状有异常甲状腺功能测试患者可接受TECENTRIQ。对症状性甲状腺功能减退症，不给TECENTRIQ和需要时开始甲状腺激素替代。用替代治疗和无皮质激素处理孤立的甲状腺功能减退症. 对症状性甲状腺功能亢进症，不给TECENTRIQ和需要时开始一种抗甲状腺药物。当甲状腺功能减退症或甲状腺功能亢进症的症状被控制和甲状腺功能正在改善恢复用TECENTRIQ治疗[见剂量和给药方法(2.2)和不良反应(6.1)]。
肾上腺功能不全
跨越临床试验0.4%(7/1978)患者发生肾上腺功能不全，包括二例患者有3级，四例患者有2级，和一例患者有1级。在两例患者肾上腺功能不全解决。
对症状性肾上腺功能不全，不给TECENTRIQ和给予甲泼尼龙1–2 mg/kg每天IV接着通过口服泼尼松1–2 mg/kg每天或等价物一旦症状改善。当症状改善至≤1级开始逐步锥形减小甾体和锥形甾体减小历时 ≥ 1个月。如12周内事件改进至≤ 1级和皮质激素已被减低至等同于 ≤ 10 mg口服泼尼松每天恢复用TECENTRIQ治疗和如需要时患者稳定用替代治疗[见剂量和给药方法(2.2)和不良反应(6.1)]。
糖尿病
在接受TECENTRIQ患者曽发生新发病糖尿病与酮症酸中毒。有尿路上皮癌患者中一例(0.2%)发生糖尿病无一个另外病因。对1型糖尿病开始用胰岛素治疗。对 ≥ 3级高血糖(空腹血糖>250–500 mg/dL)，不给TECENTRIQ。当用胰岛素替代治疗实现代谢控制恢复用TECENTRIQ治疗[见剂量和给药方法(2.2)和不良反应(6.1)]。
5.5 其他免疫相关不良反应
用TECENTRIQ治疗≤ 1.0%的患者曽发生其他免疫相关不良反应包括脑膜脑炎，肌无力综合征/重症肌无力，Guillain-Barré，眼炎症毒性，和胰腺炎，包括血清淀粉酶和脂肪酶水平增加。
脑膜炎/脑炎
监视患者脑膜炎或脑炎临床的体征和症状。对任何程度的脑膜炎或脑炎永久地终止TECENTRIQ。用IV甾体治疗(1–2 mg/kg/day甲泼尼龙或等价物)和一旦患者已改善转用至口服甾体(泼尼松 60 mg/day或等价物)。当症状改善至≤1级，在历时≥ 1 个月锥形减小甾体[见剂量和给药方法(2.2)和不良反应190(6.1)]。
运动和感觉神经病变
监视患者运动和感觉神经病变的症状。对任何程度的肌无力综合征/重症肌无力或Guillain-Barré综合证永久地终止TECENTRIQ。如适当时开始药物干预。考虑开始全身皮质激素在剂量1–2 mg/kg/day泼尼松[见剂量和给药方法(2.2)和不良反应(6.1)]。
胰腺炎
跨越临床试验在0.1%(2/1978)患者发生症状性胰腺炎无另外病因。监视患者急性胰腺炎的体征和症状。对≥3级血清淀粉或脂肪酶水平(> 2.0 ULN)，或2或3级胰腺炎不给TECENTRIQ。用1−2 mg/kg IV甲泼尼龙或等价物每天治疗。一旦症状改善，接着用1−2 mg/kg的口服泼尼松或等价物每天。如果血清淀粉酶和脂肪酶水平在12周内改善至 ≤1级， 胰腺炎的症状已解决，和皮质激素已被减低至≤ 10 mg口服泼尼松或等价物每天恢复用TECENTRIQ治疗。对复发胰腺炎4级或任何级别永久地终止TECENTRIQ[见剂量和给药方法(2.2)和不良反应(6.1)]，
5.6 感染
在接受TECENTRIQ患者发生严重感染，包括脓毒血症，疱疹性脑炎，和分枝杆菌感染导致腹膜后出血。跨越临床试验，在38.4%(759/1978)患者发生感染，在523例有尿路上皮癌患者接受TECENTRIQ，在197(37.7%)患者发生感染。在60例(11.5%)患者发生3或4级感染，而三例患者由于感染死亡。在37(7.1%)患者发生尿路感染为3或较高感染最常见原因。在一项随机试验在有非小细胞肺癌患者，用TECENTRIQ治疗患者(42%)与多西他赛[docetaxel]治疗(33%)比较感染是更常见。用TECENTRIQ治疗患者9.2%发生3或4级感染，与之比较用多西他赛治疗患者有2.2%。一例患者(0.7%)用TECENTRIQ治疗由于感染死亡，相比较用多西他赛治疗两例患者(1.5%)。肺炎是3级或更高感染最常见原因，用TECENTRIQ治疗患者发生6.3%。监视患者感染的体征和症状和用抗生素治疗怀疑或确证的细菌性感染。对≥3级感染不给TECENTRIQ[见剂量和给药方法(2.2)和不良反应(6.1)]。
5.7 输注相关反应
TECENTRIQ临床试验中患者曽发生严重输注反应。跨越临床试验1.3%(25/1978)患者发生输注相关反应和有尿路上皮癌患者中1.7%(9/523)。在有轻度或中度输注反应患者中断或减慢输注速率。在有3或4级输注反应患者永久地终止TECENTRIQ[见剂量和给药方法(2.2)和不良反应(6.1)]。
5.8 胚胎-胎儿毒性
根据其作用机制，一位当给予妊娠妇女TECENTRIQ可能致胎儿危害。动物研究曽显示PD-L1/PD-1通路的抑制作用可能导致发育中胎儿免疫相关排斥的增加风险导致胎儿死亡。如此药在妊娠期间使用，或当服用此药时患者成为妊娠，忠告患者对胎儿潜在风险。忠告生殖潜能女性在用TECENTRIQ治疗期间和末次剂量后共至少5个月使用有效避孕[见在特殊人群中使用(8.1，8.3)]。
6 不良反应
在说明书其他节中更详细讨论以下不良反应：
● 免疫相关肺炎[见警告和注意事项(5.1)]
● 免疫相关肝炎[见警告和注意事项(5.2)]
● 免疫相关结肠炎[见警告和注意事项(5.3)]
● 免疫相关内分泌病[见警告和注意事项(5.4)]
● 其他免疫相关不良反应[见警告和注意事项(5.5)]
● 感染[见警告和注意事项(5.6)]
● 输注相关反应[见警告和注意事项(5.7)]
6.1 临床研究经验
因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。
表1中数据描述反映在研究1队列2对TECENTRIQ暴露。这个队列在一个单臂试验纳入310例局部晚期或转移尿路上皮癌患者患者during或following 至少一个含铂化疗方案期间或后有疾病进展或用一个含铂新辅助或辅助化疗方案治疗12个月内有疾病进展[见临床研究(14.1)]。患者静脉每3周接受1200 mg的TECENTRIQ直至不可接受毒性或或放射影像学或临床进展。中位暴露时间为12.3周(范围：0.1，46周)。
最常见不良反应(≥ 20%)为疲乏(52%)，食欲减退(26%)，恶心(25%)，尿路感染(22%)，发热(21%)，和便秘(21%)。最常见3–4级不良反应(≥ 2%)为尿路感染，贫血，疲乏，脱水，肠梗阻，尿路梗阻，血尿，呼吸困难，急性肾损伤， 腹痛，静脉血栓栓塞，脓毒血症，和肺炎。
三例患者(0.9%)在用TECENTRIQ治疗经历或脓毒血症，肺炎，或肠梗阻导致死亡。 310例患者中3.2%(10/310)对不良反应终止TECENTRIQ。0.6%(2/310)患者因脓毒血症导致终止。 不良反应导致TECENTRIQ的中断发生在27%患者；最常见(> 1%)为肝酶增加，尿路感染，腹泻，疲乏，混乱状态，尿路梗阻，发热，呼吸困难，静脉血栓栓塞，和肺炎。严重不良反应发生在 45%患者。最频繁严重不良反应(> 2%)为尿路感染，血尿，急性肾损伤，肠梗阻，发热，静脉血栓栓塞，尿路梗阻， 肺炎，呼吸困难，腹痛，脓毒血症，和混乱状态。
表1总结在研究1队列2不良反应发生在≥ 10%患者而表2中总结发生在≥ 1%用TECENTRIQ治疗患者中 3–4级选定的实验室异常。
 


