Renflexis的适应症和用法

克罗恩病

Renflexis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成年患者的体征和症状，并诱导和维持其临床缓解。

Renflexis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

Renflexis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

Renflexis用于减轻症状和体征，诱导和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

Renflexis适用于减轻对传统疗法反应不足的中度至重度活动性溃疡性结肠炎的6岁及以上儿童患者的症状和体征，并诱导和维持其临床缓解。

类风湿关节炎

对于患有中度至重度活动性类风湿关节炎的患者，Renflexis与氨甲蝶呤联用可减少症状和体征，抑制结构损伤的进展，并改善身体机能。

强直性脊柱炎

Renflexis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

Renflexis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

Renflexis适用于治疗患有慢性严重（即，广泛和/或致残性）斑块状牛皮癣的成年患者，这些患者应进行全身治疗，而其他全身治疗在医学上不太合适。 Renflexis仅应施用于将受到密切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） ] 。

Renflexis剂量和给药

克罗恩病

Renflexis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，因此应考虑终止这些患者的Renflexis。

小儿克罗恩病

对于6岁及以上的中度至重度克罗恩氏病的小儿患者，推荐的Renflexis剂量为5 mg / kg，在0、2和6周静脉给予诱导治疗，随后每8周给予5 mg / kg维持治疗。

溃疡性结肠炎

Renflexis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，Renflexis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。

类风湿关节炎

Renflexis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。 Renflexis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

Renflexis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

Renflexis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，以治疗银屑病关节炎。 Renflexis可与或不与甲氨蝶呤一起使用。

斑块状银屑病

Renflexis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予，随后每8周以5 mg / kg的维持方案给予治疗，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

在开始使用Renflexis之前和治疗期间应定期进行评估，应评估患者是否患有活动性结核病并进行潜伏性感染检查[请参阅警告和注意事项（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。 Renflexis输注期间可能随时发生过敏反应。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Renflexis之前，可根据医师的判断酌情使用药物。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。对于在这些干预措施后不能耐受输注的患者，应停用Renflexis。

输注过程中或输注后，具有严重输注相关超敏反应的患者应停止进一步的Renflexis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

Renflexis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. 计算所需剂量的Renflexis溶液，总体积以及所需的Renflexis小瓶数量。每个Renflexis小瓶均包含100 mg英夫利昔单抗抗体。
2. 使用装有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Renflexis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Renflexis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Renflexis的体积。不要用任何其他稀释剂稀释重组的Renflexis溶液。将重建的Renflexis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. Renflexis输注应在重构和稀释后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，输液溶液中任何未使用的部分均不得存储以备重复使用。
5. 还没有进行物理生化相容性研究来评估Renflexis与其他药物的共同用药。 Renflexis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冻干英夫利昔单抗-静脉注射。

禁忌症

对于中度至重度心力衰竭患者，不应服用大于5 mg / kg的Renflexis。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）和不良反应（6.1） ] 。

对于英夫利昔单抗产品发生严重超敏反应的患者，不应再次服用Renflexis。此外，Renflexis不应给予对产品的非活性成分或任何鼠类蛋白过敏的患者。

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-受体阻滞剂已报告由细菌，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。

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Renflexis治疗。年龄大于65岁的患者，患有合并症的患者和/或同时服用免疫抑制剂（例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Renflexis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。在评估开始使用Renflexis之前是否需要对潜伏性结核病进行治疗时，即使对于先前接种了BacilleCalmette-Guérin（BCG）的患者，结核菌素皮肤试验5毫米或更大的硬结也应被视为阳性测试结果。

对于既往有潜伏性或活动性肺结核病史且无法确定适当疗程的患者，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Renflexis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Renflexis治疗期间出现新感染的患者，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密切接触的患者，应强烈考虑结核病。

监控方式

在使用Renflexis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。接受Renflexis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，应停用Renflexis。应严密监测在Renflexis治疗期间发生新感染的患者，并对其进行及时而全面的诊断检查，以适合免疫功能低下的患者，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。在进行诊断性检查时，应考虑采用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（包括英夫利昔单抗产品）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告的，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。患有克罗恩氏病，类风湿性关节炎或斑块状牛皮癣的患者，特别是患有高活性疾病和/或长期暴露于免疫抑制剂治疗的患者，即使是在淋巴瘤的发展中，也比一般人群面临更高的风险（高达几倍）。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，在接受包括英夫利昔单抗产品在内的TNF受体阻滞剂治疗的患者中，肝脾T细胞淋巴瘤（HSTCL）是一种罕见的T细胞淋巴瘤上市后病例。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Renflexis或与其他免疫抑制剂（如硫唑嘌呤或6-巯基嘌呤）联用，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）和不良反应（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） ] 。建议所有患者，尤其是有皮肤癌危险因素的患者，定期进行皮肤检查。

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。不能排除英夫利昔单抗产品与宫颈癌之间的因果关系。 Renflexis治疗的妇女应继续定期筛查[见不良反应（6.2） ] 。

