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在本页面

• 描述
• 临床药理学
• 临床研究
• 适应症和用法
• 禁忌症
• 警告事项
• 预防措施
• 药物相互作用
• 不良反应/副作用
• 过量
• 剂量和给药
• 供应/存储和处理方式

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美国已停止使用Cordarone品牌名称。如果FDA批准了该产品的通用版本，则可能会有通用的等效版本。

描述

Cordarone静脉注射（Cordarone IV）含有胺碘酮盐酸盐（C 25 H 29 I 2 NO 3 •HCl），III类抗心律不齐药物。盐酸胺碘酮为（2-丁基-3-苯并呋喃基）[4- [2-（二乙基氨基）乙氧基] -3,5-二碘苯基]甲酮盐酸盐。盐酸胺碘酮具有以下结构式：

盐酸胺碘酮为白色至微黄色的结晶性粉末，微溶于水。其分子量为681.78，并且包含37.3重量％的碘。 Cordarone IV是一种无菌的透明淡黄色胶束溶液，肉眼看不到任何颗粒。每毫升的Cordarone IV制剂含有50 mg盐酸胺碘酮，20.2 mg苯甲醇，100 mg聚山梨酯80和注射用水。

Cordarone IV包含聚山梨酯80，已知该聚山梨酯80可从聚氯乙烯（PVC）浸出邻苯二甲酸二（2-乙基己基）酯（DEHP）（请参阅剂量和管理）。

临床药理学

行动机制

胺碘酮一般被认为是III类抗心律不齐药物，但它具有所有四个沃恩·威廉姆斯类的电生理特性。像I类药物一样，胺碘酮在快速起搏频率下阻断钠通道，而像II类药物一样，它发挥非竞争性抗交感作用。随着时间的延长，其主要作用之一是延长心脏动作电位，这是III类作用。胺碘酮在淋巴结组织中的负变时性作用类似于IV类药物的作用。除阻断钠通道外，胺碘酮还阻断心肌钾通道，这有助于减慢传导和延长不应期。抗交感作用以及钙和钾离子通道的阻滞是窦房结负性趋力作用的原因，也是房室（AV）结节的传导减慢和难治性延长的原因。它的血管舒张作用可以减少心脏工作量，从而减少心肌耗氧量。

注射四氢呋喃酮可延长结节内传导（房性-His，AH）和房室结的难治性（ERP AVN），但对窦周期长度（SCL），右心房和右心室的难治性（ERP RA和ERP RV），复极（QTc），脑室内传导（QRS）和下结膜传导（His-ventricular，HV）。下表显示了Cordarone IV和口服Cordarone的电生理作用的比较。

静脉和口服可乐酮对电生理参数的影响

公式	SCL	QRS	合格证	啊	高压	企业资源计划 RA	企业资源计划 房车	企业资源计划 AVN
↔没有变化
IV	↔	↔	↔	↑	↔	↔	↔	↑
口服	↑	↔	↑	↑	↔	↑	↑	↑

在较高剂量（> 10 mg / kg）的Cordarone IV时，已观察到ERP RV的延长和QRS的适度延长。口服和静脉内给药之间的这些差异表明，Cordarone IV的最初急性作用可能主要集中在AV结，由于缓慢的通道阻滞（IV类活性）和非竞争性肾上腺素拮抗作用（类IV II活动）。

药代动力学与代谢

静脉给药后，胺碘酮显示出复杂的处置特征。在健康受试者中，单次5 mg / kg 15分钟静脉输注后的峰值血清浓度在5到41 mg / L之间。房颤（VF）或血液动力学不稳定的心动过速（VT）的患者在输注150 mg Cordarone IV 10分钟后的峰值浓度为7至26 mg / L。由于分布迅速，输注结束后30至45分钟内血清浓度降至峰值的10％。在临床试验中，连续输注48小时（125、500或1000 mg /天）加上补充输注（150 mg）（对于反复性心律失常）后，胺碘酮的平均血清浓度在0.7至1.4 mg / L之间（n = 260）。

N-去乙基胺碘酮（DEA）是胺碘酮在人体中的主要活性代谢产物。直到连续输注几天后，通常才观察到超过0.05 mg / L的DEA血清浓度，但是经过长期治疗，其浓度与胺碘酮大致相同。胺碘酮被细胞色素P450（CYP450）酶组代谢为去乙基胺碘酮，特别是细胞色素P450 3A4（CYP3A4）和CYP2C8。 CYP3A4同工酶存在于肝脏和肠道中。口服胺碘酮的全身可用度高度可变，可能是由于CYP3A4活性的个体差异较大。

胺碘酮主要通过肝代谢和胆汁排泄而消除，尿中胺碘酮或DEA的排泄量可忽略不计。胺碘酮和DEA都不可透析。胺碘酮和DEA穿过胎盘，都出现在母乳中。

目前尚无关于人体内DEA活性的数据，但在动物中，它具有显着的电生理和抗心律失常作用，通常类似于胺碘酮本身。 DEA对口服胺碘酮的抗心律失常作用的确切作用和贡献尚不确定。口服科达隆后，人类最大心室III类作用的发展与DEA随时间的积累密切相关，而不与胺碘酮的积累密切相关。另一方面（参见临床试验），在注射Cordarone IV后，有证据表明其活动早于获得高浓度的DEA。

下表总结了在健康受试者的单次剂量iv（15分钟内5 mg / kg）研究中报告的胺碘酮药代动力学参数的平均范围。

静脉内给予胺碘酮后的药代动力学概况

药品	清仓 （毫升/小时/千克）	v C案例 （升/公斤）	V SS （升/公斤）	t½ （天）
注意：V C和V SS表示来自iv研究的中心和稳态分布量。
“ –”表示不可用。
胺碘酮	90-158	0.2	40-84	20-47
去乙基胺碘酮	197-290	–	68-168	≥AMI t 1/2

去乙基胺碘酮的清除率和体积涉及未知的生物转化因子。

健康受试者口服胺碘酮的全身可用率介于33％至65％之间。根据体外研究，胺碘酮的蛋白质结合率> 96％。

在2至7天的临床研究中，VT和VF患者静脉给药后胺碘酮的清除范围为220至440 mL / h / kg。年龄，性别，肾脏疾病和肝病（肝硬化）对胺碘酮或DEA的处置没有明显影响。肾功能不损害胺碘酮的药代动力学。在肝硬化患者中单次服用Cordarone IV后，DEA的C max和平均浓度值明显降低，但胺碘酮的平均水平没有变化。 65岁以上的正常受试者的清除率（约100 mL / hr / kg）低于年轻受试者（约150 mL / hr / kg），并且t 1/2从约20天增加至47天。在患有严重左心功能不全的患者中，胺碘酮的药代动力学没有明显改变，但DEA的终末处置t 1/2延长。尽管在口服科尔达隆的长期治疗过程中未定义针对肾，肝或心脏异常患者的剂量调整，但对于老年患者和严重左心功能不全的患者，应谨慎进行临床监测。

短期静脉使用药物浓度和治疗反应之间没有确定的关系。慢性口服Cordarone治疗后，稳态胺碘酮浓度为1至2.5 mg / L与抗心律不齐作用和可接受的毒性有关。

药效学

据报道，Cordarone IV对动物和人类产生负面的正性肌力和血管舒张作用。在对难治性VF或血液动力学不稳定VT的患者进行的临床研究中，接受Cordarone IV治疗的1836例患者中有288例发生了与药物相关的低血压（16％），基线射血分数与临床意义的发生之间没有相关性输注Cordarone IV时发生低血压

临床试验

除了下文所述的对VT或VF患者的研究外，还有其他两项胺碘酮的研究表明，在积累大量DEA之前抗心律失常作用。一项安慰剂对照研究，在患有室上性和2至3次连续性搏动性室性心律失常的冠状动脉旁路移植术后，静脉注射胺碘酮（2小时内300 mg，然后1200 mg /天）显示，心律失常从12小时开始减少上。在复发性难治性VT / VF患者中使用相似的静脉方案进行的基线对照研究也显示抗心律失常活性迅速起效。与基线相比，胺碘酮治疗可减少VT发作85％。

两项随机，平行，剂量反应研究（每项约300名患者）支持了Cordarone IV抑制复发性VF或血液动力学不稳定VT的急性有效性。在这些研究中，在前24小时内至少发生两次VF或血液动力学不稳定VT的患者被随机分配为在前24小时内接受约125或1000 mg的剂量，相差8倍。在一项研究中，评估了约500 mg的中等剂量。剂量方案包括最初的快速负荷输注，然后是较慢的6小时负荷输注，然后是18小时维持输液。维持输注持续到第48小时。对于125 mg剂量组，更频繁地给予150 mg Cordarone IV的10分钟输注，以更频繁地“突破” VT / VF，从而大大减少了计划中的总计8倍差异在两项研究中，剂量分别达到1.8倍和2.6倍。

前瞻性定义的主要疗效终点是每小时VT / VF发作的比率。对于这两项研究，接受高剂量的患者的中位发生率均为每小时0.02次，接受低剂量的患者的中位发生率为每小时0.07次，即两项研究的中位数分别为每天0.5次和1.7次（p = 0.07，两面） ）。在一项研究中，首次发生VT / VF的时间显着延长（接受小剂量的患者大约10小时，接受大剂量的患者大约14小时）。在这两项研究中，大剂量组的患者接受补充输注的次数明显减少。在这些研究中，死亡率没有受到影响；在双盲治疗结束时或48小时后，所有患者都可以接受任何认为必要的治疗（包括Cordarone IV）。

适应症和用途

Cordarone IV适用于难以治疗的其他患者，可开始治疗并预防频繁发生的心室纤颤和血液动力学不稳定的心动过速。 Cordarone IV也可用于治疗需要口服Cordarone但不能口服药物的VT / VF患者。在用Cordarone IV治疗期间或之后，可将患者转至口服Cordarone治疗（请参阅剂量和用法）。

应使用Cordarone IV进行急性治疗，直到患者的室性心律失常稳定为止。大多数患者将需要48至96小时的这种疗法，但如有必要，可安全地长期服用Cordarone IV。

禁忌症

除非对心脏起搏器IV的任何成分（包括碘）过敏，否则对人有Cordarone IV禁忌，除非有可用的起搏器，否则对心源性休克，明显窦性心动过缓以及二级或三级房室传导阻滞的患者具有Cordarone IV的任何过敏症。

警告

低血压

低血压是用Cordarone IV观察到的最常见的不良反应在临床试验中，据报道，与治疗有关的，与药物有关的低血压是对1836名用Cordarone IV治疗的患者中的288人（16％）的不良反应。通常在治疗的最初几个小时内，与剂量无关，但似乎与输液速度有关。据报道，有3％的患者出现低血压，需要改变Cordarone IV治疗，而只有不到2％的患者需要永久停药。

