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[适应证和用途]

OPDIVO是一个人程序死亡受体-1(PD-1)阻断抗体适用为the 治疗of患者有不能切除或转移黑色素瘤和易普利姆玛和，如BRAF V600突变阳性，一种BRAF抑制剂后疾病进展。

这个适应症是根据肿瘤反应率和反应的持久性加速批准下被批准。对这个适应证的继续批准可能取决于验证和在验证试验中临床获益的描述。(1，14) 

[剂量和给药方法]

每2周历时60分钟静脉输注给予3 mg/kg。.(2.1) 

 

[警告和注意事项]

免疫介导不良反应：根据反应严重程度给予糖皮质激素。(5.1，5.2，5.3，5.4，5.6) 

⑴ 免疫介导肺炎：对中度不给和对严重或危及生命肺炎永久终止。(5.1)

⑵ 免疫介导结肠炎：不给对中度或严重和对危及生命结肠炎永久终止。(5.2) 

⑶ 免疫介导肝炎：监视对肝功能中变化。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终止。(5.3) 

⑷ 免疫介导肾炎和肾功能不全：监视在肾功能中变化。对中度不给和对严重或危及生命血清肌酐升高永久终止。(5.4) 

⑸ 免疫介导甲状腺功能减退和甲状腺功能亢进：监视甲状腺功能变化。需要时开始甲状腺激素替代。(5.5) 

⑹ 胚胎胎儿毒性：可能致胎儿危害。忠告对胎儿潜在风险和使用有效避孕。(5.7，8.1，8.3) 

[不良反应]

最常见不良反应(≥20%)是皮疹。(6.1) 

在特殊人群中使用

⑴ 哺乳：终止哺乳。(8.2)

完整处方资料

1 适应证和用途 

适用为有不能切除货转移黑色素瘤和易普利姆玛和，如BRAF V600突变阳性，一种BRAF抑制剂患者后疾病进展的治疗[见临床研究(14)]。

这个适应证是根据肿瘤反应率和反应的持久性在加速批准下被批准。对这个适应证的继续可能取决于验证和在验证试验中临床获益的描述。

2 剂量和给药方法 

2.1 推荐剂量 

OPDIVO的推荐剂量是每2周历时60分钟静脉输注给予3 mg/kg直至疾病进展或不可接受毒性。 

2.2 剂量调整 

对甲状腺功能减退或甲状腺功能亢进无剂量调整建议。 

对任何以下不给OPDIVO：

●2级肺炎[见警告和注意事项(5.1)] 

●2或3级结肠炎[见警告和注意事项(5.2)] 

●谷草转氨酶(AST)或谷丙转氨酶(ALT)大于正常上限(ULN)3和至5倍或总胆红素大于ULN 1.5和直至3倍[见警告和注意事项(5.3)] 

● 肌酐大于ULN 1.5和至6倍或大于基线1.5倍[见警告和注意事项(5.4)] 

● 任何其他严重或3级治疗t-相关不良反应[见警告和注意事项(5.6)] 

患者其不良反应恢复至0-1级恢复OPDIVO。

对以下任何永久终止OPDIVO：

● 任何危及生命或4级不良反应 

● 3或4级肺炎[见警告和注意事项(5.1)] 

● 4级结肠炎[见警告和注意事项(5.2)] 

● AST或ALT大于ULN 5倍或总胆红素大于ULN 3倍[见警告和注意事项(5.3)] 

● 肌酐大于ULN 6倍[见警告和注意事项(5.4)] 

● 任何严重或3级治疗-相关不良反应复发 

● 不能减低皮质激素剂量至10 mg或泼尼松[prednisone]的更低或等同物在12周内每天

● 持久2或3级治疗-相关不良反应在OPDIVO末次剂量12周内不恢复至0-1级

2.3 制备和给药 

给药前肉眼观察药物产品溶液对颗粒物质和变色。OPDIVO是清晰至乳白，无色至浅黄色溶液。如小瓶溶液除了少许半透明至白色蛋白样颗粒遗弃为雾，是变色，或含外来颗粒物质。不要摇动小瓶。

制备 

● 抽吸需要容积的OPDIVO和转移至静脉容器。 

● 用或0.9%氯化钠注射液，USP或或5%葡萄糖注射液，USP稀释OPDIVO以制备一个输注有最终浓度范围从1 mg/mL至10 mg/mL。

● 轻轻倒置混合稀释溶液。不要摇动。 

● 遗弃OPDIVO的部分使用小瓶或空小瓶。

输注的贮存 

产品不含防腐剂。在配制后贮存OPDIVO输注或：

● 在室温从制备后不超过4小时。这包括室温贮存在IV容器输注和为输注给予时间或

● 在冰箱在2°C至8°C(36°F-46°F)从输注制备时不超过24小时

不要冻结。 

给药

通过静脉线历时60分钟给予输注含一个无菌，无防腐剂，低蛋白结合在线滤膜(孔大小0.2 µm至1.2 µm)。不要在相同静脉线共同给予其他药物。结束输注时冲洗静脉线。 

3 剂型和规格 

注射液：40 mg/4 mL(10 mg/mL)和100 mg/10 mL(10 mg/mL)溶液在一次用小瓶中。

4 禁忌证 (无。)

5 警告和注意事项

5.1 免疫介导肺炎 

用OPDIVO治疗发生严重肺炎或间质性肺病，包括致命病例。跨越临床试验经验有实体肿瘤患者574例，接受OPDIVO患者发生致命性免疫介导肺炎0.9%(5/574)。在试验1中未发生致命性肺炎病例；所有五例致命性病例1例患者)。

在试验1中，接受OPDIVO患者发生肺炎，包括间质性肺病3.4%(9/268)和接受化疗102例患者无。免疫介导肺炎，被定义为需要使用皮质激素和无明确另外病因，接受OPDIVO患者发生 2.2%(6/268)：1例有3级和5例有2级肺炎。对6例至发作中位时间为2.2个月(范围：25天-3.5个月)。在2例患者中，在为其他理由终止OPDIVO后肺炎被诊断，而2级肺炎导致中断或在其余4例患者永久终止OPDIVO。所有6例患者接受高剂量皮质激素(至少40 mg泼尼松等同量每天)；在所有6例患者用皮质激素免疫介导肺炎改善至0或1级。有2例有2级肺炎患者完全解决(被定义为用皮质激素完成改善至0级)和再开始用OPDIVO无肺炎复发。

