Cimzia的适应症和用法

克罗恩病

Cimzia用于减轻克罗恩氏病的症状和体征，并维持对常规疗法反应不足的中度至重度活动性疾病成年患者的临床反应。

类风湿关节炎

Cimzia适用于治疗中度至重度活动性类风湿关节炎（RA）的成人。

银屑病关节炎

Cimzia用于治疗患有活动性银屑病关节炎（PsA）的成年患者。

强直性脊柱炎

Cimzia适用于治疗患有活动性强直性脊柱炎（AS）的成人。 [请参阅临床研究（14.4） ]

Cimzia剂量与用法

Cimzia通过皮下注射给药。应当旋转注射部位，并且不应将注射部位注入皮肤嫩，青肿，发红或坚硬的区域。当需要400 mg剂量时（两次皮下注射200 mg），应在大腿或腹部的不同部位进行注射。

给药前应仔细检查溶液中的颗粒物和变色。溶液应为无色至黄色透明液体，基本上无颗粒，如果混浊或存在异物，则不应使用。 Cimzia不包含防腐剂；因此，应将残留在注射器或小瓶中的未使用药物部分丢弃。

克罗恩病

建议的初始成人Cimzia初始剂量为400 mg（两次皮下注射200 mg），并在第2周和第4周开始。对于获得临床反应的患者，推荐的维持方案为每四周400 mg。

类风湿关节炎

成年类风湿关节炎患者的Cimzia推荐剂量最初为400毫克（两次皮下注射200毫克，在第2周和第4周注射），然后每两周200 mg。对于维持剂量，可以考虑每4周服用Cimzia 400 mg [请参阅临床研究（14.2） ] 。

银屑病关节炎

成年银屑病关节炎患者的推荐Cimzia剂量为最初（第2周和第4周）400 mg（两次皮下注射，每次200 mg），然后每两周200 mg。对于维持剂量，可以考虑每4周服用Cimzia 400 mg [请参阅临床研究（14.3） ] 。

强直性脊柱炎

成年强直性脊柱炎患者的Cimzia推荐剂量为最初（第2周和第4周）400 mg（两次皮下注射，每次200 mg），然后每2周200 mg或每4周400 mg。

注射用冻干粉的制备及给药Cimzia

Cimzia冻干粉应由医疗保健专业人员制备和使用。 Cimzia装在包装中，其中包含重构和注射药物所需的一切。下面提供了逐步的准备和管理说明。 Cimzia冻干粉应由医疗保健专业人员制备和使用。 Cimzia是在包装中提供的，其中包含重构和注射药物所需的一切[请参阅供应/储存和处理方式（16） ]。下面提供了逐步的准备和管理说明。

准备和储存

1. 从冰箱中取出Cimzia，然后将小瓶在室温下放置30分钟，然后重新配制。请勿以其他方式加热样品瓶。在准备和使用Cimzia时，请使用适当的无菌技术。将Cimzia从冰箱中取出并让小瓶在室温下静置30分钟，然后重新配制。请勿以其他方式加热样品瓶。准备和服用Cimzia时，请使用适当的无菌技术。
2. 使用提供的20号针头用1 mL无菌注射用水（USP）重建Cimzia的小瓶。注射用无菌水应直接对准小瓶壁，而不是直接放在Cimzia上。使用提供的20号针头用1 mL无菌注射用水USP配制Cimzia的小瓶。注射用无菌水应直接对准小瓶壁，而不要直接对准Cimzia。
3. 轻轻摇动Cimzia每个小瓶约一分钟，不要摇动，以确保所有粉末与无菌注射用水接触。为了避免产生起泡效果，应尽可能轻柔地旋转漩涡，轻轻摇动每个Cimzia小瓶约一分钟而不摇晃，以确保所有粉末都与无菌注射用水接触。旋流应尽可能平缓，以避免产生泡沫效应。
4. 只要观察到未溶解的颗粒，就每5分钟持续旋转一次。完全复原可能需要长达30分钟的时间。最终的复溶溶液含有200 mg / mL，应澄清至乳白色，无色至浅黄色液体，基本无颗粒。只要观察到未溶解的颗粒，则每5分钟持续旋转。完全复原可能需要长达30分钟的时间。最终的配制溶液含有200 mg / mL，应澄清至乳白色，无色至浅黄色液体，基本无颗粒。
5. 重构后，Cimzia可以在注射前在2°至8°C（36°至46°F）之间在小瓶中保存长达24小时。请勿冷冻。一旦重构，Cimzia可以在注射前在2°至8°C（36°至46°F）之间在小瓶中保存长达24小时。不要冻结。

