Tarka说明

Tarka（trandolapril / verapamil hydrochloride ER）将钙通道阻滞剂缓释制剂Verapamil hydrochloride与血管紧张素转化酶抑制剂trandolapril的速释制剂结合使用。

维拉帕米成分

维拉帕米盐酸盐在化学上被描述为苯乙腈，α[3-[[2-（3,4-二甲氧基苯基）乙基]甲基氨基]丙基] -3、4-二甲氧基-α-（1-甲基乙基）盐酸盐。它的经验公式为C 27 H 38 N 2 O 4 HCl，其结构式为：

盐酸维拉帕米为几乎白色的结晶性粉末，分子量为491.08。易溶于水，氯仿和甲醇。它几乎没有气味，带有苦味。

坦诺普利成分

Trandolapril是非巯基血管紧张素转化酶（ACE）抑制剂trandolaprilat的乙酯的前药。化学上描述为（2S，3aR，7aS）-1-[（S）-N-[（S）-1-羧基-3-苯基丙基]丙氨酰]六氢-2-二氢吲哚羧酸，1-乙酯。其经验公式为C 24 H 34 N 2 O 5 ，其结构公式为：

Trandolapril是一种白色或几乎白色的粉末，分子量为430.54。可溶于氯仿，二氯甲烷和甲醇（> 100 mg / mL）。

Tarka片剂经配制用于口服给药，其中含有盐酸维拉帕米作为控释制剂，而trandolapril作为速释制剂。片剂强度为2 mg trandolapril / 180 mg盐酸维拉帕米，2 mg trandolapril / 240 mg盐酸维拉帕米和2 mg trandolapril / 240 mg盐酸维拉帕米。片剂还包含以下成分：玉米淀粉，磺基琥珀酸二辛酯钠，乙醇，羟丙基纤维素，羟丙甲纤维素，乳糖一水合物，硬脂酸镁，微晶纤维素，聚乙二醇，聚维酮，纯净水，二氧化硅，藻酸钠，硬脂富马酸钠，合成氧化铁，滑石和二氧化钛。

Tarka-临床药理学

盐酸维拉帕米和trandolapril已单独或联合用于治疗高血压。对于四种剂量强度，组合的降压作用大约会加到各个组分上。

维拉帕米成分

维拉帕米是一种钙通道阻滞剂，它通过调节离子钙跨过动脉平滑肌细胞膜以及可传导和可收缩的心肌细胞的流入来发挥其药理作用。维拉帕米通过降低全身血管阻力来发挥降压作用，通常不会使体位性血压或反射性心动过速降低。在进行等轴测运动或动态运动时，维拉帕米不会改变具有正常心室功能的患者的心脏收缩功能。维拉帕米不改变血清总钙水平。

坦诺普利成分

Trandolapril被去酯化为其二酸代谢产物trandolaprilat。两者均抑制人类受试者和动物中的血管紧张素转换酶（ACE）。 Trandolaprilat的效力是trandolapril的8倍左右。 ACE是一种肽基二肽酶，可催化血管紧张素I向血管收缩剂血管紧张素II的转化。血管紧张素II还刺激肾上腺皮质的醛固酮分泌。

抑制ACE会导致血浆血管紧张素II降低，从而导致血管升压活性降低和醛固酮分泌降低。后者的减少可能导致血清钾的少量增加。在对照临床试验中，用Tarka治疗可使钾平均增加0.1 mEq / L（请参阅注意事项）。去除血管紧张素II对肾素分泌的负反馈会导致血浆肾素活性（PRA）升高。

ACE与激肽酶II（一种降解缓激肽的酶）相同。缓激肽（一种有效的血管抑制肽）的水平升高是否在Tarka的治疗作用中发挥作用尚待阐明。

虽然据认为，trandolapril降低血压的机制主要是抑制肾素-血管紧张素-醛固酮系统，但trandolapril甚至在低肾素高血压患者中也具有降压作用。 Trandolapril在所有研究的种族中都是有效的降压药。黑人患者（通常为低肾素组）和非黑人患者均对2-4 mg的trandolapril有反应。