6.2 免疫原性
如同所有治疗性蛋白，有免疫原性潜能。研究1的275例患者中，114例患者(41.5%)在一个或更多给药后时间点对治疗-出现测试阳性(治疗-诱发或治疗-增强)抗-治疗性抗体(ATA)。在研究1，ATAs的存在似乎对药代动力学，安全或疗效没有临床上意义影响。免疫原性分析结果是高度依赖于几种因子，包括分析灵敏度和特异性，分析方法学，样品处置，采样时间，同时药物和所患疾病。因为这些理由，对TECENTRIQ的ATAs发生率与对其他产品抗体发生率的比较可能是误导。
8 在特殊人群中使用
8.1 妊娠
风险总结
根据其作用机制，对一位妊娠妇女给药TECENTRIQ可能致胎儿危害[见临床药理学(12.1)]。对在妊娠妇女中使用TECENTRIQ没有可供利用数据。动物研究曽显示PD L1/PD-1通路的抑制作用可导致发育中胎儿发生免疫相关排斥风险增加导致胎儿死亡[见数据]。如此药在妊娠期间正在使用，或如当服用此药时患者成为妊娠，忠告患者对胎儿潜在风险。在美国一般人群，主要出生缺陷和在临床上认可中流产的估算背景风险分别是2%至4%和15%至20%。
数据
动物数据
未曽在动物用TECENTRIQ进行生殖研究以评价对生殖和胎儿发育的影响。一个基于文献评估对生殖的影响显示PD-L1/PD-1通路的中央功能是通过维持母体对胎儿的免疫耐受性以保持妊娠。妊娠的鼠类模型中曽显示PD-L1信号的阻断破坏对胎儿耐受性和导致胎儿丢失增加；所以，妊娠期间给予TECENTRIQ的潜在风险包括增加流产或死胎率。如同在文献中报道，这些动物的子代中没有与PD-L1/PD-1信号的阻断相关畸形；但是，在PD-1和PD-L1敲除作用发生免疫介导疾病，胎儿暴露于atezolizumab可能增加发生免疫介导疾病或改变正常免疫反应的风险。
8.2 哺乳
风险总结
没有有关在人乳汁中存在，对哺乳喂养婴儿影响，或对乳汁生产的影响的资料。因人IgG被排泄在人乳汁中，不知道对吸收和对婴儿危害的潜能。因为对哺乳喂养婴儿来自TECENTRIQ严重不良反应潜能，忠告哺乳妇女在治疗期间和末次剂量后共至少5个月不要哺乳喂养。
8.3 生殖潜能女性和男性
避孕
女性
根据其作用机制，当给予一位妊娠妇女TECENTRIQ可能致胎儿危害[见在特殊人群中使用(8.1)]。忠告生殖潜能女性在用TECENTRIQ治疗期间和末次剂量后共至少5个月使用有效避孕。
不孕不育
雌性
根据动物研究，当接受治疗TECENTRIQ可能损害生殖潜能雌性中生育力[见非临床毒理学(13.1)]。
8.4 儿童使用
未曽确定在儿童患者中TECENTRIQ的安全性和有效性。
8.5 老年人使用
在研究1中310例有尿路上皮癌患者用TECENTRIQ治疗，59%为65岁或以上。患者≥65岁和较年轻患者间在安全性或疗效未观察到总体差别。
8.6 肾受损
根据一项群体药代动力学分析，对有肾受损患者无TECENTRIQ的剂量调整被推荐[见临床药理学(12.3)]。
8.7 肝受损
根据一项群体药代动力学分析，对有轻度肝受损患者推荐无TECENTRIQ的剂量调整。未曽在中度或严重肝受损患者研究TECENTRIQ[见临床药理学(12.3)]。
10 药物过量
没有用TECENTRIQ过量的信息。
11 一般描述
Atezolizumab是一种Fc-工程化，人源化，单克隆抗体结合至PD-L1和阻断与PD-1和B7.1受体相互作用。Atezolizumab是一种非糖基化IgG1 kappa(希文)免疫球蛋白有一个计算的分子质量145 kDa。
TECENTRIQ注射液为静脉输注是在单剂量小瓶中一个无菌，无防腐剂，无色至浅黄色溶液。每mL的TECENTRIQ含60 mg atezolizumab和是在冰醋酸(16.5 mg)，L-组氨酸(62 mg)，蔗糖(821.6 mg)，聚山梨醇20(8 mg)，pH 5.8被制剂化。
12 临床药理学
12.1 作用机制
PD-L1可能被表达肿瘤细胞和/或肿瘤浸润免疫细胞上和可能对在肿瘤微环境中抗肿瘤免疫反应的抑制作用有贡献。PD-L1的结合至T细胞上发现PD-1和B7.1受体和抗原提呈细胞抑制细胞毒性T细胞活性，T-细胞增殖和细胞因子产生。
Atezolizumab是一个单克隆抗体结合至PD-L1和阻断它的与PD-1和B7.1受体两者相互作用。这个释放PD-L1/PD-1介导的免疫反应的抑制作用，包括抗肿瘤免疫反应的活化无诱导抗体依赖细胞细胞毒性。在同源小鼠肿瘤模型中，阻断PD-L1活性导致肿瘤生长减低。
12.3 药代动力学
跨越剂量范围1 mg/kg至20 mg/kg，包括固定剂量1200 mg给予每3周患者对atezolizumab的暴露剂量正比例地增加。根据包括在剂量范围472例患者一项群体分析，典型的群体清除率为0.20 L/day，稳态时分布容积为6.9 L，和末端半衰期为27天。群体PK分析提示在重复给药的6至9周(2至3疗程)后得到稳态。曲线下面积(AUC)，最高浓度(Cmax)和谷浓度(Cmin)的全身积蓄分别为1.91，1.46和2.75-倍。
特殊人群：年龄(21–89岁)，体重，性别，阳性抗-治疗抗体(ATA)状态，白蛋白水平，肿瘤负荷，地区或种族，轻度或中度肾受损(估算的肾小球滤过率(eGFR) 30至89 mL/min/1.73 m2)，轻度肝受损(胆红素 ≤ ULN和AST > ULN或胆红素 < 1.0至1.5 × ULN和任何AST)，PD-L1表达的水平，或ECOG状态对atezolizumab的全身暴露无临床上显著影响。
不知道严重肾受损(eGFR 15至29 mL/min/1.73 m2)或中度或严重肝受损(胆红素 > ULN和AST > ULN或胆红素 ≥ 1.0至1.5 × ULN和任何AST)对atezolizumab药代动力学的影响。
药物相互作用研究
不知道atezolizumab的药物相互作用潜能。
13 非临床毒理学
13.1 癌发生，突变发生，生育力受损
未曽进行研究测试atezolizumab对致癌性或遗传毒性的潜能。
未曽用atezolizumab进行动物生育力 研究；但是，被包括在猕猴一项26-周，重复-给药毒性研究雄性和雌性生殖器官的评估。每周给予atezolizumab至雌性猴在最高测试剂量引起不规则的月经周期模式和卵巢缺乏新形成黄体。这个效应发生在估算的AUC大约6倍于AUC在患者接受推荐剂量和是可逆的。对雄性猴生殖器官无影响。
13.2 动物毒理学和/或药理学
在动物模型中，PD-L1/PD-1信号的抑制作用增加有些感染的严重性和增强炎性反应。结核分枝杆菌感染PD-1敲除小鼠与野生型对照比较表现出生存明显减低，它与在这些动物中增加细菌增殖和炎症关联。PD-L1和PD-1敲除小鼠和接受PD-L1阻断抗体小鼠用淋巴细胞性脉络丛脑膜炎病毒感染后也显示活存减低。
14 临床研究
14.1 尿路上皮癌
在研究1研究TECENTRIQ，一项多中心，开放，两-队列试验包括有局部晚期或转移尿路上皮癌患者。在研究1队列2中，310例有局部晚期或转移尿路上皮癌患者一个含铂化疗方案期间或后患者有疾病进展或用一个含铂新辅助或辅助化疗方案治疗的12个月内疾病进展患者用TECENTRIQ治疗。本研究排除患者有：自身免疫疾病史，活动或皮质类固醇激素依赖性脑转移瘤，纳入前28天内给予活，减毒疫苗，或给予全身免疫刺激药物或全身免疫抑制药物。患者接受一个静脉输注1200 mg的TECENTRIQ每3周直至不可接受毒性或任一放射影像或临床进展。对头54周和其后每12周每9周进行肿瘤反应评估。主要疗效结局测量包括独立审查机构(IRF)使用实体瘤中疗效评价标准(RECIST v1.1)所评估的确证的客观反应率(ORR)和反应时间(DoR)。
在这个队列中，中位年龄为66岁，78%为男性，91%患者为高加索人。26%有非-膀胱尿路上皮癌和78%患者有内脏转移。62%患者有一个ECOG评分1和35%患者有基线肌酐清除率< 60 mL/min。19%患者有以前含-铂新辅助或辅助化疗后。41%患者有在转移情况中接受以前全身方案。73%患者接受以前顺铂[cisplatin]，26%有以前卡铂[carboplatin]，和1%用其他基于铂方案治疗过。肿瘤标本在一个中央实验室前瞻地用Ventana PD-L1(SP142)分析，而结果被用于确定对预先指定分析亚组。在310例患者中，32%被分类为有PD-L1表达≥ 5%(被定义为PD-L1染色的肿瘤浸润免疫细胞[ICs]覆盖 ≥ 5%肿瘤面积)。其余，68%患者，被分类为有PD-L1 表达<5%(PD-L1染色的肿瘤浸润ICs覆盖< 5%肿瘤面积)。
表3中总结了在所有患者和两个PD-L1亚组确证的ORR 。对这个队列的中位随访时间为14.4个月。在59例新辅助或辅助治疗后有疾病进展患者，ORR为22.0%(95% CI：12.3%，34.7%)。