行政

1. 注射前，重构的Cimzia应在室温下使用，但给药前请勿将重构的Cimzia在室温下放置超过两个小时。
2. 使用新的20号针头为每个小瓶将重构溶液倒入每个小瓶的单独注射器中，以便每个注射器包含1 mL Cimzia（200 mg certolizumab聚乙二醇）。
3. 用23针替换注射器上的20针针头以进行管理。用23针替换注射器上的20针针头以进行管理。
4. 通过捏住大腿或腹部的皮肤，皮下注射注射器的全部内容物。如果需要400 mg剂量，则需要两次注射，因此，每次200 mg注射应使用单独的部位。通过捏住大腿或腹部的皮肤，皮下注射注射器的全部内容物。如果需要400 mg剂量，则需要两次注射，因此，每次200 mg注射应使用单独的部位。

使用预装注射器制备和服用辛西娅

接受皮下注射技术的适当培训后，如果医生认为合适，患者可以自行注射Cimzia预填充注射器。

应指导患者使用Cimzia预填充注射器，并按照《使用说明》手册中的说明将全部量的注射器（1 mL）注入注射器。

监控评估安全

在开始使用Cimzia进行治疗之前，必须对所有患者的活动性和非活动性（潜伏性）结核感染进行评估。从结核病高发国家移民或旅行或与活动性结核病患者密切接触的患者应考虑未发现潜伏性结核病的可能性。所有患者均应进行适当的筛查检查（例如结核菌素皮肤检查和胸部X光检查）。

伴随药物

Cimzia可用作单一疗法，或与非生物疾病改良抗风湿药（DMARDs）一起使用。

不建议将Cimzia与生物DMARD或其他肿瘤坏死因子（TNF）阻断剂联合使用。

剂型和优势

注射用：冻干粉

无菌的白色冻干粉剂，可复原后皮下给药。每个一次性小瓶可提供约200毫克的Cimzia。

进样：预填充注射器

一次性使用的1 mL预填充玻璃注射器，带有固定的25号½英寸英寸薄壁针，每1 mL Cimzia提供200 mg。

禁忌症

没有。

警告和注意事项

严重感染的风险

[请参阅带框警告]

用Cimzia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，寄生虫或其他机会性病原体引起的机会性感染，包括曲霉菌病，芽孢杆菌病，念珠菌病，球虫病，组织胞浆菌病，军团病，李斯特菌病，肺囊虫病和结核病。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Cimzia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（例如皮质类固醇或甲氨蝶呤）的患者感染的风险可能更高。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
• 潜在的条件可能使他们容易感染

结核

在接受Cimzia的患者中，包括先前或同时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。报告包括肺结核和肺外（即弥散性）结核病例。在开始Cimzia之前和治疗期间定期评估患者的结核病危险因素并进行潜伏性感染的研究。在接受Cimzia的患者中，包括先前或同时接受过潜伏性或活动性治疗的患者，发现了结核病重新激活或新发结核病的案例结核。报告包括肺结核和肺外（即弥散性）结核病例。在开始Cimzia之前和治疗期间定期评估患者的结核病危险因素并测试潜伏感染。

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。开始Cimzia之前，请评估是否需要治疗潜伏性结核；并考虑结核菌素皮肤试验阳性结果的硬结5 mm或更大，即使对于先前已接种Bacille Calmette-Guerin（BCG）的患者。

对于过去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结核病感染危险因素的患者，考虑在开始Cimzia之前考虑抗结核治疗。尽管先前或同时进行过潜伏性结核治疗，但使用Cimzia治疗的患者仍发生活动性结核病。一些已经成功治疗活动性肺结核的患者在接受Cimzia治疗的同时又重新发展了结核病。建议咨询具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Cimzia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，强烈考虑结核病。在Cimzia治疗期间发生新感染的人，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。

监控方式

在用Cimzia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Cimzia进行治疗时，潜伏性结核感染的检测结果也可能是假阴性的。

如果患者出现严重感染或败血症，应停止服用Cimzia。在用Cimzia治疗期间发生新感染的患者应受到密切监测，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

对于在霉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，则应怀疑为侵袭性真菌感染。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的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