监视患者肺炎体征和症状。对2级或更大肺炎给予糖皮质激素在剂量1至2 mg/kg/day泼尼松等同物，接着皮质激素逐渐减小。对严重(3级)或危及生命(4级)肺炎永久终止OPDIVO和对中度(2级)肺炎不给OPDIVO直至解决[见剂量和给药方法(2.2)]。

5.2 免疫介导结肠炎 

在试验1中，接受OPDIVO患者21%(57/268)发生腹泻或结肠炎和接受化疗患者为18%(18/102)。 免疫介导结肠炎，被定义为需要使用皮质激素与无明确另外病因，接受OPDIVO患者发生2.2%(6/268)：5例患者有3级和1例患者有2级结肠炎。免疫介导结肠炎从开始OPDIVO至发作中位时间为2.5个月(范围：1-6个月)。在3例患者中，在为其他理由终止OPDIVO后被诊断结肠炎，而在其余3例患者中，2或3级结肠炎导致中断或永久终止OPDIVO。这些5/6例患者接受高剂量皮质激素(至少40 mg泼尼松等同量)在皮质激素逐渐减小前共中位时间1.4个月(范围：3天-2.4个月)。第6例患者对另外免疫介导不良反应继续用开始的低剂量皮质激素。在5例患者中用皮质激素免疫介导结肠炎改善至0级，包括1例有3级结肠炎患者在完全解决后再开始(被定义为皮质激素完成改善至0级)无结肠炎另外事件。1例患者2级结肠炎正在进行。

对免疫介导结肠炎监视患者。给予糖皮质激素 剂量1至2 mg/kg/day泼尼松等同量接着对严重(3级)或危及生命(4级)结肠炎逐渐减小皮质激素。对中度(2级)结肠炎超过5天时间给予糖皮质激素在剂量0.5至1 mg/kg/day 泼尼松等同量接着逐渐减小皮质激素；如尽管皮质激素开始恶化或无改善，增加剂量至1至2 mg/kg/day泼尼松等同量。对2或3级免疫介导结肠炎不给OPDIVO。对4级结肠炎或对复发性结肠炎再开始用OPDIVO永久终止OPDIVO[见剂量和给药方法(2.2)]。

5.3 免疫介导肝炎 

在试验1中，在OPDIVO-治疗组当与化疗-治疗组比较，肝测试异常发生率增加有AST增加(28%相比12%)，碱性磷酸酶(22%相比13%)，ALT(16%相比5%)，和总胆红素(9%相比0)。免疫介导肝炎，被定义为需要皮质激素和无明确另外病因，发生在1.1%(3/268)接受OPDIVO患者：2例患者有3级和1例患者有2级肝炎。至发作时间为开始OPDIVO后97，113，和86天。在1例患者中，在为其他理由终止OPDIVO后被诊断肝炎。在2例患者中，不给OPDIVO。所有这些3例患者接受高剂量皮质激素(至少40 mg泼尼松等同量)。在皮质激素开始415天内肝测试改善至1级。在2例患者中免疫介导肝炎解决和随皮质激素继续没有复发；第三例患者死于有持久肝炎疾病进展。2例患者有3级肝炎再开始OPDIVO解决和，在1例患者中，3级免疫介导肝炎 复发导致永久终止OPDIVO。

治疗前和期间定期对异常肝测试监视患者。对2级或更大转氨酶升高，有或无总胆红素同时升高给予糖皮质激素在剂量1至2 mg/kg/day泼尼松等同量。对中度(2级)不给OPDIVO和对严重(3级)或危及生命(4级)免疫介导肝炎永久终止OPDIVO[见剂量和给药方法(2.2)和不良反应(6.1)]。 

5.4 免疫介导肾炎和肾功能不全 

在试验1中，在OPDIVO-治疗组当与化疗-治疗组比较(13%相比9%)有肌酐升高发生率增加。2或3级免疫介导肾炎或肾功能不全(被定义为肌酐增加2级，需要皮质激素，和无明确另外病因) OPDIVO开始后分别在3.5和6个月发生0.7%(2/268)患者。在两例患者OPDIVO都永久终止；两例都接受高剂量皮质激素(至少40 mg泼尼松等同量)。免疫介导肾炎解决和在1例中继续皮质激素没有复发。在1例患者中正在肾功能不全。

治疗前和期间定期监视患者对升高的血清肌酐。给予糖皮质激素剂量1至2 mg/kg/day泼尼松等同量对危及生命(4级)血清肌酐升高接着皮质激素逐渐减小和永久终止OPDIVO。对严重( 3级)或中度(2级)血清肌酐升高，不给OPDIVO和给予糖皮质激素在剂量0.5至1 mg/kg/day泼尼松等同量接着逐渐减小皮质激素；如恶化或无改善发生，增加皮质激素剂量至1至2 mg/kg/day 泼尼松等同量和永久终止OPDIVO[见剂量和给药方法(2.2)和不良反应(6.1)]。 

5.5 免疫介导甲状腺功能减退和甲状腺功能亢进 

在试验1中，其中患者在基线和试验期间评价甲状腺功能，接受OPDIVO患者1或2级甲状腺功能减退发生8%(21/268)和102例接受化疗患者没有。至发作中位时间为2.5个月(范围：24 天-11.7个月)。17/21例有甲状腺功能减退患者接受左旋甲状腺素[levothyroxine]。15/17例患者接受随后OPDIVO给药同时继续接受左旋甲状腺素。 

接受OPDIVO患者1或2级甲状腺功能亢进发生3%(8/268)和接受化疗患者为1%(1/102)。OPDIVO-治疗患者至发作中位时间为1.6个月(范围：0-3.3个月)。4/5例患者有1级甲状腺功能亢进和2/3例患者有2级甲状腺功能亢进有记录的甲状腺功能亢进解决；所有3例患者对2级甲状腺功能亢进接受医疗处理。 

治疗前和治疗期间定期监视甲状腺功能。对甲状腺功能减退给予激素替代治疗。为控制甲状腺功能亢进开始医学处理。对甲状腺功能减退或甲状腺功能亢进没有OPDIVO剂量调整对建议。 

5.6 其他免疫介导不良反应 

可能发生其他临床上显著免疫介导不良反应。OPDIVO治疗终止后可能发生免疫介导不良反应。

在试验1中OPDIVO-治疗患者发生以下临床上显著免疫介导不良反应低于1%：胰腺炎，葡萄膜炎，脱髓鞘，自身免疫神经病变，肾上腺皮质功能不全，和面部和外展神经麻痹。 