药代动力学与代谢

塔尔卡

在健康受试者中单次口服Tarka之后，曲多普利在0.5-2小时内达到峰值血浆浓度，维拉帕米在4-15小时内达到峰值血浆浓度。维拉帕米，去甲维拉帕米的活性去甲基代谢产物的血浆峰值浓度在5-15小时内达到。酯基的裂解将trandolapril转化为其活性二酸代谢物tradolaprilat，后者在2-12小时内达到血浆峰值浓度。与单药治疗相比，将trandolapril与维拉帕米联用时，trandolapril和tradolaprilat的药代动力学没有改变。

当240 mg控释维拉帕米与4 mg trandolapril并用时，维拉帕米和去甲维拉帕米的AUC和C max均增加。维拉帕米和去甲维拉帕米的C max分别增加54％和30％，AUC分别增加65％和32％。高脂餐量的Tarka 4/240（4 mg trandolapril和240 mg盐酸维拉帕米ER）的给药不会改变trandolapril的生物利用度，而维拉帕米的峰值浓度和曲线下面积（AUC）分别降低37％和28％ 。食物因此降低了维拉帕米的生物利用度，并且维拉帕米和去甲维拉帕米的血药浓度达到峰值的时间延迟了大约7小时。维拉帕米的两种光学异构体都受到类似的影响。

trandolapril的消除半衰期约为6小时。在稳态下，曲妥普利拉的有效半衰期为22.5小时。像所有ACE抑制剂一样，tradolaprilat也具有延长的终末消除阶段，涉及一小部分给药药物，可能代表与血浆和组织ACE的结合。

维拉帕米的终末半衰期为6-11小时。每天一次服用Tarka约一周后，即可达到两种成分的稳态血浆浓度。在稳态下，维拉帕米和曲多普利拉的血浆浓度比单次口服Tarka剂量后观察到的浓度高两倍。

维拉帕米和曲拉普利拉特的药代动力学在老年人（≥65岁）中与年轻人相比有显着差异。在老年人中，维拉帕米和去甲维拉帕米的生物利用度分别增加了87％和77％，而trandolapril的生物利用度则增加了约35％。 AUC分别高出约80％和35％。

维拉帕米成分

对于速释制剂，在给药后1-2小时观察到的维拉帕米血浆峰值浓度吸收了超过90％的口服剂量。当与速释制剂相比时，对于缓释制剂观察到延迟的速率但相似的吸收程度。由于维拉帕米首次通过门脉循环期间迅速发生生物转化，因此绝对生物利用度范围为20％至35％。维拉帕米剂量与血浆浓度之间存在非线性关系。

在维拉帕米的早期剂量滴定中，维拉帕米的血浆浓度与PR间隔的延长之间存在关系。但是，在长期给药期间，这种关系可能会消失。维拉帕米的血浆浓度与血压降低之间尚未建立关系。

在健康受试者中，口服维拉帕米在肝脏中进行广泛的代谢。血浆中已鉴定出十二种代谢物。除诺维拉帕米外，所有其他成分均仅以痕量存在。在5天内，约70％的给药剂量以代谢产物的形式在尿中排泄，在粪便中则有16％或更多排泄。未改变药物的尿排泄量约为剂量的3％至4％。维拉帕米大约90％与血浆蛋白结合。

在肝功能不全的患者中，维拉帕米清除率降低约30％，消除半衰期延长至14至16小时（请参阅注意事项）。在肝功能不全的患者中，可能需要调整剂量。在老年人（≥65岁）中，维拉帕米清除率降低，导致消除半衰期增加。

坦诺普利成分

口服给予多多普利后，其绝对的生物利用度以多多拉普利的形式约占10％，以曲多拉普利拉形式约占70％。曲多拉普利拉而非曲多普利的血浆浓度随剂量成比例增加。曲多普利拉的血浆浓度以三重方式下降。更长的末端消除阶段可能代表了与ACE饱和结合的一小部分剂量。

口服放射性标记的trandolapril后，trandolapril和代谢产物的排泄量占尿液剂量的33％和粪便的66％。少于1％的剂量作为未改变的药物排泄在尿液中。 trandolapril的血清蛋白结合率约为80％，与浓度无关。曲拉普利拉的结合是浓度依赖性的，从1000 ng / mL时的65％到0.1 ng / mL时的94％不等，表明结合随着浓度的增加而饱和。