16 如何供应/贮存和处置
TECENTRIQ注射液是一个无菌，无防腐剂，和无色至浅黄色溶液为静脉输注供应在一个纸盒含一个1200 mg/20 mL单-剂量小瓶(NDC 50242-917-01).
贮存：贮存小瓶在冰箱中在2°C至8°C(36°F至46°F)在原始纸盒以避光保护。不要冻结。不要摇晃。
17 患者咨询资料
忠告患者阅读FDA-批准的患者说明书(用药指南)。
告知患者免疫相关不良反应的风险可能需要皮质激素治疗和TECENTRIQ的中断或终止，包括：
● 肺炎：忠告患者对任何新或恶化咳嗽，胸痛，或气短立即联系他们的卫生保健提供者[见警告和注意事项(5.1)].
● 肝炎：忠告患者对黄疸，严重恶心或呕吐，腹部右侧疼痛，昏睡，或易于瘀伤或出血立即联系他们的卫生保健提供者[见警告和注意事项(5.2)]。
● 结肠炎：忠告患者对腹泻或严重腹痛立即联系他们的卫生保健提供者[见警告和注意事项(5.3)]。
● 内分泌疾病：忠告患者对垂体炎，甲状腺功能亢进症，甲状腺功能减退症，肾上腺功能不全，或1型糖尿病，包括糖尿病酮症酸中毒的体征或症状立即联系他们的卫生保健提供者[见警告和注意事项(5.4)]
● 脑膜脑炎，肌无力综合征/重症肌无力，和Guillain-Barré综合证：忠告患者对脑膜炎，肌无力综合征/重症肌无力，或Guillain-Barré综合证的体征或症状立即联系他们的卫生保健提供者 [见警告和注意事项(5.5)]。
● 眼炎症毒性：忠告患者对眼炎症毒性的体征或症状立即联系他们的卫生保健提供者[见警告和注意事项(5.5)]。
● 胰腺炎：忠告患者对胰腺炎的体征和症状立即联系他们的卫生保健提供者[见警告和注意事项(5.5)]。
● 感染：忠告患者对感染的体征或症状立即联系他们的卫生保健提供者[见警告和注意事项(5.6)]。
● 输注-相关反应：忠告患者对输注相关反应的体征或症状立即联系他们的卫生保健提供者[见警告和注意事项(5.7)]。
● 皮疹：忠告患者对皮疹的体征或症状立即联系他们的卫生保健提供者[见剂量和给药方法(2.2)]。
胚胎-胎儿毒性
忠告女性患者TECENTRIQ可能致胎儿危害。指导生殖潜能女性治疗期间和TECENTRIQ的末次剂量后共至少5个月使用有效避孕[见在特殊人群中使用(8.1，8.3)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Indications and Usage for Tecentriq

Locally Advanced or Metastatic Urothelial Carcinoma

Tecentriq (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

are not eligible for cisplatin-containing chemotherapy, orhave disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy

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

Metastatic Non-Small Cell Lung Cancer

Tecentriq is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Tecentriq [see Clinical Studies (14.2)].

Tecentriq Dosage and Administration

Recommended Dosing

The recommended dose of Tecentriq is 1200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Do not administer Tecentriq as an intravenous push or bolus.

Dose Modifications

No dose reductions of Tecentriq are recommended.

Withhold Tecentriq for any of the following:

·         Grade 2 pneumonitis [see Warnings and Precautions (5.1)]

·         Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN [see Warnings and Precautions (5.2)]

·         Grade 2 or 3 diarrhea or colitis [see Warnings and Precautions (5.3)]

·         Symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, or Grade 3 or 4 hyperglycemia [see Warnings and Precautions (5.4)]

·         Grade 2 ocular inflammatory toxicity [see Warnings and Precautions (5.5)]

·         Grade 2 or 3 pancreatitis, or Grade 3 or 4 increases in amylase or lipase levels (greater than 2.0 times ULN) [see Warnings and Precautions (5.5)]

·         Grade 3 or 4 infection [see Warnings and Precautions (5.6)]

·         Grade 2 infusion-related reactions [see Warnings and Precautions (5.7)]

·         Grade 3 rash

Tecentriq may be resumed in patients whose adverse reactions recover to Grade 0–1.

Permanently discontinue Tecentriq for any of the following:

·         Grade 3 or 4 pneumonitis [see Warnings and Precautions (5.1)]

·         AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN [see Warnings and Precautions (5.2)]

·         Grade 4 diarrhea or colitis [see Warnings and Precautions (5.3)]

·         Grade 4 hypophysitis [see Warnings and Precautions (5.4)]

·         Myasthenic syndrome/myasthenia gravis, Guillain-Barré or meningoencephalitis (all grades) [see Warnings and Precautions (5.5)]

·         Grade 3 or 4 ocular inflammatory toxicity [see Warnings and Precautions (5.5)]

·         Grade 4 or any grade of recurrent pancreatitis [see Warnings and Precautions (5.5)]

·         Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5.7)]

·         Grade 4 rash

Preparation and Administration

Preparation

Visually inspect drug product for particulate matter and discoloration prior to administration whenever solution and container permit. Tecentriq is a colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake the vial.

Prepare the solution for infusion as follows:

·         Withdraw 20 mL of Tecentriq from the vial.

·         Dilute into a 250 mL polyvinyl chloride (PVC), polyethylene (PE), or polyolefin (PO) infusion bag containing 0.9% Sodium Chloride Injection, USP.

·         Dilute with 0.9% Sodium Chloride Injection only.

·         Mix diluted solution by gentle inversion. Do not shake.

·         Discard used or empty vials of Tecentriq.

Storage of Infusion Solution

This product does not contain a preservative.

Administer immediately once prepared. If diluted Tecentriq infusion solution is not used immediately, it can be stored either:

At room temperature for no more than 6 hours from the time of preparation. This includes room temperature storage of the infusion in the infusion bag and time for administration for infusion.Under refrigeration at 2°C–8°C (36°F–46°F) for no more than 24 hours.

Do not freeze.

Do not shake.

Administration

Administer the initial infusion over 60 minutes through an intravenous line with or without a sterile, non-pyrogenic, low-protein binding in-line filter (pore size of 0.2–0.22 micron). If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.

Do not co-administer other drugs through the same intravenous line.

Dosage Forms and Strengths

Injection: 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in a single-dose vial.

Contraindications

None.

Warnings and Precautions

Immune-Related Pneumonitis

Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving Tecentriq. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer steroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Withhold Tecentriq until resolution for Grade 2 pneumonitis. Permanently discontinue Tecentriq for Grade 3 or 4 pneumonitis [see Dosage and Administration (2.2)].

Across clinical trials, 2.6% (51/1978) of patients developed pneumonitis. Fatal pneumonitis occurred in two patients.

Urothelial Carcinoma

In 523 patients with urothelial carcinoma who received Tecentriq, pneumonitis occurred in six (1.1%) patients. Of these patients, there was one patient with fatal pneumonitis, one patient with Grade 3, three patients with Grade 2, and one patient with Grade 1 pneumonitis. Tecentriq was held in all cases. Pneumonitis resolved in three patients. The median time to onset was 2.6 months (range: 15 days to 4.2 months). The median duration was 15 days (range: 6 days to 3.1+ months). Immune-mediated pneumonitis occurred in 5 (1.0%) patients.

NSCLC

In 1027 patients with NSCLC who received Tecentriq, pneumonitis occurred in 38 (3.7%) patients. Of these patients, there was one patient with fatal pneumonitis, two patients with Grade 4, thirteen patients with Grade 3, eleven patients with Grade 2, and eleven patients with Grade 1 pneumonitis. Tecentriq was held in 24 patients and 21 patients were treated with corticosteroids. Pneumonitis resolved in 26 of the 38 patients. The median time to onset was 3.3 months (range: 3 days to 18.7 months). The median duration was 1.4 months (range: 0 days to 12.6+ months).

