Orthoclone OKT 3（静脉注射）

仅限静脉使用

Orthoclone OKT3说明

Orthoclone OKT3（muromonab-CD3）无菌溶液是鼠类抗人T细胞CD3抗原的单克隆抗体，具有免疫抑制作用。仅用于静脉内使用。该抗体是生物化学纯化的IgG 2a免疫球蛋白，重链约为50,000道尔顿，轻链约为25,000道尔顿。它涉及在人T细胞表面中分子量为20,000的糖蛋白，这对于T细胞功能至关重要。因为它是一种单克隆抗体制剂，所以Orthoclone OKT3无菌溶液是一种均质的，可重现的抗体产品，对人T细胞具有一致的，可测量的反应性。

Orthoclone OKT3无菌溶液每5毫升安瓿含5 mg（1 mg / mL）的muromonab-CD3透明无色溶液，其中可能含有一些细小的半透明蛋白质颗粒。每个安瓿瓶中含有注射用磷酸氢二钠（2.25 mg），磷酸氢二钠（9.0 mg），氯化钠（43 mg）和聚山梨酯80（1.0 mg）的缓冲溶液（pH 7.0±0.5）。

专有名称muromonab-CD3源自描述性术语鼠单克隆抗体。 CD3名称将抗体的特异性识别为“第一届国际人类白细胞分化抗原国际研讨会”所定义的细胞分化（CD）簇3。

Orthoclone OKT3-临床药理学

Orthoclone OKT3可能通过阻断在急性同种异体排斥中起主要作用的T细胞的功能来逆转移植排斥。 OTHOCLONE OKT3与人T细胞膜中的20,000道尔顿分子（CD3）反应并阻止其功能，该膜已在体外与T细胞的抗原识别结构相关联，并且对于信号转导至关重要。在体外溶细胞试验中，Orthoclone OKT3阻断效应细胞的产生和功能。邻位克隆OKT3与T淋巴细胞的结合导致T细胞的早期活化，从而导致细胞因子释放，进而阻断T细胞功能。 Orthoclone OKT3治疗终止后，T细胞功能通常在一周内恢复正常。

在体内，邻位克隆OKT3与大多数外周血T细胞和人体组织中的T细胞发生反应，但尚未发现与其他造血成分或人体其他组织发生反应。

在服用Orthoclone OKT3后几分钟之内，已观察到的患者中，循环中的CD3阳性细胞（包括CD2，CD4或CD8阳性细胞）数量迅速减少。 CD3阳性T细胞数量的减少是由于Orthoclone OKT3与所有T淋巴细胞表面的CD3抗原之间的特异性相互作用所致。 T细胞活化导致大量细胞因子/淋巴因子的释放，这被认为是施用Orthoclone OKT3后所见的许多急性临床表现的原因。 （请参阅：警告：细胞因子释放综合征，中枢神经系统事件。）

尽管在第二天到第七天之间无法检测到CD3阳性细胞，但已观察到循环中的CD2，CD4和CD8阳性细胞数量增加。这些CD2，CD4和CD8阳性细胞的存在尚未显示会影响排斥反应的逆转。 Orthoclone OKT3治疗终止后，CD3阳性细胞迅速重新出现，并在一周内达到治疗前水平。但是，在某些患者中，在终止Orthoclone OKT3治疗之前已观察到CD3阳性细胞数量增加。 CD3阳性细胞的这种重新出现归因于针对Orthoclone OKT3的中和抗体的发展，这反过来又阻碍了其与T淋巴细胞上CD3抗原结合的能力。 （请参阅：注意事项：敏化。）

已知小儿患者的CD3淋巴细胞计数高于成人。接收ORTHOCLONE OKT®3治疗儿科患者通常需要逐渐更高的剂量ORTHOCLONE OKT3的实现CD3阳性细胞的耗竭（<25个/ mm 3），并确保治疗ORTHOCLONE OKT3血清浓度（> 800毫微克/毫升）。 （请参阅：剂量和管理；预防措施：实验室测试。）

使用酶联免疫吸附测定（ELISA）可测量Orthoclone OKT3的血清水平。在肾同种异体移植排斥反应的初始临床试验中，每天接受5 mg药物治疗14天的患者，其平均血清谷水平在前三天上升，然后在第3至14天平均为900 ng / mL。肾，肝和心脏同种异体移植接受者在接受Orthoclone OKT3治疗期间每天进行的测量显示，小于10岁的儿科患者的血脂水平高于10至50岁的儿科患者。随后的临床经验表明，血清水平大于或等于800 ORTHOCLONE OKT3的毫微克/毫升块体外和体内的细胞毒性T细胞的功能。 T细胞清除率降低或血浆Orthoclone OKT3水平降低为调整Orthoclone OKT3剂量或终止治疗提供了依据。 （请参阅：警告：过敏反应；预防措施：实验室测试；不良事件：超敏反应；剂量和管理。）

在体内施用Orthoclone OKT3后，在脑脊液和腹膜液中观察到白细胞。这种作用的机理尚不完全清楚，但可能与改变膜通透性的细胞因子有关，而不是与活跃的炎症过程有关。 （请参阅：警告：细胞因子释放综合征，中枢神经系统事件。）