在某些TNF阻滞剂的临床研究的对照部分中，与对照患者相比，在接受TNF阻滞剂的患者中观察到了更多的恶性肿瘤病例。在Cimzia的克罗恩氏病和其他疾病的对照和开放标签研究中，观察到的恶性肿瘤（不包括非黑素瘤皮肤癌）每100病人年中的恶性肿瘤（95％置信区间）为0.5（0.4，0.7）在1,319名接受安慰剂治疗的患者中，接受Cimzia治疗的患者为4,650名，而每100名患者-年的比率为0.6（0.1，1.7）。对照组的大小和受控部分的持续时间有限，因此无法得出肯定的结论。在某些TNF受体阻滞剂的临床研究的受控部分中，与相比，接受TNF阻滞剂的患者观察到更多的恶性肿瘤病例。控制病人。在Cimzia的克罗恩氏病和其他疾病的对照和开放标签研究中，观察到的恶性肿瘤（不包括非黑素瘤皮肤癌）每100病人年中的恶性肿瘤（95％置信区间）为0.5（0.4，0.7）在1,319名接受安慰剂治疗的患者中，接受Cimzia治疗的患者为4,650名，而每100名患者-年的比率为0.6（0.1，1.7）。对照组的大小和受控部分的持续时间有限，因此无法得出明确的结论。

据报导，接受Cimzia治疗的TNF阻断剂（治疗开始≤18岁）的儿童，青少年和年轻人恶性肿瘤是致命的。大约一半的病例是淋巴瘤，包括霍奇金淋巴瘤和非霍奇金淋巴瘤。其他病例代表各种不同的恶性肿瘤，包括通常与免疫抑制相关的罕见恶性肿瘤和儿童和青少年通常不观察到的恶性肿瘤。中位治疗30个月（范围1到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。这些案件是在上市后报告的，并来自各种来源，包括注册管理机构和自发的上市后报告。尚无Cimzia用于儿童患者的研究。据报道，接受TNF阻断剂治疗（开始治疗≤18岁）的儿童，青少年和年轻人中的恶性肿瘤是致命的。会员。大约一半的病例是淋巴瘤，包括霍奇金淋巴瘤和非霍奇金淋巴瘤。其他病例代表各种不同的恶性肿瘤，包括通常与免疫抑制相关的罕见恶性肿瘤和儿童和青少年通常不观察到的恶性肿瘤。中位治疗30个月（范围1到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，并且来自各种来源，包括注册管理机构和自发的上市后报告。 Cimzia未指定用于儿科患者。

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。在针对Cimzia的克罗恩病和其他研究用途的对照研究中，在2657名接受Cimzia治疗的患者中有1例淋巴瘤，在1319例安慰剂治疗的患者中有1例霍奇金淋巴瘤。在所有TNF阻滞剂临床试验的对照部分中与对照组相比，在接受TNF阻滞剂治疗的患者中观察到更多的淋巴瘤病例。在针对Cimzia的克罗恩病和其他研究用途的对照研究中，在2657名接受Cimzia治疗的患者中有1例淋巴瘤，在1319例安慰剂治疗的患者中有1例霍奇金淋巴瘤。

在Cimzia RA临床试验（安慰剂对照和开放标签）中，在2367名患者中共观察到3例淋巴瘤。这比一般人群的预期值高约2倍。患有RA的患者，特别是患有高度活跃疾病的患者，罹患淋巴瘤的风险更高。在Cimzia RA临床试验中（安慰剂对照和开放标签），在2367名患者中共观察到三例淋巴瘤。这比一般人群的预期值高约2倍。 RA患者，特别是患有高活性疾病的患者，罹患淋巴瘤的风险更高。

Cimzia的临床研究比率无法与其他TNF阻滞剂的临床试验比率进行比较，并且可能无法预测将Cimzia用于更广泛的患者群体时观察到的比率。需要长期暴露于免疫抑制剂治疗的克罗恩病患者，即使没有TNF阻断剂治疗，其发生淋巴瘤的风险也可能比一般人群更高。 TNF阻断剂治疗在成人恶性肿瘤发展中的潜在作用尚不清楚。 Cimzia的临床研究比率无法与其他TNF阻滞剂的临床试验比率进行比较，并且可能无法预测将Cimzia用于更广泛的患者群体时观察到的比率。需要长期暴露于免疫抑制剂治疗的克罗恩病患者，即使没有TNF阻断剂治疗，其发生淋巴瘤的风险也可能比一般人群更高[见不良反应（6.1） ] 。 TNF阻断剂治疗在成人恶性肿瘤发展中的潜在作用尚不清楚。