Immune-Related Hepatitis

Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving Tecentriq treatment. Liver test abnormalities occurred in patients who received Tecentriq. Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment with Tecentriq. Administer corticosteroids at a dose of 1–2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin, followed by corticosteroid taper. Withhold Tecentriq for Grade 2 and permanently discontinue Tecentriq for Grade 3 or 4 immune-mediated hepatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Across clinical trials (n=1978), Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%).

Urothelial Carcinoma

In patients with urothelial carcinoma (n=523), Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.5%), and total bilirubin (2.1%). Immune-mediated hepatitis occurred in 1.3% (7/523) of patients. Of these cases, one patient died from hepatitis, five patients had Grade 3, and one patient had Grade 2 hepatitis. The median time to onset was 1.1 months (range: 0.4 to 7.7 months). Tecentriq was temporarily interrupted in four patients; none of these patients developed recurrence of hepatitis after resuming Tecentriq.

NSCLC

In patients with NSCLC, Grade 3 or 4 elevation occurred in ALT (1.4%), AST (1.3%), and total bilirubin (0.6%). Immune-mediated hepatitis occurred in 0.9% (9/1027) of patients. Of these nine patients, one patient had Grade 4, four patients had Grade 3, three patients had Grade 2, and one patient had Grade 1 immune-mediated hepatitis. The median time to onset was 28 days (range: 15 days to 4.2 months). Tecentriq was temporarily interrupted in seven patients; none of these patients developed recurrence of hepatitis after resuming Tecentriq.

Immune-Related Colitis

Immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving Tecentriq. Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with Tecentriq for Grade 2 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer 1–2 mg/kg prednisone or equivalent per day. Withhold treatment with Tecentriq for Grade 3 diarrhea or colitis. Treat with IV methylprednisolone 1–2 mg/kg per day and convert to oral steroids once the patient has improved. For both Grade 2 and Grade 3 diarrhea or colitis, when symptoms improve to Grade 0 or Grade 1, taper steroids over ≥ 1 month. Resume treatment with Tecentriq if the event improves to Grade 0 or 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg oral prednisone per day. Permanently discontinue Tecentriq for Grade 4 diarrhea or colitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Across clinical trials, colitis or diarrhea occurred in 19.7% (389/1978) of all patients.

Urothelial Carcinoma

In 523 patients with urothelial carcinoma who received Tecentriq, colitis or diarrhea occurred in 98 (18.7%) patients. Ten patients (1.9%) developed Grade 3 or 4 diarrhea. Four patients (0.8%) had immune-mediated colitis or diarrhea with a median time to onset of 1.7 months (range: 1.1 to 3.1 months). Immune-mediated colitis resolved with corticosteroid administration in three of these patients, while the other patient died without resolution of colitis in the setting of diarrhea-associated renal failure.

NSCLC

In 1027 patients with NSCLC who received Tecentriq, colitis or diarrhea occurred in 198 (19.3%) patients. Twelve patients (1.2%) developed Grade 3 colitis or diarrhea. Five patients (0.5%) had immune-mediated colitis or diarrhea with a median time to onset of 21 days (range: 12 days to 3.4 months). Of these patients, one had Grade 3, two had Grade 2, and two had Grade 1 immune-mediated colitis or diarrhea. Immune-mediated colitis or diarrhea resolved with corticosteroid administration in four of these patients, while the fifth patient died due to disease progression prior to resolution of colitis.

Immune-Related Endocrinopathies

Immune-related thyroid disorders, adrenal insufficiency, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving Tecentriq. Monitor patients for clinical signs and symptoms of endocrinopathies.

Hypophysitis

Hypophysitis occurred in 0.2% (1/523) of patients with urothelial cancer receiving Tecentriq. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids and hormone replacement as clinically indicated. Withhold Tecentriq for Grade 2 or Grade 3 and permanently discontinue for Grade 4 hypophysitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Thyroid Disorders

Thyroid function was assessed routinely only at baseline and the end of the study. Monitor thyroid function prior to and periodically during treatment with Tecentriq. Asymptomatic patients with abnormal thyroid function tests can receive Tecentriq. For symptomatic hypothyroidism, withhold Tecentriq and initiate thyroid hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold Tecentriq and initiate an anti-thyroid drug as needed. Resume treatment with Tecentriq when symptoms of hypothyroidism or hyperthyroidism are controlled and thyroid function is improving [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Across clinical trials, hypothyroidism and hyperthyroidism occurred in 3.9% (77/1978) and 1.0% (20/1978) of patients, respectively.

Urothelial Carcinoma

In 523 patients with urothelial carcinoma who received Tecentriq, hypothyroidism occurred in 2.5% (13/523). One patient had Grade 3 and twelve patients had Grade 1–2 hypothyroidism. The median time to first onset was 5.4 months (range: 21 days to 11.3 months). Thyroid stimulating hormone (TSH) was elevated and above the patient's baseline in 16% (21/131) of patients with a follow-up measurement.

Hyperthyroidism occurred in 0.6% (3/523) of patients with urothelial carcinoma. Of the three urothelial carcinoma patients, one patient had Grade 2 and two patients had Grade 1 hyperthyroidism. The median time to onset was 3.2 months (range: 1.4 to 5.8 months). TSH was decreased and below the patient's baseline in 3.8% (5/131) of patients with a follow-up measurement.

NSCLC

In 1027 patients with NSCLC who received Tecentriq, hypothyroidism occurred in 4.2% (43/1027). Three patients had Grade 3 and forty patients had Grade 1–2 hypothyroidism. The median time to onset was 4.8 months (range 15 days to 31 months.) TSH was elevated and above the patient's baseline in 17% (54/315) of patients with follow-up measurement.

Hyperthyroidism occurred in 1.1% (11/1027) of patients with NSCLC. Eight patients had Grade 2 and three patients had Grade 1 hyperthyroidism. The median time to onset was 4.9 months (range: 21 days to 31 months). TSH was decreased and below the patient's baseline in 7.6% (24/315) of patients with a follow-up measurement.

Adrenal Insufficiency

Adrenal insufficiency occurred in 0.4% (7/1978) of patients across clinical trials, including two patients with Grade 3, four patients with Grade 2, and one patient with Grade 1. Adrenal insufficiency resolved in two patients.

For symptomatic adrenal insufficiency, withhold Tecentriq and administer methylprednisolone 1–2 mg/kg per day IV followed by oral prednisone 1–2 mg/kg per day or equivalent once symptoms improve. Start steroid taper when symptoms improve to ≤ Grade 1 and taper steroids over ≥ 1 month. Resume treatment with Tecentriq if the event improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of ≤ 10 mg oral prednisone per day and the patient is stable on replacement therapy, if required [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Diabetes Mellitus

New onset diabetes with ketoacidosis has occurred in patients receiving Tecentriq. Diabetes mellitus without an alternative etiology occurred in one (0.2%) patient with urothelial carcinoma and three (0.3%) patients with NSCLC.

Initiate treatment with insulin for type 1 diabetes mellitus. For ≥ Grade 3 hyperglycemia (fasting glucose >250–500 mg/dL), withhold Tecentriq. Resume treatment with Tecentriq when metabolic control is achieved on insulin replacement therapy [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Other Immune-Related Adverse Reactions

Other immune-related adverse reactions including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barré, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in ≤ 1.0% of patients treated with Tecentriq.

Meningitis / Encephalitis

Monitor patients for clinical signs and symptoms of meningitis or encephalitis. Permanently discontinue Tecentriq for any grade of meningitis or encephalitis. Treat with IV steroids (1–2 mg/kg/day methylprednisolone or equivalent) and convert to oral steroids (prednisone 60 mg/day or equivalent) once the patient has improved. When symptoms improve to ≤ Grade 1, taper steroids over ≥ 1 month [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Motor and Sensory Neuropathy

Monitor patients for symptoms of motor and sensory neuropathy. Permanently discontinue Tecentriq for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Institute medical intervention as appropriate. Consider initiation of systemic corticosteroids at a dose of 1–2 mg/kg/day prednisone [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Pancreatitis

Symptomatic pancreatitis without an alternative etiology occurred in 0.1% (2/1978) of patients across clinical trials. Monitor patients for signs and symptoms of acute pancreatitis. Withhold Tecentriq for ≥ Grade 3 serum amylase or lipase levels (> 2.0 ULN), or Grade 2 or 3 pancreatitis. Treat with 1–2 mg/kg IV methylprednisolone or equivalent per day. Once symptoms improve, follow with 1–2 mg/kg of oral prednisone or equivalent per day. Resume treatment with Tecentriq when serum amylase and lipase levels improve to ≤ Grade 1 within 12 weeks or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤ 10 mg oral prednisone or equivalent per day. Permanently discontinue Tecentriq for Grade 4 or any grade of recurrent pancreatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Infection

Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving Tecentriq. Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold Tecentriq for ≥ Grade 3 infection [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Across clinical trials, infections occurred in 38.4% (759/1978) of patients.