临床研究

急性肾排斥

在一项随机对照临床试验中，比较了Orthoclone OKT3与常规大剂量类固醇疗法在逆转急性肾移植排斥反应中的作用。在该试验中，对122例接受尸体肾移植急性排斥反应的可评估患者进行Orthoclone OKT3每天平均治疗14天，同时降低硫唑嘌呤和维持类固醇的剂量（62例），或常规大剂量治疗类固醇（60例）。与传统的大剂量类固醇治疗获得的75％的逆转率相比，Orthoclone OKT3逆转了94％的排斥反应（p = 0.006）。 Kaplan-Meier（精算）对这些急性排斥反应患者的移植存活率的一年估计值分别为Orthoclone OKT3和类固醇治疗患者（62％）和45％（p = 0.04）。两年时，该比率分别为56％和42％（p = 0.06）。

两组的一年和两年患者存活率无显着差异，用Orthoclone OKT3治疗的患者分别为85％和75％，而使用类固醇治疗的患者分别为90％和85％。

在其他开放临床试验中，邻位克隆OKT3疗法观察到的急性肾移植排斥反应的逆转率为92％（n = 126）。在禁忌使用或未成功使用类固醇和淋巴细胞免疫球蛋白的病例中，65％（n = 225）的情况下，Orthoclone OKT3还可有效逆转急性肾移植排斥反应。

尚未确定Orthoclone OKT3预防肾移植的排斥反应的有效性。

急性心脏或肝移植排斥反应

研究了Orthoclone OKT3用于逆转对高剂量类固醇无反应的患者的急性心脏和肝脏同种异体移植排斥反应。在对类固醇治疗无反应的患者中，急性心脏异体移植排斥的逆转率为90％（n = 61），肝异体移植排斥的逆转率为83％（n = 124）。

与常规治疗相比，Orthoclone OKT3作为急性心脏和肝脏异体移植排斥的一线治疗，尚未进行对照随机试验来评估其有效性。

Orthoclone OKT3的适应症和用法

Orthoclone OKT3适用于肾移植患者的急性同种异体移植排斥反应。

Orthoclone OKT3被指定用于治疗心脏和肝移植患者的类固醇抵抗性急性同种异体移植排斥反应。

与Orthoclone OKT3联合使用的其他免疫抑制剂的剂量应降低至与有效治疗反应兼容的最低水平。 （请参阅：警告和不良事件：感染，瘤形成，剂量和管理。）

禁忌症

不应将Orthoclone OKT3给予以下患者：

• 对这种或任何其他鼠源产品过敏;
• 抗小鼠抗体滴度≥1：1000；
• 在计划的Orthoclone OKT3给药前一周内，胸部X线检查或体重增加大于3％证明患有心律失常或体液超负荷；
• 有无法控制的高血压；
• 有癫痫病史或易患癫痫病;
• 被确定或怀疑怀孕，或正在哺乳。 （请参阅：预防措施：怀孕，哺乳的母亲。）

警告事项

见盒装警告

细胞因子释放综合征

大部分患者发生急性临床综合征[即，细胞因子释放综合征（CRS）]已通过活化的淋巴细胞或单核细胞归因于细胞因子的释放，并在时间上与所述第一几剂ORTHOCLONE OKT®3的施用相关联（特别是，前两到三剂）。该临床综合征的范围从更频繁报告的轻度，自限性“流感样”疾病到不太频繁报告的严重的，危及生命的休克样反应，其中可能包括严重的心血管和中枢神经系统表现。该综合征通常在施用一定剂量的Orthoclone OKT3后约30至60分钟开始（但可能会在以后发生），并且可能持续数小时。这种症状复合物的频率和严重性通常在第一剂中最大。每次连续施用Orthoclone OKT3，细胞因子释放综合征的发生频率和严重程度均趋于降低。中断后增加Orthoclone OKT3的量或恢复治疗可能会导致CRS的重新出现。

CRS的常见临床表现可能包括：高烧（经常加标，最高至107°F），发冷/严厉，头痛，震颤，恶心/呕吐，腹泻，腹痛，全身不适，肌肉/关节疼痛和疼痛以及全身无力。较少报道的不良经历包括：轻微的皮肤病学反应（例如皮疹，瘙痒等）以及一系列经常是严重的，偶发性的致命性，心肺和中枢神经系统不良经历。

心脏呼吸检查结果可能包括：呼吸困难，呼吸急促，支气管痉挛/喘息，呼吸急促，呼吸骤停/衰竭/窘迫，心血管衰竭，心脏骤停，心绞痛/心肌梗塞，胸痛/紧张，心动过速（包括心室），高血压，血流动力学不稳定，低血压，包括严重休克，心力衰竭，肺水肿（心源性和非心源性），成人呼吸窘迫综合征，低氧血症，呼吸暂停和心律不齐。 （请参阅：盒装警告；注意事项；不良事件。）