低血压应首先通过减慢输注速度来治疗；可能需要其他标准疗法，包括以下各项：升压药，正性肌力药和容量增加。初始输注速率应严密监控，且不得超过剂量和管理规定。

在某些情况下，低血压可能是难治性的，导致致命的后果（请参阅“不良反应”，售后报告）。

心动过缓和房室传导阻滞

在1836例临床试验中，有90例（4.9％）患者发生了与药物有关的心动过缓，而他们因危及生命的VT / VF接受了Cordarone IV治疗。它与剂量无关。心动过缓应通过减慢输注速度或停用Cordarone IV来治疗。在某些患者中，需要插入起搏器。尽管采取了这些措施，但在对照试验中，心动过缓仍是进行性且终末为1例患者。已知有心动过缓或房室传导阻滞易感性的患者，应在可使用临时起搏器的环境中使用Cordarone IV进行治疗。

肝酶升高

在立即危及生命的VT / VF患者中，常见的是血液中肝酶值的升高（丙氨酸转氨酶（ALT），天冬氨酸转氨酶（AST）和γ-谷氨酰转氨酶（GGT））。解释AST活性升高可能很困难，因为在最近患有心肌梗塞，充血性心力衰竭或多次电击除颤的患者中，该值可能会升高。在临床研究中，约有54％的接受Cordarone IV的患者基线肝酶升高，而13％的患者临床上显着升高。在81％既有基线数据又有治疗数据的患者中，肝酶升高要么在治疗过程中有所改善，要么保持在基线水平。肝酶的基线异常不是治疗的禁忌证。

急性，小叶融合性肝细胞坏死导致肝昏迷，急性肾功能衰竭和死亡，与剂量和管理中建议的剂量剂量高得多，输注速度快得多的Cordarone IV给药有关。因此，应密切监测初始浓度和输注速度，且不得超过剂量和管理规定的剂量（请参阅剂量和管理）。

对于危及生命的心律不齐的患者，应权衡潜在的肝损伤风险与Cordarone IV治疗的潜在益处，但应仔细监测接受Cordarone IV的患者是否有进行性肝损伤的证据。在这种情况下，应考虑降低给药速度或撤回Cordarone IV。

心律失常

像所有抗心律不齐药物一样，Cordarone IV可能导致现有的心律不齐恶化或引起新的心律不齐。心律失常，主要是足尖扭转性眼病（TdP），与Cordarone IV将QTc间隔延长至500 ms或更长有关。尽管接受Cordarone IV的患者经常发生QTc延长，但很少发生扭转性扭转性室速或新发VF（少于2％）。应在使用Cordarone IV输注期间监测患者的QTc延长。将胺碘酮与其他延长QTc的抗心律不齐疗法联用应留给对单一药物反应不完全的危及生命的室性心律不齐的患者。

已知氟喹诺酮类，大环内酯类抗生素和唑类会导致QTc延长。有报道称，同时使用氟喹诺酮类，大环内酯类抗生素或唑类药物的胺碘酮患者，不论是否使用TdP，QTc延长。 （请参阅药物相互作用，其他报道的与胺碘酮的相互作用。）

必须将胺碘酮与已知延长QTc间隔的任何其他药物合用，必须基于对每位患者这样做的潜在风险和益处的仔细评估。

由于心律不齐突破或加剧心律失常的可能，导致这些患者的甲状腺功能障碍，必须仔细评估使用Cordarone IV的潜在风险和益处。

肺部疾病

早发性肺毒性

上市后有报道称，用Cordarone IV治疗的患者出现急性发作（数日至数周）的肺损伤。发现包括X线，支气管痉挛，喘息，发烧，呼吸困难，咳嗽，咯血和缺氧等症状的肺浸润和/或肿块。一些病例已经发展为呼吸衰竭和/或死亡。

ARDS

据报道，在涉及48小时治疗的临床研究中，有2％（2％）的患者患有成人呼吸窘迫综合征（ARDS）。 ARDS是一种以双侧弥漫性肺浸润为特征的疾病，伴有肺水肿和不同程度的呼吸功能不全。临床和放射影像可出现在多种肺部损伤之后，例如由创伤，休克，长时间的心肺复苏和吸入性肺炎引起的那些损伤，这些是许多参加临床研究的患者的状况。已有Cordarone IV患者ARDS上市后的报道。那些患者中，Cordarone IV可能引起或加重了肺部疾病。

术后，据报道接受口服Cordarone治疗的患者接受了心脏或非心脏手术后，ARDS的发生率更高。尽管患者通常对剧烈的呼吸疗法反应良好，但在极少数情况下，结果却是致命的。在进行进一步的研究之前，建议对科达隆的患者密切监测FiO 2和向组织输送的氧气的决定因素（例如SaO 2 ，PaO 2 ）。

肺纤维化

在临床研究中，在1000多名使用Cordarone IV治疗的患者中，只有1名发生了肺纤维化。在该患者中，使用Cordarone IV治疗3个月后诊断出该病，在此期间她接受了口服Cordarone。肺毒性是长期使用Cordarone的公认的并发症（请参阅口服Cordarone的标签）。

视力丧失

口服胺碘酮治疗的患者中有视神经病变和/或视神经炎的病例，通常会导致视力障碍。在某些情况下，视力障碍已发展为永久性失明。胺碘酮IV用于治疗和预防难治性其他患者的频繁发生的心室纤颤（VF）和血流动力学不稳定的室性心动过速（VT），也可用于治疗口服胺碘酮的VT / VF患者指出，但谁不能服用口服药物。在开始治疗后的任何时间都可能发生视神经病变和/或神经炎。与药物的因果关系尚未明确建立。如果出现视力障碍症状，例如视力变化和周围视力下降，建议立即进行眼科检查。视神经病变和/或神经炎的出现要求对胺碘酮治疗进行重新评估。胺碘酮抗心律不齐治疗的风险和并发症必须权衡其对心律不齐威胁生命的患者的益处。在胺碘酮给药期间，建议定期进行眼科检查，包括眼底镜检查和裂隙灯检查。 （请参阅不良反应。）

长期使用

参见口服卡达隆的标签。接受Cordarone IV超过3周的患者经验有限。

甲状腺毒症

Cordarone诱发的甲状腺功能亢进症可能导致甲状腺毒症和/或心律不齐突破或加重的可能性。有报道称胺碘酮引起的甲状腺毒症会导致死亡。如果出现任何新的心律失常迹象，则应考虑甲状腺功能亢进症的可能性（请参阅预防措施，甲状腺异常）。

新生儿甲状腺功能低下或甲亢

尽管在怀孕期间使用Cordarone的情况很少见，但已经有少量已发表的口服先天性甲状腺肿/甲状腺功能低下和甲状腺功能亢进的报道。如果在怀孕期间使用四氢可待因酮，应告知患者对胎儿的潜在危害。

预防措施

应仅由具有治疗致命性心律失常经验的医生，完全熟悉Cordarone治疗的风险和益处，并具有足够的设施来监控治疗效果和副作用的医师来管理Cordarone IV。

甲状腺异常

胺碘酮抑制甲状腺素的外围转换（T 4）以三碘甲状腺氨酸（T 3），并且可能导致增加的甲状腺素水平，降低Ť3倍的水平，和增加的在临床甲状腺机能正常的患者（RT 3）不活动的倒T 3的水平。它也是大量无机碘的潜在来源。由于其释放的无机碘或其他原因，Cordarone可能导致甲状腺功能减退或甲状腺功能亢进。治疗前应定期监测甲状腺功能，此后应定期监测甲状腺功能，特别是在老年患者以及任何有甲状腺结节，甲状腺肿或其他甲状腺功能异常病史的患者中。由于Cordarone及其代谢产物的清除速度较慢，因此在停用Cordarone之后，血浆碘化物水平较高，甲状腺功能改变和甲状腺功能异常检查可能会持续数周甚至数月。

在大多数系列中，已报告甲状腺功能减退症的患者为2％至4％，但在某些系列中为8％至10％。可以通过相关的临床症状，尤其是血清TSH水平升高来确定这种状况。在一些临床甲减胺碘酮治疗的患者中，游离甲状腺素指数值可能是正常的。降低甲状腺功能减退症最好通过降低Cordarone剂量和/或补充甲状腺激素来解决。然而，治疗必须个体化，并可能需要停止胺碘酮®片在一些病人。

甲亢患者中约有2％发生甲状腺功能亢进，但以前饮食中碘摄入不足的患者中甲亢的发生率可能更高。与甲状腺机能减退相比，虫草酮引起的甲状腺功能亢进通常对患者构成更大的危险，因为甲状腺毒症和/或心律不齐的突破或加重可能导致死亡。有报道称胺碘酮引起的甲状腺毒症会导致死亡。如果出现任何新的心律失常迹象，则应考虑到甲状腺功能亢进症的可能性。

甲状腺功能亢进最好通过相关的临床症状和体征来识别，通常伴有血清T 3 RIA水平异常升高，血清T 4进一步升高以及血清TSH水平低于正常水平（使用足够敏感的TSH分析）。 TSH对TRH反应平缓的发现可证实甲亢，在模棱两可的情况下可寻求。由于心律失常的突破可能伴随着Cordarone诱发的甲状腺功能亢进，因此需要积极治疗，包括在可能的情况下降低剂量或停用Cordarone。

可能需要使用抗甲状腺药物，β-肾上腺素能阻滞剂和/或临时使用皮质类固醇激素。抗甲状腺药物的作用在胺碘酮引起的甲状腺毒症中可能会特别延迟，因为腺体中储存了大量的预先形成的甲状腺激素。有报道说胺碘酮引起的甲状腺毒症会导致死亡。放射性碘疗法是禁忌的，因为与胺碘酮引起的甲亢相关的放射性碘摄取低。 Cordarone诱发的甲状腺功能亢进症可能会伴随短暂的甲状腺功能减退症（参见“警告，甲状腺毒症” ）。

当胺碘酮引起的甲状腺毒症的积极治疗失败或胺碘酮是唯一可抵抗耐药性心律失常的药物时，不能停用胺碘酮时，可以选择手术治疗。甲状腺切除术作为胺碘酮诱发的甲状腺毒症的治疗经验有限，这种治疗形式可能会诱发甲状腺风暴。因此，手术和麻醉管理需要仔细计划。

有上市后的报道表明，用Cordarone治疗的患者甲状腺结节/甲状腺癌。在某些情况下，还会出现甲状腺功能亢进（请参阅“警告”和“不良反应” ）。

手术

对于接受胺碘酮治疗的全麻患者，建议对其围手术期进行密切监测，因为它们可能对卤化吸入麻醉药的心肌抑制药和传导缺陷更为敏感。

角膜屈光激光手术

应建议患者，大多数制造角膜屈光激光手术设备的人禁止在服用Cordarone的患者中进行该手术。

药物相互作用

胺碘酮被细胞色素P450（CYP450）酶组代谢为去乙基胺碘酮，特别是细胞色素P450 3A4（CYP3A4）和CYP2C8。 CYP3A4同工酶存在于肝和肠中（见临床药理，药代动力学和代谢）。胺碘酮是CYP3A4和p-糖蛋白的抑制剂。因此，胺碘酮具有与可能是CYP3A4底物，抑制剂或诱导剂以及p-糖蛋白底物的药物或物质相互作用的潜力。虽然仅报道了与胺碘酮的体内药物相互作用的有限次数，主要是口服制剂，但应预料到其他相互作用的可能性。这对于与严重毒性相关的药物（例如其他抗心律不齐药物）尤其重要。如果需要此类药物，应重新评估其剂量，并在适当的情况下测量血浆浓度。鉴于胺碘酮的半衰期较长且变化不定，因此不仅与伴随用药而且在胺碘酮停用后给药的药物之间都存在药物相互作用的可能性。

