Tekamlo

适应症和用途

Tekamlo可单独或与其他降压药一起用于治疗高血压以降低血压。降低血压可降低致命和非致命性心血管事件（主要是中风和心肌梗塞）的风险。这些益处已在包括氨氯地平在内的多种药理学类别的抗高血压药物的对照试验中看到。没有可证明使用Tekamlo降低风险的对照试验。

高血压的控制应成为全面心血管风险管理的一部分，包括适当地控制血脂，控制糖尿病，抗血栓治疗，戒烟，运动和限制钠摄入量。许多患者需要多种药物才能达到血压目标。有关目标和管理的具体建议，请参见已发布的指南，例如国家高血压教育计划的全国预防，检测，评估和治疗高血压联合委员会（JNC）的指南。

随机对照试验显示，来自各种药理学类别且作用机制不同的多种降压药可降低心血管疾病的发病率和死亡率，可以得出结论，这是降低血压，而不是降低其某些药理特性。药物，这是造成这些好处的主要原因。最大和最一致的心血管预后获益是降低中风风险，但也经常观察到心肌梗塞和心血管死亡率降低。

收缩压或舒张压升高会增加心血管疾病的风险，而在较高的血压下，每mmHg的绝对危险度增加更大，因此，即使是轻度降低严重的高血压也可以带来实质性的益处。在绝对风险各不相同的人群中，降低血压带来的相对风险降低是相似的，因此，相对于高血压独立存在较高风险的患者（例如糖尿病或高脂血症患者），绝对收益更大。受益于更积极的治疗以降低血压目标。

一些抗高血压药对黑人患者的血压影响较小（如单一疗法），许多抗高血压药还具有其他批准的适应症和作用（例如，对心绞痛，心力衰竭或糖尿病肾病）。这些考虑因素可以指导治疗的选择。

来自大剂量多因素研究的数据[参见临床研究（14）]提供了与阿利吉仑或氨氯地平单药治疗相比，Tekamlo达到目标血压的可能性的估计值。图1-4提供了基于基线收缩压或舒张压的Tekamlo 300 mg / 10 mg达到收缩压或舒张压控制的可能性的估计值。每个治疗组的曲线通过逻辑回归模型估计。由于基线血压较高的受试者人数很少，因此在每条曲线右尾的估计可能性不太可靠。

图1：实现收缩压（SBP）小于140 mmHg的可能性

图2：舒张压（DBP）低于90 mmHg的可能性

图3：实现收缩压（SBP）小于130 mmHg的可能性

图4：舒张压（DBP）低于80 mmHg的可能性

图1和3提供了研究中评估的高剂量组达到目标血压目标（例如SBP小于140 mmHg或小于130 mmHg）的可能性的近似值。在基线血压的所有水平下，与任何单一疗法相比，联合使用均能达到任何给定的舒张或收缩目标的可能性更高。例如，参加该多因素研究的患者的平均基线SBP / DBP为157/100 mmHg。基线血压为157/100 mmHg的患者，仅阿利吉仑有49％的可能性达到小于140 mmHg（收缩压）的可能性，50％的可能性达到小于90 mmHg（舒张压）的可能性，以及这种可能性仅在氨氯地平上实现这些目标的比例约为62％（收缩期）和69％（舒张期）。在Tekamlo上实现这些目标的可能性上升到大约74％（收缩期）和83％（舒张期）。在安慰剂上实现这些目标的可能性约为25％（收缩期）和27％（舒张期） [参见剂量和给药方法（2）和临床研究（14）] 。