在最初的肾移植排斥反应研究中，最初的107例患者中有5％发生了可能致命的严重肺水肿。在所有这些情况下，治疗前均存在体液超负荷。随后的311例接受首剂量/重量限制的患者均无此病。在随后的试验中和在上市后的经验中，似乎是运动性血液病的患者发生了严重的肺水肿。肺水肿的发病机制可能涉及以下全部或部分：容量超负荷；肺血管通透性增加；和/或左心室顺应性/收缩力降低。在Orthoclone OKT3治疗的前1-3天，一些患者经历了肾小球滤过率（GFR）的急性和短暂下降，尿液排出量减少，从而导致血清肌酐水平升高。细胞因子的大量释放似乎导致可逆的肾功能损害和/或肾同种异体移植功能延迟。类似地，已经报道了在施用最初几剂Orthoclone OKT3后肝转氨酶的短暂升高。

有严重CRS并发症风险的患者可能包括以下情况：不稳定型心绞痛；最近的心肌梗塞或症状性缺血性心脏病；任何病因的心力衰竭；任何病因的肺水肿；任何形式的慢性阻塞性肺疾病；血管内容量超负荷或任何病因耗竭（例如，过度透析，近期密集利尿，失血等）；脑血管疾病;有晚期症状性血管疾病或神经病的患者；癫痫病史；和败血性休克。在开始治疗之前，应努力纠正或稳定背景条件。 （请参阅：注意事项。）

在施用Orthoclone OKT3之前，应评估患者的体液（液体）状态和胸部X光片，以排除体液超负荷，高血压不受控制或心律失常。在注射前的一周内，患者的体重不应超过其最低体重的3％以上。

细胞因子释放综合征与血清中增加的细胞因子（例如TNF-α，IL-2，IL-6，IFN-γ）水平升高有关，在施用Orthoclone OKT3后1至4小时内达到峰值。可以在第一次服用Orthoclone OKT3之前1-4小时给予8 mg / kg甲基强的松龙（即高剂量类固醇）预处理，以降低血清中的细胞因子水平和CRS表现。遵循有关剂量和治疗持续时间的建议。 （请参阅：剂量和管理。）尚不知道皮质类固醇激素预处理是否可以减少与CRS相关的器官损害和后遗症。例如，尽管用目前推荐的剂量和时间表的甲基强的松龙进行了预处理，但颅内压升高和脑疝已经发生。

如果发生任何较严重的细胞因子释放综合征表现，则可能需要加强治疗，包括氧气，静脉输液，皮质类固醇，加压胺，抗组胺药，插管等。

中枢神经系统事件

癫痫，脑病，脑水肿，无菌性脑膜炎和头痛据报道，即使ORTHOCLONE OKT后的第一个剂量，治疗期间®3.癫痫，有的伴有意识或心跳呼吸骤停或死亡的损失，已独立或发生与以下所述的任何神经系统综合症同时使用。

据报道有几例脑水肿致死性脑疝。在开始使用Orthoclone OKT3治疗之前，必须仔细评估所有患者，尤其是儿科患者的体液retention留和高血压。在注射Orthoclone OKT3前几剂后的头二十四（24）小时内，必须对神经系统症状进行严密监测。

应密切监测患者的惊厥和脑病表现，包括：认知障碍，意识混乱，精神错乱，精神状态改变，迷失方向，听觉/视觉幻觉，精神病（（妄，妄想症），情绪变化（例如躁狂，躁动，好斗，等等），弥漫性肌张力减退，反射亢进，肌阵挛，震颤，星状，非自愿运动，主要运动性癫痫发作，嗜睡/昏迷/昏迷和弥漫性无力。约有三分之一被诊断为脑病的患者可能合并了无菌性脑膜炎综合征。

与Orthoclone OKT3的使用相关的无菌性脑膜炎综合征的体征和症状包括：发烧，头痛，脑膜炎（僵硬的脖子）和畏光。通过脑脊液（CSF）分析证实诊断，表明白细胞增多症伴有细胞增多，蛋白质升高，葡萄糖正常或降低，病毒，细菌和真菌培养阴性。对于任何免疫抑制的移植患者，如果发现临床表现为脑膜炎，应评估感染的可能性。被诊断为无菌性脑膜炎的患者中约有三分之一患有脑病的体征和症状并存。大多数患有无菌性脑膜炎综合征的患者在治疗过程中或完成或中断治疗后，其病程为良性且无任何永久性后遗症。但是，由于脑膜炎是小儿同种异体移植受者中经常遇到的感染，并且与移植相关的免疫抑制会增加机会性感染的风险，因此，有体征或症状提示脑膜刺激的儿科患者在接受Orthoclone OKT3时应进行腰穿以排除传染病因。 （请参阅：注意事项：小儿使用。）

脑病，脑膜炎，癫痫发作和脑水肿的症状或体征，无论有无头痛，通常都是可逆的。尽管继续使用Orthoclone OKT3进行治疗，但大多数患者仍可解决头痛，无菌性脑膜炎，癫痫发作和轻度脑病。但是，某些事件导致永久性神经系统损害。

分别报告了以下其他中枢神经系统事件：不可逆性失明，视力受损，四肢或瘫痪/瘫痪，脑血管意外（偏瘫/瘫痪），失语症，短暂性脑缺血发作，蛛网膜下腔出血，VI颅神经麻痹，听力减少和耳聋。

中枢神经系统不良经历风险较高的患者包括：患有已知或疑似中枢神经系统疾病（例如癫痫病史等）的患者；脑血管疾病（小血管或大血管）；具有相关神经系统疾病（例如头部外伤，尿毒症，感染，体液和电解质紊乱等）的疾病；有潜在的血管疾病；或同时服用可能会影响中枢神经系统的药物。 （请参阅：警告，注意事项和不良事件：细胞因子释放综合征。）