由于胺碘酮是CYP3A4和CYP2C8的底物，因此抑制这些同功酶的药物/物质可能会减少代谢并增加胺碘酮的血清浓度。报告的示例包括以下内容：

蛋白酶抑制剂：

已知蛋白酶抑制剂会不同程度地抑制CYP3A4。一名患者一天三次服用胺碘酮200 mg和茚地那韦800 mg的病例报告导致胺碘酮浓度从0.9 mg / L增加到1.3 mg / L。 DEA浓度不受影响。没有毒性的证据。应考虑在伴随蛋白酶抑制剂治疗期间监测胺碘酮的毒性并连续测量胺碘酮的血清浓度。

组胺H 1拮抗剂：

氯雷他定是一种非镇静抗组胺药，主要经CYP3A4代谢。与氯雷他定和胺碘酮合用时，有报告说QT间期延长和尖端扭转型室速。

组胺H 2拮抗剂：

西咪替丁抑制CYP3A4并能增加血清胺碘酮水平。

抗抑郁药：

曲唑酮是一种抗抑郁药，主要经CYP3A4代谢。据报道，曲唑酮与胺碘酮合用可延长QT间隔和扭转扭转性发作。

其他物质：

给健康志愿者葡萄柚汁增加50％胺碘达隆AUC和Cmax 84％，从而导致胺碘酮血浆水平升高。口服胺碘酮治疗期间不应服用葡萄柚汁。从静脉胺碘酮改为口服胺碘酮时，应考虑此信息（请参阅剂量和管理，静脉内至口服过渡）。

胺碘酮抑制p-糖蛋白和某些CYP450酶，包括CYP1A2，CYP2C9，CYP2D6和CYP3A4。这种抑制可能导致其他药物的血浆水平出乎意料地高，这些药物被那些CYP450酶代谢或成为p-糖蛋白的底物。报告的这种交互的示例包括：

免疫抑制剂：

据报道，与环磷酰胺（口服胺碘酮）合用时，环孢霉素（CYP3A4底物）可使环孢霉素的血浆浓度持续升高，导致肌酐升高，尽管环孢霉素的剂量减少。

HMG-CoA还原酶抑制剂：

辛伐他汀（CYP3A4底物）与胺碘酮合用与肌病/横纹肌溶解的报道有关。

心血管：

心脏甙：在接受地高辛治疗的患者中，口服胺碘酮定期导致血清地高辛浓度增加，可能达到毒性水平，从而导致临床毒性。与地高辛同时服用的胺碘酮在一天后可使血清地高辛浓度增加70％。口服胺碘酮给药时，应检查对洋地黄疗法的需要，并将剂量减少约50％或停止使用。如果继续进行洋地黄治疗，应密切监测血清水平，并观察患者的毒性临床证据。这些预防措施可能也应适用于洋地黄毒的管理。

抗心律不齐药物：其他抗心律不齐药物，例如奎尼丁，普鲁卡因酰胺，二吡酰胺和苯妥英钠已与胺碘酮同时使用。有病例报告在与胺碘酮同时治疗期间，奎尼丁，普鲁卡因酰胺和苯妥英的稳态水平增加。苯妥英钠降低血清胺碘酮水平。与奎尼丁同时服用的胺碘酮在两天后可使奎尼丁的血清浓度增加33％。胺碘酮与普鲁卡因酰胺同时服用不到7天，可使普鲁卡因酰胺和正乙酰普鲁卡因酰胺的血浆浓度分别增加55％和33％。与胺碘酮合用时，奎尼丁和普鲁卡因酰胺的剂量应减少三分之一。据报道，在口服胺碘酮的存在下，氟卡尼的血浆水平会升高。因此，当同时使用这些药物时，应调整氟卡尼的剂量。一般而言，任何添加的抗心律不齐药物应以低于通常的剂量开始，并进行仔细监测。胺碘酮与其他抗心律不齐疗法的组合应保留用于对单药反应不完全或对胺碘酮反应不完全的危及生命的室性心律失常患者。在转移至口服胺碘酮期间，应在添加口服胺碘酮几天后将先前给药的药物剂量水平降低30％至50％（请参阅剂量和用法，静脉内至口服过渡）。在确定胺碘酮的作用后，应重新考虑是否继续需要其他抗心律不齐药物，并且通常应尝试停用。如果继续治疗，应继续对这些患者进行特别仔细的监测，以监测不良反应，尤其是随着胺碘酮的持续使用，其传导障碍和快速性心律失常加重。在需要额外抗心律不齐治疗的胺碘酮治疗患者中，此类药物的初始剂量应约为通常推荐剂量的一半。

降压药：接受β受体阻滞剂（如普萘洛尔，CYP3A4抑制剂）或钙通道拮抗剂（如维拉帕米，CYP3A4底物和地尔硫卓，CYP3A4抑制剂）的患者应谨慎使用胺碘酮心动过缓，窦性阻滞和房室传导阻滞；如有必要，严重心动过缓或窦性心律停止的患者在插入起搏器后仍可继续使用胺碘酮。

抗凝剂：华法林型（CYP2C9和CYP3A4底物）的抗凝作用在接受胺碘酮的患者中几乎总是可见，并可能导致严重或致命的出血。 Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely. A similar effect has been reported with fluindione , an oral vitamin K antagonist, when administered concomitantly with Cordarone.

Clopidogrel , an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A4 to an active metabolite. A potential interaction between clopidogrel and Cordarone resulting in ineffective inhibition of platelet aggregation has been reported.

Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A4 (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Reported examples of this interaction include the following:

Antibiotics:

Rifampin is a potent inducer of CYP3A4. Administration of rifampin concomitantly with oral amiodarone has been shown to result in decreases in serum concentrations of amiodarone and desethylamiodarone.

Other substances, including herbal preparations:

St. John's Wort (Hypericum perforatum) induces CYP3A4. Since amiodarone is a substrate for CYP3A4, there is the potential that the use of St. John's Wort in patients receiving amiodarone could result in reduced amiodarone levels.

Other reported interactions with amiodarone:

Fentanyl (CYP3A4 substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A4 substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.

Dextromethorphan is a substrate for both CYP2D6 and CYP3A4. Amiodarone inhibits CYP2D6.

Cholestyramine increases enterohepatic elimination of amiodarone and may reduce its serum levels and t 1/2 .

Disopyramide increases QT prolongation which could cause arrhythmia.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. (See PRECAUTIONS, Proarrhythmia .)

Hemodynamic and electrophysiologic interactions have also been observed after concomitant administration with propranolol, diltiazem, and verapamil .

Volatile Anesthetic Agents: (see PRECAUTIONS, Surgery ).

In addition to the interactions noted above, chronic (> 2 weeks) oral Cordarone administration impairs metabolism of phenytoin, dextromethorphan, and methotrexate.

电解质紊乱

Patients with hypokalemia or hypomagnesemia should have the condition corrected whenever possible before being treated with Cordarone IV, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

致癌，诱变，生育力受损

No carcinogenicity studies were conducted with Cordarone IV However, oral Cordarone caused a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors in rats was greater than the incidence in controls even at the lowest dose level tested, ie, 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose1).

Mutagenicity studies conducted with amiodarone HCl (Ames, micronucleus, and lysogenic induction tests) were negative.

No fertility studies were conducted with Cordarone IV However, in a study in which amiodarone HCl was orally administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose1).

1个

600 mg in a 50 kg patient (dose compared on a body surface area basis)

怀孕

Category D . See WARNINGS, Neonatal Hypo- or Hyperthyroidism . In addition to causing infrequent congenital goiter/hypothyroidism and hyperthyroidism, amiodarone has caused a variety of adverse effects in animals.

In a reproductive study in which amiodarone was given intravenouslyto rabbits at dosages of 5, 10, or 25 mg/kg per day (about 0.1, 0.3, and 0.7 times the maximum recommended human dose [MRHD] on a body surface area basis), maternal deaths occurred in all groups, including controls. Embryotoxicity (as manifested by fewer full-term fetuses and increased resorptions with concomitantly lower litter weights) occurred at dosages of 10 mg/kg and above. No evidence of embryotoxicity was observed at 5 mg/kg and no teratogenicity was observed at any dosages.

In a teratology study in which amiodarone was administered by continuous iv infusion to rats at dosages of 25, 50, or 100 mg/kg per day (about 0.4, 0.7, and 1.4 times the MRHD when compared on a body surface area basis), maternal toxicity (as evidenced by reduced weight gain and food consumption) and embryotoxicity (as evidenced by increased resorptions, decreased live litter size, reduced body weights, and retarded sternum and metacarpal ossification) were observed in the 100 mg/kg group.

Cordarone ® IV should be used during pregnancy only if the potential benefit to the mother justifies the risk to the fetus.

护理母亲

Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone should be weighed against the potential benefit of arrhythmia suppression in the mother. The mother should be advised to discontinue nursing.

人工与分娩

It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.

儿科用

The safety and efficacy of Cordarone in the pediatric population have not been established; therefore, its use in pediatric patients is not recommended. In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and atrio-ventricular block (15%) were common dose-related adverse events and were severe or life-threatening in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients receiving Cordarone IV through a peripheral vein irrespective of dose regimen.

Cordarone IV contains the preservative benzyl alcohol (see DESCRIPTION ). There have been reports of fatal “gasping syndrome” in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

老人用

Clinical studies of Cordarone IV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.一般而言，老年患者的剂量选择应谨慎，通常从给药范围的低端开始，这反映出肝，肾或心脏功能下降以及伴随疾病或其他药物治疗的频率更高。

不良反应

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received Cordarone IV for at least 1 week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

The most important treatment-emergent adverse effects were hypotension, asystole/cardiac arrest/electromechanical dissociation (EMD), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse effects. The most common adverse effects leading to discontinuation of Cordarone IV therapy were hypotension (1.6%), asystole/cardiac arrest/EMD (1.2%), VT (1.1%), and cardiogenic shock (1%).

The following table lists the most common (incidence ≥ 2%) treatment-emergent adverse events during Cordarone IV therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse events appeared to be dose-related.

SUMMARY TABULATION OF TREATMENT-EMERGENT DRUG-RELATED STUDY EVENTS IN PATIENTS RECEIVING Cordarone IV IN CONTROLLED AND OPEN-LABEL STUDIES (≥ 2% INCIDENCE)

Study Event	Controlled Studies (n=814)	Open-Label Studies (n=1022)	总 (n=1836)
身体整体
发热	24 (2.9%)	13 (1.2%)	37 (2.0%)
心血管系统
心动过缓	49 (6.0%)	41 (4.0%)	90 (4.9%)
Congestive heart failure	18 (2.2%)	21 (2.0%)	39 (2.1%)
Heart arrest	29 (3.5%)	26 (2.5%)	55 (2.9%)
Hypotension	165 (20.2%)	123 (12.0%)	288 (15.6%)
Ventricular tachycardia	15 (1.8%)	30 (2.9%)	45 (2.4%)
消化系统
肝功能检查异常	35 (4.2%)	29 (2.8%)	64 (3.4%)
恶心	29 (3.5%)	43 (4.2%)	72 (3.9%)

Other treatment-emergent possibly drug-related adverse events reported in less than 2% of patients receiving Cordarone IV in Wyeth-Ayerst controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting.

