Inflectra（静脉注射）

Inflectra的适应症和用法

克罗恩病

Inflectra适用于减轻对常规疗法反应不足的中度至重度活动性克罗恩病的成年患者的体征和症状，并诱导和维持其临床缓解。

Inflectra适用于减少患有克罗恩病的成年患者的引流性肠内和直肠阴道瘘的数量，并维持瘘管闭合。

小儿克罗恩病

Inflectra适用于减轻6岁及以上患有中度至重度活动性克罗恩病的小儿患者的症状和体征，并诱导和维持其临床缓解，这些小儿患者对常规疗法的反应不足。

溃疡性结肠炎

Inflectra可以减轻症状和体征，诱导并维持临床缓解和粘膜愈合，并消除对传统疗法反应不足的中度至重度活动性溃疡性结肠炎成年患者的皮质类固醇激素使用。

小儿溃疡性结肠炎

Inflectra可减轻6岁及以上患有中度至重度活动性溃疡性结肠炎的小儿患者的症状和症状，并诱导和维持其临床缓解，而这些患者对常规疗法的反应不足。

类风湿关节炎

Inflectra与甲氨蝶呤联用可减轻中度至重度活动性类风湿关节炎患者的体征和症状，抑制结构损伤的进展，并改善身体机能。

强直性脊柱炎

Inflectra适用于减轻活动性强直性脊柱炎患者的体征和症状。

银屑病关节炎

Inflectra可减轻银屑病关节炎患者的活动性关节炎症状和体征，抑制结构性损伤的进展并改善身体机能。

斑块状银屑病

Inflectra适用于治疗患有慢性严重（即，广泛和/或致残）斑块状牛皮癣的成年患者，这些患者适合进行全身性治疗，而其他全身性治疗在医学上较不适合。仅应将Inflectra应用于将受到严密监视并定期与医生进行随访的患者[请参阅带框警告，警告和注意事项（5） ] 。

Inflectra剂量和管理

克罗恩病

Inflectra的推荐剂量为5 mg / kg，在第0、2和6周以静脉内诱导方案给药，随后每8周以5 mg / kg的维持方案给药，以治疗中度至重度活动性克罗恩病或瘘管克罗恩病。对于有反应然后失去反应的成年患者，可以考虑以10 mg / kg的剂量治疗。到第14周仍无反应的患者不太可能继续给药，因此应考虑中断这些患者的Inflectra。

小儿克罗恩病

对于6岁及以上的中度至重度克罗恩病的小儿患者，Inflectra的推荐剂量为5 mg / kg，在0、2和6周静脉给予诱导方案，随后每8周给予5 mg / kg维持方案。

溃疡性结肠炎

Inflectra的推荐剂量为5 mg / kg，在第0、2和6周以静脉内诱导方案给药，随后每8周以5 mg / kg的维持方案给药，用于治疗中度至重度活动性溃疡性结肠炎的成年患者。

小儿溃疡性结肠炎

对于6岁及以上的中度至重度活动性溃疡性结肠炎的小儿患者，推荐的Inflectra剂量为5 mg / kg，在第0、2和6周采用静脉内诱导方案，随后每8周维持5 mg / kg的维持方案。

类风湿关节炎

Inflectra的推荐剂量为3 mg / kg，在第0、2和6周以静脉内诱导方案给药，随后每8周以3 mg / kg的维持方案给药，以治疗中度至重度活动性类风湿关节炎。 Inflectra应与甲氨蝶呤联用。对于反应不完全的患者，考虑到较高的剂量会增加严重感染的风险，可考虑将剂量调整至最高10 mg / kg或每4周进行一次治疗[见不良反应（6.1） ] 。

强直性脊柱炎

Inflectra的推荐剂量为5 mg / kg，在第0、2和6周以静脉内诱导方案给药，随后每6周以5 mg / kg的维持方案给药，以治疗活动性强直性脊柱炎。

银屑病关节炎

Inflectra的推荐剂量为5 mg / kg，在0、2和6周以静脉内诱导方案给药，随后每8周以5 mg / kg的维持方案进行治疗，以治疗银屑病关节炎。 Inflectra可与或不与甲氨蝶呤一起使用。