过敏反应

据报道，用Orthoclone OKT3治疗的患者出现严重的，有时是致命的，立即（通常在10分钟内）的超敏反应（过敏性）。过敏反应的表现可能类似于细胞因子释放综合征（如上所述）的表现。可能无法确定引起任何全身性反应的机制。据报道，归因于超敏反应的反应发生频率低于归因于细胞因子释放的反应。急性超敏反应的特征可能在于：心血管衰竭，心肺骤停，意识丧失，低血压/休克，心动过速，刺痛，血管性水肿（包括喉，咽或面部浮肿），气道阻塞，支气管痉挛，呼吸困难，荨麻疹和瘙痒。

据报道，在初始治疗过程后再次暴露于Orthoclone OKT3的患者中出现了严重的过敏事件，包括过敏性或类过敏反应。在这种情况下，使用抗组胺药和/或类固醇进行预处理可能无法可靠地预防过敏反应。重新治疗的可能的过敏性危害应与预期的治疗益处和替代方案进行权衡。如果患者接受Orthoclone OKT3治疗，则应立即提供肾上腺素和其他紧急生命支持设备，这一点尤其重要。

如果怀疑超敏反应，请立即停药。不要恢复治疗或将患者再次暴露于Orthoclone OKT3中。严重的急性超敏反应可能需要紧急治疗，皮下注射0.3 mL至0.5 mL肾上腺素水溶液（1：1000稀释），并采取其他复苏措施，包括氧气，静脉输液，抗组胺药，皮质类固醇，加压胺和气道处理，如临床指示。 （请参阅：注意事项：细胞因子释放综合征与过敏反应；不良事件：超敏反应。）

免疫抑制的后果

严重，有时甚至致命的感染和肿瘤形成有报道伴随所有免疫抑制治疗，包括含ORTHOCLONE OKT®3的方案。

通常将Orthoclone OKT3添加到免疫抑制治疗方案中，从而增加免疫抑制的程度。免疫抑制总量的增加可能会改变所观察到的感染范围，并增加感染并发症的风险，严重程度和发病率。在移植后的第一个月中，患者受到以下感染的风险最高：（1）移植前存在的感染，可能由于移植后的免疫抑制而加剧； （二）供体器官感染； （3）由于细菌性病原体引起的通常的术后尿路，静脉内相关，伤口或肺部感染。 （请参阅：不良事件：感染。）

移植后大约一到六个月，患者处于病毒感染的风险中[​​例如，巨细胞病毒（CMV），爱泼斯坦-巴尔病毒（EBV），单纯疱疹病毒（HSV）等]，这些病毒会引起严重的全身性疾病，并且增加免疫抑制的整体状态。

据报道，EBV和CMV会重新激活（移植后1-4个月）。当给予包括Orthoclone OKT3在内的抗淋巴细胞抗体，然后给予包括环孢菌素在内的免疫抑制方案时，重新激活CMV的风险增加，并且限制其增殖的能力受损，从而导致症状性和弥散性疾病。 EBV感染，无论是原发性还是重新激活，都可能在移植后淋巴细胞增生性疾病的发展中发挥重要作用。 （请参阅：警告和不良事件：肿瘤形成。）

在小儿移植人群中，病毒感染通常包括成人罕见的病原体，例如水痘带状疱疹病毒（VZV），腺病毒和呼吸道合胞病毒（RSV）。大部分儿科患者在移植前尚未感染疱疹病毒，因此，很容易从移植的器官和/或血液制品中产生原发性感染。

老年患者在强烈的免疫抑制过程中克服感染的能力可能降低。没有关于老年患者使用OKT3的信息。在年龄分层分析中，在年龄较大（51至64岁）和年龄较小（≤30岁）的患者之间，OKT3安全性没有总体差异。给老年患者服用免疫抑制剂时应谨慎。

预防性使用抗感染药可以降低与某些潜在病原体相关的发病率，因此对于小儿及其他高危患者应考虑使用。明智地使用免疫抑制药物，包括类型，剂量和持续时间，可能会限制某些机会性感染的风险和严重性。通过避免将CMV血清阳性（供体）和/或EBV血清阳性（供体）器官移植到血清阴性患者中，也可以降低严重CMV或EBV感染的风险。

由于细胞介导的免疫抑制剂免疫力下降，器官移植患者罹患恶性肿瘤的风险增加。这种风险几乎完全由淋巴增生性疾病，皮肤和嘴唇的鳞状细胞癌以及肉瘤的发生来证明。在免疫抑制的患者中，T细胞的细胞毒性被削弱，从而允许被EBV感染的B淋巴细胞转化和增殖。据认为，转化的B淋巴细胞可引发肿瘤发生，最终导致大多数移植后淋巴细胞增生性疾病的发展。原发性EBV感染的患者，尤其是儿科患者，与EBV相关的淋巴增生性疾病发展的风险可能更高。数据支持小儿异体肝移植受者主动EBV感染时淋巴细胞增生性疾病的发展与Orthoclone OKT3给药之间的关联。 （请参阅：不良事件，感染，瘤形成。）