跨越OPDIVO临床试验给予剂量3 mg/kg和10 mg/kg被鉴定以下附加临床上显著，免疫介导不良反应：垂体炎，糖尿病酮症酸中毒，垂体机能减退，Guillain-Barré综合症，和肌无力综合症。

对任何怀疑对免疫介导不良反应，除外其他原因。根据不良反应的严重程度，不给OPDIVO，给予高剂量皮质激素，和如适当，开始激素替代。改善至1级或更低，开始皮质激素逐渐减小和继续逐渐减小超过至少1个月。在皮质激素逐渐减小完成后根据事件严重程度考虑再开始OPDIVO [见剂量和给药方法(2.2)]。 

5.7 胚胎胎儿毒性 

根据其作用机制和来自动物研究数据，当给予妊娠妇女OPDIVO可能致胎儿危害。在动物生殖研究中，对食蟹猴从器官形成期开始至分娩给予nivolumab导致流产增加和婴儿早产死亡。忠告妊娠妇女对胎儿潜在风险。忠告有生殖潜能女性在用OPDIVO治疗期间和OPDIVO末次剂量后至少5个月使用有效避孕[见特殊人群中使用(8.1，8.3)]。

6 不良反应 

在说明书其他节内更详细讨论以下不良反应：

● 免疫介导肺炎[见警告和注意事项(5.1)]

● 免疫介导结肠炎[见警告和注意事项(5.2)] 

● 免疫介导肝炎[见警告和注意事项(5.3)] 

● 免疫介导肾炎和肾功能不全[见警告和注意事项(5.4)]

● 免疫介导甲状腺功能减退和甲状腺功能亢进[见警告和注意事项(5.5)] 

● 其他免疫介导不良反应[见警告和注意事项(5.6)] 

6.1 临床试验经验

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。

在警告和注意事项节描述数据和在试验1中以下反映对OPDIVO暴露，一项随机化，开放试验其中370例有不能切除或转移黑色素瘤患者每2周接受OPDIVO 3 mg/kg(n=268)或研究者选择的化疗(n=102)，或氮烯咪胺[dacarbazine]1000 mg/m2每3周或卡铂AUC 6每3周加紫杉醇175 mg/m2每3周联用[见临床研究(14)]。在OPDIVO-治疗患者中位暴露时间是5.3个月(范围：1天-13.8+个月)与中位8剂(范围：1至31)和在化疗治疗患者为 2个月(范围：1天-9.6+个月)。在这个正在进行试验中，24%患者接受OPDIVO共大于6个月和3%患者接受OPDIVO共大于1年。

在574例纳入在两项临床试验有实体肿瘤患者每2周接受OPDIVO剂量0.1至10 mg/kg，还评价临床上显著不良反应。跨越正在进行临床试验免疫介导不良反应报告被补充[见警告和注意事项(5.1，5.6)]。

在试验1中，患者用易普利姆玛治疗后和，如BRAF V600突变阳性，一个BRAF抑制剂曾记录疾病进展。试验排除患者有自身免疫疾病，以前易普利姆玛-相关4级不良反应(除了对内分泌病)或3级易普利姆玛-相关不良反应没有解决或在开始事件12周内被不适当地控制，患者有情况需要用皮质激素全身慢性治疗(>10 mg每天泼尼松等同量)或其他免疫抑制药物，对乙型或丙型肝炎测试阳性，和一个HIV病史。

在OPDIVO组和化疗组研究人群特征是相似：66%男性，中位年龄59.5岁，98%白种人，基线 ECOG体能状态0(59%)或1(41%)，74%有M1c期疾病，73%有皮肤黑色素瘤，11%有粘膜黑色素瘤，对晚期或转移疾病73%接受两次或更多以前治疗，和18%有脑转移。在OPDIVO组有更多患者在基线时升高的LDH(51%相比38%)。

在9%患者对不良反应OPDIVO被终止。26%接受OPDIVO患者有对一种不良反应药物延迟。接受OPDIVO患者41%发生严重不良反应。接受OPDIVO患者42%发生3和4级不良反应。报告最频发3和4级不良反应在2%至较低于5%患者接受OPDIVO 是腹痛，低钠血症，谷草转氨酶增加，和脂肪酶增加。 

用OPDIVO治疗患者小于10%其他临床上重要不良反应是：

心脏疾病：室性心律失常 

眼疾病：虹膜睫状体炎 

一般疾病和给药部位情况：感染-相关反应

调查：淀粉酶增加，脂肪每增加 

神经系统疾病：眩晕，外周和感觉神经病变 

皮肤和皮下组织疾病：剥脱性皮炎，多形性红斑，白癜风，银屑病。

 

6.2 免疫原性

如同所有治疗性蛋白，存在免疫原性潜能。 

在281例每2周用OPDIVO 3 mg/kg治疗患者和可评价对存在抗产品抗体，24例患者(8.5%)用一种电化学发光(ECL)分析对治疗-出现抗-产品抗体测试阳性。在两例患者(0.7%)检测到中和抗体。根据群体药代动力学和暴露-反应分析没有与抗-产品结合抗体发展改变的药代动力学图形或毒性图形证据。

抗体形成的检测是高度依赖于分析的灵敏度和特异性。此外，在某个分析中观察到抗体阳性发生率(包括中和抗体)可能受几种因素影响包括分析方法学，样品处置，采样时间，同时药物，和所患疾病。因为这些理由，比较对OPDIVO抗体发生率与其他产品抗体的发生率可能是误导。

7 药物相互作用

未曾用OPDIVO进行正式药代动力学药物-药物相互作用研究。 

8 特殊人群中使用

8.1 妊娠 

风险总结

根据其作用机制[见临床药理学(12.1)]和来自动物研究，当给予妊娠妇女OPDIVO可致胎儿危害[见临床药理学(12.1)]。在动物生殖研究中，在器官形成期开始至分娩给予nivolumab至食蟹猴导致流产增加和早产婴儿死亡[见数据]。人IgG4已知跨越胎盘屏障和nivolumab是一种免疫球蛋白G4(IgG4)；因此，nivolumab有潜力可从母亲传递到发育中的胎儿。在妊娠第二和第三个三个月期间OPDIVO的效应可能更大。药物相关联风险没有可供利用的人数据。忠告妊娠妇女对胎儿的潜在风险。