斑块状银屑病

Inflectra的推荐剂量为5 mg / kg，在第0、2和6周以静脉内诱导方案给药，随后每8周以5 mg / kg的维持方案给药，用于治疗慢性重症（即广泛和/或致残）斑块状牛皮癣。

监控评估安全

在开始用力弯曲术之前和治疗期间应定期对患者进行活动性结核病评估并进行潜伏性感染检查[见警告和注意事项（5.1） ] 。

有关输注反应的管理说明

英夫利昔单抗产品给药期间的不良反应包括流感样症状，头痛，呼吸困难，低血压，短暂发烧，发冷，胃肠道症状和皮疹。在Inflectra输注过程中，随时可能发生过敏反应。在英夫利昔单抗的所有临床试验中，约有20％的患者经历了输液反应，而安慰剂治疗的患者为10​​％ [见不良反应（6.1） ] 。在输注Inflectra之前，可以根据医生的判断来进行药物治疗。处方药可能包括抗组胺药（抗H1 +/-抗H2），对乙酰氨基酚和/或皮质类固醇。

在输注期间，在缓慢或中止输注后，轻度至中度输注反应可能会改善，并且在反应消退后，可以以较低的输注速率重新启动和/或治疗性施用抗组胺药，对乙酰氨基酚和/或皮质类固醇。对于这些干预后不能耐受输注的患者，应停用Inflectra。

在输注过程中或输注后，患有严重输注相关的超敏反应的患者应停止进一步的Inflectra治疗。严重输注反应的处理应由反应的体征和症状决定。如果发生过敏反应，应有适当的人员和药物治疗。

准备和管理的一般注意事项和说明

Inflectra旨在在医师的指导和监督下使用。重构的输液应由经过培训的医学专家使用无菌技术按照以下步骤制备：

1. 计算所需的剂量，重构的Inflectra溶液的总体积以及所需的Inflectra小瓶数量。每个Inflectra小瓶均包含100 mg的infliximab-dyyb抗体。
2. 使用配有21号或更小针头的注射器，用10 mL无菌注射用水（USP）重构每个Inflectra小瓶，如下所示：从小瓶中取出翻盖并用酒精棉签擦拭顶部。通过橡胶塞的中心将注射器针头插入小瓶中，并将无菌注射用水（USP）引导至小瓶的玻璃壁。通过旋转小瓶轻轻旋转溶液以溶解冻干的粉末。避免长时间或剧烈搅动。请勿摇动。起泡的重建解决方案并不罕见。让重新配制的溶液静置5分钟。重构溶液浓度为10 mg / mL。溶液应为无色至浅黄色和乳白色，并且溶液可能会形成一些半透明的颗粒，因为英夫利昔单抗-dyyb是一种蛋白质。如果冻干的饼没有完全溶解，或者存在不透明的颗粒，变色或其他异物，请不要使用。
3. 用无菌的0.9％氯化钠注射液USP将重构的Inflectra溶液的总体积稀释至250 mL，方法是从0.9％的氯化钠注射液USP抽取250 mL瓶或袋中的体积等于重构的Inflectra的体积。不要用任何其他稀释剂稀释重构的Inflectra溶液。将重建的Inflectra溶液的总体积缓慢添加到250 mL输液瓶或输液袋中。轻轻混合。所得的输注浓度应在0.4 mg / mL和4 mg / mL之间。
4. Inflectra输液应在重组和稀释后的3小时内开始。输注必须持续不少于2小时，并且必须使用带有在线，无菌，无热原，低蛋白结合过滤器（孔径为1.2μm或更小）的输注套件。小瓶不含抗菌防腐剂。因此，输注溶液中任何未使用的部分均不得存储以备重复使用。
5. 没有进行物理生化相容性研究来评估Inflectra与其他药物的共同给药。 Inflectra不应与其他药物在同一静脉内同时注入。
6. 在溶液和容器允许的情况下，在配制之前和之后，应在注射前后目视检查肠胃外药品是否有颗粒物质和变色。如果观察到明显不透明的颗粒，变色或其他异物，则不应使用该溶液。