Postmarketing Reports

In postmarketing surveillance, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, renal impairment, renal insufficiency, acute renal failure, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pleuritis, pseudotumor cerebri, syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, hallucination, confusional state, disorientation, delirium, epididymitis, and impotence also have been reported with amiodarone therapy.

Also, in patients receiving recommended dosages of Cordarone IV, there have been postmarketing reports of the following injection site reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing (see DOSAGE AND ADMINISTRATION ).

过量

There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of Cordarone IV include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Hypotension and cardiogenic shock should be treated by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Hepatic enzyme concentrations should be monitored closely. Amiodarone is not dialyzable.

剂量和给药

Amiodarone shows considerable interindividual variation in response. Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose as needed is essential. The recommended starting dose of Cordarone IV is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:

Cordarone IV DOSE RECOMMENDATIONS– FIRST 24 HOURS –

Loading infusions	First Rapid:	150 mg over the FIRST 10 minutes (15 mg/min).
		Add 3 mL of Cordarone IV (150 mg) to 100 mL D 5 W (concentration = 1.5 mg/mL). Infuse 100 mL over 10 minutes.
	Followed by Slow:	360 mg over the NEXT 6 hours (1 mg/min).
		Add 18 mL of Cordarone IV (900 mg) to 500 mL D 5 W (concentration = 1.8 mg/mL).
Maintenance infusion		540 mg over the REMAINING 18 hours (0.5 mg/min).
		Decrease the rate of the slow loading infusion to 0.5 mg/min.

After the first 24 hours , the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should be continued utilizing a concentration of 1 to 6 mg/mL (Cordarone IV concentrations greater than 2 mg/mL should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, 150-mg supplemental infusions of Cordarone IV mixed in 100 mL of D 5 W may be administered. Such infusions should be administered over 10 minutes to minimize the potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.

The first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2100 mg were associated with an increased risk of hypotension. The initial infusion rate should not exceed 30 mg/min.

Based on the experience from clinical studies of Cordarone IV, a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient's age, renal function, or left ventricular function. There has been limited experience in patients receiving Cordarone IV for longer than 3 weeks.

The surface properties of solutions containing injectable amiodarone are altered such that the drop size may be reduced. This reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used. Cordarone IV must be delivered by a volumetric infusion pump.

Cordarone IV should, whenever possible, be administered through a central venous catheter dedicated to that purpose. An in-line filter should be used during administration.

Cordarone IV loading infusions at much higher concentrations and rates of infusion much faster than recommended have resulted in hepatocellular necrosis and acute renal failure, leading to death (see PRECAUTIONS, Liver Enzyme Elevations ).

Cordarone IV concentrations greater than 3 mg/mL in D 5 W have been associated with a high incidence of peripheral vein phlebitis; however, concentrations of 2.5 mg/mL or less appear to be less irritating. Therefore, for infusions longer than 1 hour, Cordarone IV concentrations should not exceed 2 mg/mL unless a central venous catheter is used (see ADVERSE REACTIONS, Postmarketing Reports ).

Cordarone IV infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D 5 W. Use of evacuated glass containers for admixing Cordarone IV is not recommended as incompatibility with a buffer in the container may cause precipitation.

It is well known that amiodarone adsorbs to polyvinyl chloride (PVC) tubing and the clinical trial dose administration schedule was designed to account for this adsorption. All of the clinical trials were conducted using PVC tubing and its use is therefore recommended. The concentrations and rates of infusion provided in DOSAGE AND ADMINISTRATION reflect doses identified in these studies. Cordarone IV has been found to leach out plasticizers, including DEHP [di-(2-ethylhexyl)phthalate] from intravenous tubing (including PVC tubing). The degree of leaching increases when infusing Cordarone IV at higher concentrations and lower flow rates than provided in DOSAGE AND ADMINISTRATION . In addition, polysorbate 80, a component of Cordarone IV, is also known to leach

注意：本文档包含有关胺碘酮的副作用信息。此页面上列出的某些剂型可能不适用于品牌名称Cordarone。

对于消费者

适用于胺碘酮：口服片剂

其他剂型：

• 静脉内溶液

警告

口服途径（平板电脑）

胺碘酮口服片剂仅适用于具有所指示的危及生命的心律不齐的患者，因为其使用会带来明显的毒性。胺碘酮可引起肺部毒性（超敏性肺炎或间质/肺泡性肺炎），在某些系列患者中，其临床表现的疾病发病率高达17％。大约10％的时间，肺毒性是致命的。开始治疗时，应获得基线的胸部X射线和肺功能检查，包括扩散能力。每3至6个月重复病史，体格检查和胸部X光检查。胺碘酮可引起肝毒性，这可能是致命的。获得基线和定期肝转氨酶，如果增加超过正常水平的三倍，则中止或降低剂量，或者基线升高的患者加倍。如果患者出现临床肝损伤的体征或症状，请中止治疗。胺碘酮可加剧心律不齐。在可获得连续心电图和心脏复苏的临床环境中开始。

需要立即就医的副作用

胺碘酮（Cordarone中包含的活性成分）及其所需的作用可能会引起某些不良作用。尽管并非所有这些副作用都可能发生，但如果确实发生了，则可能需要医疗护理。

服用胺碘酮时，如果有下列任何副作用，请立即咨询医生：

比较普遍;普遍上

• 咳嗽
• 头晕，头晕或昏厥
• 发烧（轻微）
• 手指或脚趾麻木或刺痛
• 痛苦的呼吸
• 皮肤对阳光的敏感性
• 颤抖或握手
• 走路有麻烦
• 身体的异常和不受控制的运动
• 手臂或腿部无力

不常见

• 脸部，颈部和手臂的皮肤呈蓝灰色
• 在物体周围看到视线模糊或蓝绿色光晕
• 寒冷
• 眼睛干涩
• 干燥，浮肿的皮肤
• 快速或不规则心跳
• 紧张
• 阴囊疼痛和肿胀
• 眼睛对光的敏感性
• 对热敏感
• 心跳缓慢
• 出汗
• 脚或小腿肿胀
• 睡觉有麻烦
• 不寻常的疲倦
• 体重增加或减少

罕见

• 皮疹
• 眼睛或皮肤发黄

发病率未知

• 搅动
• 背部，腿部或胃部疼痛
• 牙龈出血
• 皮肤起泡，脱皮或松弛
• 腹胀
• 尿液中的血液
• 血腥，黑色或柏油样的粪便
• 嘴唇，指甲或皮肤发蓝
• 模糊或双眼
• 胸痛
• 发冷
• 黏土色凳子
• 混乱
• 时间，地点或人的困惑
• 咳嗽或吐血
• 皮肤裂缝
• 黑尿
• 意识或反应能力下降
• 尿量减少
• 萧条
• 腹泻
• 呼吸困难或劳累
• 小便困难
• 干咳
• 眼痛
• 快速的心跳
• 全身肿胀
• 高烧
• 持有无法通过事实改变的错误信念
• 敌意
• 无法勃起或勃起
• 消化不良
• 不规则，快速或缓慢或呼吸浅
• 易怒
• 瘙痒
• 关节或肌肉疼痛
• 面部，眼睑，嘴唇，舌头，喉咙，手，腿，脚或生殖器上的大型蜂巢状肿胀
• 性能力，欲望，动力或表现丧失
• 意识丧失
• 身体热量散失
• 下背部或侧面疼痛
• 情绪或精神变化
• 肌肉抽筋，痉挛，抽搐，疼痛或僵硬
• 没有呼吸
• 嘈杂的呼吸
• 流鼻血
• 腹部，腹股沟或阴囊疼痛
• 疼痛或排尿灼痛
• 胃部，侧面或腹部疼痛，可能放射到背部
• 皮肤苍白
• 查明皮肤上的红色斑点
• 体重快速增加
• 皮肤病变为红色，中心常为紫色
• 眼睛发红
• 皮肤红肿
• 鳞状皮
• 看到，听到或感觉不到的东西
• 癫痫发作
• 严重头痛
• 严重嗜睡
• 打喷嚏
• 咽喉痛
• 嘴唇或嘴中的疮，溃疡或白斑
• 肚子痛
• 脸，脚踝或手肿胀
• 阴囊肿胀
• 腺体肿胀或疼痛
• 胸闷
• 呼吸困难
• 难闻的呼吸异味
• 异常出血或瘀伤
• 不寻常的嗜睡，迟钝，疲倦，虚弱或懒散的感觉
• 异常兴奋，紧张或躁动
• 吐血

不需要立即就医的副作用

胺碘酮可能会发生一些通常不需要医疗的副作用。随着身体对药物的适应，这些副作用可能会在治疗期间消失。另外，您的医疗保健专业人员可能会告诉您一些预防或减少这些副作用的方法。

请咨询您的医疗保健专业人员，是否持续存在以下不良反应或令人讨厌，或者是否对这些副作用有任何疑问：

比较普遍;普遍上

• 便秘
• 头痛
• 食欲不振
• 恶心
• 呕吐

不常见

• 苦味或金属味
• 性兴趣减少
• 男性性能力下降
• 温暖的感觉
• 脸部，颈部，手臂发红，偶尔上胸部发红

对于医疗保健专业人员

适用于胺碘酮：复方散剂，静脉内溶液剂，口服片剂

一般

最常见的不良反应是角膜微沉积，低血压和光敏性。 ^[参考]

心血管的

很常见（10％或更高）：低血压（高达20.2％）

常见（1％至10％）：心动过缓，血压下降，充血性心力衰竭，心跳骤停，室性心动过速，心律不齐，窦房结功能障碍，潮红

罕见（0.1％至1％）：传导干扰

非常罕见（少于0.01％）：明显的心动过缓，窦性骤停，血管炎，潮热

未报告频率：扭转性尖锐湿疣，崩溃，房颤，淋巴结节律性心律失常，QT间隔延长，窦性心动过缓，心室纤颤，休克，心搏停止，无脉电活动，心源性休克，房室传导阻滞，严重低血压

上市后报告：窦房传导阻滞，脑室内传导障碍，束支传导阻滞，His-His传导阻滞，心室前收缩，通过辅助途径进行顺行传导^[参考]

肝的

常见（1％至10％）：急性肝病，血清转氨酶和/或黄疸高，包括肝功能衰竭，肝功能检查异常，非特异性肝病

非常罕见（少于0.01％）：假性酒精性肝炎，肝硬化，血清转氨酶升高

未报告频率：ALT增加，AST增加

上市后报告：胆汁淤积性肝炎，胆汁淤积，黄疸，碱性磷酸酶升高，血液乳酸脱氢酶升高，肝炎^[参考]

呼吸道

常见（1％至10％）：肺毒性，肺部炎症或纤维化，成人呼吸窘迫综合征

非常罕见（少于0.01％）：支气管痉挛，间质性肺炎，严重的呼吸系统并发症，呼吸暂停

未报告频率：肺出血，肺水肿，呼吸系统疾病，肺泡性肺炎

售后报告：可能致命的呼吸系统疾病，闭塞性细支气管炎，肺炎，呼吸困难，咳嗽，咯血，喘息，缺氧，肺部浸润，肺部肿块，胸膜炎，肺磷脂血症，胸腔积液，嗜酸性粒细胞性肺炎，急性呼吸窘迫综合征^[参考]