开始使用Orthoclone OKT3治疗后，应通过体格检查和任何可疑淋巴组织的组织学评估，持续监测患者是否存在淋巴细胞增生性疾病的证据。建议进行密切监视，因为早期发现并随后降低总免疫抑制可能会导致这些淋巴细胞增生性疾病中的某些消退。由于发生淋巴增生性疾病的可能性与总免疫抑制的持续时间和程度（强度）有关，因此建议医师：遵守Orthoclone OKT3治疗的推荐剂量和持续时间；限制在短时间内施用Orthoclone OKT3和其他抗T淋巴细胞抗体制剂的疗程数；如果合适的话，将与之同时使用的免疫抑制药物的剂量降低至与有效治疗反应相容的最低水平。 （请参阅：剂量和管理。）

最近的一项研究检查了45,000名肾移植受者和7500多名心脏移植受者中非霍奇金淋巴瘤（NHL）的发生率。这项研究表明，所有移植患者，无论采用何种免疫抑制方案，都比普通人群患NHL的风险更高。在接受最积极治疗方案的患者中，相对风险最高。

尚未确定接受Orthoclone OKT3治疗的患者发生肿瘤事件的长期风险。

预防措施

一般

当使用免疫抑制剂的组合，每个代理，包括ORTHOCLONE OKT®3，剂量应减少到最低水平与有效的治疗响应兼容，以便减少感染和恶性转化的所述潜在和严重程度。

如果患者的体温超过37.8°C（100°F），则应在每次服用Orthoclone OKT3剂量前通过退热药降低体温。应该评估感染的可能性。

可能无法区分急性超敏反应（例如过敏反应，血管性水肿等）和细胞因子释放综合征。服用Orthoclone OKT3后立即发作（通常在10分钟内）的潜在严重征兆和症状可能是由于急性超敏反应引起的。如果怀疑超敏反应，请立即停药。不要恢复治疗或将患者重新暴露于Orthoclone OKT3中。施用Orthoclone OKT3后约30至60分钟（或更晚）开始的临床表现更可能是细胞因子介导的。 （请参阅：警告：细胞因子释放综合征，过敏反应。）

由于服用Orthoclone OKT3后某些癫痫发作（和其他严重的中枢神经系统事件）已危及生命，因此应采取抗癫痫预防措施（例如，必要时准备使用气道）。 （请参阅：警告和不良事件：中枢神经系统事件。）

如果发生感染或病毒引起的淋巴增生性疾病，请尽快进行培养或活检，立即采取适当的抗感染治疗，并（如果可能）减少/停止免疫抑制治疗。 （请参阅：警告，不良事件。）

使用蛋白质结合力低的0.2或0.22微米（µm）过滤器准备进样。 （请参阅：管理说明。）

Orthoclone OKT3是一种小鼠（免疫球蛋白）蛋白，在某些暴露后的患者中可以诱导人抗小鼠抗体的产生（即致敏）。效价≥1：1000是禁忌。 （请参阅：警告，不良事件。）

在最初的临床试验中，在用Orthoclone OKT3治疗肾同种异体移植排斥反应期间使用低剂量的泼尼松和硫唑嘌呤，观察到Orthoclone OKT3抗体的IgM发生率为21％（n = 43），IgG发生率为86％（n = 43）。 IgE占29％（n = 35）。 IgG抗体的平均出现时间为20±2天（平均值±SD）。在治疗的第二周末，早期的IgG抗体出现在3％（n = 86）的患者中。

随后的临床经验表明，与Orthoclone OKT3组合使用的免疫抑制药物的剂量，持续时间和类型可能会影响宿主抗体反应的发生率和强度。此外，与Orthoclone OKT3（即类固醇，硫唑嘌呤，泼尼松或环孢霉素）同时使用的免疫抑制剂已改变了抗小鼠抗体发展的时间进程和所形成抗体的特异性（即，独特型，同型，同种异型）。

与其他免疫抑制疗法一样，已经报道了用Orthoclone OKT3治疗的患者的同种异体移植物和其他血管床（例如心脏，肺，脑，肠等）的动脉，静脉和毛细血管血栓形成。另外，已经报道了在一些患有微血管病性溶血性贫血的患者中，与肾脏同种异体移植相关的微血管病性改变（例如血小板微血栓）。 93名患者中有5名（5％）接受了高于推荐剂量的剂量观察到这种情况。与剂量的关系仍然不确定。 however, the relative risk appears to be greater with doses above the recommended dose. Patients with a history of thrombosis or underlying vascular disease should be given Orthoclone OKT3 only when the potential benefits clearly outweigh the increased risks of therapy.

给患者的信息

应建议患者：

• of the signs and symptoms associated with the Cytokine Release Syndrome and the potentially serious nature of this syndrome (eg, systemic, cardiovascular, central nervous system events).
• to seek medical attention for skin rash, urticaria, rapid heart beat, respiratory distress, dysphagia, or any swelling suggesting an allergic reaction or angioedema.
• that Orthoclone OKT3 may impair mental alertness and coordination and may effect the ability to operate an automobile or machinery.
• of other risks associated with the use of Orthoclone OKT3. (See: BOXED WARNING ; WARNINGS ; PRECAUTIONS ; ADVERSE EVENTS .)