剂型和优势

注射：100 mg小瓶：20 mg小瓶中的100 mg冻干的英夫利昔单抗-dyyb，用于静脉注射。

禁忌症

中度至重度心力衰竭患者不应使用剂量大于5 mg / kg的Inflectra。在一项评估中度至重度心力衰竭患者中英夫利昔单抗的随机研究中（纽约心脏协会[NYHA]功能性III / IV级），英夫利昔单抗10 mg / kg的治疗与因心脏恶化导致的死亡和住院率增加相关失败[请参阅警告和注意事项（5.5） ，不良反应（6.1） ] 。

对于对英夫利昔单抗产品发生严重超敏反应的患者，不应重新使用Inflectra。此外，不应将Inflectra应用于已知对该产品的非活性成分或任何鼠类蛋白质过敏的患者。

警告和注意事项

严重感染

用英夫利昔单抗产品治疗的患者发生严重感染的风险增加，涉及各种器官系统和部位，可能导致住院或死亡。

TNF阻滞剂已报道由细菌，分枝杆菌，侵入性真菌，病毒或寄生生物引起的机会性感染，包括曲霉菌病，芽孢杆菌病，念珠菌病，球虫病，隐球菌病，组织胞浆菌病，军团病，李斯特氏菌病，肺囊虫病，沙门氏菌病和结核病。患者经常表现为传播性疾病而非局部性疾病。

对于患有活动性感染（包括临床上重要的局部感染）的患者，不应开始使用Inflectra进行治疗。年龄大于65岁的患者，合并症患者和/或同时服用免疫抑制剂（如皮质类固醇或甲氨蝶呤）的患者感染风险更高。在开始对患者进行治疗之前，应考虑治疗的风险和益处：

• 患有慢性或复发性感染；
• 曾患结核病的人；
• 有机会感染史；
• 在地方性肺结核或地方性真菌病（例如组织胞浆菌病，球孢子菌病或胚芽菌病）地区居住或旅行的人；要么
• 具有可能使他们容易感染的潜在条件。

结核

在接受英夫利昔单抗产品的患者中，包括先前曾接受过潜伏性或活动性肺结核治疗的患者中，已经观察到结核病重新激活或新的结核感染的病例。在潜伏性结核病治疗期间接受英夫利昔单抗产品治疗的患者中也发生了活动性结核病。

在开始使用Inflectra之前和治疗期间应定期评估患者的结核病危险因素并进行潜伏性感染测试。已显示在用TNF阻断剂治疗之前治疗潜伏性结核感染可降低治疗过程中结核再激活的风险。在评估是否需要在开始Inflectra之前就需要对潜伏性结核病进行治疗时，结核菌素皮肤测试的硬结5mm或更大的硬度应被视为阳性测试结果，即使以前接种过Bacille Calmette-Guerin（BCG）的患者也是如此。

对于既往有潜伏性或活动性肺结核病史且无法确定适当治疗方案的患者，以及对于潜伏性结核病呈阴性反应但存在危险因素的患者，也应在开始Inflectra之前考虑抗结核治疗。结核感染。建议咨询有结核治疗专业知识的医生，以帮助决定是否开始抗结核治疗适合个别患者。

对于在Inflectra治疗期间发生新感染的患者，尤其是以前或最近去过结核病高发国家或与活动性结核病患者有密切接触的患者，应强烈考虑结核病。

监控方式

在用Inflectra治疗期间和之后，应密切监测患者的感染迹象和症状的发展，包括在开始治疗前对潜伏性结核感染测试呈阴性的患者的结核病发展。在用Inflectra进行治疗时，潜伏性结核感染测试的结果也可能是假阴性的。

如果患者出现严重感染或败血症，应停止使用Inflectra。在用Inflectra治疗期间发生新感染的患者应受到密切监视，并应针对免疫功能低下的患者进行迅速而全面的诊断检查，并应开始适当的抗菌治疗。