剂量和给药

一般注意事项

Tekamlo的每日建议初始剂量为150 mg / 5 mg。根据需要滴定至最大300 mg / 10 mg。

在1至2周内可以达到降血压的效果。如果在治疗2至4周后血压仍无法控制，则每天一次将剂量最大Tekamlo 300 mg / 10 mg滴定。

附加疗法

对于不能单独用阿利吉仑或苯磺酸氨氯地平（或另一种二氢吡啶钙通道阻滞剂）不能充分控制的患者，请使用Tekamlo。

将在任一成分上遇到剂量限制性不良反应的患者换成含有较低剂量该成分的Tekamlo，再与另一成分组合使用，以实现相似的血压降低。

替代疗法

将接受阿利吉仑和苯磺酸氨氯地平治疗的患者从单独的片剂改为单片含相同成分剂量的Tekamlo。替代单个成分时，如果血压控制效果不理想，则增加一种或两种成分的剂量。

与用餐的关系

患者应制定饮食习惯，不论是否进餐。高脂饮食会大大降低吸收[见临床药理学（12.3）] 。

剂量形式和强度

• 150毫克aliskiren / 5毫克氨氯地平片：非刻痕浅黄色椭圆形凸膜包衣片，其斜角边缘在片的一侧凹有“ T2”，在片的反面具有“ NVR”。
  
• 150毫克阿利吉仑/ 10毫克氨氯地平片：无划痕的黄色，椭圆形凸形薄膜衣片，其斜角边缘在片的一侧凹有“ T7”，在片的反面具有“ NVR”。
  
• 300毫克阿利吉仑/ 5毫克氨氯地平片：无痕的深黄色椭圆形凸状薄膜衣片，其斜边在片的一面有凹痕“ T11”，反面有“ NVR”。
  
• 300毫克阿利吉仑/ 10毫克氨氯地平片：非刻痕棕黄色椭圆形凸膜包衣片，其斜角边缘在片的一侧凹陷有“ T12”，在片的反侧凹陷。

禁忌症

糖尿病患者请勿将阿利吉仑与ARB或ACEI一起使用[请参阅警告和注意事项（5.2）和临床研究（14.2）] 。

Tekamlo是已知对任何成分过敏的患者的禁忌症[参见警告和注意事项（5.3）] 。

警告和注意事项

胎儿毒性

怀孕类别D

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。当检测到怀孕时，应尽快终止Tekamlo [请参阅在特定人群中使用（8.1）] 。

Tekamlo与ARB或ACEI联用时的肾功能不全/高钾血症/低血压

Tekamlo是接受ARB或ACEI的糖尿病患者的禁忌症，因为它会增加肾功能不全，高血钾和低血压的风险。通常，避免将阿利吉仑与ACE抑制剂或ARB并用，尤其是在肌酐清除率（CrCl）低于60 mL / min的患者中[见禁忌症（4），药物相互作用（7）和临床研究（14.3）] 。

过敏反应和头颈部血管性水肿

阿里斯基伦

据报道，在使用阿利吉仑治疗的患者中出现过敏反应，例如过敏反应和面部，四肢，嘴唇，舌头，声门和/或喉头的血管性水肿，需要住院和插管。这可能在治疗期间的任何时间发生，并且已经在有或没有ACEI或血管紧张素受体拮抗剂血管性水肿病史的患者中发生。从上市后的经验中已经报告了过敏反应，其发生频率未知。如果血管性水肿累及喉咙，舌头，声门或喉部，或者患者有上呼吸道手术史，则可能发生气道阻塞并致命。即使没有呼吸窘迫，也要经历这些影响的患者需要长时间观察并采取适当的监测措施，因为用抗组胺药和皮质类固醇治疗可能不足以预防呼吸系统受累。迅速给予1：1000皮下肾上腺素溶液（0.3 mL至0.5 mL），并采取措施以确保呼吸道通畅。

出现过敏性反应或血管性水肿且不重新给药的患者应立即停用Tekamlo [请参阅剂量和给药方法（2.1）禁忌症（4）] 。

低血压

在体征明显减少，盐分减少或联合使用阿利吉仑和其他作用于肾素-血管紧张素-醛固酮系统（RAAS）的患者中，开始用Tekamlo治疗后可能会出现症状性低血压。在服用Tekamlo之前应纠正体积或盐分的消耗，否则治疗应在密切的医学指导下开始。