实验室测试

The following tests should be monitored prior to and during ORTHOCLONE OKT ® 3 therapy:

• Renal: BUN, serum creatinine, etc.;
• Hepatic: transaminases, alkaline phosphatase, bilirubin;
• Hematopoietic: WBCs and differential, platelet count, etc.;
• Chest X-ray within 24 hours before initiating Orthoclone OKT3 treatment to rule out heart failure or fluid overload.
• Blood Tests: Periodic assessment of organ system functions (renal, hepatic, and hematopoietic) should be performed.

During therapy with Orthoclone OKT3: In adults, periodic monitoring to ensure plasma Orthoclone OKT3 levels (≥800 ng/mL) or T cell clearance (CD3 positive T cells <25 cells/mm 3 ) is recommended. In pediatric patients, both plasma Orthoclone OKT3 levels (≥800 ng/mL) and T cell clearance (CD3 positive T cells <25 cells/mm 3 ) should be monitored daily. (See: CLINICAL PHARMACOLOGY .)

致癌作用

Long-term studies have not been performed in laboratory animals to evaluate the carcinogenic potential of Orthoclone OKT3; however, neoplasia has been reported in patients receiving this product. (See: WARNINGS and ADVERSE EVENTS: Neoplasia .)

怀孕类别C

Animal reproductive studies have not been conducted with Orthoclone OKT3. It is also not known whether Orthoclone OKT3 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. However, Orthoclone OKT3 is an IgG antibody and may cross the human placenta. The effect on the fetus of the release of cytokines and/or immunosuppression after treatment with Orthoclone OKT3 is not known. Orthoclone OKT3 should be given to a pregnant woman only if clearly needed. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. (See: CONTRAINDICATIONS , WARNINGS , and ADVERSE EVENTS .)

护理母亲

It is not known whether Orthoclone OKT3 is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse events/oncogenesis shown for Orthoclone OKT3 in human studies, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See: CONTRAINDICATIONS .)

儿科用

Safety and effectiveness have been established in infants (1 mo. up to 2 yr.); children (2 yr. up to 12 yr.); and adolescents (12 yr. up to 16 yr.). Use of Orthoclone OKT3 in these age groups is supported by clinical studies that included adults and pediatric patients. In those studies, the safety and efficacy of Orthoclone OKT3 in pediatric patients receiving renal or hepatic transplants was similar to that in the overall cohort. There were insufficient data to compare the safety and efficacy of Orthoclone OKT3 in pediatric patients in a study of patients receiving cardiac transplants. Additional pharmacokinetic, pharmacodynamic, and clinical studies in infants, children, and adolescents have been reported in published literature.

Pediatric patients are known to have higher CD3 lymphocyte counts than adults; therefore, progressively higher doses of Orthoclone OKT3 are often required to achieve therapeutic levels of lymphocyte clearance. (See: DOSAGE AND ADMINISTRATION .)

Deaths Due to Cerebral Herniation

The postmarketing data base indicates that pediatric patients may be at increased risk of developing cerebral edema with or without herniation compared to adults. In the period between 1986 and 1996, twenty-five cases (6 in pediatric patients) of cerebral edema were identified with subsequent cerebral herniation and death in five cases (4 in pediatric patients). Herniation in the pediatric patients and one 19 year old subject occurred within a few hours to one day after the first dose (2.5 or 5 mg) of Orthoclone OKT3 administered in the investigational setting for prophylaxis of renal allograft rejection. All pediatric patients and especially those receiving a renal allograft must be carefully evaluated for fluid retention and hypertension before the initiation of Orthoclone OKT3 therapy. (See: WARNINGS: Cytokine Release Syndrome ; DOSAGE AND ADMINISTRATION: General .) Patients should be closely monitored for neurologic symptoms during the first twenty four (24) hours following each of the first few doses of Orthoclone OKT3 injection.

Other Serious Central Nervous System Adverse Events

Other significant neurologic complications reported in pediatric transplant recipients receiving Orthoclone OKT3 include status epilepticus, cerebral edema, diffuse encephalopathy, cerebritis, seizures, cortical dysfunction, and intracranial hemorrhage. Permanent neurologic impairments (eg, blindness, deafness, paralysis) have been reported rarely. Because meningitis is a frequent infection encountered in pediatric allograft recipients, and the immunosuppression associated with transplantation increases the risk of opportunistic infection, patients with meningeal irritation following treatment with Orthoclone OKT3 therapy should be evaluated with lumbar puncture as early as possible to rule out an infectious etiology.

病毒感染

The overall incidence of infections appeared to be similar in pediatric patients compared to the overall population studied. In the pediatric population, viral infections often include pathogens uncommon in adults, such as varicella zoster virus (VZV), adenovirus, enterovirus, parainfluenza virus, and respiratory syncytial virus (RSV). In addition, many viral diseases often manifest differently in pediatric patients than they do in adults. Because a large proportion of pediatric patients have not been infected by herpes viruses (eg, EBV, HSV, CMV) prior to transplantation they may be more susceptible to acquiring primary infections from the grafted organ and/or blood products when immunosuppressed. Antiviral prophylactic therapy may be particularly useful in these high risk pediatric patients. (See: ADVERSE EVENTS: Infections .)