侵袭性真菌感染

对于在真菌病流行地区居住或旅行的患者，如果他们发展为严重的全身性疾病，则应怀疑是侵入性真菌感染。在进行诊断检查时，应考虑适当的经验性抗真菌治疗。在某些活动性感染患者中，用于组织胞浆菌病的抗原和抗体检测可能为阴性。在可行的情况下，应对这些患者进行经验性抗真菌治疗的决定应咨询具有侵入性真菌感染诊断和治疗经验的专业医生，并应考虑到严重真菌感染的风险和抗真菌治疗的风险。 。

恶性肿瘤

据报道，接受英夫利昔单抗产品治疗的儿童，青少年和年轻人接受TNF阻断剂治疗（开始治疗≤18岁）的恶性肿瘤是致命的。这些病例中约有一半是淋巴瘤，包括霍奇金淋巴瘤和非霍奇金淋巴瘤。其他病例代表各种恶性肿瘤，包括通常与免疫抑制相关的罕见恶性肿瘤和通常在儿童和青少年中不常见的恶性肿瘤。在首剂TNF阻断剂治疗中位30个月（1至84个月）后发生恶性肿瘤。大多数患者正在接受伴随的免疫抑制剂。这些案例是在上市后报道的，并来自各种来源，包括注册管理机构和自发的上市后报告。

淋巴瘤

在所有TNF阻断剂的临床试验的对照部分中，与对照患者相比，在接受TNF阻断剂的患者中观察到更多的淋巴瘤病例。在英夫利昔单抗临床试验的对照和开放标签部分中，在接受英夫利昔单抗治疗的5707例患者中，有5例发展为淋巴瘤（中位随访时间为1.0年），而1600例对照患者为0淋巴瘤（中位随访时间为0.4年）。 ）。在类风湿关节炎患者中，每100名患者-年的随访中观察到2例淋巴瘤，发病率为0.08例，比一般人群的预期值高大约三倍。在类风湿性关节炎，克罗恩病，牛皮癣性关节炎，强直性脊柱炎，溃疡性结肠炎和斑块状牛皮癣的综合临床试验人群中，每100个患者-年的随访中观察到5例淋巴瘤，占0.10例，约为4例比一般人群高出预期的两倍。患者克罗恩病，类风湿性关节炎或牛皮癣，特别是患者的高活性的疾病和/或慢性暴露于免疫抑制剂疗法，可以在更高的风险（高达几倍）淋巴瘤的发展一般人群中，即使在没有TNF阻断疗法。据报道，在风湿性关节炎和其他适应症中，上市后使用TNF阻滞剂可治疗急性和慢性白血病。即使没有TNF阻断剂治疗，类风湿关节炎患者的发生白血病的风险也可能比一般人群更高（约2倍）。

肝脾T细胞淋巴瘤（HSTCL）

据报道，使用英夫利昔单抗产品治疗的TNF受体阻滞剂治疗的患者患有肝脾性T细胞淋巴瘤（HSTCL），这是一种罕见的T细胞淋巴瘤。这些病例的病程非常激进并且致命。在诊断之前或诊断之前，几乎所有患者均接受了免疫抑制剂硫唑嘌呤或6-巯基嘌呤治疗，并伴有TNF阻滞剂。报告的大多数病例发生在克罗恩病或溃疡性结肠炎患者中，大多数发生在青春期和成年男性中。尚不确定HSTCL的发生是否与TNF阻滞剂或与这些其他免疫抑制剂联合使用的TNF阻滞剂有关。在治疗患者时，应考虑是否单独使用Inflectra或与其他免疫抑制剂（如硫唑嘌呤或6-巯基嘌呤）联合使用，应考虑到联合治疗HSTCL的风险较高，而免疫原性和超敏反应的风险增加来自英夫利昔单抗研究的临床试验数据得出英夫利昔单抗产品单一疗法的不良反应[见警告和注意事项（5.7） ，不良反应（6.1） ]。

皮肤癌

在包括英夫利昔单抗产品在内的TNF阻断剂治疗的患者中，已有黑色素瘤和默克尔细胞癌的报道[见不良反应（6.2） ] 。建议对所有患者进行定期皮肤检查，尤其是那些有皮肤癌危险因素的患者。