Urothelial Carcinoma

In 523 patients with urothelial carcinoma who received Tecentriq, infection occurred in 197 (37.7%) patients. Grade 3 or 4 infection occurred in sixty (11.5%) patients, while three patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 37 (7.1%) patients.

NSCLC

In Study 3, a randomized trial in patients with NSCLC, infections were more common in patients treated with Tecentriq (43%) compared with those treated with docetaxel (34%). Grade 3 or 4 infections occurred in 9.2% of patients treated with Tecentriq compared with 2.2% in patients treated with docetaxel. Two patients (1.4%) treated with Tecentriq and three patients (2.2%) treated with docetaxel died due to infection. Pneumonia was the most common cause of Grade 3 or higher infection, occurring in 7.7% of patients treated with Tecentriq.

Infusion-Related Reactions

Severe infusion reactions have occurred in patients in clinical trials of Tecentriq. Infusion-related reactions occurred in 1.3% (25/1978) of patients across clinical trials, 1.7% (9/523) of patients with urothelial carcinoma, and 1.6% (16/1027) of patients with NSCLC. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue Tecentriq in patients with Grade 3 or 4 infusion reactions [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Based on its mechanism of action, Tecentriq can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Tecentriq and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

Immune-Related Pneumonitis [see Warnings and Precautions (5.1)]Immune-Related Hepatitis [see Warnings and Precautions (5.2)]Immune-Related Colitis [see Warnings and Precautions (5.3)]Immune-Related Endocrinopathies [see Warnings and Precautions (5.4)]Other Immune-Related Adverse Reactions [see Warnings and Precautions (5.5)]Infection [see Warnings and Precautions (5.6)]Infusion-Related Reactions [see Warnings and Precautions (5.7)]

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.

Urothelial Carcinoma

Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

The safety of Tecentriq was evaluated in Study 4, a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy [see Clinical Studies (14.1)]. Patients received 1200 mg of Tecentriq intravenously every 3 weeks until either unacceptable toxicity or disease progression. The median duration of exposure was 15.0 weeks (range 0, 87 weeks).

The most common adverse reactions (≥ 20%) were fatigue (52%), decreased appetite (24%), diarrhea (24%), and nausea (22%). The most common Grade 3–4 adverse reactions (≥ 2%) were fatigue, urinary tract infection, anemia, diarrhea, blood creatinine increase, intestinal obstruction, ALT increase, hyponatremia, decreased appetite, sepsis, back/neck pain, renal failure, and hypotension.

Five patients (4.2%) who were treated with Tecentriq experienced one of the following events which led to death: sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. One additional patient (0.8%) was experiencing herpetic meningoencephalitis and disease progression at the time of death. Tecentriq was discontinued for adverse reactions in 4.2% (5/119) of patients. The adverse reactions leading to discontinuation were diarrhea/colitis (1.7%), fatigue (0.8%), hypersensitivity (0.8%), and dyspnea (0.8%). Adverse reactions leading to interruption of Tecentriq occurred in 35% of patients, the most common (≥ 1%) were intestinal obstruction, fatigue, diarrhea, urinary tract infection, infusion related reaction, cough, abdominal pain, peripheral edema, pyrexia, respiratory tract infection, upper respiratory tract infection, creatinine increase, decreased appetite, hyponatremia, back pain, pruritus, and venous thromboembolism. Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (≥ 2%) were diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure.

Immune-related adverse reactions requiring systemic corticosteroids or hormone replacement therapy occurred in 19.3% (23/119) patients, including 12.6% (15/119) patients who required systemic corticosteroid therapy and 6.7% (8/119) patients who required only hormone replacement therapy.

Six patients (5.0%) received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)].

Table 1 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 2 summarizes Grade 3–4 selected laboratory abnormalities that occurred in ≥ 1% of patients treated with Tecentriq in Study 4.

Table 1: All Grade Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in Study 4
	Tecentriq N = 119
Adverse Reaction	All Grades (%)		Grades 3–4 (%)
* Includes fatigue, asthenia, lethargy, and malaise † Includes edema peripheral, scrotal edema, lymphedema, and edema ‡ Includes diarrhea, colitis, frequent bowel movements, autoimmune colitis § Includes abdominal pain, upper abdominal pain, lower abdominal pain, and flank pain ¶ Includes decreased appetite and early satiety # Includes rash, dermatitis, dermatitis acneiform, rash maculo-papular, rash erythematous, rash pruritic, rash macular, and rash papular Þ Includes urinary tract infection, urinary tract infection bacterial, cystitis, and urosepsis ß Includes cough and productive cough à Includes dyspnea and exertional dyspnea
General Disorders
Fatigue*	52		8
Peripheral edema†	17		2
Pyrexia	14		0.8
Gastrointestinal Disorders
Diarrhea‡	24		5
Nausea	22		2
Vomiting	16		0.8
Constipation	15		2
Abdominal pain§	15		0.8
Metabolism and Nutrition Disorders
Decreased appetite¶	24		3
Musculoskeletal and Connective Tissue Disorders
Back/Neck pain	18		3
Arthralgia	13		0
Skin and Subcutaneous Tissue Disorders
Pruritus	18		0.8
Rash#	17		0.8
Infections
Urinary tract infectionÞ	17		5
Respiratory, Thoracic, and Mediastinal Disorders
Coughß	14		0
Dyspneaà	12		0
Table 2: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 4 in ≥ 1% of Patients
Laboratory Test		Grades 3–4 (%)
Hyponatremia		15
Hyperglycemia		10
Lymphopenia		9
Anemia		7
Increased Alkaline phosphatase		7
Increased Creatinine		5
Hypophosphatemia		4
Increased ALT		4
Increased AST		4
Hyperkalemia		3
Hypermagnesemia		3
Hyperbilirubinemia		3

Previously Treated Patients with Locally Advanced or Metastatic Urothelial Carcinoma

The safety of Tecentriq was evaluated in Study 1, a multicenter, open-label, single-arm trial that included 310 patients in a single arm trial with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received 1200 mg of Tecentriq intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (range: 0.1, 46 weeks).

The most common adverse reactions (≥ 20%) were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most common Grade 3–4 adverse reactions (≥ 2%) were urinary tract infection, anemia, fatigue, dehydration, intestinal obstruction, urinary obstruction, hematuria, dyspnea, acute kidney injury, abdominal pain, venous thromboembolism, sepsis, and pneumonia.

Three patients (1.0%) who were treated with Tecentriq experienced one of the following events which led to death: sepsis, pneumonitis, or intestinal obstruction. Tecentriq was discontinued for adverse reactions in 3.2% (10/310) of the 310 patients. Sepsis led to discontinuation in 0.6% (2/310) of patients. Adverse reactions leading to interruption of Tecentriq occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state.

Immune-related adverse reactions requiring systemic corticosteroids or hormone replacement therapy occurred in 11.0% (34/310) patients, including 8.4% (26/310) patients who required systemic corticosteroid therapy and 2.6% (8/310) patients who required only hormone replacement therapy.

Eighteen patients (5.8%) received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)].

Table 3 summarizes the adverse reactions that occurred in ≥ 10% of patients while Table 4 summarizes Grade 3–4 selected laboratory abnormalities that occurred in ≥ 1% of patients treated with Tecentriq in Study 1.

Table 3: All Grade Adverse Reactions in ≥ 10% of Patients with Urothelial Carcinoma in Study 1
	Tecentriq N=310
Adverse Reaction	All Grades (%)		Grades 3–4 (%)
Gastrointestinal Disorders
Nausea	25		2
Constipation	21		0.3
Diarrhea	18		1
Abdominal pain	17		4
Vomiting	17		1
General Disorders
Fatigue	52		6
Pyrexia	21		1
Peripheral edema	18		1
Infections
Urinary tract infection	22		9
Metabolism and Nutrition Disorders
Decreased appetite	26		1
Musculoskeletal and Connective Tissue Disorders
Back/Neck pain	15		2
Arthralgia	14		1
Renal and urinary disorders
Hematuria	14		3
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea	16		4
Cough	14		0.3
Skin and Subcutaneous Tissue Disorders
Rash	15		0.3
Pruritus	13		0.3
Table 4: Grade 3–4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 1 in ≥ 1% of Patients
Laboratory Test		Grades 3–4 (%)
Lymphopenia		10
Hyponatremia		10
Anemia		8
Hyperglycemia		5
Increased Alkaline phosphatase		4
Increased Creatinine		3
Increased ALT		2
Increased AST		2
Hypoalbuminemia		1

NSCLC

The safety of Tecentriq was evaluated in Study 3, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.2)]. Patients received 1200 mg of Tecentriq (n=142) administered intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression or docetaxel (n=135) administered intravenously at 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. The median duration of exposure was 3.7 months (range: 0–19 months) in Tecentriq-treated patients and 2.1 months (range: 0–17 months) in docetaxel-treated patients.

