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.

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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