宫颈癌

一项基于人群的回顾性队列研究使用了瑞典国家卫生注册中心的数据，发现与非生物制剂患者或普通人群相比，用英夫利昔单抗治疗的类风湿关节炎妇女的浸润性宫颈癌发生率增加了2到3倍，尤其是那些60岁。英夫利昔单抗产品与宫颈癌之间的因果关系不能排除。接受Inflectra治疗的妇女应继续进行定期筛查[见不良反应（6.2） ] 。

其他恶性肿瘤

在某些TNF阻断剂（包括英夫利昔单抗产品）的临床试验的对照部分中，与对照患者相比，接受这些TNF阻断剂的患者观察到了更多的恶性肿瘤（淋巴瘤和非黑色素瘤皮肤癌[NMSC]）。在英夫利昔单抗试验的对照部分中，中度至重度类风湿性关节炎，克罗恩病，牛皮癣性关节炎，强直性脊柱炎，溃疡性结肠炎和斑块状牛皮癣患者中，有40例英夫利昔单抗中有14例被诊断为恶性肿瘤（淋巴瘤和NMSC）治疗的患者与1597名对照患者中的1名相比（用英夫利昔单抗治疗的患者中的比例为0.52 / 100患者-年，而对照组中的患者为0.11 / 100患者-年）用英夫利昔单抗治疗的患者需要5年，对照患者需要0。4年。其中，最常见的恶性肿瘤是乳腺癌，结肠直肠癌和黑色素瘤。用英夫利昔单抗治疗的患者中的恶性肿瘤发生率与一般人群中预期的相似，而对照患者中的恶性肿瘤发生率低于预期。

在一项探索英夫利昔单抗在中度至重度慢性阻塞性肺疾病（COPD）患者中使用的临床试验中，与对照组相比，用英夫利昔单抗治疗的患者报告了更多的恶性肿瘤，大部分是肺部或头颈部起源。所有患者都有重度吸烟史[见不良反应（6.1） ] 。在中度至重度COPD患者中考虑使用Inflectra时，开药者应谨慎行事。

应该监测牛皮癣患者的NMSC，特别是那些事先接受过长期光疗的患者。在英夫利昔单抗临床试验的维持部分中，先前接受过光疗的患者更常见NMSC [见不良反应（6.1） ] 。

TNF阻断疗法在恶性肿瘤发展中的潜在作用尚不清楚[见不良反应（6.1） ] 。英夫利昔单抗的临床试验率不能与其他TNF阻断剂的临床试验率相比较，并且可能无法预测在更广泛的患者群体中观察到的率。对于有恶性病史的患者考虑使用Inflectra进行治疗或接受Inflectra期间发生恶性肿瘤的患者继续治疗时应谨慎行事。

乙肝病毒激活

TNF阻滞剂（包括英夫利昔单抗产品）的使用已与慢性乙型肝炎病毒（HBV）患者的再激活有关。在某些情况下，与TNF受体阻滞剂疗法联合发生的HBV再激活是致命的。这些报告大多数发生在同时接受抑制免疫系统的其他药物的患者中，这也可能有助于HBV的重新激活。在开始使用包括Inflectra在内的TNF阻断剂治疗之前，应对患者进行HBV感染测试。对于乙型肝炎表面抗原测试呈阳性的患者，建议咨询专业的乙型肝炎治疗医生。关于抗病毒治疗结合TNF阻断剂治疗来预防HBV激活的HBV携带者患者的安全性或有效性，尚无足够的数据。在整个治疗过程中以及治疗终止后的几个月内，应密切监测HBV携带者且需要TNF阻滞剂治疗的患者的活动性HBV感染的临床和实验室体征。对于发生HBV激活的患者，应停止TNF阻滞剂，并应开始抗病毒治疗及适当的支持治疗。在控制HBV激活后恢复TNF阻断剂治疗的安全性尚不清楚。因此，在这种情况下考虑重新使用TNF阻断剂时，开药者应谨慎行事，并密切监视患者。