与正常受试者相比，在肌酐清除率低于30 mL / min的患者和接受血液透析的患者中，trandolapril和trandolaprilat的血浆浓度约高2倍，肾清除率降低约85％。建议在肾功能不全的患者中调整剂量（请参阅剂量和管理）。

在轻度至中度酒精性肝硬化患者中口服后，曲多普利和曲多普利拉的血浆浓度分别比正常受试者高9倍和2倍，但对ACE活性的抑制作用不受影响。肝功能不全的患者应考虑降低剂量（参见剂量和用法）。

药效学

塔尔卡

维拉帕米不干扰曲多普利对ACE的抑制作用。 Trandolapril不会改变维拉帕米对心脏内传导的影响。

维拉帕米成分

维拉帕米可扩张正常和缺血区域的主要冠状动脉和冠状动脉，并且是冠状动脉痉挛的有效抑制剂。该特性增加了冠状​​动脉痉挛患者的心肌氧输送，是维拉帕米在血管痉挛（Prinzmetal's或变种）以及静止性不稳定型心绞痛中的有效性的原因。

维拉帕米通过扩张外周小动脉定期降低总的全身抵抗力（后负荷）。通过减少钙的流入，维拉帕米可延长房室结内的有效不应期，并以速率相关的方式减慢房室传导。

正常的窦性心律通常不受影响，但是在患有恶性鼻窦综合征的患者中，维拉帕米可能会干扰窦房结冲动的产生，并可能导致窦性阻滞或窦房阻塞。没有预先存在的传导缺陷的患者可以发生房室传导阻滞（请参阅警告）。

维拉帕米不会改变正常的心房动作电位或心室内传导时间，但会降低心房纤维凹陷的幅度，去极化速度和传导速度。维拉帕米可能会缩短副旁路的顺行有效不应期。在服用维拉帕米后出现房扑或房颤并伴有辅助性AV通路的患者中，心室率和/或室颤的加速已有报道（见警告）。

血液动力学和心肌代谢：维拉帕米降低后负荷和心肌收缩力。维拉帕米治疗还观察到特发性肥厚性主动脉瓣狭窄（IHSS）患者和冠心病患者的左心室舒张功能得到改善。在大多数患者中，包括那些患有器质性心脏病的患者，维拉帕米的负性肌力作用可通过减少后负荷来抵消，而心脏指数通常不会降低。但是，在患有严重左心功能不全的患者（例如，肺楔形压力约20 mmHg或射血分数低于30％）或正在服用β-肾上腺素能阻断剂或其他抗抑郁药的患者中，心室功能可能会恶化（请参阅预防措施-药物相互作用）。

肺功能：维拉帕米不会引起支气管收缩，因此不会损害呼吸功能。

坦诺普利成分

单次服用2 mg的trandolapril后，ACE活性的抑制作用在4小时达到最大（70-85％），在24小时下降约10％。给药八天后，ACE抑制率仍为40％。

在827例轻度至中度高血压的黑人和非黑人患者中，每天使用一次口服trandolapril，剂量为0.25至16 mg，进行了四次安慰剂对照的剂量反应研究。非黑人患者每日最小一次有效剂量为1.0 mg，黑人患者为2.0 mg。高剂量非黑人患者的谷底仰卧舒张压进一步降低，超过4 mg（最高16 mg）的剂量未见进一步反应。在给药间隔结束时，抗高血压作用有所减弱。

在慢性治疗期间，任何剂量的血压均可在一周内达到最大降低。在轻度至中度高血压患者的安慰剂对照试验中进行了6周的单药治疗后，每日一次2至4 mg的剂量在给药后24小时降低仰卧或站立时收缩压/舒张压的平均水平为7-10 / 4-5 mmHg在非黑人患者中低于安慰剂反应。黑人患者每天服用2到4毫克的剂量可使血压降低4-6 / 3-4 mmHg，低于安慰剂反应。

临床研究

在对照临床试验中，每日一次服用Tarka，trandolapril 4 mg /维拉帕米HCl ER 240 mg或trandolapril 2 mg / verapamil HCl ER 180 mg每天一次，在给药后24小时，安慰剂校正的坐位压力（收缩压/舒张压）降低约7 12 / 6-8毫米汞柱。塔卡（Tarka）的每种成分均增加了降压作用。不同年龄组（<65岁，≥65岁）和性别（男性，女性）的治疗效果均一致。