眼科

很常见（10％或更多）：角膜微沉积物（高达90％或更多）

常见（1％至10％）：视觉障碍

非常罕见（少于0.01％）：视神经病变/神经炎

未报告频率：永久性失明，乳头水肿，角膜变性，眼睛不适，葡萄球菌，晶状体混浊，黄斑变性，角膜病，眼睛僵硬，瘙痒，灼痛

上市后报告：视野缺损，视力模糊^[参考]

皮肤科

非常常见（10％或更高）：光敏性（高达10％）

常见（1％至10％）：轻度暴露的皮肤呈灰白色或蓝色沉淀

非常罕见（少于0.01％）：红斑，皮疹，剥脱性皮炎，脱发，出汗

未报告频率：肉芽肿，血管性水肿，荨麻疹，史蒂文斯-约翰逊综合征，自发性瘀斑，脓疱型牛皮癣

上市后报告：有毒的表皮坏死，多形性红斑，皮肤癌，瘙痒，大疱性皮炎，伴有嗜酸性粒细胞增多症和全身症状（DRESS）的皮疹，湿疹^[参考]

神经系统

常见（1％至10％）：锥体外系症状，锥体外系震颤，震颤/不自主运动异常，缺乏协调能力，步态异常/共济失调，头晕，感觉异常，头痛，味觉和气味异常

罕见（0.1％至1％）：周围感觉运动神经病

非常罕见（少于0.01％）：小脑共济失调，良性颅内高压，眩晕

未报告频率：周围神经病变，脱髓鞘性多神经病，神经传导异常，神经脂质异常，神经肌病，妄想症

上市后报告：混乱状态，迷失方向，del妄，颅内压升高，感觉不足，帕金森病症状^[参考]

精神科

常见（1％至10％）：噩梦，睡眠障碍，性欲下降，失眠，睡眠障碍

未报告频率：梦dream以求的慢性焦虑症

上市后报告：幻觉^[参考]

胃肠道

常见（1％至10％）：恶心，便秘，腹痛，流涎异常

未报告频率：呕吐，消化不良，腹泻

上市后报道：胰腺炎，急性胰腺炎，口干^[参考]

其他

常见（1％至10％）：发烧，全身乏力，疲劳^[参考]

内分泌

很常见（10％或更多）：甲状腺功能减退（高达10％）

常见（1％至10％）：甲状腺功能亢进

非常罕见（少于0.01％）：抗利尿激素分泌不当综合征

未报告频率：甲状腺功能检查异常

上市后报告：甲状腺结节/癌症^[参考]

新陈代谢

常见（1％至10％）：厌食症，水肿

未报告频率：体重增加，症状性高钙血症，食欲下降^[参考]

血液学

常见（1％至10％）：凝血异常

非常罕见（少于0.01％）：溶血性贫血，再生障碍性贫血，血小板减少

未报告频率：骨髓肉芽肿，骨髓抑制

上市后报告：全血细胞减少，中性粒细胞减少，粒细胞缺乏症，粒细胞缺乏症^[参考]

肌肉骨骼

常见（1％至10％）：肌肉无力

未报告频率：腰痛

上市后报道：肌病，横纹肌溶解，肌肉痉挛，狼疮样综合征^[参考]

本地

常见（1％至10％）：注射部位反应^[参考]

泌尿生殖

非常罕见（少于0.01％）：附睾睾丸炎，阳imp

上市后报告：附睾炎^[参考]

免疫学的

非常罕见（小于0.01％）：过敏性休克

未报告频率：过敏反应，抗核抗体阳性，免疫球蛋白水平升高

上市后报告：过敏/类过敏反应^[参考]

肾的

非常罕见（少于0.01％）：血液肌酐增加

未报告频率：肾功能异常，慢性肾功能衰竭加重

上市后报告：肾功能不全，肾功能不全，急性肾衰竭^[参考]

参考文献

1.“产品信息。Cordarone（胺碘酮）。”宾夕法尼亚州费城惠氏-爱思德实验室。

2. Cerner Multum，Inc.“澳大利亚产品信息”。 00

3. Cerner Multum，Inc.“英国产品特性摘要”。 00

4.“产品信息。Cordarone静脉注射（胺碘酮）。”宾夕法尼亚州费城惠氏-爱思德实验室。

某些副作用可能没有报道。您可以将其报告给FDA。

Cordarone说明

Cordarone（盐酸胺碘酮）是一类抗心律不齐药物，主要具有III类（Vaughan Williams分类）的作用，可以粉红色，刻痕片剂的形式口服，含200毫克盐酸胺碘酮。存在的非活性成分是胶体二氧化硅，乳糖，硬脂酸镁，聚维酮，淀粉和FD＆C Red40。Cordarone是苯并呋喃衍生物：2-丁基-3-苯并呋喃基4- [2-（二乙氨基）-乙氧基] -3， 5-二碘苯基酮盐酸盐。

结构式如下：

盐酸胺碘酮是白色至米黄色的结晶性粉末。微溶于水，溶于乙醇，易溶于氯仿。它包含按重量计37.3％的碘。

Cordarone-临床药理学

电生理学/作用机制

在动物中，Cordarone可有效预防或抑制实验性心律失常。 Cordarone的抗心律不齐作用可能归因于至少两个主要特性：

1. 延长心肌细胞动作电位的持续时间和不应期
2. α和β肾上腺素受体的非竞争性拮抗作用。

Cordarone延长了所有心脏纤维动作电位的持续时间，同时使dV / dt的降低最小（动作电位的最大上冲速度）。所有心脏组织的不应期均延长。除了在自动细胞中，电势的斜率减小（通常会降低自动性）之外，Cordarone可以增加心脏不应期，而不会影响静止的膜电位。这些电生理效应反映为窦率降低15％至20％，PR和QT间隔增加约10％，U波的发展以及T波轮廓的变化。这些变化不应要求终止Cordarone，因为它们是其药理作用的证据，尽管Cordarone可以引起明显的窦性心动过缓或窦性阻滞和心脏传导阻滞。在极少数情况下，QT延长与心律不齐恶化有关（请参阅“警告” ）。

血液动力学

在动物研究中和在人中静脉内给药后，Cordarone可使血管平滑肌松弛，降低外周血管阻力（后负荷），并略微增加心脏指数。但是，口服给药后，即使在LVEF降低的患者中，Cordarone也不会使左心室射血分数（LVEF）产生明显变化。在对人进行急性静脉内给药后，Cordarone可能具有轻度的负性肌力作用。

药代动力学

人体口服后，Cordarone缓慢而可变地吸收。 Cordarone的生物利用度约为50％，但在各种研究中，其生物利​​用度在35％和65％之间变化。单次给药后3至7小时可达到最大血浆浓度。尽管如此，起效可能在2到3天之内发生，但更常见的是需要1到3周，即使是加药剂量也是如此。慢性剂量为100至600毫克/天的血浆浓度与剂量成正比，每100毫克/天平均增加0.5毫克/升。然而，这些手段包括相当大的个体可变性。食物会增加Cordarone的吸收率和吸收程度。在30名健康受试者中研究了食物对Cordarone生物利用度的影响，这些受试者在食用高脂餐后和通宵禁食后立即接受了600 mg单剂量。在有食物的情况下，胺碘酮的血浆浓度-时间曲线下面积（AUC）和峰值血浆浓度（C max ）分别增加了2.3倍（范围为1.7至3.6）和3.8倍（范围为2.7至4.4）。食物还增加了胺碘酮的吸收率，使达到血浆峰值浓度（T max ）的时间减少了37％。胺碘酮，去乙基胺碘酮（DEA）的主要代谢物的平均AUC和平均C max分别增加了55％（范围为58至101％）和32％（范围为4至84％），但T值没有变化Max在食物的存在。

由于在各种部位，特别是脂肪组织和高度灌注的器官，例如肝，肺和脾脏中大量积累，Cordarone的分布体积非常大，但变化很大，平均约为60 L / kg。人体中已发现一种Cordarone的主要代谢物DEA。它几乎在所有组织中积累。目前尚无关于人体内DEA活性的数据，但在动物中，它具有显着的电生理和抗心律失常作用，通常类似于胺碘酮本身。 DEA对口服胺碘酮的抗心律失常作用的确切作用和贡献尚不确定。口服科达隆后，人类最大心室III类作用的发展与DEA随时间的积累比与胺碘酮的积累更紧密相关。

胺碘酮被细胞色素P450（CYP）酶组代谢为DEA，特别是CYP3A和CYP2C8。 CYP3A同工酶存在于肝脏和肠道中。在体外，胺碘酮和DEA具有抑制CYP2C9，CYP2C19，CYP2D6，CYP3A，CYP2A6，CYP2B6和CYP2C8的潜能。胺碘酮和DEA也具有抑制某些转运蛋白（如P-糖蛋白和有机阳离子转运蛋白（OCT2））的潜力。

胺碘酮主要通过肝代谢和胆汁排泄而消除，尿中胺碘酮或DEA的排泄量可忽略不计。胺碘酮和DEA都不可透析。

在2到7天的临床研究中，VT和VF患者静脉给药后胺碘酮的清除范围为220至440 ml / hr / kg。年龄，性别，肾脏疾病和肝病（肝硬化）对胺碘酮或DEA的处置没有明显影响。肾功能不损害胺碘酮的药代动力学。在肝硬化患者中单剂量静脉注射胺碘酮后，DEA的C max和平均浓度值明显降低，但胺碘酮的平均水平未改变。 65岁以上的正常受试者的清除率（约100 ml / hr / kg）低于年轻受试者（约150 ml / hr / kg）， t½从约20天增加至47天。在患有严重左心功能不全的患者中，胺碘酮的药代动力学没有明显改变，但DEA的终末处置t½延长。尽管在用Cordarone进行慢性治疗期间未定义针对肾，肝或心脏异常患者的剂量调整，但对于老年患者和严重左心功能不全的患者，应谨慎进行临床监测。

在12位健康受试者中单次给药后，Cordarone表现出多室药代动力学，胺碘酮的平均表观血浆末端消除半衰期为58天（范围为15至142天），而活性成分为36天（范围为14至75天）。代谢物（DEA）。在患者中，停止长期口服治疗后，Cordarone已被证明具有两相消除作用，在2.5至10天后血浆水平最初降低了一半。末端血浆消除阶段要慢得多，显示出母体化合物的半衰期为26至107天，平均约为53天，大多数患者为40至55天。因此，在没有加药期的情况下，在恒定口服剂量下，稳态血浆浓度将在130天至535天之间达到平均265天。对于代谢物，平均血浆消除半衰期约为61天。这些数据可能反映了从灌注良好的组织中最初清除了药物（2.5至10天的半衰期阶段），然后是代表从灌注不良的组织隔室（例如脂肪）中清除极慢的最终阶段。