据报道，使用Cimzia进行TNF受体阻滞剂治疗的患者，有肝脾T细胞淋巴瘤（HSTCL）上市后病例，这是一种罕见的T细胞淋巴瘤，具有很强的病程，通常是致命的。大部分报道的TNF阻滞剂病例发生在患有克罗恩氏病或溃疡性结肠炎的青春期和成年男性中。在诊断之前或诊断之前，几乎所有这些患者均接受了免疫抑制剂硫唑嘌呤和/或6-巯基嘌呤（6-MP）以及TNF阻断剂的治疗。尚不确定HSTCL的发生是否与TNF阻滞剂或TNF阻滞剂与这些其他免疫抑制剂联合使用有关。应慎重考虑将TNF阻滞剂与硫唑嘌呤或6-MP组合使用的潜在风险。肝脾T细胞淋巴瘤（HSTCL）的上市后案例是一种罕见的T细胞淋巴瘤，具有很强的病程，是在包括Cimzia在内的TNF受体阻滞剂治疗的患者中，通常会致命。大部分报道的TNF阻滞剂病例发生在患有克罗恩氏病或溃疡性结肠炎的青春期和成年男性中。在诊断之前或诊断之前，几乎所有这些患者均接受了免疫抑制剂硫唑嘌呤和/或6-巯基嘌呤（6-MP）以及TNF阻滞剂的治疗。尚不确定HSTCL的发生是否与TNF阻滞剂或TNF阻滞剂与这些其他免疫抑制剂联合使用有关。应仔细考虑将TNF阻滞剂与硫唑嘌呤或6-MP组合使用的潜在风险。

据报道，在RA和其他适应症中，上市后使用TNF-受体阻滞剂可导致急性和慢性白血病。即使没有TNF受体阻滞剂治疗，RA患白血病的风险也可能比一般人群高（约2倍）。据报道，上市后有急性和慢性白血病案例TNF阻滞剂用于RA和其他适应症。即使没有TNF受体阻滞剂治疗，RA患白血病的风险也可能比一般人群高（约2倍）。

在包括Cimzia在内的TNF拮抗剂治疗的患者中，已有黑色素瘤和默克尔细胞癌的报道。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。

心脏衰竭

包括Cimzia在内的TNF阻滞剂已报道了充血性心力衰竭（CHF）和新发性CHF恶化的病例。 Cimzia尚未在CHF患者中进行正式研究。然而，在对患有另一种TNF阻滞剂的CHF患者的临床研究中，发现充血性心力衰竭（CHF）恶化且CHF导致死亡率增加。心力衰竭患者要格外小心，并仔细监测[见不良反应（6.1） ]。

过敏反应

服用Cimzia后很少报告以下可能与超敏反应相适应的症状：血管性水肿，呼吸困难，低血压，皮疹，血清病和荨麻疹。其中一些反应是在首次服用Cimzia之后发生的。如果发生此类反应，请停止进一步给予Cimzia并采取适当的治疗方法。目前尚无关于对另一种TNF阻断剂发生严重超敏反应的患者使用Cimzia的风险的数据。在这些患者中，需要谨慎[见不良反应（6.1） ] 。

乙肝病毒激活

TNF阻滞剂（包括Cimzia）的使用与慢性乙型肝炎病毒携带者的乙肝病毒（HBV）活化有关。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。大多数报告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。

开始用Cimzia治疗之前，先测试患者的HBV感染情况。对于测试为HBV感染呈阳性的患者，建议咨询专业的乙肝治疗医生。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。 HBV携带者且需要Cimzia治疗的患者应在整个治疗过程中以及治疗终止后的几个月内密切监测活动性HBV感染的临床和实验室迹象。

在发生HBV激活的患者中，应停止Cimzia并开始进行有效的抗病毒治疗以及适当的支持治疗。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，在这种情况下考虑恢复Cimzia治疗时应谨慎行事，并密切监视患者。