Tarka 4/240组合的降压幅度明显大于单独使用的任何一种组分。

Tarka的抗高血压作用在治疗期间持续了至少1年。

塔卡的适应症和用法

Tarka适用于治疗高血压。

此固定组合药物未指定用于高血压的初始治疗（请参阅剂量和管理）。

在使用Tarka时，应考虑以下事实：血管紧张素转化酶抑制剂卡托普利会引起粒细胞缺乏症，尤其是在肾功能不全或胶原血管疾病患者中，并且现有数据不足以表明trandolapril没有类似风险（请参阅警告-中性粒细胞减少/粒细胞缺乏症）。

禁忌症

对任何ACE抑制剂或维拉帕米过敏的患者禁用Tarka。

由于存在维拉帕米成分，Tarka禁忌于：

1. 严重的左心功能不全（请参阅警告）。
2. 低血压（收缩压小于90 mmHg）或心源性休克。
3. 病态窦房结综合征（具有功能性人工心室起搏器的患者除外）。
4. 二级或三级房室传导阻滞（人工心律起搏器功能正常的患者除外）。
5. 患有房扑或房颤的患者，并伴有旁路道（例如Wolff-Parkinson-White，Lowen-Ganong-Levine综合征）（请参阅警告）。
6. 服用氟班色林的患者（请参阅预防措施，药物相互作用）。

由于存在trandolapril成分，在有与先前使用血管紧张素转化酶（ACE）抑制剂治疗有关的血管水肿病史的患者中禁用Tarka。

糖尿病患者请勿将阿利吉仑与Tarka并用（请参见预防措施，药物相互作用）。

禁止将Tarka与中性溶酶抑制剂（例如沙比特利）联合使用。不要在中性溶酶抑制剂沙比特利/缬沙坦换药或换药后的36小时内服用Tarka（请参阅警告）。

警告事项

心脏衰竭

维拉帕米成分

维拉帕米具有负性肌力作用，在大多数患者中，其后负荷减少（全身血管阻力降低）特性可以弥补心律失常，而不会对心室功能造成任何净损害。在4,954位患者的临床经验中，有87位（1.8％）出现充血性心力衰竭或肺水肿。严重左心功能不全的患者（例如射血分数低于30％，肺楔压超过20 mmHg或严重的心力衰竭症状）以及任何程度的心室功能不全的患者（如果接受Beta）应避免使用维拉帕米肾上腺素能阻滞剂（请参阅预防措施-药物相互作用）。患者更温和的心功能不全应，如果可能的话，可以用最佳剂量洋地黄和/或利尿剂治疗维拉帕米之前（下注相互作用与地高辛：控制注意事项）。

坦诺普利成分

Trandolapril作为ACE抑制剂，可能导致充血性心力衰竭患者过度低血压（请参阅警告-低血压）。

低血压

维拉帕米成分

有时维拉帕米的药理作用可能会使血压降低至正常水平以下，这可能导致头晕或症状性低血压。

坦诺普利成分

替诺拉普利可引起症状性低血压。像其他ACE抑制剂一样，在非复杂性高血压患者中，trandolapril仅很少与症状性低血压相关。由于长期使用利尿剂，限制饮食盐分，透析，腹泻或呕吐而导致盐分或体积减少的患者，最有可能出现症状性低血压。在开始使用trandolapril治疗之前，应纠正体积和/或盐分的消耗（请参阅预防措施-药物相互作用和不良反应）。

在对照研究中，接受trandolapril和verapamil HCl ER任意组合的患者中有0.6％观察到低血压。

在伴有充血性心力衰竭，伴有或不伴有肾功能不全的患者中，ACEI抑制剂治疗可能会导致血压过低，这可能与少尿或氮质血症有关，很少发生急性肾功能衰竭和死亡（参见剂量和用法）。

如果出现症状性低血压，应将患者仰卧，如有必要，可以静脉内注射生理盐水。短暂性降压反应不是进一步剂量的禁忌证；但是，应考虑使用较低剂量的维拉帕米HCl ER和/或trandolapril或减少伴随的利尿剂治疗。