The most common adverse reactions (≥ 20%) in patients receiving Tecentriq were fatigue (46%), decreased appetite (35%), dyspnea (32%), cough (30%), nausea (22%), musculoskeletal pain (22%), and constipation (20%). The most common Grade 3-4 adverse reactions (≥2%) were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia.

Nine patients (6.3%) who were treated with Tecentriq experienced either pulmonary embolism (2), pneumonia (2), pneumothorax, ulcer hemorrhage, cachexia secondary to dysphagia, myocardial infarction, or large intestinal perforation which led to death. Tecentriq was discontinued due to adverse reactions in 4% (6/142) of patients. Adverse reactions leading to interruption of Tecentriq occurred in 24% of patients; the most common (>1%) were pneumonia, liver function test abnormality, upper respiratory tract infection, pneumonitis, acute kidney injury, hypoxia, hypothyroidism, dyspnea, anemia, and fatigue. Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (> 2%) were pneumonia, dyspnea, pleural effusion, pyrexia, and venous thromboembolism.

Table 5 summarizes adverse reactions that occurred in at least 10% of Tecentriq-treated patients and at a higher incidence than in the docetaxel arm. Table 6 summarizes selected laboratory abnormalities worsening from baseline that occurred in ≥10% of Tecentriq-treated patients and at a higher incidence than in the docetaxel arm.

Table 5: Adverse Reactions Occurring in ≥10% of Tecentriq-Treated Patients with NSCLC and at a Higher Incidence than in the Docetaxel Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3–4]) (Study 3)
	Tecentriq (n=142)		Docetaxel (n=135)
Adverse Reaction	All grades	Grade 3–4	All grades	Grade 3–4
	Percentage (%) of Patients
General Disorders
Pyrexia	18	0	13	0
Infections
Pneumonia	18	6	4	2
Metabolism and nutrition disorders
Decreased appetite	35	1	22	0
Musculoskeletal and connective tissue disorders
Arthralgia	16	2	9	2
Back pain	14	1	9	1
Psychiatric Disorders
Insomnia	14	0	8	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	32	7	24	2
Cough	30	1	25	0
Table 6: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Tecentriq-Treated Patients with NSCLC and at a Higher Incidence than in the Docetaxel Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3–4]) (Study 3)
	Percentage of Patients with Worsening Laboratory Test from Baseline
	Tecentriq		Docetaxel
Test	All grades %	Grade 3–4 %	All grades %	Grade 3–4 %
Hyponatremia	48	13	28	8
Hypoalbuminemia	48	5	49	1
Alkaline Phosphatase increased	42	2	24	1
Aspartate aminotransferase increased	33	2	15	0
Alanine aminotransferase increased	31	2	9	1
Creatinine increased	19	1	14	2
Hypokalemia	18	2	11	4
Hypercalcemia	13	0	5	0
Total Bilirubin increased	11	0	5	1

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Among 275 patients in Study 1, 114 patients (41.5%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) anti-therapeutic antibodies (ATA) at one or more post-dose time points. Among 135 patients in Study 3, 73 patients (54.1%) tested positive for treatment-emergent ATAs at one or more post-dose time points. Among 111 patients in Study 4, 53 patients (47.7%) tested positive for treatment-emergent ATAs at one or more post-dose time points. In Study 1, Study 3, and Study 4, the presence of ATAs did not appear to have a clinically significant impact on pharmacokinetics, safety or efficacy.

Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of ATAs to Tecentriq with the incidence of antibodies to other products may be misleading.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action, Tecentriq can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of Tecentriq in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

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

Data

Animal Data

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

Lactation

Risk Summary

There is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from Tecentriq, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose.

Females and Males of Reproductive Potential

Contraception

Females

Based on its mechanism of action, Tecentriq 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 Tecentriq and for at least 5 months following the last dose.

Infertility

Females

Based on animal studies, Tecentriq may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].

Pediatric Use

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

Geriatric Use

Of the 310 previously-treated patients with urothelial carcinoma treated with Tecentriq in Study 1, 59% were 65 years or older. Of the 142 patients with NSCLC treated with Tecentriq in Study 3, 39% were 65 years or older. No overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients.

Of the 119 cisplatin-ineligible patients with urothelial carcinoma treated with Tecentriq in Study 4, 83% were 65 years or older and 41% were 75 years or older. The overall response rate in patients 65 years or older was 23% (23/99) and in patients 75 years or older was 29% (14/49). Grade 3 or 4 adverse reactions occurred in 53% (52/99) of patients 65 years or older and 51% (25/49) of patients 75 years or older. No overall differences in safety or efficacy were observed between patients ≥ 75 years of age and younger patients.

Renal Impairment

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is recommended for patients with mild hepatic impairment. Tecentriq has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].

Overdosage

There is no information on overdose with Tecentriq.

Tecentriq Description

Atezolizumab is an Fc-engineered, humanized, monoclonal antibody that binds to PD-L1 and blocks interactions with the PD-1 and B7.1 receptors. Atezolizumab is a non-glycosylated IgG1 kappa immunoglobulin that has a calculated molecular mass of 145 kDa.

Tecentriq injection for intravenous infusion is a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials. Each mL of Tecentriq contains 60 mg of atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), sucrose (821.6 mg), polysorbate 20 (8 mg), pH 5.8.

Tecentriq - Clinical Pharmacology

Mechanism of Action

PD-L1 may be expressed on tumor cells and/or tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.

Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 mediated inhibition of the immune response, including activation of the anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

Pharmacokinetics

Patients' exposures to atezolizumab increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg, including the fixed dose 1200 mg administered every 3 weeks. Based on a population analysis that included 472 patients in the dose range, the typical population clearance was 0.20 L/day, volume of distribution at steady state was 6.9 L, and the terminal half-life was 27 days. The population PK analysis suggests steady state is obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the curve (AUC), maximum concentration (Cmax) and trough concentration (Cmin) was 1.91, 1.46 and 2.75-fold, respectively. In a post hoc analysis, atezolizumab clearance was found to decrease over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline value of approximately 17.1% (40.6%). However, the decrease in CL was not considered clinically relevant.

Specific Populations: Age (21–89 years), body weight, gender, positive anti-therapeutic antibody (ATA) status, albumin levels, tumor burden, region or race, mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin < 1.0 to 1.5 × ULN and any AST), level of PD-L1 expression, or ECOG status had no clinically significant effect on the systemic exposure of atezolizumab.

The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) or moderate or severe hepatic impairment (bilirubin > ULN and AST > ULN or bilirubin ≥ 1.0 to 1.5 × ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.

Drug Interaction Studies

The drug interaction potential of atezolizumab is unknown.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to test the potential of atezolizumab for carcinogenicity or genotoxicity.

Animal fertility studies have not been conducted with atezolizumab; however, an assessment of the male and female reproductive organs was included in a 26-week, repeat-dose toxicity study in cynomolgus monkeys. Weekly administration of atezolizumab to female monkeys at the highest dose tested caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries. This effect occurred at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose and was reversible. There was no effect on the male monkey reproductive organs.

Animal Toxicology and/or Pharmacology

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

Clinical Studies

Urothelial Carcinoma

Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Carcinoma

The efficacy of Tecentriq was investigated in Study 4, a multicenter, open-label, single-arm trial that included 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. Patients were considered cisplatin-ineligible if they met any one of the following criteria at study entry: impaired renal function (creatinine clearance of > 30 but < 60 mL/min), ECOG score of 2, hearing loss of ≥ 25 dB at two contiguous frequencies, or ≥ Grade 2 peripheral neuropathy. This study excluded patients who had: a history of autoimmune disease; active or corticosteroid-dependent brain metastases; administration of a live, attenuated vaccine within 28 days prior to enrollment; or administration of systemic immunostimulatory agents within 6 weeks or systemic immunosuppressive medications within 2 weeks prior to enrollment. Patients received an intravenous infusion of 1200 mg of Tecentriq every 3 weeks until unacceptable toxicity or disease progression. Tumor response assessments were conducted every 9 weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), duration of response (DoR) and overall survival (OS).