肝毒性

接受英夫利昔单抗产品治疗的患者在上市后的数据中很少报道严重的肝反应，包括急性肝衰竭，黄疸，肝炎和胆汁淤积。在某些情况下，已诊断出自身免疫性肝炎。英夫利昔单抗开始后2周至1年以上发生严重肝反应。在许多此类病例中，在发现肝损伤之前未发现肝转氨酶水平升高。其中一些病例是致命的或必须进行肝移植。有肝功能异常症状或体征的患者应进行肝损伤证据评估。如果出现黄疸和/或明显的肝酶升高（例如，≥正常上限的5倍），应停用Inflectra，并对异常进行彻底检查。在临床试验中，在接受英夫利昔单抗产品治疗的患者中观察到ALT和AST的轻度或中度升高，而没有进展为严重的肝损伤[见不良反应（6.1） ] 。

心力衰竭患者

英夫利昔单抗产品与心力衰竭患者的不良预后相关，仅在考虑其他治疗方案后，才应将英夫力克单抗用于心力衰竭患者。一项评估英夫利昔单抗在心力衰竭患者中使用的随机研究结果（NYHA功能级别III / IV）表明，接受10 mg / kg英夫利昔单抗的患者死亡率更高，并且在5 mg / kg剂量下心血管不良事件发生率更高千克和10毫克/千克。服用英夫利昔单抗的患者在上市后有心衰恶化的报道，无论有无可诱发的沉淀因素。上市后也有罕见的新发作心力衰竭的报道，包括没有已知预先存在的心血管疾病的患者的心力衰竭。这些患者中有些未满50岁。如果决定对患有心力衰竭的患者使用Inflectra，则应在治疗期间对其进行密切监测；如果出现新的或恶化的心力衰竭症状，应停用Inflectra [请参阅禁忌症（4） ，不良反应（6.1） ] 。

血液学反应

据报道，接受英夫利昔单抗产品治疗的患者出现了白细胞减少症，中性粒细胞减少症，血小板减少症和全血细胞减少症，但有致命的后果。与英夫利昔单抗产品治疗之间的因果关系仍不清楚。尽管尚未确定高危人群，但是在接受Inflectra治疗的患者中有持续或有明显血液学异常史的患者应格外小心。如果在Inflectra上出现任何迹象表明出现血液异常或感染（例如持续发烧），则应建议所有患者立即就医。发生严重血液学异常的患者应考虑停用Inflectra治疗。

过敏症

英夫利昔单抗产品与超敏反应有关，这些超敏反应的起效时间不同，在某些情况下需要住院治疗。大部分过敏反应，包括过敏反应，荨麻疹，呼吸困难和/或低血压，都发生在输注过程中或输注后2小时内。但是，在某些情况下，在最初用英夫利昔单抗治疗后（即最早在第二剂之后），以及在长时间不治疗后重新开始英夫利昔单抗治疗后，观察到血清样反应。与这些反应有关的症状包括发烧，皮疹，头痛，喉咙痛，肌痛，多关节痛，手和面部浮肿和/或吞咽困难。这些反应与英夫利昔单抗产品的抗体显着增加，英夫利昔单抗产品的可检测血清浓度降低以及药物功效可能降低有关。

对于严重的超敏反应，应停止使用Inflectra。发生反应时，应立即使用用于治疗超敏反应的药物（例如，对乙酰氨基酚，抗组胺药，皮质类固醇和/或肾上腺素） [请参阅不良反应（6.1） ] 。

在类风湿性关节炎，克罗恩氏病和牛皮癣的临床试验中，与常规维持治疗相比，未经治疗一段时间后英夫利昔单抗的重新给药导致输注反应的发生率更高[见不良反应（6.1） ] 。一般而言，应谨慎考虑一段时间不治疗后再次使用Inflectra的益处风险，尤其是作为第0、2和6周的减量方案。如果Inflectra牛皮癣维持治疗中断，应以单一剂量重新启动Inflectra，然后进行维持治疗。