神经反应

使用Cimzia成员的TNF阻滞剂与罕见的新发病例或临床症状的新发作或加重和/或中枢神经系统脱髓鞘疾病（包括多发性硬化症）和放射影像学证据，以及周围性脱髓鞘疾病（包括Guillain）有关-巴雷综合症。在已有或近期发作的中枢或周围神经系统脱髓鞘疾病的患者中考虑使用Cimzia时应谨慎行事。据报道，接受Cimzia治疗的患者很少见神经系统疾病，包括癫痫发作，视神经炎和周围神经病变[见不良反应（6.1） ] 。

血液学反应

TNF阻滞剂报道了罕见的全血细胞减少症，包括再生障碍性贫血。 Cimzia很少报道血液系统的不良反应，包括医学上重要的血细胞减少症（如白细胞减少症，全血细胞减少症，血小板减少症） [见不良反应（6.1） ] 。这些事件与Cimzia的因果关系仍不清楚。

尽管尚未确定高危人群，但在接受Cimzia治疗的患有持续性血液病或有明显血液学异常史的患者中要谨慎行事。劝告所有患者在服用Cimzia时出现迹象表明血液异常或感染（例如持续发烧，瘀伤，出血，苍白），应立即就医。对于已确认患有严重血液学异常的患者，请考虑停止Cimzia治疗。

与修饰生物疾病的抗风湿药（Biological DMARDs）一起使用

在临床研究中发现严重感染是同时使用anakinra（一种白介素1拮抗剂）和另一种TNF阻断剂etanercept，与单独使用etanercept相比，没有其他好处。 TNF阻滞剂与阿巴西普和利妥昔单抗联合使用时，还发现了发生严重感染的较高风险。由于这种联合疗法所见的不良事件的性质，在这种联合疗法中使用辛西娅也可能产生类似的毒性。因此，不建议将Cimzia与其他生物DMARD组合使用[见药物相互作用（7.1） ]。

自身免疫

用Cimzia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Cimzia治疗后出现暗示狼疮样综合征的症状，请停止治疗[见不良反应（6.1） ] 。

免疫接种

除活疫苗或减毒活疫苗外，接受奇姆齐亚治疗的患者都可以接种疫苗。尚无关于接受Cimzia的患者对活疫苗反应或活疫苗继发感染的反应的数据。

在风湿性关节炎患者的安慰剂对照临床试验中，当肺炎球菌多糖疫苗和流感疫苗与Cimzia并用时，Cimzia与安慰剂治疗组之间对疫苗的抗体反应未发现差异。 Cimzia和安慰剂治疗组之间有相似比例的患者产生了抗疫苗抗体的保护水平；然而，与仅接受Cimzia的患者相比，接受Cimzia和伴随的甲氨蝶呤的患者的体液反应较低。其临床意义尚不清楚。

免疫抑制

由于TNF介导炎症并调节细胞免疫反应，因此包括Cimzia在内的TNF阻断剂可能会影响宿主抵抗感染和恶性肿瘤的防御能力。治疗与的Cimzia的开发，当然恶性肿瘤的影响，以及主动和/或慢性感染，尚不完全清楚[见警告和注意事项（5.1 ， 5.2 ， 5.5）和不良反应（6.1） ]。尚未正式评估Cimzia在免疫抑制患者中的安全性和有效性。

不良反应

临床试验经验

最严重的不良反应是：

• 严重感染[请参阅警告和注意事项（5.1） ]
• 恶性肿瘤[请参阅警告和注意事项（5.2） ]
• 心力衰竭[请参阅警告和注意事项（5.3） ]

由于临床研究是在广泛变化和可控制的条件下进行的，因此不能将在某种药物的临床研究中观察到的不良反应率直接与另一种药物的临床研究中观察到的不良反应率相比较，并且可能无法预测在更广泛的临床人群中观察到的不良反应率实践。

在所有患者人群的上市前对照试验中，最常见的不良反应（≥8％）是上呼吸道感染（18％），皮疹（9％）和尿路感染（8％）。

不良反应最常见的是导致在上市前对照试验中终止治疗

在对照的临床研究中，因不良反应而终止治疗的克罗恩病患者比例为Cimzia为8％，安慰剂为7％。导致Cimzia终止的最常见不良反应（至少2例患者，发生率高于安慰剂）是腹痛（Cimzia为0.4％，安慰剂为0.2％），腹泻（Cimzia为0.4％，安慰剂为0％）和肠梗阻（0.4％Cimzia，0％安慰剂）。