不知道对适应证人群主要出生缺陷和流产背景风险；但是，在美国一般人群临床上认可的妊娠主要出生缺陷的背景风险为2-4%和流产为15-20%。

数据

动物数据

PD-1/PD-L1通路的中央功能是通过维持母体对胎儿的免疫耐受性保存妊娠。在鼠类妊娠模型中PD-L1信号的阻断曾显示破坏对胎儿耐受性和增加胎儿丢失。在器官形成期开始至分娩接受每周2次，在nivolumab暴露水平较高于在临床剂量3 mg/kg的nivolumab(根据AUC)观察到9和42 倍间猴中评价nivolumab对围产期(产前和产后)发育的影响。Nivolumab给予导致一个非-剂量-相关增加自发性流产和增加新生猴死亡。根据其作用机制，胎儿暴露于nivolumab可能增加发生免疫介导疾病风险或改变正常免疫反应和在PD-1敲除小鼠曾报道免疫介导疾病。在用nivolumab处理的食蟹猴的活存婴猴(18/32与媒介物暴露婴猴11/16比较)，在6个月产后期自始至终没有明显畸形和对神经行为，免疫学或临床病理学参数影响。

8.2 哺乳 

风险总结

不知道OPDIVO是否存在人乳汁中。因为许多药物，包括抗体被排泄在人乳汁和因为哺乳婴儿来自OPDIVO严重不良反应的潜能，忠告妇女用OPDIVO治疗期间终止哺乳。 

8.3 生殖潜能女性和男性 

避孕 

根据其作用机制，当给予妊娠妇女时OPDIVO可能致胎儿危害[见特殊人群中使用(8.1)]。忠告有生殖潜能女性，用OPDIVO 治疗期间和OPDIVO末次剂量后共至少5个月使用有效避孕。

8.4 儿童使用

尚未在儿童患者中确定OPDIVO的安全性和有效性。 

8.5 老年人使用

OPDIVO的临床研究没有包括充分数量年龄65岁和以上患者以确定他们的反应是否不同于较年轻患者。在试验1中，随机化至OPDIVO 272例患者，35%患者为65岁或以上和15%为75岁或以上。

8.6 肾受损 

根据一项群体药代动力学分析，在有肾受损患者无剂量调整建议[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无剂量调整建议。尚未在有中度或严重肝受损患者中研究OPDIVO[见临床药理学(12.3)]。

10 药物过量 

没有用OPDIVO药物过量的资料。

11 一般描述

Nivolumab是一个人单克隆抗体阻断PD-1及其配体，PD-L1和PD-L2间相互作用。Nivolumab是一种IgG4 kappa免疫球蛋白有计算的分子质量146 kDa。

OPDIVO是一种无菌，无防腐剂，无热原，清晰至乳白色，无色至至浅黄色的液体含光(少许)颗粒。OPDIVO注射液为静脉输注以一次用小瓶中供应，每mL的OPDIVO溶液含nivolumab 10 mg，甘露醇(30 mg)，喷替酸(0.008 mg)，聚山梨醇80(0.2 mg)，氯化钠(2.92 mg)，柠檬酸钠二水合物(5.88 mg)，和 注射用水，USP。可能含盐酸和/或氢氧化钠调整pH至6。

12 临床药理学

12.1 作用机制 

PD-1配体，PD-L1和PD-L2，与T细胞发现PD-1受体的结合，抑制T-细胞增殖和细胞因子产生。在有些肿瘤发生PD-1配体的上调和通过这个通路信号可能对肿瘤活性T-细胞免疫监视的抑制作用有贡献。Nivolumab是一种人免疫球蛋白G4(IgG4)单克隆抗体结合至PD-1受体和阻断它与PD-L1和PD-L2相互作用，释放PD-1通路-介导的免疫反应的抑制作用，包括抗-肿瘤免疫反应。在同基因型小鼠肿瘤模型中，阻断PD-1活性导致肿瘤生长减低。

12.3 药代动力学

在患者中跨越剂量范围0.1至20 mg/kg作为一个单剂量或作为多剂量OPDIVO每2或3周给予研究nivolumab的药代动力学(PK)。根据一项群体药代动力学(PK)分析利用来自909例患者数据，几何均数(变异系数%[CV%])清除率(CL)为9.5 mL/h(49.7%)，在稳态时分布容积几何均数(Vss)是8.0 L(30.4%)，而消除半衰期(t1/2)几何均数为26.7天(101%)。当在3 mg/kg每2周给予时，在12周时达到nivolumab的稳态浓度，而全身积蓄约3-倍。在跨越剂量范围0.1至10 mg/kg给予每2周The exposure 对nivolumab的暴露与剂量正比例地增加。

特殊人群：利用数据来自909例患者根据一项群体PK分析，nivolumab的清除率随体重增加支持基于体重剂量。群体PK分析提示以下因子对nivolumab清除率没有临床上重要影响：年龄(29 至87岁)，性别，种族，基线LDH，PD-L1表达，肿瘤类型，肿瘤大小，肾受损，和轻度肝受损。

肾受损：通过在有轻度(eGFR 60至89 mL/min/1.73 m2; n=313)，中度(eGFR 30至59 mL/min/1.73 m2; n=140)，或严重(eGFR 15至29 mL/min/1.73 m2; n=3)肾受损患者中一项群体PK分析评价肾受损对nivolumab的影响。发现有肾受损患者和有正常肾功能患者间nivolumab的清除率无临床上重要差别[见特殊人群中使用(8.6)]。 

肝受损：在有轻度肝受损(总胆红素[TB]低于或等于正常上限[ULN]和AST大于ULN或TB低于ULN 1至1.5倍和任何AST; n=92)患者中一项群体PK分析评价肝受损对nivolumab清除率的影响。发现在有轻度肝受损患者和有正常肝功能患者间nivolumab的清除率无临床上重要差别。未曾在有中度(TB大于 ULN 1.5至3倍和任何AST)患者或严重肝受损(TB大于ULN 3倍和任何AST)中研究Nivolumab[见特殊人群中使用(8.7)]。

13 非临床毒理学

13.1 癌发生，突变发生，生育力受损 

未进行研究评估nivolumab对致癌性或遗传毒性潜能。未用nivolumab进行生育力研究。在猴中1-个月和3-个月重复给药毒理学研究，在雄性和雌性生殖器官无令人注目影响；但是，在这些研究大多数动物没有性成熟。

13.2 动物毒理学和/或药理学 

在动物模型中，PD-1信号的抑制作用增加有些感染严重程度和增强炎症反应。结核分枝杆菌感染的PD-1基因敲除小鼠与野生型对照比较表现出明显减低活存，它与在这些动物中细菌增殖和炎症反应相关。PD-1敲除小鼠也曾显示用淋巴细胞性脉络丛脑膜炎病毒感染后活存减低. 