肝酶升高/肝功能衰竭

维拉帕米成分

据报道转氨酶升高，碱性磷酸酶和胆红素升高或降低。这种升高有时是短暂的，甚至在继续接受维拉帕米治疗的情况下也可能消失。再挑战已证实了几例与维拉帕米有关的肝细胞损伤病例。除SGOT，SGPT和碱性磷酸酶升高外，其中一半有临床症状（不适，发烧和/或右上腹疼痛）。

坦诺普利成分

ACE抑制剂很少与胆汁淤积性黄疸，暴发性肝坏死和死亡综合征相关。该综合征的机制尚不清楚。出现黄疸的接受ACE抑制剂的患者应停用ACE抑制剂并接受适当的医学随访。

在服用trandolapril / verapamil几种剂量组合的任何患者中，有3.2％的患者出现肝脏异常。因此，应谨慎监测服用Tarka的患者的肝功能。

附件旁路道（Wolff-Parkinson-White或Lown-Ganong-Levine综合征）

维拉帕米成分

一些阵发性和/或慢性房颤或房扑并存的辅助性AV通路的患者绕过AV结点通过辅助通路发展了顺行传导，在接受静脉内维拉帕米（或洋地黄）治疗后产生非常快速的心室反应或心室纤颤。 。虽然口服维拉帕米发生这种情况的风险尚未确定，接受口服维拉帕米此类患者可能存在风险及在这些患者中的使用禁忌（见禁忌）。

治疗通常是直流心脏复律。口服维拉帕米后已安全有效地使用了电复律。

房室传导阻滞

维拉帕米成分

维拉帕米对房室传导和SA结的影响可能导致无症状的一级房室传导阻滞和短暂性心动过缓，有时伴有结节性心律失常。 PR间隔时间的延长与维拉帕米血浆浓度有关，尤其是在治疗的早期滴定阶段。但是，很少观察到较高程度的房室传导阻滞（0.8％）。明显的一级阻断或逐步发展为二级或三级房室传导阻滞需要减少剂量，或者在极少数情况下，根据临床情况，停用维拉帕米HCl并采取适当的治疗方法。

肥厚性心肌病（IHSS）

维拉帕米成分

在接受最高剂量为720 mg /天维拉帕米治疗的120例肥厚型心肌病（其中大多数患者对普萘洛尔难治或不耐受）中，发现了各种严重的不良反应。 3例患者死于肺水肿。所有患者均患有严重的左心室流出道梗阻以及过去的左心室功能障碍史。其他八名患者出现肺水肿和/或严重低血压；这些患者中的大多数患者出现异常高的毛细血管楔压（超过20 mmHg）和明显的左心室流出道梗阻。窦性心动过缓发生在11％的患者中，二级房室传导阻滞发生在4％的患者中，窦房颤发生在2％的患者中。必须意识到，这组患者患有严重的疾病，死亡率很高。大多数不良反应对降低剂量反应良好，只有极少数必须停用维拉帕米。

过敏反应和可能相关的反应

据推测，由于血管紧张素转换酶抑制剂会影响类花生酸和多肽（包括内源缓激肽）的代谢，因此接受包括trandolapril在内的ACE抑制剂的患者可能会发生多种不良反应，其中一些反应很严重。

血管性水肿

据报道，接受ACE抑制剂（包括trandolapril）治疗的患者的面部，四肢，嘴唇，舌头，声门和喉部血管性水肿。 0.13％的trandolapril治疗患者出现了提示血管性水肿或面部水肿的症状。四例中有两例危及生命，未经治疗或药物治疗（皮质类固醇）即可治愈。与喉头水肿相关的血管性水肿可能是致命的。如果出现喉部喘鸣或面部，舌头或声门血管性水肿，应立即停止使用Tarka的治疗，并按照公认的医疗方法治疗患者，并仔细观察直至肿胀消失。在肿胀仅限于脸部和嘴唇的情况下，这种情况通常无需治疗即可缓解；抗组胺药可能有助于缓解症状。如果舌，声门或喉部受累可能导致气道阻塞，应立即进行紧急治疗，包括但不限于皮下肾上腺素溶液1：1,000（0.3至0.5 mL） （请参阅注意事项和不良反应） 。

接受ACE抑制剂与mTOR（雷帕霉素的哺乳动物靶标）抑制剂（例如，西罗莫司，西罗莫司，依维莫司）或中性溶酶抑制剂（例如，沙库比特）共同给药的患者可能会出现血管性水肿的风险增加。