一旦通过负荷剂量实现了心律失常控制，消除的两个阶段中受试者之间的显着差异以及不确定哪个药室对药物作用至关重要的不确定性就需要注意各个个体的反应，因为正确的维持剂量部分取决于药物的剂量。消除率。 Cordarone的每日维持剂量应根据患者的个人需求（请参阅“剂量和管理” ）。

Cordarone及其代谢产物的经胎盘转移量有限，约为10％至5​​0％。母乳中已检测到母体药物及其代谢产物。

Cordarone高度结合蛋白质（约96％）。

尽管可以在肠胃外注射Cordarone后数小时内看到电生理效应（例如QTc延长），但对异常节律的影响在2到3天之前看不到，即使使用负荷剂量也通常需要1到3周。效果可能会持续持续更长的时间。有证据表明，使用加药剂量方案时，作用时间更短。

与缓慢的消除速度相一致，在停用Cordarone后，抗心律失常作用持续数周或数月，但复发时间可变且无法预测。通常，当心律失常复发后恢复药物治疗时，与初始反应相比，控制建立得相对较快，这可能是因为在复发时组织存储并未完全耗尽。

药效学

血浆浓度与有效性之间没有公认的关系，但似乎确实低于1 mg / L的浓度通常是无效的，并且通常不需要高于2.5 mg / L的浓度。在个体内降低剂量并随之降低血浆浓度可能会导致心律失常控制丧失。血浆浓度测量可用于识别水平异常低，可能受益于剂量增加或异常高，并且可能减少剂量以最大程度降低副作用的患者。一些观察结果表明，血浆浓度，剂量或剂量/持续时间关系对诸如肺纤维化，肝酶升高，角膜沉积和面部色素沉着，周围神经病变，胃肠道和中枢神经系统影响等副作用具有影响。

监控效果

预测任何抗心律失常药物在长期预防复发性室性心动过速和心室纤颤中的有效性是困难且有争议的，高素质的研究人员建议使用动态监护，程序性电刺激和各种刺激方案或两者结合来评估响应。目前，关于如何最好地评估有效性的许多方面尚无共识，但在某些方面存在合理的共识：

1. 如果有心脏骤停病史的患者在治疗前的心电图监测过程中未表现出血液动力学不稳定的心律失常，则对Cordarone有效性的评估需要采取一些刺激性方法，包括运动或程序性电刺激（PES）。
2. 确实会威胁生命的心律不齐的患者是否也需要挑衅尚不确定，但是有理由考虑在此类患者中考虑使用PES或其他挑衅。在部分患者中，Cordarone可以使PES诱导的心律失常无法诱导（这一比例在各个系列中从不到10％到几乎40％都有很大差异，可能是由于不同的刺激标准所致），预后几乎是一致的极好，复发率极低（室性心动过速或猝死）。更具争议性的是持续可诱导性的含义。有一种印象是，Cordarone患者的持续可诱导性可能不会预示不良的预后，但实际上，许多观察者发现，仍可诱导的患者的复发率高于未诱导的患者。然而，已经提出了许多标准，用于鉴定仍可诱导但似乎仍在Cordarone上表现良好的患者。这些标准包括增加的诱导难度（更多的刺激或更快的刺激），据报道其预测较低的复发率，以及耐受无严重症状的诱发性室性心动过速的能力，据报道这一发现与更好的相关性有关。生存率，但复发率较低。虽然这些标准需要确认并总体上需要进一步研究，但更容易诱导或导致对心律失常的耐受性较差，应建议考虑修改治疗方法。

还提出了一些不基于PES的成功预测指标，包括动态监测中完全消除所有非持续性室性心动过速和非常低的室性早搏率（小于1 VPB / 1,000正常搏动）。

尽管这些问题对于Cordarone而言仍然未解决，但对于其他药物而言，Cordarone的开药者应能够（直接或通过转诊）接触并熟悉用于危及生命的心律不齐患者的所有评估程序。

很难描述Cordarone的有效率，因为这些取决于所治疗的特定心律失常，成功的标准，患者的潜在心脏病，求助于Cordarone之前尝试的药物数量，随访时间，虫草酮的剂量，使用其他抗心律不齐药物以及许多其他因素。由于Cordarone主要针对难治性危及生命的室性心律失常患者进行研究，因此必须根据反应选择药物治疗且不能随意分配药物治疗，因此不可能与其他药物或安慰剂进行随机比较。一系列具有心脏骤停史且平均随访时间为一年或一年以上的治疗患者的报告给出的死亡率（由于心律不齐）变化很大，范围从小于5％到超过30％，在大多数情况下在10％到15％的范围内。总体心律失常复发率（致命和非致命）也存在很大差异（如上所述，取决于对PES的反应和其他措施），并且取决于是否包括最初似乎没有反应的患者。在大多数情况下，仅考虑看起来反应良好且可以接受长期治疗的患者，复发率范围为20％至40％，平均随访时间为一年或一年以上。

虫草酮的适应症和用法

由于其危及生命的副作用以及与其使用相关的大量管理困难（请参阅下面的“警告” ），Cordarone仅适用于治疗以下已记录的，危及生命的复发性室性心律失常，而这些反应仍未得到证实足够剂量的其他可用抗心律失常药物或无法耐受替代药物时。

1. 反复发生心室纤颤。
2. 反复出现血液动力学不稳定的室性心动过速。

与其他抗心律不齐药物一样，对照试验也没有证据表明使用Cordarone片剂会有利地影响生存。

只能由熟悉并能够（直接或通过转介）使用所有可用方法来治疗复发性危及生命的室性心律失常的医师，并有权使用适当的监视设施，包括医院内和门诊连续检查心电图监测和电生理技术。由于所治疗的心律失常危及生命的性质，与先前治疗的潜在相互作用以及心律失常的可能加重，应在医院内开始使用Cordarone进行治疗。

禁忌症

心源性休克患者禁用卡达酮。严重的窦房结功能障碍，引起明显的窦性心动过缓；二级或三级房室传导阻滞；以及心动过缓发作引起晕厥时（与起搏器配合使用时除外）。

在对药物或其任何成分（包括碘）过敏的患者中，Cordarone是禁忌的。

警告事项

死亡

在美国国家心脏，血液和血液研究所的心律失常抑制试验（CAST）中，一项长期，多中心，随机，双盲研究针对无症状，无危及生命的室性心律失常患者，其心肌梗死超过在六天前不到两年的时间里，与分配给匹配安慰剂治疗组的患者相比，用恩卡尼酯或氟卡尼治疗的患者（56/730）死亡率高或非致命性心脏骤停率高（22/725） ）。在这项研究中，恩卡尼或氟卡尼的平均治疗时间为十个月。

在两项涉及心梗后患者的1202（加拿大胺碘酮心肌梗死心律失常试验； CAMIAT）和1486（欧洲心肌梗塞胺碘酮试验； EMIAT）随访的两项多中心，随机，双盲，安慰剂对照试验中评估了Cordarone治疗。到2年。 CAMIAT的患者具有室性心律失常的资格，随机分组使用胺碘酮的患者接受体重和反应调整后的剂量为200至400 mg / day。符合EMIAT标准的射血分数< 40％的患者，随机分组为胺碘酮的患者接受200毫克/天的固定剂量。两项研究都有长达数周的负荷剂量计划。意向性治疗全因死亡率结果如下：

这些数据与涉及结构性心脏病（包括心肌梗死）患者的较小规模，对照研究的汇总分析结果一致。

肺毒性

上市后的报告显示，口服或不使用初始IV治疗的口服Cordarone治疗的患者，其急性发作（数天至数周）的肺损伤。发现包括X线检查的肺部浸润和/或肿块，肺泡出血，胸腔积液，支气管痉挛，喘息，发烧，呼吸困难，咳嗽，咯血和缺氧。一些病例已经发展为呼吸衰竭和/或死亡。上市后报告描述了用低剂量的虫草酮治疗的患者的肺毒性病例；然而，报告表明使用较低的负荷量和维持剂量的Cordarone与降低Cordarone引起的肺毒性的发生有关。

Cordarone片可能会导致临床咳嗽和进行性呼吸困难，并伴有与肺毒性相一致的功能，影像学，镓扫描和病理数据，在大多数已发表的报告中，其频率在2％至7％之间变化，但高达在某些报告中占10％到17％。因此，在开始进行Cordarone治疗时，应进行基线胸部X射线和肺功能检查，包括扩散能力。患者应每3至6个月返回病史，体格检查和胸部X光检查。

继可达酮后的肺毒性似乎是由分别为超敏性肺炎（包括嗜酸性粒细胞性肺炎）或间质/肺泡性肺炎代表的间接或直接毒性引起的。

如果存在肺毒性，则先前患有肺部疾病的患者预后较差。

过敏性肺炎通常在治疗过程中出现较早，对这些患者使用Cordarone进行再治疗会导致更快的复发速度和更大的严重程度。

支气管肺泡灌洗是确定该诊断的首选方法，当发现T抑制物/细胞毒性（CD8阳性）淋巴细胞增多时，可以进行此检查。这些患者应开始类固醇治疗，并停用Cordarone治疗。

间质/肺泡性肺炎可能是由于氧自由基的释放和/或磷脂化所致，其特征是在肺活检标本中发现了弥漫性肺泡损伤，间质性肺炎或纤维化。在大多数由Cordarone引起的肺毒性病例中，都会由于磷脂酶的抑制而导致磷脂病（泡沫细胞，泡沫巨噬细胞）。然而，这些变化也出现在所有接受Cordarone治疗的患者中，约50％。这些细胞应被用作治疗的标志物，而不是毒性的证据。诊断卡达隆诱发的间质/肺泡性肺炎至少应导致剂量减少或最好是撤回卡达隆以建立可逆性，尤其是在可获得其他可接受的抗心律不齐疗法的情况下。如果采取了这些措施，通常会在第一周内发现胺碘酮引起的肺毒性症状减轻，而在最初的两到三周内临床改善最大。胸部X光改变通常在两到四个月内消失。一些专家认为，类固醇可能是有益的。已经给予泼尼松40至60毫克/天的剂量或等效剂量的其他类固醇，并根据患者的病情在数周内逐渐减少。在某些情况下，以较低剂量的Cordarone进行再攻击并没有导致毒性的恢复。

对于接受Cordarone的患者，任何新的呼吸道症状均应提示可能发生肺毒性，并应重复病史，体格检查，胸部X线检查和肺功能检查（具有弥散能力）。扩散能力降低15％具有较高的敏感性，但对肺毒性只有中等的特异性。随着扩散能力的降低接近30％，灵敏度降低，但特异性提高。镓扫描也可以作为诊断检查的一部分进行。

约10％的病例因肺毒性继发死亡。然而，对于有致命性心律失常的患者，应谨慎考虑因怀疑药物诱发的肺毒性而终止Cordarone治疗，因为这些患者最常见的死亡原因是心源性猝死。因此，在这些患者中止使用Cordarone之前，应尽一切努力排除其他引起呼吸障碍的原因（例如，必要时用Swan-Ganz导管进行充血性心力衰竭，呼吸道感染，肺栓塞，恶性肿瘤等）。此外，可能需要进行支气管肺泡灌洗，经支气管肺活检和/或肺开放性活检以确认诊断，尤其是在没有可接受的替代疗法的情况下。