14 临床研究

试验1是一项多中心，开放试验随机化(2:1)有不能切除或转移黑色素瘤患者接受或静脉给予OPDIVO在3 mg/kg每2周或研究者选择的化疗，或单药氮烯咪胺1000 mg/m2每3周或卡铂AUC 6每3周加紫杉醇175 mg/m2每3周联用。患者被要求有用或易普利姆玛和，如BRAF V600突变阳性，一个BRAF抑制剂治疗后疾病进展。试验排除患者有自身免疫疾病，医疗情况需要全身免疫抑制，眼黑色素瘤，活动性脑转移，或易普利姆玛-相关4级不良反应病史(除了对内分泌疾病)或易普利姆玛相关3级不良反应没有解决或开始事件12周内被不是当地控制。对第一年随机化9周，然后每6周，其后每12周进行肿瘤评估。

在试验1中，在一项单臂，无对比药，计划单中期分析第一个120例患者接受OPDIVO评价疗效和患者的最小随访时间为6个月。在这个人群中主要疗效结局测量由盲态独立中央评审利用实体肿瘤中反应评价标准(RECIST 1.1)和反应时间验证客观反应率(ORR)。

在120例用OPDIVO治疗患者中，中位年龄为58岁(范围：25-88)，65%患者是男性，98%是白种人，而ECOG PS为0(58%)或1(42%)。疾病特征为M1c疾病(76%)，BRAF V600突变阳性(22%)，升高的LDH(56%)，脑转移病史(18%)，和对转移疾病2种或更多以前全身治疗(68%)。

ORR为32%(95%可信区间：23，41)，OPDIVO-治疗患者中由4例完全缓解和34例部分缓解组成。有反应的38例患者中，33例患者(87%)已正在反应有时间范围从2.6+至10+个月，其中包括13例患者站在反应6个月或更长。

在有和无BRAF V600突变阳性-黑色素瘤患者都有客观反应。

16 如何供应贮存和处置 

OPDIVO®(nivolumab)可得到如下：

 冰箱2°C至8°C(36°F-46°F)下贮存OPDIVO。用前在原始包装避光保护OPDIVO。不要冻结或摇动。 

 室内25度以下存放不超过48小时

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)。

告知患者免疫介导不良反应的风险可能需要皮质激素治疗和中断或OPDIVO的终止，包括：

●肺炎：忠告患者对任何咳嗽，胸痛，或气短新或恶化立即联系其卫生保健提供者[见警告和注意事项(5.1)]。

●结肠炎：忠告患者对腹泻或严重腹痛立即联系其卫生保健提供者[见警告和注意事项(5.2)]。 

●肝炎：忠告患者对黄疸，严重恶心或呕吐，右腹痛，昏睡，或易瘀伤或出血立即联系其卫生保健提供者[见警告和注意事项(5.3)]。

●肾炎和肾功能不全：忠告患者对肾炎的体征和症状包括尿输出减低，尿中血，脚踝肿胀，无食欲，和肾功能不全任何其他症状立即联系其卫生保健提供者[见警告和注意事项(5.4)]。

●甲状腺功能减退和甲状腺功能亢进：忠告患者对甲状腺功能减退和甲状腺功能亢进体征和症状立即联系其卫生保健提供者[见警告和注意事项(5.5)]。

忠告患者保持按计划约定血工作或其他实验室测试的重要性[见警告和注意事项(5.3，5.4，5.5，5.6)]。

忠告有生殖潜能女性对胎儿潜在风险和已知或怀疑妊娠告知其卫生保健提供者[见警告和注意事项(5.7)，特殊人群中使用(8.1)]. 

忠告有生殖潜能女性在用OPDIVO治疗期间和OPDIVO末次剂量后共至少5个月使用有效避孕[见特殊人群中使用(8.3)]。

忠告妇女当用OPDIVO时不要哺乳[见特殊人群中使用(8.2)]

 