脱敏过程中的类过敏反应

两名在接受ACE抑制剂的同时接受膜翅目毒液脱敏治疗的患者持续威胁生命的类过敏反应。在同一例患者中，当暂时停用ACE抑制剂时不会发生这些反应，但是当意外地再次使用ACE抑制剂时它们会再次出现。

膜暴露过程中的类过敏反应

已经报道了用高通量膜透析并同时使用ACE抑制剂治疗的患者发生类过敏反应。低密度脂蛋白单采与硫酸右旋糖酐吸收的患者也有过敏样反应的报道。

中性粒细胞减少/粒细胞缺乏症

坦诺普利成分

已显示另一种ACE抑制剂卡托普利在没有并发症的高血压患者中很少引起粒细胞缺乏症和骨髓抑制，但在肾功能不全的患者中更常见，特别是如果他们还患有胶原性血管疾病，例如系统性红斑狼疮或硬皮病。 trandolapril或Tarka临床试验的可用数据不足以显示trandolapril不会以相似的速率引起粒细胞缺乏症。与其他ACE抑制剂一样，应考虑定期监测胶原蛋白血管疾病和/或肾脏疾病患者的白细胞计数。

胎儿毒性

坦诺普利成分

在妊娠的中期和晚期使用药物作用于肾素-血管紧张素系统会降低胎儿的肾功能，并增加胎儿和新生儿的发病率和死亡率。羊水过少可能与胎儿肺发育不全和骨骼变形有关。潜在的新生儿不良反应包括颅骨发育不全，无尿，低血压，肾功能衰竭和死亡。如果检测到怀孕，请尽快终止Tarka。这些不良后果通常与妊娠中期和中期使用这些药物有关。多数在妊娠前三个月检查过抗高血压药后检查胎儿异常的流行病学研究并未将影响肾素-血管紧张素系统的药物与其他抗高血压药区分开。孕期适当控制母体高血压对于优化母体和胎儿的结局非常重要。

在特殊情况下，除了针对特定患者的影响肾素-血管紧张素系统的药物治疗之外，没有其他适当的替代方法，请告知母亲母亲对胎儿的潜在风险。进行连续超声检查以评估羊膜内环境。如果发现羊水过少，请停止使用Tarka，除非它被认为可以挽救母亲的生命。根据怀孕的一周，可能需要进行胎儿检查。但是，患者和医生应该意识到，羊水过少可能要等到胎儿遭受不可逆转的伤害之后才会出现。密切观察有子宫内接触过Tarka的低血压，少尿和高钾血症病史的婴儿（请参阅预防措施-小儿使用）。

兔子的剂量为0.8 mg / kg /天（9.4 mg / m2 /天），大鼠的剂量为1000 mg / kg /天（7000 mg / m2 /天），25 mg / kg /天（295 mg / m2 /天） ）在食蟹猴中未产生致畸作用。这些剂量分别代表根据体重和体表面积计算的4 mg人体最大预计剂量的10倍和3倍（兔子），1250倍和2564倍（大鼠）以及312和108倍（猴子）。 50公斤重的女人。

替诺拉普利在兔子中的剂量为0.8 mg / kg /天，在大鼠中为100.0 mg / kg /天，在食蟹猴中为25 mg / kg /天（分别是最大预期人类剂量的10倍，1250和312倍）。 50公斤重的女性）没有产生致畸作用。

预防措施

用于肝功能受损的患者

Tarka尚未在肝功能受损的受试者中进行评估。

维拉帕米成分

由于维拉帕米被肝脏高度代谢，因此对肝功能受损的患者应谨慎服用。严重的肝功能障碍将速释维拉帕米的消除半衰期延长至约14至16小时。因此，应向这些肝功能正常的患者服用大约30％的剂量。

应当仔细监测PR间隔的异常延长或其他药理作用过度的迹象（参见OVERDOSAGE ）。

坦诺普利成分

肝功能受损的患者中Trandolapril和trandolaprilat的浓度增加。

用于肾功能不全的患者

肾功能受损的患者尚未评估Tarka。

维拉帕米成分

维拉帕米给药剂量的约70％作为代谢产物排泄在尿液中。维拉帕米不能通过血液透析去除。在没有进一步的数据可用之前，对肾功能受损的患者应谨慎使用维拉帕米。应仔细监测这些患者的PR间隔异常延长或其他用药过量迹象（请参阅OVERDOSAGE ）。