In this study, the median age was 73 years, 81% were male, and 91% were Caucasian. Thirty-five percent of patients had non-bladder urothelial carcinoma and 66% had visceral metastases. Eighty percent of patients had an ECOG score of 0-1. Reasons for patients' ineligibility for cisplatin-containing chemotherapy were: 70% had impaired renal function, 20% had an ECOG score of 2, 14% had a hearing loss of ≥ 25db, and 6% had ≥ Grade 2 peripheral neuropathy at baseline. Twenty percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy.

Tumor specimens were evaluated prospectively using the Ventana PD-L1 (SP142) Assay at a central laboratory, and the results were used to define subgroups for pre-specified analyses. Of the 119 patients, 27% were classified as having PD-L1 expression of ≥ 5% (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area). The remaining 73% of patients were classified as having PD-L1 expression of < 5% (PD-L1 stained tumor-infiltrating IC covering < 5% of the tumor area).

Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 7. The median follow-up time for this study was 14.4 months. In 24 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 33.0% (95% CI: 16%, 55%).

Table 7: Summary of Efficacy from Study 4
	All Patients	PD-L1 Expression Subgroups
	N=119	PD-L1 Expression of < 5% in ICs* (N=87)	PD-L1 Expression of ≥ 5% in ICs* (N=32)
NR = Not reached
* PD-L1 expression in tumor-infiltrating immune cells (ICs) † Denotes a censored value
Number of IRF-assessed Confirmed Responders	28	19	9
ORR % (95% CI)	23.5% (16.2, 32.2)	21.8% (13.7, 32.0)	28.1% (13.8, 46.8)
Complete Response (CR) (%)	6.7%	6.9%	6.3%
Partial Response (PR) (%)	16.8%	14.9%	21.9%
Median DoR, months (range)	NR (3.7, 16.6†)	NR (3.7, 16.6†)	NR (8.1, 15.6†)

Previously Treated Patients with Locally Advanced or Metastatic Urothelial Carcinoma

The efficacy of Tecentriq was investigated in Study 1, a multicenter, open-label, single-arm trial that included 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following a platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. This study excluded patients who had: a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrollment, or administration of systemic immunostimulatory agents within 6 weeks or systemic immunosuppressive medications within 2 weeks prior to enrollment. Patients received an intravenous infusion of 1200 mg of Tecentriq every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 9 weeks for the first 54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DOR).

In this study, the median age was 66 years, 78% were male, 91% of patients were Caucasian. Twenty-six percent had non-bladder urothelial carcinoma and 78% of patients had visceral metastases. Sixty-two percent of patients had an ECOG score of 1 and 35% of patients had a baseline creatinine clearance of < 60 mL/min. Nineteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Forty-one percent of patients had received ≥ 2 prior systemic regimens in the metastatic setting. Seventy-three percent of patients received prior cisplatin, 26% had prior carboplatin, and 1% were treated with other platinum-based regimens.

Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 310 patients, 32% were classified as having PD-L1 expression of ≥ 5% (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 5% of the tumor area). The remaining 68% of patients were classified as having PD-L1 expression of < 5% (PD-L1 stained tumor-infiltrating IC covering < 5% of the tumor area).

Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 8. The median follow-up time for this study was 14.4 months. In 59 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 22.0% (95% CI: 12.3%, 34.7%).

Table 8: Summary of Efficacy from Study 1
	All Patients	PD-L1 Expression Subgroups
	N=310	PD-L1 Expression of < 5% in IC* (N=210)	PD-L1 Expression of ≥ 5% in IC* (N=100)
NR = Not reached
* PD-L1 expression in tumor-infiltrating immune cells (IC) † Denotes a censored value
Number of IRF-assessed Confirmed Responders	46	20	26
ORR % (95% CI)	14.8% (11.1, 19.3)	9.5% (5.9, 14.3)	26.0% (17.7, 35.7)
Complete Response (CR) (%)	5.5%	2.4%	12.0%
Partial Response (PR) (%)	9.4%	7.1%	14.0%
Median DOR, months (range)	NR (2.1†, 13.8†)	12.7 (2.1†, 12.7)	NR (4.2, 13.8†)

Metastatic Non-Small Cell Lung Cancer

Previously Treated Patients with Metastatic NSCLC

The efficacy of Tecentriq was investigated in two multicenter, international, randomized, open-label trials in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen. Study 2 was a trial in 1225 patients with the primary analysis population consisting of the first 850 randomized patients and Study 3 was a trial in 287 patients. In both studies, eligible patients were stratified by PD-L1 expression status in tumor-infiltrating immune cells (IC), by the number of prior chemotherapy regimens, and by histology. Patients were randomized (1:1) to receive either Tecentriq administered intravenously at 1200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical progression or docetaxel administered intravenously at 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. These studies excluded patients who had: a history of autoimmune disease, had active or corticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 days prior to enrollment, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to enrollment. Tumor assessments were conducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter. In Study 2, tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and IC using the VENTANA PD-L1 (SP142) Assay and the results were used to define the PD-L1 expression subgroups for the analyses described below.

In Study 2, among patients in the primary analysis population, the median age was 64 years (range: 33 to 85), and 61% of patients were male. The majority of patients were white (70%). Approximately three-fourths of patients had non-squamous disease (74%), 10% had known EGFR mutation, 0.2% had known ALK rearrangements, and most patients were current or previous smokers (82%). Baseline ECOG performance status was 0 (37%) or 1 (63%). Seventy five percent of patients received only one prior platinum-based therapeutic regimen. In Study 3, the median age was 62 years (range: 36 to 84), and 59% of patients were male. The majority of patients were white (79%). Approximately two-thirds of patients had non-squamous disease (66%), 7% had known EGFR mutation, 1% had ALK rearrangements, and most patients were current or previous smokers (80%). Baseline ECOG performance status was 0 (33%) or 1 (67%). Approximately two-thirds of patients received only one prior platinum-based therapeutic regimen.

The major efficacy outcome measure of Study 2 was overall survival (OS) in the primary analysis population (first 850 randomized patients). The major efficacy outcome measure of Study 3 was overall survival (OS). Other efficacy outcome measures for Study 3 included investigator-assessed objective response rates and duration of response per RECIST v1.1. The results of Study 2 with a median follow up of 21 months are presented in Table 9 and Figure 1.

Table 9: Efficacy Results in the Primary Analysis Population from Study 2
	Tecentriq (n=425)	Docetaxel (n=425)
CI=confidence interval
* Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology † Based on the stratified log-rank test
Overall Survival
Deaths (%)	271 (64%)	298 (70%)
Median, months	13.8	9.6
(95% CI)	(11.8, 15.7)	(8.6, 11.2)
Hazard ratio* (95% CI)	0.74 (0.63, 0.87)
p-value†	0.0004
Figure 1: Kaplan-Meier Plot of Overall Survival in the Primary Analysis Population in Study 2

Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define the PD-L1 expression subgroups for pre-specified analyses. Of the 850 patients, 16% were classified as having high PD-L1 expression, defined as having PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was 0.41 (95% CI: 0.27, 0.64) in the high PD-L1 expression subgroup and 0.82 (95% CI: 0.68, 0.98) in patients who did not have high PD-L1 expression.

Results of an updated survival analysis in Study 3 with a median follow-up of 22 months are provided for all randomized patients (Table 10 and Figure 2).

Table 10: Efficacy Results from Study 3
	Tecentriq (n=144)	Docetaxel (n=143)
CI=confidence interval; NE=not estimable
* Stratified by PD-L1 expression in tumor-infiltrating immune cells, the number of prior chemotherapy regimens, and histology † per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1)
Overall Survival
Deaths (%)	90 (63%)	110 (77%)
Median, months	12.6	9.7
(95% CI)	(9.7, 16.0)	(8.6, 12.0)
Hazard ratio* (95% CI)	0.69 (0.52, 0.92)
Objective Response Rate†n (%)	22 (15%)	21 (15%)
(95% CI)	(10%, 22%)	(9%, 22%)
Complete response	1 (0.7%)	0
Partial response	21 (15%)	21 (15%)
Duration of Response†	n=22	n=21
Median (months)	18.6	7.2
(95% CI)	(11.6, NE)	(5.6, 12.5)
Figure 2: Kaplan-Meier Plot of updated Overall Survival in Study 3

How Supplied/Storage and Handling

Tecentriq injection is a sterile, preservative-free, and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 1200 mg/20 mL single-dose vial (NDC 50242-917-01).

Storage: Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

Patient Counseling Information

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

Inform patients of the risk of immune-related adverse reactions that may require corticosteroid treatment and interruption or discontinuation of Tecentriq, including:

·         Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].

·         Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2)].

·         Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.3)].

·         Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.4)]

·         Meningoencephalitis, Myasthenic syndrome/Myasthenia Gravis, and Guillain-Barré syndrome: Advise patients to contact their healthcare provider immediately for signs or symptoms of meningitis, myasthenic syndrome/myasthenia gravis, or Guillain-Barré syndrome [see Warnings and Precautions (5.5)].