输注期间和之后的心血管和脑血管反应

在英夫利昔单抗产品输注开始期间和开始后的24小时内，已报告发生严重的脑血管意外，心肌缺血/梗塞（某些致命），低血压，高血压和心律不齐。据报道，在英夫利昔单抗产品输注过程中或输注后2小时内出现短暂性视力丧失的情况。在输液期间监视患者，如果发生严重反应，请停止输液。应根据症状和体征确定对反应的进一步管理[见不良反应（6） ] 。

神经反应

在极少数情况下，抑制TNF的药物与中枢神经系统表现为全身性血管炎，癫痫发作和新出现或加剧的临床症状和/或影像学证据表明中枢神经系统发生脱髓鞘疾病，包括多发性硬化症和视神经炎以及周围性脱髓鞘疾病，包括Guillain-Barré综合征。在患有这些神经系统疾病的患者中考虑使用Inflectra时，处方者应谨慎行事，如果这些疾病发展，应考虑停用Inflectra。

与Anakinra一起使用

在临床研究中观察到严重的感染和嗜中性白血球减少症，同时使用Anakinra和另一种TNFα阻断剂etanercept，与单独使用etanercept相比，没有增加的临床益处。由于依那西普和anakinra疗法联合出现的不良反应的性质，anakinra和其他TNFα阻断剂的组合也可能产生类似的毒性。因此，不建议将Inflectra和anakinra结合使用。

与Abatacept一起使用

在临床研究中，与单独使用TNF阻断剂相比，同时使用TNF阻断剂和abatacept会增加包括严重感染在内的感染风险，而不会增加临床获益。因此，不推荐使用Inflectra和abatacept的组合[见药物相互作用（7.1） ] 。

与其他生物疗法同时给药

关于英夫利昔单抗产品与其他可与Inflectra治疗相同疾病的生物疗法同时使用的信息尚不足。不建议将Inflectra与这些生物制剂同时使用，因为这有可能增加感染的风险[见药物相互作用（7.3） ] 。

改变生物疾病的抗风湿药（DMARD）之间的切换

从一种生物制剂切换到另一种生物制剂时应小心，因为重叠的生物活性可能会进一步增加感染的风险。

自身免疫

用英夫利昔单抗产品治疗可能会导致自身抗体的形成，很少会导致狼疮样综合征的发展。如果患者在用Inflectra治疗后出现暗示狼疮样综合征的症状，应停止治疗[见不良反应（6.1） ] 。

活疫苗/治疗性传染病

在接受抗TNF治疗的患者中，关于活疫苗接种的反应或活疫苗感染的二次传播的可用数据有限。使用活疫苗可能会导致临床感染，包括传播感染。不建议将活疫苗与Inflectra同时使用。

据报道，婴儿在子宫内暴露于英夫利昔单抗产品后接受了卡介苗疫苗接种，这是由于散播的卡介苗感染所致的致命结果。英夫利昔单抗产品可穿过胎盘，并已在出生后6个月内被检测到。建议在出生后至少有六个月的等待期，然后再对在子宫内暴露于英夫利昔单抗产品的婴儿接种活疫苗。

治疗性传染病的其他用途，例如减毒活细菌（例如，BCG膀胱滴注法用于治疗癌症）可能会导致临床感染，包括传播感染。建议不要与Inflectra同时使用治疗性传染病。

建议在开始Inflectra治疗之前，让所有儿科患者都接受所有疫苗接种。疫苗接种和开始Inflectra治疗之间的间隔应符合当前的疫苗接种指南。

不良反应

临床试验经验

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

Adverse Reactions in Adults

The data described herein reflect exposure to infliximab in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn's disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [ For information on adverse reactions in pediatric patients [see Adverse Reactions (6.1) ] . One of the most common reasons for discontinuation of treatment was infusion-related reactions (eg, dyspnea, flushing, headache and rash).

Infusion-related Reactions

An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase 3 clinical studies, 18% of patients treated with infliximab experienced an infusion reaction compared to 5% of placebo-treated patients. Of these infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.

Among all infusions with infliximab, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued treatment with infliximab because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. Infliximab infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (ie, an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.

Patients who became positive for antibodies to infliximab were more likely (approximately two to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.1) , Drug Interactions (7.4) ] .