在对照的临床研究中，由于不良反应而停止治疗的类风湿关节炎患者的比例为Cimzia为5％，安慰剂为2.5％。导致Cimzia中断的最常见不良反应是结核感染（0.5％）；和发热，荨麻疹，肺炎和皮疹（0.3％）。

克罗恩病对照研究

下文所述数据反映了在克罗恩氏病患者的研究中，皮下给药400 mg后对Cimzia的暴露。在对照研究的安全人群中，总共620名克罗恩病患者接受400 mg剂量的Cimzia，614名受试者接受安慰剂（包括在第0、2周接受Cimzia开放标签给药后随机分配至研究CD2中的安慰剂的受试者） ，4）。在对照和非对照研究中，有1,564名患者接受了一定剂量的Cimzia，其中1,350名患者接受了400 mg Cimzia。大约55％的受试者是女性，45％是男性，94％是白种人。活动组中的大多数患者年龄在18至64岁之间。

During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for Cimzia and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of Cimzia-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with Cimzia were upper respiratory infections (eg nasopharyngitis, laryngitis, viral infection) in 20% of Cimzia-treated patients and 13% of placebo-treated patients, urinary tract infections (eg bladder infection, bacteriuria, cystitis) in 7% of Cimzia-treated patients and in 6% of placebo-treated patients, and arthralgia (6% Cimzia, 4% placebo).

Other Adverse Reactions

The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving Cimzia at doses of 400 mg or other doses include:

Blood and lymphatic system disorders: Anemia, leukopenia, lymphadenopathy, pancytopenia, and thrombophilia.

Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac failure, hypertensive heart disease, myocardial infarction, myocardial ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack.

Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis.

General disorders and administration site conditions: Bleeding and injection site reactions.

Hepatobiliary disorders : Elevated liver enzymes and hepatitis.

Immune system disorders : Alopecia totalis.

Psychiatric disorders: Anxiety, bipolar disorder, and suicide attempt.

Renal and urinary disorders: Nephrotic syndrome and renal failure.

Reproductive system and breast disorders: Menstrual disorder.

Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and urticaria.

Vascular disorders: Thrombophlebitis, vasculitis.

Controlled Studies with Rheumatoid Arthritis

Cimzia was studied primarily in placebo-controlled trials and in long-term follow-up studies. The data described below reflect the exposure to Cimzia in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least one year and 282 for at least 2 years; and 1,774 in adequate and well-controlled studies. In placebo-controlled studies, the population had a median age of 53 years at entry; approximately 80% were females, 93% were Caucasian and all patients were suffering from active rheumatoid arthritis, with a median disease duration of 6.2 years. Most patients received the recommended dose of Cimzia or higher.

Table 1 summarizes the reactions reported at a rate of at least 3% in patients treated with Cimzia 200 mg every other week compared to placebo (saline formulation), given concomitantly with methotrexate.

Hypertensive adverse reactions were observed more frequently in patients receiving Cimzia than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs.

Patients receiving Cimzia 400 mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical trials had similar adverse reactions to those patients receiving Cimzia 200 mg every other week.

Other Adverse Reactions

Other infrequent adverse reactions (occurring in less than 3% of RA patients) were similar to those seen in Crohn's disease patients.

Psoriatic Arthritis Clinical Study

Cimzia has been studied in 409 patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The safety profile for patients with PsA treated with Cimzia was similar to the safety profile seen in patients with RA and previous experience with Cimzia .

Ankylosing Spondylitis Clinical Study

Cimzia has been studied in 325 patients with axial spondyloarthritis of whom the majority had ankylosing spondylitis (AS) in a placebo-controlled study (AS-1). The safety profile for patients in study AS-1 treated with Cimzia was similar to the safety profile seen in patients with RA.

传染病

The incidence of infections in controlled studies in Crohn's disease was 38% for Cimzia-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infections (20% for Cimzia, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for Cimzia-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis.

The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0.91 per patient-year for all Cimzia-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the Cimzia treatment groups, compared to the placebo groups (0.06 per patient-year for all Cimzia doses vs. 0.02 per patient-year for placebo). Rates of serious infections in the 200 mg every other week dose group were 0.06 per patient-year and in the 400 mg every 4 weeks dose group were 0.04 per patient-year. Serious infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, no serious infection occurred in more than one subject. There is no evidence of increased risk of infections with continued exposure over time [see Warnings and Precautions (5.1) ] .