Neoplasia

Patients with primary EBV infection may be at higher risk for the development of EBV-associated lymphoproliferative disorders. There are data to support an association between the development of lymphoproliferative disorders at the time of active EBV infection and ORTHOCLONE OKT ® 3 administration in pediatric liver allograft recipients. Antiviral prophylactic therapy may be particularly useful in these high risk pediatric patients.

Gastrointestinal Fluid Losses

Parenteral hydration may be required for gastrointestinal fluid loss secondary to diarrhea and/or vomiting resulting from the "Cytokine Release Syndrome."

血栓形成

Pediatric patients may be at an increased risk of thrombosis. Pediatric patients weighing less than 15 kg are at high-risk for hepatic artery thrombosis. Thrombosis has been reported in pediatric transplant recipients treated with Orthoclone OKT3. A number of factors, including surgical technique, the presence of a hypercoaguable state, and the absence of prior dialysis experience may be relevant to the pathophysiology of the increased risk of thrombosis. (See: BOXED WARNING ; WARNINGS ; PRECAUTIONS ; ADVERSE EVENTS ; DOSAGE AND ADMINISTRATION .)

老人用

There is no information on the use of OKT3 in geriatric patients. Caution should be used when prescribing immunosuppressive agents to elderly patients.

ADVERSE EVENTS

Cytokine Release Syndrome

In controlled clinical trials for treatment of acute renal allograft rejection, patients treated with Orthoclone OKT3 plus concomitant low-dose immunosuppressive therapy (primarily azathioprine and corticosteroids) were observed to have an increased incidence of adverse experiences during the first two days of treatment, as compared with the group of patients receiving azathioprine and high-dose steroid therapy. During this period the majority of patients experienced pyrexia (90%), of which 19% were 40.0°C (104°F) or above, and chills (59%). In addition, other adverse experiences occurring in 8% or more of the patients during the first two days of Orthoclone OKT3 therapy included: dyspnea (21%), nausea (19%), vomiting (19%), chest pain (14%), diarrhea (14%), tremor (13%), wheezing (13%), headache (11%), tachycardia (10%), rigor (8%), and hypertension (8%). A similar spectrum of clinical manifestations has been observed in open clinical studies and in post-marketing experience involving patients treated with Orthoclone OKT3 for rejection following renal, cardiac, and hepatic transplantation.

Additional serious and occasionally fatal cardiorespiratory manifestations have been reported following any of the first few doses. (See: WARNINGS: Cytokine Release Syndrome ; ADVERSE EVENTS: Cardiovascular, Respiratory.)

In the acute renal allograft rejection trials, potentially fatal pulmonary edema had been reported following the first two doses in less than 2% of the patients treated with Orthoclone OKT3. Pulmonary edema was usually associated with fluid overload. However, post-marketing experience revealed that pulmonary edema has occurred in patients who appeared to be euvolemic, presumably as a consequence of cytokine-mediated increased vascular permeability ("leaky capillaries") and/or reduced myocardial contractility/compliance (ie, left ventricular dysfunction). (See: WARNINGS: Cytokine Release Syndrome ; DOSAGE AND ADMINISTRATION .)

传染病

In the controlled randomized renal allograft rejection trial conducted before cyclosporine was marketed, the most common infections during the first 45 days of Orthoclone OKT3 therapy were due to herpes simplex virus (27%) and cytomegalovirus (19%). Other severe and life-threatening infections were Staphylococcus epidermidis (5%), Pneumocystis carinii (3%), Legionella (2%), Cryptococcus (2%), Serratia (2%) and gram-negative bacteria (2%). The incidence of infections was similar in patients treated with Orthoclone OKT3 and in patients treated with high-dose steroids.

In a clinical trial of acute hepatic allograft rejection, refractory to conventional treatment, the most common infections reported in patients treated with Orthoclone OKT3 during the first 45 days of the study were cytomegalovirus (16% of patients, of which 43% of infections were severe), fungal infections (15% of patients, of which 30% were severe), and herpes simplex virus (8% of patients, of which 10% were severe). Other severe and life-threatening infections were gram-positive infections (9% of patients), gram-negative infections (8% of patients), viral infections (2% of patients), and Legionella (1% of patients). In another trial studying the use of ORTHOCLONE OKT ® 3 in patients with hepatic allografts, the incidence of fungal infections was 34% and infections with the herpes simplex virus was 31%.

In a clinical trial studying the use of Orthoclone OKT3 in patients with acute cardiac rejection refractory to conventional treatment, the most common infections in the Orthoclone OKT3 group reported during the first 45 days of the study were herpes simplex virus (5% of patients, of which 20% were severe), fungal infections (4% of patients, of which 75% were severe), and cytomegalovirus (3% of patients, of which 33% were severe). No other severe or life-threatening infections were reported during this period.

In a retrospective analysis of pediatric patients treated for acute hepatic rejection, the most common infections reported in patients treated with Orthoclone OKT3 therapy were due to bacterial infections (47%), fungal infections (21%), cytomegalovirus (19%), herpes simplex virus (15%), adenovirus (8%), and Epstein-Barr virus (8%). The overall rates of viral, fungal, and bacterial infections were similar in patients treated with Orthoclone OKT3 (n = 53) and in patients whose rejection was treated with steroids alone (n = 27). In another study of 149 pediatric liver allograft patients where 59 episodes of steroid-resistant rejection were treated with Orthoclone OKT3, the incidence of invasive cytomegalovirus infection was higher in patients receiving Orthoclone OKT3 than in those receiving steroids alone.