This medicine is subject to additional monitoring. This will allow quick identification of new safety
information. You can help by reporting any side effects you may get. See the end of section 4 for how
to report side effects.
Read all of this leaflet carefully before you start using this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- It is important that you keep the Alert Card with you during treatment.
- If you have any further questions, ask your doctor.
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed in
this leaflet. See section 4.
What is in this leaflet
1. What OPDIVO is and what it is used for
2. What you need to know before you use OPDIVO
3. How to use OPDIVO
4. Possible side effects
5. How to store OPDIVO
6. Contents of the pack and other information
1. What OPDIVO is and what it is used for
OPDIVO is a medicine used to treat:
 advanced melanoma (a type of skin cancer) in adults
 advanced non-small cell lung cancer (a type of lung cancer) in adults
 advanced renal cell carcinoma (advanced kidney cancer) in adults
 classical Hodgkin lymphoma that has come back after or has not responded to previous therapies,
including an autologous stem-cell transplant (a transplant of your own blood-producing cells) in
adults
 advanced cancer of the head and neck in adults
 advanced urothelial carcinoma (bladder and urinary tract cancer) in adults.
It contains the active substance nivolumab, which is a monoclonal antibody, a type of protein designed
to recognise and attach to a specific target substance in the body.
Nivolumab attaches to a target protein called programmed death-1 receptor (PD-1) that can switch off
the activity of T cells (a type of white blood cell that forms part of the immune system, the body’s
natural defences). By attaching to PD-1, nivolumab blocks its action and prevents it from switching
off your T cells. This helps increase their activity against the melanoma, lung, kidney, lymphoid, head
and neck or bladder cancer cells.
OPDIVO may be given in combination with ipilimumab. It is important that you also read the package
leaflet for this medicine. If you have any questions about ipilimumab, please ask your doctor.
2. What you need to know before you use OPDIVO
You should not be given OPDIVO
 if you are allergic to nivolumab or any of the other ingredients of this medicine (listed in section 6
"Contents of the pack and other information"). Talk to your doctor if you are not sure.
2
Warnings and precautions
Talk to your doctor before using OPDIVO as it may cause:
 Problems with your lungs such as breathing difficulties or cough. These may be signs of
inflammation of the lungs (pneumonitis or interstitial lung disease).
 Diarrhoea (watery, loose or soft stools) or any symptoms of inflammation of the intestines
(colitis), such as stomach pain and mucus or blood in stool.
 Inflammation of the liver (hepatitis). Signs and symptoms of hepatitis may include abnormal
liver function tests, eye or skin yellowing (jaundice), pain on the right side of your stomach area,
or tiredness.
 Inflammation or problems with your kidneys. Signs and symptoms may include abnormal
kidney function tests, or decreased volume of urine.
 Problems with your hormone producing glands (including the pituitary, the thyroid and adrenal
glands) that may affect how these glands work. Signs and symptoms that these glands are not
working properly may include fatigue (extreme tiredness), weight change or headache and visual
disturbances.
 Diabetes (symptoms include excessive thirst, the passing of a greatly increased amount of urine,
increase in appetite with a loss of weight, feeling tired, drowsy, weak, depressed, irritable and
generally unwell) or diabetic ketoacidosis (acid in the blood produced from diabetes).
 Inflammation of the skin that can lead to severe skin reaction (known as toxic epidermal
necrolysis and Stevens-Johnson syndrome). Signs and symptoms of severe skin reaction may
include rash, itching, and peeling of the skin (possibly fatal).
 Inflammation of the muscles such as myocarditis (inflammation of the heart muscle), myositis
(inflammation of the muscles) and rhabdomyolysis (stiffness in muscles and joints, muscle
spasm). Signs and symptoms may include muscle pain, stiffness, weakness, chest pain, or severe
fatigue.
 Solid organ transplant rejection.
Tell your doctor immediately if you have any of these signs or symptoms or if they get worse. Do
not try to treat your symptoms with other medicines on your own. Your doctor may
 give you other medicines in order to prevent complications and reduce your symptoms,
 withhold the next dose of OPDIVO,
 or stop your treatment with OPDIVO altogether.
Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months
after your last dose. Before treatment, your doctor will check your general health. You will also have
blood tests during your treatment.
Check with your doctor or nurse before you are given OPDIVO if:
 you have an autoimmune disease (a condition where the body attacks its own cells);
 you have melanoma of the eye;
 you were previously given ipilimumab, another medicine for treating melanoma, and experienced
serious side effects because of that medicine;
 you have been told that your cancer has spread to your brain;
 you have any history of inflammation of the lungs;
 you have been taken medicines to suppress your immune system.
Complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with
OPDIVO. These complications can be severe and can lead to death. Your healthcare provider will
monitor you for signs of complications if you have an allogeneic stem cell transplant.
Children and adolescents
OPDIVO should not be used in children and adolescents below 18 years of age.
Other medicines and OPDIVO
Before you are given OPDIVO, tell your doctor if you are taking any medicines that suppress your
immune system, such as corticosteroids, since these medicines may interfere with the effect of
OPDIVO. However, once you are treated with OPDIVO, your doctor may give you corticosteroids to 
3
reduce any possible side effects that you may have during your treatment and this will not impact the
effect of the medicine.
Tell your doctor if you are taking or have recently taken any other medicines. Do not take any other
medicines during your treatment without talking to your doctor first.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or think you might be, if you are planning to become pregnant,
or if you are breast-feeding.
Do not use OPDIVO if you are pregnant unless your doctor specifically tells you to. The effects of
OPDIVO in pregnant women are not known, but it is possible that the active substance, nivolumab,
could harm an unborn baby.
 You must use effective contraception while you are being treated with OPDIVO and for at least
5 months following the last dose of OPDIVO, if you are a woman who could become pregnant.
 If you become pregnant while using OPDIVO tell your doctor.
It is not known whether nivolumab gets into breast milk. A risk to the breast-fed infant cannot be
excluded. Ask your doctor if you can breast-feed during or after treatment with OPDIVO.
Driving and using machines
Nivolumab is unlikely to affect your ability to drive or use machines; however, use caution when
performing these activities until you are sure that nivolumab does not adversely affect you.
OPDIVO contains sodium
Tell your doctor if you are on a low-sodium (low-salt) diet before you are given OPDIVO. This
medicine contains 2.5 mg sodium per mL of concentrate.
You will also find this information in the Patient Alert Card you have been given by your doctor. It is
important that you keep this Alert Card and show it to your partner or caregivers.
3. How to use OPDIVO
How much OPDIVO is given
When OPDIVO is given on its own, the recommended dose is either 240 mg given every 2 weeks or
480 mg given every 4 weeks depending on indication.
When OPDIVO is given in combination with ipilimumab the recommended dose of OPDIVO is 1 mg
of nivolumab per kilogram of your body weight for the first 4 doses (combination phase). Thereafter
the recommended dose of OPDIVO is 240 mg given every 2 weeks or 480 mg given every 4 weeks
(single-agent phase).
Depending on your dose, the appropriate amount of OPDIVO will be diluted with sodium
chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection
before use. More than one vial of OPDIVO may be necessary to obtain the required dose.
How OPDIVO is given
You will receive treatment with OPDIVO in a hospital or clinic, under the supervision of an
experienced doctor.
OPDIVO will be given to you as an infusion (a drip) into a vein (intravenously) over a period of 30 or
60 minutes, every 2 weeks or 4 weeks, depending on the dose you are receiving. Your doctor will
continue giving you OPDIVO for as long as you keep benefitting from it or until you no longer
tolerate the treatment.
4
When OPDIVO is given in combination with ipilimumab, you will be given an infusion over a period
of 30 minutes, every 3 weeks for the first 4 doses (combination phase). Thereafter it will be given as
an infusion over a period of 30 or 60 minutes, every 2 weeks or 4 weeks, depending on the dose you
are receiving (single-agent phase).
If you miss a dose of OPDIVO
It is very important for you to keep all your appointments to receive OPDIVO. If you miss an
appointment, ask your doctor when to schedule your next dose.
If you stop using OPDIVO
Stopping your treatment may stop the effect of the medicine. Do not stop treatment with OPDIVO
unless you have discussed this with your doctor.
If you have any further questions about your treatment or on the use of this medicine, ask your doctor.
When OPDIVO is given in combination with ipilimumab, you will first be given OPDIVO followed
by ipilimumab.
Please refer to the package leaflet of ipilimumab in order to understand the use of this medicine. If you
have questions about this medicine, please ask your doctor.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. Your
doctor will discuss these with you and will explain the risks and benefits of your treatment.
Be aware of important symptoms of inflammation. OPDIVO acts on your immune system and may
cause inflammation in parts of your body. Inflammation may cause serious damage to your body and