·         Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity [see Warnings and Precautions (5.5)].

·         Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)].

·         Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)].

·         Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)].

·         Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash [see Dosage and Administration (2.2)].

Embryo-Fetal Toxicity

Advise female patients that Tecentriq can cause fetal harm. Instruct females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of Tecentriq [see Use in Specific Populations (8.1, 8.3)].

Lactation

Advise female patients not to breastfeed while taking Tecentriq and for at least 5 months after the last dose [see Use in Specific Populations (8.2)].

Tecentriq® [atezolizumab]

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

Tecentriq is a registered trademark of Genentech, Inc.
©2017 Genentech, Inc.

U.S. License No. 1048

This Medication Guide has been approved by the U.S. Food and Drug Administration.			Revised: 4/2017
MEDICATION GUIDE Tecentriq® (te-SEN-trik) (atezolizumab) injection
What is the most important information I should know about Tecentriq?
Tecentriq is a medicine that may treat your bladder cancer or lung cancer by working with your immune system. Tecentriq can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.
Call or see your healthcare provider right away if you get any symptoms of the following problems or these symptoms get worse:
Lung problems (pneumonitis). Signs and symptoms of pneumonitis may include:
	·         new or worsening cough	·         shortness of breath	·         chest pain
Liver problems (hepatitis). Signs and symptoms of hepatitis may include:
·         yellowing of your skin or the whites of your eyes ·         severe nausea or vomiting ·         pain on the right side of your stomach area (abdomen) ·         drowsiness		·         dark urine (tea colored) ·         bleeding or bruising more easily than normal ·         feeling less hungry than usual
Intestinal problems (colitis). Signs and symptoms of colitis may include: ·         diarrhea (loose stools) or more bowel movements than usual ·         blood in your stools or dark, tarry, sticky stools ·         severe stomach area (abdomen) pain or tenderness
Hormone gland problems (especially the pituitary, thyroid, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include:
·         headaches that will not go away or unusual headaches ·         extreme tiredness ·         weight gain or weight loss ·         dizziness or fainting ·         feeling more hungry or thirsty than usual ·         hair loss		·         feeling cold ·         constipation ·         your voice gets deeper ·         urinating more often than usual ·         nausea or vomiting ·         stomach area (abdomen) pain
·         changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
Nervous system problems (neuropathy, meningitis, encephalitis). Signs and symptoms of nervous system problems may include:
·         severe muscle weakness ·         numbness or tingling in hands or feet ·         fever ·         confusion		·         changes in mood or behavior ·         extreme sensitivity to light ·         neck stiffness
Inflammation of the eyes. Signs and symptoms may include:
·         blurry vision, double vision, or other vision problems		·         eye pain or redness
Severe infections. Signs and symptoms of infection may include:
·         fever ·         cough ·         frequent urination		·         flu-like symptoms ·         pain when urinating
Severe infusion reactions. Signs and symptoms of infusion reactions may include:
·         chills or shaking ·         itching or rash ·         flushing ·         shortness of breath or wheezing ·         swelling of your face or lips		·         dizziness ·         fever ·         feeling like passing out ·         back or neck pain
Getting medical treatment right away may help keep these problems from becoming more serious.
Your healthcare provider will check you for these problems during your treatment with Tecentriq. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may delay or completely stop treatment with Tecentriq if you have severe side effects.
What is Tecentriq?
Tecentriq is a prescription medicine used to treat: a type of bladder and urinary tract cancer called urothelial carcinoma. ·         Tecentriq may be used when your bladder cancer: o    has spread or cannot be removed by surgery (advanced urothelial carcinoma), and o    you are not able to take chemotherapy that contains a medicine called cisplatin, or o    you have tried chemotherapy that contains platinum, and it did not work or is no longer working. a type of lung cancer called non-small cell lung cancer (NSCLC) ·         Tecentriq may be used when your lung cancer: o    has spread or grown, and o    you have tried chemotherapy that contains platinum, and it did not work or is no longer working. If your tumor has an abnormal EGFR or ALK gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.
It is not known if Tecentriq is safe and effective in children.
Before you receive Tecentriq, tell your healthcare provider about all of your medical conditions, including if you: ·         have immune system problems such as Crohn's disease, ulcerative colitis, or lupus ·         have had an organ transplant ·         have lung or breathing problems ·         have liver problems ·         have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome ·         are being treated for an infection ·         are pregnant or plan to become pregnant. Tecentriq can harm your unborn baby. If you are able to become pregnant, you should use an effective method of birth control during your treatment and for at least 5 months after the last dose of Tecentriq. ·         are breastfeeding or plan to breastfeed. It is not known if Tecentriq passes into your breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of Tecentriq.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How will I receive Tecentriq? ·         Your healthcare provider will give you Tecentriq into your vein through an intravenous (IV) line over 30 to 60 minutes. ·         Tecentriq is usually given every 3 weeks. ·         Your healthcare provider will decide how many treatments you need. ·         Your healthcare provider will test your blood to check you for certain side effects. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.
What are the possible side effects of Tecentriq?
Tecentriq can cause serious side effects, including: ·         See "What is the most important information I should know about Tecentriq?"
The most common side effects of Tecentriq in people with urothelial carcinoma include:
·         feeling tired ·         decreased appetite ·         nausea ·         constipation		·         urinary tract infection ·         diarrhea ·         fever
The most common side effects of Tecentriq in people with non-small cell lung cancer include:
·         feeling tired ·         decreased appetite ·         shortness of breath ·         cough		·         nausea ·         muscle or bone pain ·         constipation
Tecentriq may cause fertility problems in females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility.
These are not all the possible side effects of Tecentriq. Ask your healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Tecentriq.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about Tecentriq, talk with your healthcare provider. You can ask your healthcare provider for information about Tecentriq that is written for health professionals.
What are the ingredients in Tecentriq?
Active ingredient: atezolizumab
Inactive ingredients: glacial acetic acid, L-histidine, sucrose, polysorbate 20
Manufactured by: Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 USA
U.S. License No. 1048 Tecentriq is a registered trademark of Genentech, Inc.
For more information, call 1-844-832-3687 or go to www.Tecentriq.com.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 20 mL Vial Carton

NDC 50242-917-01

Tecentriq®
(atezolizumab)
Injection

1200 mg/20 mL
(60 mg/mL)

For Intravenous Infusion After Dilution
Single-Dose Vial
Discard Unused Portion
No preservative.

Attention Pharmacist: Dispense the
accompanying Medication Guide
to each patient.

Rx only

1 vial

Genentech

10181373

Tecentriq atezolizumab injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50242-917 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength atezolizumab (atezolizumab) atezolizumab 1200 mg  in 20 mL

Inactive Ingredients Ingredient Name Strength histidine 62 mg  in 20 mL acetic acid 16.5 mg  in 20 mL sucrose 821.6 mg  in 20 mL polysorbate 20 8 mg  in 20 mL water

Packaging # Item Code Package Description 1 NDC:50242-917-01 1 VIAL, SINGLE-USE in 1 CARTON 1 20 mL in 1 VIAL, SINGLE-USE 2 NDC:50242-917-86 1 VIAL, SINGLE-USE in 1 CARTON 2 20 mL in 1 VIAL, SINGLE-USE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA761034 05/18/2016

Labeler - Genentech, Inc. (080129000)

Establishment
Name	Address	ID/FEI	Operations
Roche Diagnostics GmbH		315028860	MANUFACTURE(50242-917), ANALYSIS(50242-917)
Establishment
Name	Address	ID/FEI	Operations
F. Hoffmann-La Roche Ltd		485244961	ANALYSIS(50242-917), LABEL(50242-917)

Establishment
Name		Address	ID/FEI	Operations
Genentech, Inc. (Hillsboro)			833220176	LABEL(50242-917)
Establishment
Name	Address	ID/FEI	Operations
F. Hoffmann-La Roche Ltd		482242971	API MANUFACTURE(50242-917), ANALYSIS(50242-917)

Establishment
Name	Address	ID/FEI	Operations
Genentech, Inc. (SSF)		080129000	ANALYSIS(50242-917)
Establishment
Name	Address	ID/FEI	Operations
Genentech, Inc. (OCN)		146373191	ANALYSIS(50242-917)

Establishment
Name		Address	ID/FEI		Operations
Roche Singapore Technical Operation, Pte. Ltd. (RSTO)			937189173		ANALYSIS(50242-917)
Establishment
Name	Address	ID/FEI		Operations
Roche Diagnostics GmbH		323105205		ANALYSIS(50242-917)

Revised: 11/2017

Genentech, Inc.