Clinically significant infections (eg, pneumonia, sepsis, etc.) due to the following pathogens have been reported:

As a consequence of being a potent immunosuppressive, the incidence and severity of infections with designated( * ) pathogens, especially the herpes family of viruses, may be increased. (See: WARNINGS: Infections .)

Neoplasia

In patients treated with Orthoclone OKT3, post-transplant lymphoproliferative disorders have ranged from lymphadenopathy or benign polyclonal B cell hyperplasias to malignant and often fatal monoclonal B cell lymphomas. In post-marketing experience, approximately one-third of the lymphoproliferations reported were benign and two-thirds were malignant. Lymphoma types included: B cell, large cell, polyclonal, non-Hodgkin's, lymphocytic, T cell, Burkitt's. The majority were not histologically classified. Malignant lymphomas appear to develop early after transplantation, the majority within the first four months post-treatment. Many of these have been rapidly progressive. Some were fulminant, involving the allografted organ and were widely disseminated at the time of diagnosis. Carcinomas of the skin included: basal cell, squamous cell, sarcoma, melanoma, and keratoacanthoma. Other neoplasms infrequently reported include: multiple myeloma, leukemia, carcinoma of the breast, adenocarcinoma, cholangiocarcinoma, and recurrences of pre-existing hepatoma and renal cell carcinoma. (See: WARNINGS: Neoplasia .)

过敏反应

Reported adverse reactions resulting from the formation of antibodies to Orthoclone OKT3 have included antigen-antibody (immune complex) mediated syndromes and IgE-mediated reactions. Hypersensitivity reactions have ranged from a mild, self-limited rash or pruritus to severe, life-threatening anaphylactic reactions/shock or angioedema (including: swelling of lips, eyelids, laryngeal spasm and airway obstruction with hypoxia). (See: WARNINGS: Anaphylactic Reactions .)

Other hypersensitivity reactions have included: ineffectiveness of treatment, serum sickness, arthritis, allergic interstitial nephritis, immune complex deposition resulting in glomerulonephritis, vasculitis (including temporal and retinal), and eosinophilia.

Adverse Reactions by Body System

Adverse events reported in greater than or equal to 1% of clinical trial patients treated with Orthoclone OKT3 (n=393) are shown in Table 1:

Selected Adverse Events Reported In Clinical Trials (< 1% incidence, n=393)

Cardiovascular Disorders, General: Angina, Cardiac Arrest, Fluctuation in Blood Pressure, Heart Failure, Myocardial Infarction, Shock, Thrombosis.

Central and Peripheral Nervous System Disorders: Coma, Encephalopathy, Epilepsy, Hypotonia.

Gastrointestinal Disorders: Gastrointestinal Hemorrhage.

Hemapoietic Disorders: Coagulation Disorder, Lymphadenopathy, Lymphopenia.

Hepatobiliary: Hepatitis, SGOT Increased, SGPT Increased.

Psychiatric Disorders: Hallucinations, Mood Changes, Paranoia, Psychosis.

Renal Disorders: Anuria, Oliguria.

Respiratory System Disorders: Apnea, Pneumonitis.

Special Senses: Conjunctivitis, Hearing Decrease.

Worldwide Postmarketing Experience - Body Systems/Events Listed Alphabetically

Body as a Whole, General Disorders: Fever (including spiking temperatures as high as 107°F), Flu-like Syndrome.

Cardiovascular Disorders: Cardiovascular Collapse, Hemodynamic Instability, Left Ventricular Dysfunction.

Central and Peripheral Nervous System Disorders: Agitation, Aphasia, Asterixis, Cerebritis, Cerebral Edema, Cerebral Herniation, Cerebrovascular Accident, CNS Infection, CNS Malignancy, Cranial Nerve VI Palsy, Encephalitis, Hyperreflexia, Involuntary Movements, Intracranial Hemorrhage, Impaired Cognition, Myoclonus, Obnubilation, Paresis/plegia including quadriparesis/plegia, Status Epilepticus, Stupor, Transient Ischemic Attack, Vertigo.

In a post-marketing survey involving 214 renal transplant patients, the incidence of aseptic meningitis syndrome was 6%. Fever (89%), headache (44%), neck stiffness (14%), and photophobia (10%) were the most commonly reported symptoms; a combination of these four symptoms occurred in 5% of patients.

Between 1987 and 1992, 75 post-marketing reports have described seizures, averaging about 12 per year, and including 23 fatalities. More than two-thirds of these reports (53) were of domestic spontaneous origin, and their age and sex distributions were broad. Post-licensure reports generally provide insufficient data to allow accurate estimation of risk or of incidence.

Gastrointestinal Disorders: Bowel Infarction.

Hematopoietic Disorders: Aplastic anemia, Arterial, Venous and Capillary Thrombosis of allografts and other vascular beds eg, heart, lung, brain and bowel etc., Disseminated Intravascu