Infusion reactions following re-administration

In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab following disease flare, 4% (8/219) of patients in the re-treatment therapy arm experienced serious infusion reactions versus <1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, treatment with infliximab was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.

Delayed Reactions/Reactions Following Readministration

In psoriasis studies, approximately 1% of patients treated with infliximab experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.

传染病

In infliximab clinical studies, treated infections were reported in 36% of patients treated with infliximab (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among patients treated with infliximab, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported postmarketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with infliximab and may reflect recrudescence of latent disease [see Warnings and Precautions (5.1) ] . In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with methotrexate (MTX) developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving infliximab, 1.7% developed pneumonia and 0.4% developed tuberculosis, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg infusions with infliximab at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg infliximab group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn's II Study, 15% of patients with fistulizing Crohn's disease developed a new fistula-related abscess.

In clinical studies with infliximab in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of patients treated with infliximab (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies.

The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.

Autoantibodies/Lupus-like Syndrome

Approximately half of patients treated with infliximab in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of patients treated with infliximab compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

恶性肿瘤

In controlled trials, more patients treated with infliximab developed malignancies than placebo-treated patients [see Warnings and Precautions (5.2) ] .

In a randomized controlled clinical trial exploring the use of infliximab in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Of these patients treated with infliximab, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% confidence interval [CI] 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck.

Patients with Heart Failure

In a randomized study evaluating infliximab in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of infliximab at 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg infliximab dose. At 1 year, 8 patients in the 10 mg/kg infliximab group had died compared with 4 deaths each in the 5 mg/kg infliximab and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg infliximab treatment groups, versus placebo. Infliximab has not been studied in patients with mild heart failure (NYHA Class I/II) [see Contraindications (4) , Warnings and Precautions (5.5) ].

免疫原性

As with all therapeutic proteins, there is potential for immunogenicity.抗体形成的检测高度依赖于测定的灵敏度和特异性。 Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other infliximab products may be misleading.

Treatment with infliximab products can be associated with the development of antibodies to infliximab products. An enzyme immunoassay (EIA) method was originally used to measure anti-infliximab antibodies in clinical studies of infliximab. The EIA method is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. A separate, drug-tolerant electrochemiluminescence immunoassay (ECLIA) method for detecting antibodies to infliximab was subsequently developed and validated. This method is 60-fold more sensitive than the original EIA. With the ECLIA method, all clinical samples can be classified as either positive or negative for antibodies to infliximab without the need for the inconclusive category.

The incidence of antibodies to infliximab was based on the original EIA method in all clinical studies of infliximab except for the Phase 3 study in pediatric patients with ulcerative colitis where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods [see Adverse Reactions, Pediatric Ulcerative Colitis (6.1) ] .

The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of treatment with infliximab. A higher incidence of antibodies to infliximab was observed in Crohn's disease patients receiving infliximab after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction [see Adverse Reactions (6.1) ] than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosuppressant therapies such as 6-mercaptopurine /azathioprine (6-MP/AZA) or MTX.

In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1% – 23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with infliximab products over the long term is not known.

肝毒性

Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving infliximab products [see Warnings and Precautions (5.4) ] . Reactivation of HBV has occurred in patients receiving TNF blocking agents, including infliximab products, who are chronic carriers of this virus [see Warnings and Precautions (5.3) ] .

In clinical trials in rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls (Table 1), both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant medications.

Adverse Reactions in Psoriasis Studies

During the placebo-controlled portion across the 3 clinical trials up to week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg infliximab group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg infliximab group.

Among patients in the 2 Phase 3 studies, 12.4% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving infliximab 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.

One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg of infliximab. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving infliximab 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving infliximab 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg infliximab group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting infliximab.

In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received infliximab at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.

In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.

Other Adverse Reactions

Safety data are available from 4779 adult patients treated with infliximab, including 1304 with rheumatoid arthritis, 1106 with Crohn's disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [ For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1) ] . Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn's disease patients treated with infliximab except for abdominal pain, which occurred in 26% of patients with Crohn's disease. In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received infliximab to provide meaningful comparisons.