some inflammatory conditions may be life-threatening and need treatment or withdrawal of
nivolumab.
The following side effects have been reported in clinical trials with nivolumab alone:
Very common (may affect more than 1 in 10 people)
 Decrease in some white blood cells
 Diarrhoea (watery, loose or soft stools), nausea
 Skin rash sometimes with blisters, itching
 Feeling tired or weak
Common (may affect up to 1 in 10 people)
 Infections of the upper respiratory tract
 Allergic reaction, reactions related to the infusion of the medicine
 Underactive thyroid gland (which can cause tiredness or weight gain), overactive thyroid gland
(which can cause rapid heart rate, sweating and weight loss)
 Decreased appetite
 Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and
legs), headache, dizziness
 High blood pressure (hypertension)
 Inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing),
shortness of breath (dyspnoea), cough
 Inflammation of the intestines (colitis), mouth ulcers and cold sores (stomatitis), vomiting,
stomach pain, constipation, dry mouth
 Skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or thinning
 Pain in the muscles, bones (musculoskeletal pain) and joints (arthralgia)
 Fever, oedema (swelling)
5
Uncommon (may affect up to 1 in 100 people)
 Serious lung infection (pneumonia), bronchitis
 Increase in some white blood cells
 Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys),
underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland
situated at the base of the brain, swelling of the thyroid gland, diabetes
 Dehydration, increased acid levels in the blood
 Inflammation of the liver (hepatitis)
 Damage to nerves causing numbness and weakness (polyneuropathy), inflammation of the nerves
caused by the body attacking itself, causing numbness, weakness, tingling or burning pain
(autoimmune neuropathy)
 Inflammation of the eye (which causes pain and redness), blurred vision, dry eyes
 Fast heart rate
 Fluid around the lungs
 Inflammation of the pancreas (pancreatitis), inflammation of the stomach (gastritis)
 Severe condition of the skin that causes red, often itchy spots, similar to the rash of measles,
which starts on the limbs and sometimes on the face and the rest of the body (erythema
multiforme), skin disease with thickened patches of red skin, often with silvery scales (psoriasis),
skin condition of the face where the nose and cheeks are unusually red (rosacea), hives (itchy,
bumpy rash)
 Inflammation of the muscles causing pain or stiffness (polymyalgia rheumatica), inflammation of
the joints (arthritis)
 Inflammation of the kidney, kidney failure (including abrupt loss of kidney function)
 Pain, chest pain
Rare (may affect up to 1 in 1000 people)
 A disease causing the inflammation or enlargement of a lymph node (Kikuchi lymphadenitis)
 Life-threatening allergic reaction
 Acid in the blood produced from diabetes (diabetic ketoacidosis)
 Blockage of bile ducts
 A temporary inflammation of the nerves that causes pain, weakness, and paralysis in the
extremities (Guillain- Barré syndrome), loss of the protective sheath around nerves
(demyelination), a condition in which the muscles become weak and tire easily (myasthenic
syndrome)
 Inflammation of the brain
 Changes in the rhythm or rate of the heartbeat, abnormal heart rhythm, inflammation of the heart
muscle
 Inflammatory disease of blood vessels
 Fluid in the lungs
 Ulcer of the small intestines
 Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis or Stevens-Johnson
syndrome)
 Disease in which the immune system attacks the glands that make moisture for the body, such as
tears and saliva (Sjogren’s syndrome), aching muscles, muscle tenderness or weakness, not caused
by exercise (myopathy), inflammation of the muscles (myositis), stiffness in muscles and joints,
muscle spasm (rhabdomyolysis)
The following side effects have been reported in clinical trials with nivolumab in combination with
ipilimumab:
Very common (may affect more than 1 in 10 people)
 Underactive thyroid gland (which can cause tiredness or weight gain)
 Decreased appetite
 Headache
 Shortness of breath (dyspnoea)
 Inflammation of the intestines (colitis), diarrhoea (watery, loose or soft stools), vomiting, nausea,
stomach pain
6
 Skin rash sometimes with blisters, itching
 Pain in the joints (arthralgia)
 Feeling tired or weak, fever
Common (may affect up to 1 in 10 people)
 Serious lung infection (pneumonia), infections of the upper respiratory tract
 Increase in some white blood cells
 Allergic reaction, reactions related to the infusion of the medicine
 Decreased secretion of hormones produced by adrenal glands (glands situated above the kidneys),
underactive function (hypopituitarism) or inflammation (hypophysitis) of the pituitary gland
situated at the base of the brain, overactive thyroid gland (which can cause rapid heart rate,
sweating and weight loss), inflammation of the thyroid gland, swelling of the thyroid gland
 Dehydration
 Inflammation of the liver
 Inflammation of the nerves (causing numbness, weakness, tingling or burning pain of the arms and
legs), dizziness
 Inflammation of the eye (which causes pain and redness), blurred vision
 Fast heart rate
 High blood pressure (hypertension)
 Inflammation of the lungs (pneumonitis, characterised by coughing and difficulty breathing),
blood clots, cough
 Mouth ulcers and cold sores (stomatitis), inflammation of the pancreas (pancreatitis), constipation,
dry mouth
 Skin colour change in patches (vitiligo), dry skin, redness of the skin, unusual hair loss or
thinning, hives (itchy rash)
 Pain in the muscles and bones (musculoskeletal pain)
 Kidney failure (including abrupt loss of kidney function)
 Oedema (swelling), pain
Uncommon (may affect up to 1 in 100 people)
 Bronchitis
 Chronic diseases associated with a build-up of inflammatory cells in various organs and tissues,
most commonly the lungs (sarcoidosis)
 Acid in the blood produced from diabetes (diabetic ketoacidosis), diabetes
 A temporary inflammation of the nerves that causes pain, weakness and paralysis in the
extremities (Guillain-Barré syndrome); damage to nerves causing numbness and weakness
(polyneuropathy); inflammation of the nerves; foot drop (peroneal nerve palsy); inflammation of
the nerves caused by the body attacking itself, causing numbness, weakness, tingling or burning
pain (autoimmune neuropathy)
 Inflammation of the brain
 Changes in the rhythm or rate of the heartbeat, abnormal heart rhythm, inflammation of the heart
muscle
 Fluid around the lungs
 Intestinal perforation, inflammation of the stomach (gastritis), inflammation of the duodenum
 Skin disease with thickened patches of red skin, often with silvery scales (psoriasis)
 Chronic disease of joints (spondyloarthropathy), disease in which the immune system attacks the
glands that make moisture for the body, such as tears and saliva (Sjogren’s syndrome),
inflammation of the joints (arthritis), aching muscles, muscle tenderness of weakness, not caused
by exercise (myopathy), inflammation of the muscles (myositis), stiffness in muscles and joints,
muscle spasm (rhabdomyolysis)
 Inflammation of the kidney
 Chest pain
Rare (may affect up to 1 in 1000 people)
 Severe and possibly fatal peeling of the skin (toxic epidermal necrolysis or Stevens-Johnson
syndrome)
7
Other side effects that have been reported (frequency not known) with nivolumab alone and
nivolumab in combination with ipilimumab include:
 A group of metabolic complications occurring after cancer treatment characterised by high blood
levels of potassium and phosphate, and low blood levels of calcium (tumour lysis syndrome)
Tell your doctor immediately if you get any of the side effects listed above. Do not try to treat your
symptoms with other medicines on your own.
Changes in test results
OPDIVO alone or in combination with ipilimumab may cause changes in the results of tests carried
out by your doctor. These include:
 Abnormal liver function tests (increased amounts of the liver enzymes aspartate aminotransferase,
alanine aminotransferase or alkaline phosphatase in your blood, higher blood levels of the waste
product bilirubin)
 Abnormal kidney function tests (increased amounts of creatinine in your blood)
 High (hyperglycaemia) or low (hypoglycaemia) sugar levels in the blood
 A decreased number of red blood cells (which carry oxygen), white blood cells (which are
important in fighting infection) or platelets (cells which help the blood to clot)
 An increased level of the enzyme that breaks down fats and of the enzyme that breaks down starch
 Increased or decreased amount of calcium or potassium
 Increased or decreased blood levels of magnesium or sodium
 Decrease in body weight
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in
this leaflet. You can also report side effects directly (see details below). By reporting side effects you
can help provide more information on the safety of this medicine.
5. How to store OPDIVO
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and the vial label after
EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C to 8°C).
Do not freeze.
Store in the original package in order to protect from light.
8
The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to
48 hours.
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste
material should be disposed of in accordance with local requirements.
6. Contents of the pack and other information
What OPDIVO contains
 The active substance is nivolumab.
Each mL of concentrate for solution for infusion contains 10 mg of nivolumab.
Each vial contains either 40 mg (in 4 mL) or 100 mg (in 10 mL) of nivolumab.
 The other ingredients are sodium citrate dihydrate, sodium chloride (see section 2 "OPDIVO
contains sodium"), mannitol (E421), pentetic acid, polysorbate 80, sodium hydroxide,
hydrochloric acid and water for injections.
What OPDIVO looks like and contents of the pack
OPDIVO concentrate for solution for infusion (sterile concentrate) is a clear to opalescent, colourless
to pale yellow liquid that may contain few light particles.
It is available in packs containing either 1 vial of 4 mL or 1 vial of 10 mL.
Not all pack sizes may be marketed.