如果确诊为Cordarone诱发的超敏性肺炎，应停用Cordarone，并应开始使用类固醇治疗。如果确诊为Cordarone诱发的间质性/肺泡性肺炎，应开始进行类固醇治疗，最好停止使用Cordarone或至少减少剂量。在降低Cordarone剂量并同时服用类固醇后，Cordarone诱导的间质性/肺泡性肺炎的某些病例可能会缓解。在某些患者中，以较低剂量进行再挑战并没有导致间质/肺泡性肺炎的复发。但是，在某些患者中（可能是由于严重的肺泡损伤），肺部病变是不可逆的。

心律失常恶化

像其他抗心律失常药一样，Cordarone可能导致所出现的心律失常严重加重，并且在大多数系列中已报道其占2％到5％，并且包括新的心室纤颤，持续的心动过速，对复律的抵抗力增加以及与之相关的多形性室性心动过速QTc延长（Torsade de Pointes [TdP]）。另外，Cordarone引起症状性心动过缓或窦性阻滞，并有2％至4％的患者抑制了逃逸灶。如果存在其他危险因素，例如电解紊乱或同时使用抗心律失常药或其他相互作用药物，则加剧病情的风险可能会增加（请参阅“药物相互作用，其他报道的与胺碘酮的相互作用” ）。

在开始使用Cordarone治疗之前，应尽可能纠正低钾血症，低镁血症或低钙血症，因为这些疾病会夸大QTc延长的程度并增加TdP的可能性。患有严重或长期腹泻的患者或接受利尿剂和泻药，全身性皮质类固醇，两性霉素B（IV）或其他影响电解质水平的药物的患者，应特别注意电解质和酸碱平衡。

必须将胺碘酮与已知延长QTc间隔的任何其他药物合用，必须基于对每位患者这样做的潜在风险和益处的仔细评估。

与Ledipasvir / Sofosbuvir或Sofosbuvir与Simeprevir并用时会出现严重的症状性心动过缓

有胺碘酮的患者开始使用ledipasvir / sofosbuvir或sofosbuvir联合simeprevir时，有症状性心动过缓上市后病例的报道，其中一些需要起搏器插入且至少致命。心动过缓通常发生在数小时至数天之内，但在某些情况下，开始抗病毒治疗后长达2周。在停用抗病毒药物后，心动过缓通常会缓解。这种作用的机制尚不清楚。在开始抗病毒治疗时，监测正在服用或近期停用胺碘酮的患者的心率。

植入式心脏设备

对于植入了除颤器或起搏器的患者，长期服用抗心律不齐药物可能会影响起搏或除颤阈值。因此，在胺碘酮治疗开始时和治疗期间，应评估起搏和除颤阈值。

甲状腺毒症

Cordarone诱发的甲状腺功能亢进症可能导致甲状腺毒症和/或心律不齐突破或加重的可能性。有报道称胺碘酮引起的甲状腺毒症会导致死亡。如果出现任何新的心律失常迹象，则应考虑甲状腺功能亢进症的可能性（请参阅“预防措施，甲状腺异常” ）。

肝损伤

暴露于Cordarone的患者中肝酶水平经常升高，并且在大多数情况下是无症状的。如果增加量超过正常水平的三倍，或基线水平升高的患者增加一倍，则应考虑停用Cordarone或降低剂量。在少数进行活检的情况下，其组织学类似于酒精性肝炎或肝硬化。肝衰竭一直是用Cordarone治疗的患者罕见的死亡原因。

视力丧失

胺碘酮治疗的患者中有视神经病变和/或视神经炎的病例，通常会导致视力障碍。在某些情况下，视力障碍已发展为永久性失明。在开始治疗后的任何时间都可能发生视神经病变和/或神经炎。与药物的因果关系尚未明确建立。如果出现视力障碍症状，例如视力变化和周围视力下降，建议立即进行眼科检查。视神经病变和/或神经炎的出现要求重新评估Cordarone疗法。必须权衡使用Cordarone进行抗心律不齐治疗的风险和并发症以及其对因心律不齐威胁生命的患者的益处。建议在服用Cordarone期间进行常规眼科检查，包括眼底镜检查和裂隙灯检查。 （请参阅“不良反应” ）。

新生儿损伤

给孕妇服用时，胺碘酮会引起胎儿伤害。 Fetal exposure may increase the potential for adverse experiences including cardiac, thyroid, neurodevelopmental, neurological and growth effects in neonate. Inform the patient of the potential hazard to the fetus if Cordarone is administered during pregnancy or if the patient becomes pregnant while taking Cordarone.

In pregnant rats and rabbits, amiodarone HCl in doses of 25 mg/kg/day (approximately 0.4 and 0.9 times, respectively, the maximum recommended human maintenance dose 1 ) had no adverse effects on the fetus. In the rabbit, 75 mg/kg/day (approximately 2.7 times the maximum recommended human maintenance dose 1 ) caused abortions in greater than 90% of the animals. In the rat, doses of 50 mg/kg/day or more were associated with slight displacement of the testes and an increased incidence of incomplete ossification of some skull and digital bones; at 100 mg/kg/day or more, fetal body weights were reduced; at 200 mg/kg/day, there was an increased incidence of fetal resorption. (These doses in the rat are approximately 0.8, 1.6 and 3.2 times the maximum recommended human maintenance dose. 1 ) Adverse effects on fetal growth and survival also were noted in one of two strains of mice at a dose of 5 mg/kg/day (approximately 0.04 times the maximum recommended human maintenance dose 1 ).

1个

600 mg in a 50 kg patient (doses compared on a body surface area basis)

预防措施

Impairment of Vision

Cases of optic neuropathy and optic neuritis have been reported (see "WARNINGS" ).

Corneal microdeposits appear in the majority of adults treated with Cordarone. They are usually discernible only by slit-lamp examination, but give rise to symptoms such as visual halos or blurred vision in as many as 10% of patients. Corneal microdeposits are reversible upon reduction of dose or termination of treatment. Asymptomatic microdeposits alone are not a reason to reduce dose or discontinue treatment (see "ADVERSE REACTIONS" ).

神经学的

Chronic administration of oral amiodarone in rare instances may lead to the development of peripheral neuropathy that may resolve when amiodarone is discontinued, but this resolution has been slow and incomplete.

光敏性

Cordarone has induced photosensitization in about 10% of patients; some protection may be afforded by the use of sun-barrier creams or protective clothing. During long-term treatment, a blue-gray discoloration of the exposed skin may occur. The risk may be increased in patients of fair complexion or those with excessive sun exposure, and may be related to cumulative dose and duration of therapy.

Thyroid Abnormalities

Cordarone inhibits peripheral conversion of thyroxine (T 4 ) to triiodothyronine (T 3 ) and may cause increased thyroxine levels, decreased T 3 levels, and increased levels of inactive reverse T 3 (rT 3 ) in clinically euthyroid patients. It is also a potential source of large amounts of inorganic iodine. Because of its release of inorganic iodine, or perhaps for other reasons, Cordarone can cause either hypothyroidism or hyperthyroidism. Thyroid function should be monitored prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of Cordarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid-function tests may persist for several weeks or even months following Cordarone withdrawal.

Hypothyroidism has been reported in 2 to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing Cordarone and considering the need for thyroid hormone supplement.

Hyperthyroidism occurs in about 2% of patients receiving Cordarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Cordarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and/or arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. IF ANY NEW SIGNS OF ARRHYTHMIA APPEAR, THE POSSIBILITY OF HYPERTHYROIDISM SHOULD BE CONSIDERED.

Hyperthyroidism is best identified by relevant clinical symptoms and signs, accompanied usually by abnormally elevated levels of serum T 3 RIA, and further elevations of serum T 4 , and a subnormal serum TSH level (using a sufficiently sensitive TSH assay). The finding of a flat TSH response to TRH is confirmatory of hyperthyroidism and may be sought in equivocal cases. Since arrhythmia breakthroughs may accompany Cordarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of Cordarone.

The institution of antithyroid drugs, β-adrenergic blockers and/or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. Cordarone-induced hyperthyroidism may be followed by a transient period of hypothyroidism (see "WARNINGS, Thyrotoxicosis" ).

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with Cordarone. In some instances hyperthyroidism was also present (see "WARNINGS" and "ADVERSE REACTIONS" ).

手术

Close perioperative monitoring is recommended in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction effects of halogenated inhalational anesthetics.

Rare occurrences of hypotension upon discontinuation of cardiopulmonary bypass during open-heart surgery in patients receiving Cordarone have been reported. The relationship of this event to Cordarone therapy is unknown.

Postoperatively, occurrences of ARDS have been reported in patients receiving Cordarone therapy who have undergone either cardiac or noncardiac surgery. Although patients usually respond well to vigorous respiratory therapy, in rare instances the outcome has been fatal. Until further studies have been performed, it is recommended that FiO 2 and the determinants of oxygen delivery to the tissues (eg, SaO 2 , PaO 2 ) be closely monitored in patients on Cordarone.

Corneal Refractive Laser Surgery

Patients should be advised that most manufacturers of corneal refractive laser surgery devices contraindicate that procedure in patients taking Cordarone.

给患者的信息

Patients should be instructed to read the accompanying Medication Guide each time they refill their prescription.本文末尾会重印《用药指南》的全文。

实验室测试

Elevations in liver enzymes (aspartate aminotransferase and alanine aminotransferase) can occur. Liver enzymes in patients on relatively high maintenance doses should be monitored on a regular basis. Persistent significant elevations in the liver enzymes or hepatomegaly should alert the physician to consider reducing the maintenance dose of Cordarone or discontinuing therapy.

Cordarone alters the results of thyroid-function tests, causing an increase in serum T 4 and serum reverse T 3 , and a decline in serum T 3 levels. Despite these biochemical changes, most patients remain clinically euthyroid.

药物相互作用

In view of the long and variable half-life of amiodarone, potential for drug interactions exists, not only with concomitant medication, but also with drugs administered after discontinuation of amiodarone.

Drugs inducing TdP or prolonging QT

Co-administration of amiodarone with drugs known to prolong the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, IV pentamidine, and azole antifungals) increases the risk of Torsades de Points. Avoid concomitant use of drugs that prolong the QT interval.

Drugs lowering heart rate or causing automaticity or conduction disorders

Concomitant use of drugs with depressant effects on the sinus and AV node (eg, digoxin, beta blockers, verapamil, diltiazem, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate.

Effects of other medicinal products on amiodarone

Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit CYP3A (eg, certain protease inhibitors, loratadine, cimetidine, trazodone) may decrease the metabolism and increase serum concentrations of amiodarone. Concomitant use of CYP3A inducers (rifampin, St. John's Wort), may lead to decreased serum concentrations and loss of efficacy. Consider serial measurement of amiodarone serum concentration during concomitant use of drugs affecting CYP3A activity.

Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and C max by 84%, and decreased DEA to unquantifiable concentrations. Grapefruit juice inhibits CYP3A-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone; therefore, grapefruit juice should not be taken during treatment with oral amiodarone. This information should be considered when transitioning from intravenous to oral amiodarone. Cholestyramine reduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life.