其他恶性肿瘤

在包括英夫利昔单抗产品在内的某些TNF阻断剂的临床试验的对照部分中，与对照组相比，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]）。在对中度至重度活动性类风湿性关节炎，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患者进行英夫利昔单抗试验的受控部分期间，在接受4019剂英夫利昔单抗治疗的患者中，有14例被诊断为恶性肿瘤（淋巴瘤和NMSC）患者与1597例对照患者中的1个患者（用英夫利昔单抗治疗的患者中0.52 / 100个患者-年的比率与对照患者中0.11 / 100个患者-年的比率），中位随访时间为0.5年英夫利昔单抗治疗的患者和对照组的患者为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） ] 。在中重度COPD患者中考虑使用Renflexis时，开药者应谨慎行事。

应该监测牛皮癣患者的非黑素瘤皮肤癌（NMSCs），尤其是那些事先经过长期光疗治疗的患者。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阻滞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。在有恶性病史的患者中考虑使用Renflexis进行治疗或在接受Renflexis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Renflexis在内的TNF阻断剂治疗之前，应对患者进行HBV感染检测。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阻断剂治疗的患者的活动性HBV感染的临床和实验室体征。在发生HBV激活的患者中，应停止TNF阻滞剂，并应开始进行适当支持治疗的抗病毒治疗。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，开药者在这种情况下考虑恢复TNF阻滞剂治疗时应谨慎行事，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已经报道了严重的肝反应，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Renflexis，并应彻底检查异常情况。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结局相关，仅在考虑其他治疗方案后才应在心力衰竭患者中使用英夫利昔单抗产品。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。上市后有报道称服用英夫利昔单抗的患者有或没有可诱发的促发因素，心力衰竭恶化。上市后也有罕见的关于新发性心力衰竭的报道，包括未患有已知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服用Renflexis，则应在治疗过程中对其进行密切监测；如果出现新的或恶化的心力衰竭症状，应停用Renflexis [请参阅禁忌症（4）和不良反应（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Renflexis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Renflexis上出现任何迹象表明出现血液异常或感染（例如持续发烧），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Renflexis治疗。

过敏症

英夫利昔单抗产品与超敏反应相关，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。大多数超敏反应，包括过敏性反应，荨麻疹，呼吸困难和/或低血压，都在输注期间或输注2小时内发生。

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，应停用Renflexis。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） [见不良反应（6.1） ] 。

在类风湿性关节炎，克罗恩病和牛皮癣的临床试验中，与常规维持治疗相比，一段时间未治疗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） ] 。通常，应仔细考虑经过一段时间不治疗后再次服用Renflexis的益处风险，尤其是作为第0、2和6周的再诱导方案。如果银屑病的Renflexis维持治疗中断，则应以单剂量重新开始Renflexis，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。在英夫利昔单抗产品的输注过程中或输注后2小时内有短暂视力丧失的报道。在输液期间监视患者，如果发生严重反应，请中断输液。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

抑制TNF的药物已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重临床症状和/或影像学证据的中枢神经系统脱髓鞘疾病，包括多发性硬化症和视神经炎，以及外周脱髓鞘疾病，包括Guillain-巴雷综合症。在患有这些神经系统疾病的患者中考虑使用Renflexis时，开药者应谨慎行事，如果这些疾病发展，应考虑停用Renflexis。

与Anakinra一起使用

在临床研究中观察到严重的感染和中性粒细胞减少症，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。由于依那西普与anakinra疗法相结合所产生的不良反应的性质，anakinra与其他TNFα阻断剂的组合也可能产生类似的毒性。因此，不建议使用Renflexis和anakinra的组合。

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Renflexis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用于治疗与Renflexis病情相同的生物疗法的并用的信息不足。 The concomitant use of Renflexis with these biologics is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.3) ] .

Switching between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)

Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

Autoimmunity

Treatment with infliximab products may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Renflexis, treatment should be discontinued [see Adverse Reactions (6.1) ] .

Live Vaccines/Therapeutic Infectious Agents

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with Renflexis is not recommended.

Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab products. Infliximab products are known to cross the placenta and have been detected up to 6 months following birth. At least a six month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab products.

Other uses of therapeutic infectious agents such as live attenuated bacteria (eg, BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Renflexis.

It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating Renflexis therapy. The interval between vaccination and initiation of Renflexis therapy should be in accordance with current vaccination guidelines.

不良反应

临床试验经验

由于临床试验是在广泛不同的条件下进行的，因此无法将在某种药物的临床试验中观察到的不良反应率直接与另一种药物在临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

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 infliximab-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients. Of 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 infliximab infusions, 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 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) and 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, infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.

Delayed Reactions/Reactions Following Re-administration

In psoriasis studies, approximately 1% of infliximab-treated patients 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.