坦诺普利成分

由于抑制了肾素-血管紧张素-醛固酮系统，因此易感人群的肾功能可能会发生变化。在严重心力衰竭的患者中，其肾功能可能取决于肾素-血管紧张素-醛固酮系统的活性，ACEI抑制剂（包括trandolapril）的治疗可能与少尿和/或进行性氮质血症有关，很少与急性肾衰竭和/或死亡。

在患有单侧或双侧肾动脉狭窄的高血压患者中，在某些ACE抑制剂治疗后的患者中观察到血尿素氮和血清肌酐升高。停用ACE抑制剂和/或利尿剂治疗后，这些增加几乎总是可逆的。在此类患者中，应在治疗的最初几周内监测肾功能。

一些没有明显的既往存在的肾血管疾病的高血压患者血尿素和血清肌酐升高，通常是轻微和短暂的升高，尤其是当ACEI抑制剂与利尿剂同时使用时。既往有肾功能不全的患者更容易发生这种情况。可能需要减少剂量和/或停用任何利尿剂和/或ACE抑制剂。

对高血压患者的评估应始终包括对肾功能的评估（参见剂量和管理）。

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

Verapamil Component

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission (see PRECAUTIONS - Surgery/Anesthesia ).

Hyperkalemia and Potassium-sparing Diuretics

Trandolapril Component

In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4 percent of hypertensive patients receiving trandolapril and in 0.8% of patients receiving a dose of trandolapril (0.5-8 mg) in combination with a dose of verapamil SR (120-240 mg). In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with trandolapril (see PRECAUTIONS - Drug Interactions ).

咳嗽

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose.

Surgery/anesthesia

Trandolapril Component

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion (see PRECAUTIONS - Use in Patients with Attenuated (Decreased) Neuromuscular Transmission ).

药物相互作用

In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 including CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp).

Clinically significant interactions have been reported with inhibitors of CYP3A4 (eg erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (eg rifampin) have caused a lowering of plasma levels of verapamil. Therefore, patients receiving inhibitors or inducers of the cytochrome P450 system should be monitored for drug interactions.

Ivabradine

Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid co‑administration of verapamil and ivabradine.

Digitalis

Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digoxin toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance digoxin doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over- or under-digitalization. Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or temporarily discontinued. Upon discontinuation of any verapamil-containing regime including Tarka (trandolapril/verapamil hydrochloride ER), the patient should be reassessed to avoid underdigitalization. No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and digoxin.

Lithium

Verapamil Component

Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Tarka and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Clarithromycin

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent clarithromycin.

Erythromycin

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent erythromycin ethylsuccinate.

Cimetidine

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and cimetidine.

Antiarrhythmic Agents

Verapamil Component

Disopyramide Phosphate

Data on possible interactions between verapamil and disopyramide phosphate are not available. Therefore, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

氟卡尼

A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

奎尼丁

In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.

The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Antihypertensive Agents

Concomitant use of Tarka with other antihypertensive agents including diuretics, vasodilators, beta-adrenergic blockers, and alpha-antagonists may result in additive hypotensive effects. There are reports that verapamil may result in higher concentrations of the alpha-agonists prazosin and terazosin.

Dual Blockade of the Renin-Angiotensin System (RAS)

Trandolapril Component

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Tarka and other agents that affect the RAS.

Do not co-administer aliskiren with Tarka in patients with diabetes. Avoid use of aliskiren with Tarka in patients with renal impairment (GFR <60 ml/min).

Beta Blockers

Verapamil Component

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. Drug interaction studies have indicated that the maximum concentrations of metoprolol and propanolol are increased after the administration of verapamil. The use of verapamil in combination with a beta-adrenergic blocker should be used only with caution, and close monitoring.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

Concomitant Diuretic Therapy

Trandolapril Component

As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Tarka. The possibility of exacerbation of hypotensive effects with Tarka may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Tarka. If it is not possible to discontinue the diuretic, the starting dose of Tarka should be reduced (see DOSAGE AND ADMINISTRATION ). No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and furosemide.

Agents Increasing Serum Potassium

Trandolapril Component

Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium (see PRECAUTIONS ).