Effects of amiodarone on other medicinal products

Amiodarone inhibits P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates of P-glycoprotein. Reported examples of this interaction include the following:

Cyclosporine (CYP3A substrate) administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine. Monitor cyclosporine drug levels and renal function in patients taking both drugs.

HMG-CoA reductase inhibitors

The use of HMG-CoA reductase inhibitors that are CYP3A substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A substrates (eg, atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.

Digoxin

In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in the serum digoxin concentration. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. On initiation of oral amiodarone, the need for digitalis therapy should be reviewed and the dose reduced by approximately 50% or discontinued. If digitalis treatment is continued, serum levels should be closely monitored and patients observed for clinical evidence of toxicity.

Antiarrhythmics

The metabolism of quinidine, procainamide, flecainide can be inhibited by amiodarone. Amiodarone taken concomitantly with quinidine increases quinidine serum concentration by 33% after two days. Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. In general, any added antiarrhythmic drug should be initiated at a lower than usual dose with careful monitoring.

Combination of amiodarone with other antiarrhythmic therapy should be reserved for patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent or incompletely responsive to amiodarone. During transition to amiodarone the dose levels of previously administered agents should be reduced by 30 to 50% several days after the addition of amiodarone, when arrhythmia suppression should be beginning. The continued need for the other antiarrhythmic agent should be reviewed after the effects of amiodarone have been established, and discontinuation ordinarily should be attempted. If the treatment is continued, these patients should be particularly carefully monitored for adverse effects, especially conduction disturbances and exacerbation of tachyarrhythmias, as amiodarone is continued. In amiodarone-treated patients who require additional antiarrhythmic therapy, the initial dose of such agents should be approximately half of the usual recommended dose.

Metabolism of lidocaine (CYP3A substrate) can be inhibited by amiodarone resulting in increased lidocaine concentrations. Sinus bradycardia and seizure has been reported in patients receiving concomitant lidocaine and amiodarone.

Anticoagulants

Potentiation of warfarin-type (CYP2C9 and CYP3A substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases the prothrombin time by 100% after 3 to 4 days, the dose of the anticoagulant should be reduced by one-third to one-half, and prothrombin times should be monitored closely .

A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.

Dabigatran etexilate when taken concomitantly with amiodarone may result in elevated serum concentration of dabigatran.

Fentanyl (CYP3A substrate) in combination with amiodarone may cause hypotension, bradycardia, and decreased cardiac output.

Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported. Monitor phenytoin levels in patients taking both drugs.

Dextromethorphan is a substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6 and CYP3A. Chronic (>2 weeks) amiodarone treatment impairs metabolism of dextromethorphan leading to increased serum concentration.

致癌，诱变，生育力受损

Amiodarone HCl was associated with a statistically significant, dose-related increase in the incidence of thyroid tumors (follicular adenoma and/or carcinoma) in rats. The incidence of thyroid tumors was greater than control even at the lowest dose level tested, ie, 5 mg/kg/day (approximately 0.08 times the maximum recommended human maintenance dose 2 ).

Mutagenicity studies (Ames, micronucleus, and lysogenic tests) with Cordarone were negative.

In a study in which amiodarone HCl was administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose 2 ).

2

600 mg in a 50 kg patient (dose compared on a body surface area basis)

怀孕

See "WARNINGS, Neonatal Injury" .

Amiodarone and desethylamiodarone cross the placenta.

Reported risks include:

• neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles
• neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure
• neonatal hyperthyroxinemia
• neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia.
• jerk nystagmus with synchronous head titubation
• fetal growth retardation
• premature birth

人工与分娩

It is not known whether the use of Cordarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect of Cordarone on the duration of gestation or on parturition.

护理母亲

Amiodarone and one of its major metabolites, DEA, are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have been shown to be less viable and have reduced body-weight gains. The risk of exposing the infant to amiodarone and DEA must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing.

儿科用

The safety and effectiveness of Cordarone Tablets in pediatric patients have not been established.

老人用

Clinical studies of Cordarone Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.一般而言，老年患者的剂量选择应谨慎，通常从给药范围的低端开始，这反映出肝，肾或心脏功能下降以及伴随疾病或其他药物治疗的频率更高。

不良反应

Adverse reactions have been very common in virtually all series of patients treated with Cordarone for ventricular arrhythmias with relatively large doses of drug (400 mg/day and above), occurring in about three-fourths of all patients and causing discontinuation in 7 to 18%. The most serious reactions are pulmonary toxicity, exacerbation of arrhythmia, and rare serious liver injury (see "WARNINGS" ), but other adverse effects constitute important problems. They are often reversible with dose reduction or cessation of Cordarone treatment. Most of the adverse effects appear to become more frequent with continued treatment beyond six months, although rates appear to remain relatively constant beyond one year. The time and dose relationships of adverse effects are under continued study.

Neurologic problems are extremely common, occurring in 20 to 40% of patients and including malaise and fatigue, tremor and involuntary movements, poor coordination and gait, and peripheral neuropathy; they are rarely a reason to stop therapy and may respond to dose reductions or discontinuation (see "PRECAUTIONS" ). There have been spontaneous reports of demyelinating polyneuropathy.

Gastrointestinal complaints, most commonly nausea, vomiting, constipation, and anorexia, occur in about 25% of patients but rarely require discontinuation of drug. These commonly occur during high-dose administration (ie, loading dose) and usually respond to dose reduction or divided doses.

Ophthalmic abnormalities including optic neuropathy and/or optic neuritis, in some cases progressing to permanent blindness, papilledema, corneal degeneration, photosensitivity, eye discomfort, scotoma, lens opacities, and macular degeneration have been reported. (See "WARNINGS" .)

Asymptomatic corneal microdeposits are present in virtually all adult patients who have been on drug for more than 6 months. Some patients develop eye symptoms of halos, photophobia, and dry eyes. Vision is rarely affected and drug discontinuation is rarely needed.

Dermatological adverse reactions occur in about 15% of patients, with photosensitivity being most common (about 10%). Sunscreen and protection from sun exposure may be helpful, and drug discontinuation is not usually necessary. Prolonged exposure to Cordarone occasionally results in a blue-gray pigmentation. This is slowly and occasionally incompletely reversible on discontinuation of drug but is of cosmetic importance only.

Cardiovascular adverse reactions, other than exacerbation of the arrhythmias, include the uncommon occurrence of congestive heart failure (3%) and bradycardia. Bradycardia usually responds to dosage reduction but may require a pacemaker for control. CHF rarely requires drug discontinuation. Cardiac conduction abnormalities occur infrequently and are reversible on discontinuation of drug.

The following side-effect rates are based on a retrospective study of 241 patients treated for 2 to 1,515 days (mean 441.3 days).

The following side effects were each reported in 10 to 33% of patients

Gastrointestinal: Nausea and vomiting.

The following side effects were each reported in 4 to 9% of patients

Dermatologic: Solar dermatitis/photosensitivity.

Neurologic: Malaise and fatigue, tremor/abnormal involuntary movements, lack of coordination, abnormal gait/ataxia, dizziness, paresthesias.

Gastrointestinal: Constipation, anorexia.

Ophthalmologic: Visual disturbances.

Hepatic: Abnormal liver-function tests.

Respiratory: Pulmonary inflammation or fibrosis.

The following side effects were each reported in 1 to 3% of patients

Thyroid: Hypothyroidism, hyperthyroidism.

Neurologic: Decreased libido, insomnia, headache, sleep disturbances.

Cardiovascular: Congestive heart failure, cardiac arrhythmias, SA node dysfunction.

Gastrointestinal: Abdominal pain.

Hepatic: Nonspecific hepatic disorders.

Other: Flushing, abnormal taste and smell, edema, abnormal salivation, coagulation abnormalities.

The following side effects were each reported in less than 1% of patients

Blue skin discoloration, rash, spontaneous ecchymosis, alopecia, hypotension, and cardiac conduction abnormalities.

In surveys of almost 5,000 patients treated in open US studies and in published reports of treatment with Cordarone, the adverse reactions most frequently requiring discontinuation of Cordarone included pulmonary infiltrates or fibrosis, paroxysmal ventricular tachycardia, congestive heart failure, and elevation of liver enzymes. Other symptoms causing discontinuations less often included visual disturbances, solar dermatitis, blue skin discoloration, hyperthyroidism, and hypothyroidism.

Postmarketing Reports

In postmarketing surveillance, serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir/sofosbuvir or with sofosbuvir with simeprevir, hypotension (sometimes fatal), sinus arrest, anaphylactic/anaphylactoid reaction (including shock), angioedema, urticaria, eosinophilic pneumonia, hepatitis, cholestatic hepatitis, cirrhosis, pancreatitis, acute pancreatitis, renal impairment, renal insufficiency, acute renal failure, acute respiratory distress syndrome in the post-operative setting, bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest, and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), fever, dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and/or mass, pulmonary alveolar hemorrhage, pleural effusion, pleuritis, pseudotumor cerebri, parkinsonian symptoms such as akinesia and bradykinesia (sometimes reversible with discontinuation of therapy), syndrome of inappropriate antidiuretic hormone secretion (SIADH), thyroid nodules/thyroid cancer, toxic epidermal necrolysis (sometimes fatal), erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, bullous dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, skin cancer, vasculitis, pruritus, hemolytic anemia, aplastic anemia, pancytopenia, neutropenia, thrombocytopenia, agranulocytosis, granuloma, myopathy, muscle weakness, rhabdomyolysis, demyelinating polyneuropathy, hallucination, confusional state, disorientation, delirium, epididymitis, impotence and dry mouth, also have been reported with amiodarone therapy.

过量

There have been cases, some fatal, of Cordarone overdose.

In addition to general supportive measures, the patient's cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Cordarone nor its metabolite is dialyzable.

The acute oral LD 50 of amiodarone HCl in mice and rats is greater than 3,000 mg/kg.

Cordarone Dosage and Administration

BECAUSE OF THE UNIQUE PHARMACOKINETIC PROPERTIES, DIFFICULT DOSING SCHEDULE, AND SEVERITY OF THE SIDE EFFECTS IF PATIENTS ARE IMPROPERLY MONITORED, Cordarone SHOULD BE ADMINISTERED ONLY BY PHYSICIANS WHO ARE EXPERIENCED IN THE TREATMENT OF LIFE-THREATENING ARRHYTHMIAS WHO ARE THOROUGHLY FAMILIAR WITH THE RISKS AND BENEFITS OF Cordarone THERAPY, AND WHO HAVE ACCESS TO LABORATORY FACILITIES CAPABLE OF ADEQUATELY MONITORING THE EFFECTIVENESS AND SIDE EFFECTS OF TREATMENT.

In order to insure that an antiarrhythmic effect will be observed without waiting several months, loading doses are required. A uniform, optimal dosage schedule for administration of Cordarone has not been determined. Because of the food effect on absorption, Cordarone should be administered consistently with regard to meals (see "CLINICAL PHARMACOLOGY" ). Individual patient titration is suggested according to the following guidelines:

For life-threatening ventricular arrhythmias, such as ventricular fibrillation or hemodynamically unstable ventricular tachycardia

Close monitoring of the patients is indicated during the loading phase, particularly until risk of recurrent ventricular tachycardia or fibrillation has abated. Bec