Infections

In infliximab clinical studies, treated infections were reported in 36% of infliximab-treated patients (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 infliximab-treated patients, 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 post-marketing. 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 1year placebo-controlled studies RA I and RA II, 5.3% of patients receiving infliximab every 8 weeks with 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 TB, 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 infliximab infusions 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 infliximab clinical studies in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of infliximab-treated patients (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 infliximab-treated patients 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 infliximab-treated patients 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 infliximab-treated patients 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 infliximab-treated patients, 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% 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 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) and Warnings and Precautions (5.5) ].

Immunogenicity

与所有治疗性蛋白质一样，具有免疫原性的潜力。抗体形成的检测高度依赖于测定的灵敏度和特异性。另外，在测定中观察到的抗体（包括中和抗体）阳性的发生率可能受到几个因素的影响，包括测定方法，样品处理，样品收集的时间，伴随用药和潜在疾病。 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-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 in patients receiving infliximab products [see Warnings and Precautions (5.4) ] . Reactivation of hepatitis B virus 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 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.

其他不良反应

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.

Table 2 Adverse reactions occurring in 5% or more of patients receiving 4 or more infusions for rheumatoid arthritis

	Placebo	英夫利昔单抗
	(n = 350)	(n = 1129)
Average weeks of follow-up	5 药物相互作用（395） 疾病相互作用（9） 已知共有395种药物与Renflexis（infliximab）相互作用。 230种主要药物相互作用 158种中等程度的药物相互作用 7小药物相互作用 在数据库中显示可能与Renflexis（infliximab）相互作用的所有药物。 检查互动 输入药物名称以检查与Renflexis（infliximab）的相互作用。 最常检查的互动 查看Renflexis（infliximab）与下列药物的相互作用报告。 巴氯芬 Benadryl（苯海拉明） mb（度洛西汀） 地塞米松 埃索美拉唑 Flexeril（环苯扎林） 叶酸 加巴喷丁 氢可酮 硫酸铁（硫酸亚铁） 左甲状腺素 奥美拉唑 恩丹西酮 普拉尼（羟氯喹） 强的松 柳氮磺吡啶 曲马多 泰诺（对乙酰氨基酚） 文拉法辛 维生素D3（胆钙化固醇） Renflexis（infliximab）疾病相互作用 与Renflexis（infliximab）有9种疾病相互作用，包括： 心脏衰竭 肝病 感染 恶性肿瘤 神经反应 结核 慢性阻塞性肺病 血液学异常 乙肝 药物相互作用分类 这些分类只是一个准则。特定药物相互作用与特定个体之间的相关性很难确定。在开始或停止任何药物治疗之前，请务必咨询您的医疗保健提供者。 重大的 具有高度临床意义。避免组合；互动的风险大于收益。 中等 具有中等临床意义。通常避免组合；仅在特殊情况下使用。 次要 临床意义最小。降低风险；评估风险并考虑使用替代药物，采取措施规避相互作用风险和/或制定监测计划。 未知 没有可用的互动信息。 药物状态 可用性 仅处方 怀孕和哺乳 现有风险数据 CSA时间表* 不是管制药物 审批历史 FDA的药物史 相关药物 强的松 谢尔詹兹 萘普生 甲氨蝶呤 奥特兹拉 斯泰拉拉 村村 阿拉瓦 氢化可的松 奥伦西亚 美国日本医生 Heather Benjamin MD 经验：11-20年 Heather Benjamin MD 经验：11-20年 Suzanne Reitz MD 经验：11-20年 Heather Miske DO 经验：11-20年 Heather Miske DO 经验：11-20年 渡邊剛 经验：21年以上 村上和成 教授 经验：21年以上 中山秀章 教授 经验：21年以上 村田朗 经验：21年以上 溝上裕士 医院教授 经验：21年以上 临床试验 Balstilimab或Balstilimab联合Zalifrelimab治疗宫颈癌研究 AK104加含铂化疗联合/不联合贝伐珠单抗用于一线治疗持续、复发或转移性宫颈癌 卡瑞利珠单抗联合法米替尼对比含铂化疗治疗宫颈癌的III期临床研究 SG001注射液治疗复发或转移性宫颈癌的II期临床研究 一项关于BCD-100加含铂化疗联合与未联合贝伐珠单抗对比安慰剂加含铂化疗联合与未联合贝伐珠单抗作为晚期宫颈癌受试者的一线治疗的国际、随机、双盲临床试验 AdvanTIG-202:抗PD-1单克隆抗体替雷利珠单抗（BGB-A317）联合或不联合抗TIGIT单克隆抗体 Ociperlimab （BGB-A1217) 治疗用于既往经治的复发或转移性宫颈癌患者的研究 HPV疫苗（Cervarix）上市后数据库有效性研究 HPV疫苗（Cervarix）上市后数据库安全性研究 HLX10/安慰剂联合卡铂/顺铂和紫杉醇一线治疗宫颈癌的III期研究 PD-1/CTLA-4双抗AK104治疗复发或转移性宫颈癌