HMG-CoA Reductase Inhibitors (“Statins”)

Verapamil component

The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis.

Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (eg, atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

Trandolapril component

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure.这些影响通常是可逆的。 Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.

Neprilysin Inhibitor

Trandolapril component

Patients taking concomitant neprilysin inhibitors (eg, sacubitril) may be at increased risk for angioedema (see WARNINGS ).

Flibanserin

Verapamil component

Use of a moderate CYP3A4 inhibitor such as verapamil with flibanserin significantly increases flibanserin concentrations, which can lead to severe hypotension and syncope. Concomitant use is contraindicated (see CONTRAINDICATIONS ). Discontinue Tarka at least 2 weeks prior to starting flibanserin. Do not administer Tarka within 2 days of discontinuing flibanserin.

Other (Verapamil Component)

Nitrates

Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

Carbamazepine

Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

Anti-infective Agents

Therapy with rifampin may markedly reduce oral verapamil bioavailability. There have been reports that erythromycin and telithromycin may increase concentrations of verapamil.

Barbiturates

Phenobarbital therapy may increase verapamil clearance.

Immunosuppressive Agents

Verapamil therapy may increase serum levels of cyclosporin, sirolimus and tacrolimus.

茶碱

Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline.

Tranquilizers/ Anti-depressants

Due to metabolism via the CYP enzyme system, there have been reports that verapamil may increase the concentrations of buspirone, midazolam, almotriptan and imipramine.

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine (see PRECAUTIONS - Drug Interactions ).

Dabigatran

Verapamil, a P-gp inhibitor, increases exposure to dabigatran (a thrombin inhibitor) when administered concomitantly; however, no dose adjustment of dabigatran is required when administered with verapamil.

其他

Concentrations of verapamil may be increased by the concomitant administration of protease inhibitors such as ritonavir, and reduced by the concomitant administration of sulfinpyrazone, or St John's Wort.

Concentrations of doxorubicin may be increased by the administration of verapamil.

There have been reports that verapamil may elevate the concentrations of the oral anti-diabetic glyburide.

Inhalation Anesthetics

Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

神经肌肉阻滞剂

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Tarka.

Other (Trandolapril Component)

No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and nifedipine.

The anticoagulant effect of warfarin was not significantly changed by trandolapril.

Mammalian Target of Rapamycin (mTOR) Inhibitors

Patients taking concomitant mTOR inhibitor (eg, temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS - Angioedema ).

Anti-diabetic Agents

The concomitant use of ACE inhibitors such as trandolapril with antidiabetic medications (insulin or oral hypoglycemic agents) may result in increased blood glucose lowering effects.

致癌，诱变，生育力受损

Verapamil Component

An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Trandolapril Component

Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m 2 /day) or rats dosed up to 8 mg/kg/day (60 mg/m 2 /day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these in vitro and in vivo assays.

Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m 2 /day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.

怀孕

Female patients of childbearing age should be told about the consequences of exposure to Tarka during pregnancy (see WARNINGS ). Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

护理母亲

Verapamil is excreted in human milk. Radiolabeled trandolapril or its metabolites are secreted in rat milk. Tarka should not be administered to nursing mothers.

老人用

In placebo-controlled studies, where 23% of patients receiving Tarka were 65 years and older, and 2.4% were 75 years and older, no overall differences in effectiveness or safety were observed between these patients and younger patients. However, greater sensitivity of some older individual patients cannot be ruled out.

儿科用

Neonates with a history of in utero exposure to Tarka:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The safety and effectiveness of Tarka in children below the age of 18 have not been established.

Animal Pharmacology and/or Animal Toxicology

In chronic animal toxicology studies, verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man.

不良反应

Tarka has been evaluated in over 1,957 subjects and patients. Of these, 541 patients, including 23% elderly patients, participated in US controlled clinical trials, and 251 were studied in foreign controlled clinical trials. In clinical trials with Tarka, no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred have been limited to those that have been previously reported with verapamil or trandolapril. Tarka has been evaluated for long-term safety in 272 patients treated for 1 year or more. Adverse experiences were usually mild and transient.

Discontinuation of therapy because of adverse events in US placebo-controlled hypertension studies was required in 2.6% and 1.9% of patients treated with Tarka and placebo, respectively.

Adverse experiences occurring in 1% or more of the 541 patients in placebo-c