Tuberculosis and Opportunistic Infections

In completed and ongoing global clinical studies in all indications including 5,118 Cimzia-treated patients, the overall rate of tuberculosis is approximately 0.61 per 100 patient-years across all indications.

The majority of cases occurred in countries with high endemic rates of TB. Reports include cases of miliary, lymphatic, peritoneal, as well as pulmonary TB. The median time to onset of TB for all patients exposed to Cimzia across all indications was 345 days. In the studies with Cimzia in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials [see Warnings and Precautions (5.1) ].

恶性肿瘤

In clinical studies of Cimzia, the overall incidence rate of malignancies was similar for Cimzia-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients [see Warnings and Precautions (5.2) ].

心脏衰竭

In placebo-controlled and open-label rheumatoid arthritis studies, cases of new or worsening heart failure have been reported for Cimzia-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure [see Warnings and Precautions (5.3) ].

Autoantibodies

In clinical studies in Crohn's disease, 4% of patients treated with Cimzia and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with Cimzia developed symptoms of a lupus-like syndrome.

In clinical trials of TNF blockers, including Cimzia, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with Cimzia in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown [see Warnings and Precautions (5.9) ].

Immunogenicity

Patients with Crohn's disease were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. In patients continuously exposed to Cimzia,the overall percentage of patients who were antibody positive to Cimzia on at least one occasion was 8%; approximately 6% were neutralizing in vitro . No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn's disease patients who were antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.

In two long-term (up to 7 years of exposure), open-label Crohn's disease studies, overall 23% (207/903) of patients developed antibodies against certolizumab pegol on at least one occasion. Of the 207 patients who were antibody positive, 152 (73%) had a persistent reduction of drug plasma concentration, which represents 17% (152/903) of the study population. The data from these two studies do not suggest an association between the development of antibodies and adverse events.

The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro . Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall than patients treated with Cimzia monotherapy in RA-IV (2% vs. 8%). Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use of MTX were associated with reduced immunogenicity.

Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended Cimzia dosage of 200 mg every other week with concomitant MTX, the ACR20 response was lower among antibody positive patients than among antibody-negative patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, respectively). In Study RA-III, too few patients developed antibodies to allow for meaningful analysis of ACR20 response by antibody status. In Study RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive versus antibody-negative status, respectively [see Clinical Pharmacology (12.3) ]. No association was seen between antibody development and the development of adverse events.

The data reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol with the incidence of antibodies to other products may be misleading.

过敏反应

The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following Cimzia administration to patients: angioedema, dermatitis allergic, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see Warnings and Precautions (5.4) ] .

上市后经验

The following adverse reactions have been identified during post-approval use of Cimzia.由于这些反应是从不确定大小的人群中自愿报告的，因此并非总是能够可靠地估计其发生频率或建立与药物暴露的因果关系。

Vascular disorder : systemic vasculitis has been identified during post-approval use of TNF blockers.

Skin : case of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and new or worsening psoriasis (all sub-types including pustular and palmoplantar) have been identified during post-approval use of TNF blockers.

Immune System Disorders : sarcoidosis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Melanoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin) [see Warnings and Precautions (5.2) ].

药物相互作用

Use with Anakinra, Abatacept, Rituximab, and Natalizumab

An increased risk of serious infections has been seen in clinical studies of other TNF-blocking agents used in combination with anakinra or abatacept, with no added benefit. Formal drug interaction studies have not been performed with rituximab or natalizumab. Because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of Cimzia in these combinations. There is not enough information to assess the safety and efficacy of such combination therapy. Therefore, the use of Cimzia in combination with anakinra, abatacept, rituximab, or natalizumab is not recommended [see Warnings and Precautions (5.8) ] .

Live Vaccines

Avoid use of live (including attenuated) vaccines concurrently with Cimzia [see Warnings and Precautions (5.10) ] .

实验室测试

Interference with certain coagulation assays has been detected in patients treated with Cimzia. Certolizumab pegol may cause erroneously elevated activated partial thromboplastin time (aPTT) assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. Interference with thrombin time (TT) and prothrombin time (PT) assays has not been observed. There is no evidence that Cimzia therapy has an effect on in vivo coagulation.