This leaflet was last revised in April 2018
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
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The following information is intended for healthcare professionals only:
Preparation and administration of OPDIVO
Preparation should be performed by trained personnel in accordance with good practices rules,
especially with respect to asepsis.
Calculating the dose
More than one vial of OPDIVO concentrate may be needed to give the total dose for the patient.
Nivolumab monotherapy:
The prescribed dose for the patient is 240 mg or 480 mg given regardless of body weight depending on
indication.
Nivolumab in combination with ipilimumab:
The prescribed dose for the patient is given in mg/kg. Based on this prescribed dose, calculate the
total dose to be given.
 The total nivolumab dose in mg = the patient’s weight in kg × the prescribed dose in mg/kg.
 The volume of OPDIVO concentrate to prepare the dose (mL) = the total dose in mg, divided
by 10 (the OPDIVO concentrate strength is 10 mg/mL).
Preparing the infusion
Take care to ensure aseptic handling when you prepare the infusion.
OPDIVO can be used for intravenous administration either:
 without dilution, after transfer to an infusion container using an appropriate sterile syringe;
or
 after diluting according to the following instructions:
 the final infusion concentration should range between 1 and 10 mg/mL.
 the total volume of infusion must not exceed 160 mL. For patients weighing less than 40 kg,
the total volume of infusion must not exceed 4 mL per kilogram of patient weight.
 OPDIVO concentrate may be diluted with either:
 sodium chloride 9 mg/mL (0.9%) solution for injection; or
 50 mg/mL (5%) glucose solution for injection.
STEP 1
 Inspect the OPDIVO concentrate for particulate matter or discoloration. Do not shake the vial.
OPDIVO concentrate is a clear to opalescent, colourless to pale yellow liquid. Discard the vial if
the solution is cloudy, is discoloured, or contains particulate matter other than a few translucentto-white
particles.
 Withdraw the required volume of OPDIVO concentrate using an appropriate sterile syringe.
STEP 2
 Transfer the concentrate into a sterile, evacuated glass bottle or intravenous container (PVC or
polyolefin).
 If applicable, dilute with the required volume of sodium chloride 9 mg/mL (0.9%) solution for
injection or 50 mg/mL (5%) glucose solution for injection. For ease of preparation, the concentrate
can be transferred directly into a pre-filled bag containing the appropriate volume of sodium
chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) glucose solution for injection.
11
 Gently mix the infusion by manual rotation. Do not shake.
Administration
OPDIVO infusion must not be administered as an intravenous push or bolus injection.
Administer the OPDIVO infusion intravenously over a period of 30 or 60 minutes depending on
the dose.
OPDIVO infusion should not be infused at the same time in the same intravenous line with other
agents. Use a separate infusion line for the infusion.
Use an infusion set and an in-line, sterile, non-pyrogenic, low protein binding filter (pore size
of 0.2 μm to 1.2 μm).
OPDIVO infusion is compatible with:
 PVC containers
 Polyolefin containers
 Glass bottles
 PVC infusion sets
 In-line filters with polyethersulfone membranes with pore sizes of 0.2 µm to 1.2 µm.
After administration of the nivolumab dose, flush the line with sodium chloride 9 mg/mL (0.9%)
solution for injection or 50 mg/mL (5%) glucose solution for injection.
Storage conditions and shelf life
Unopened vial
OPDIVO must be stored in a refrigerator (2°C to 8°C). The vials must be kept in the original
package in order to protect from light. OPDIVO should not be frozen.
The unopened vial can be stored at controlled room temperature up to 25°C with room light for up to
48 hours.
Do not use OPDIVO after the expiry date which is stated on the carton and on the vial label after EXP.
The expiry date refers to the last day of that month.
OPDIVO infusion
OPDIVO infusion must be completed within 24 hours of preparation. If not used immediately, the
solution may be stored under refrigeration conditions (2°C-8°C) and protected from light for up
to 24 hours [a maximum of 8 hours of the total 24 hours can be at room temperature (20°C-25°C) and
room light]. Other in-use storage time and conditions are the responsibility of the user.
Disposal
Do not store any unused portion of the infusion solution for reuse. Any unused medicine or waste
material should be disposed of in accordance with local requirements.