在特定人群中的使用

怀孕

怀孕暴露登记

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Cimzia during pregnancy. For more information, healthcare providers or patients can contact:

MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). The OTIS AutoImmune Diseases Study at 1-877-311-8972 or visit http://mothertobaby.org/pregnancy-studies/

风险摘要

Limited data from the ongoing pregnancy registry on use of Cimzia in pregnant women are not sufficient to inform a risk of major birth defects or other adverse pregnancy outcomes. Certolizumab pegol plasma concentrations obtained from 10 women treated with Cimzia during pregnancy and their newborn infants demonstrated low placental transfer of certolizumab pegol. Cimzia may be eliminated at a slower rate in exposed infants than in adult patients [see Data ] . There are risks to the mother and fetus associated with active rheumatoid arthritis or Crohn's disease. The theoretical risks of administration of live or live-attenuated vaccines to the infants exposed in utero to Cimzia should be weighed against the benefits of vaccinations [see Clinical Considerations ] . No adverse developmental effects were observed in animal reproduction studies during which pregnant rats were administered intravenously a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol during organogenesis at up to 2.4 times the recommended human dose of 400 mg per month.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown.所有怀孕都有出生缺陷，流产或其他不良后果的背景风险。 In the US general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

临床注意事项

与疾病相关的孕产妇和/或胚胎/胎儿风险

Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis or Crohn's disease is correlated with maternal disease activity and that active disease increases the risk of adverse pregnancy outcomes, including fetal loss, preterm delivery (before 37 weeks of gestation), low birth weight (<2500 g) and small for gestational age birth.

胎儿/新生儿不良反应

Due to its inhibition of TNFα, Cimzia administered during pregnancy could affect immune responses in the in utero -exposed newborn and infant. Although certolizumab pegol levels were low in 12 infants exposed to Cimzia in utero , the clinical significance of these low levels is unknown. Additional data available from one exposed infant suggests that Cimzia may be eliminated at a slower rate in infants than in adults [see Data ]. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

数据

人数据

A limited number of pregnancies have been reported in the ongoing pregnancy exposure registry. Due to the small number of Cimzia-exposed pregnancies with known outcomes (n=23), no meaningful comparisons between the exposed group and control groups may be conducted to determine an association with Cimzia and major birth defects or adverse pregnancy outcomes.

In an independent clinical study conducted in 10 pregnant women with Crohn´s disease treated with Cimzia, certolizumab pegol concentrations were measured in maternal blood as well as in cord and infant blood (n=12) at the day of birth. The last dose of Cimzia (400 mg for every mother) was given on average 19 days prior to delivery (range 5-42 days). Plasma certolizumab pegol concentrations were <0.41 –1.66 μg/mL in cord blood, <0.41 – 1.58 μg/mL in infant blood, and 1.87–59.57 μg/mL in maternal blood. Plasma certolizumab pegol concentrations were lower (by at least 75%) in the infants than in mothers suggesting low placental transfer of certolizumab pegol. In one infant, the plasma certolizumab pegol concentration declined from 1.02 to 0.84 μg /mL over 4 weeks suggesting that Cimzia may be eliminated at a slower rate in infants than adults.

动物资料

Because certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol. Animal reproduction studies have been performed in rats during organogenesis at intravenous doses up to 100 mg/kg (about 2.4 times the recommended human dose of 400 mg, based on the surface area) and have revealed no evidence of harm to the fetus due to cTN3 PF.

哺乳期

风险摘要

No data are available regarding the presence of certolizumab pegol in human milk, the effects on the breast fed infant, or the effects on milk production. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because certolizumab pegol is a large molecule and is degraded in the gastrointestinal tract. However, if certolizumab pegol is transferred into human milk, effects of local exposure in the gastrointestinal tract are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Cimzia and any potential adverse effects on the breastfed child from Cimzia or from the underlying maternal condition.

儿科用

儿科患者的安全性和有效性尚未确定。 Due to its inhibition of TNFα, Cimzia administered during pregnancy could affect immune responses in the in utero -exposed newborn and infant [see Use in Specific Populations (8.1) ].

老人用

Clinical studies of Cimzia did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.其他报告的临床经验尚未发现老年患者和年轻患者在反应方面的差异。 Population pharmacokinetic analyses of patients enrolled in Cimzia clinical studies concluded that there was no apparent difference in drug concentration regardless of age. Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly with Cimzia [see Warnings and Precautions (5.1) ] .

过量

The maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without evidence of dose-limiting toxicities. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.

Cimzia Description

Cimzia (certolizumab pegol) is a TNF blocker. Cimzia is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' frag