短暂性降压反应不是进一步治疗的禁忌症，一旦血压稳定，通常可以毫无困难地继续治疗。

苯磺酸氨氯地平

有症状的低血压是可能的，特别是在患有严重主动脉瓣狭窄的患者中。由于作用逐渐开始，急性低血压不太可能发生。

心肌梗塞或心绞痛增加的风险

开始或增加氨氯地平的剂量后，尤其是严重的阻塞性冠状动脉疾病，可能会加剧心绞痛和急性心肌梗塞。

肾功能受损

定期监测接受Tekamlo治疗的患者的肾功能。影响RAAS的药物可能引起肾功能变化，包括急性肾衰竭。肾功能可能部分取决于RAAS活动的患者（例如，肾动脉狭窄，严重心力衰竭，心肌梗塞后或容量减少的患者）或接受ARB，ACEI或非甾体抗炎药（NSAID，包括选择性的环氧合酶2抑制剂（COX-2抑制剂），在Tekamlo上发生急性肾衰竭的治疗可能特别危险[请参阅警告和注意事项（5.2），药物相互作用（7），在特定人群中使用（8.7）和临床研究（14.2） ..对于临床上肾功能显着下降的患者，应考虑停药或中止治疗[见剂量和给药方法（2.1）] 。

环孢霉素或伊曲康唑

阿里斯基伦

当阿利吉仑与环孢霉素或伊曲康唑一起使用时，阿利吉仑的血药浓度显着增加。避免将阿利吉仑与环孢素或伊曲康唑同时使用[见药物相互作用（7）]。

高钾血症

阿里斯基伦

定期监测接受阿利吉仑治疗的患者的血钾水平。影响RAAS的药物可引起高钾血症。高钾血症发生的危险因素包括肾功能不全，糖尿病，与ARB或ACEI并用[见禁忌症（4），警告和注意事项（5.2）和临床研究（14.2）] ，NSAID，包括选择性的环氧合酶2抑制剂（ COX-2抑制剂）或钾补充剂或保钾利尿剂。

不良反应

临床研究经验

标签的其他部分详细讨论了以下严重不良反应：

• 胎儿毒性[见警告和注意事项（5.1）]
• 过敏反应和头颈部血管性水肿[请参阅警告和注意事项（5.3）]
• 低血压[请参阅警告和注意事项（5.4）]

由于临床试验是在广泛不同的条件下进行的，因此不能将在一种药物的临床试验中观察到的不良反应率直接与另一种药物在临床试验中观察到的不良反应率进行比较，并且可能无法反映实际中观察到的不良反应率。

Tekamlo

Tekamlo已针对2800多名患者进行了安全性评估，包括372名1年或更长时间的患者。

在安慰剂对照研究中，年龄在65岁以上的男性为51％，白种人为62％，黑人为20％，西班牙裔为18％，而17％为。在这项研究中，Tekamlo治疗不良事件的总发生率与单个成分相似。在这项研究中，由于临床不良事件导致的治疗中止发生在1.7％的Tekamlo治疗患者中（最高剂量组为2.2％），而接受安慰剂的患者为1.5％。

周围水肿是氨氯地平的一种已知的，剂量依赖性的不良反应。在短期双盲安慰剂对照研究中，Tekamlo周围性水肿的发生率低于或等于相应的氨氯地平剂量。

安慰剂对照试验的不良事件发生在至少2％的Tekamlo治疗患者中，其发生率高于安慰剂，为外周水肿（6.2％对1.0％）。高剂量时周围性水肿的发生率为8.9％。

在长期安全性试验中，不良事件的安全性与短期对照试验相似。

阿里斯基伦

已评估Aliskiren在6460位患者中的安全性，其中包括接受治疗的1740例患者超过6个月，以及1250例患者超过1年。在安慰剂对照的临床试验中，由于阿利吉仑治疗的患者中有2.2％的患者因临床不良事件（包括不受控制的高血压）而终止治疗，而接受安慰剂的患者为3.5％。这些数据不包括来自ALTITUDE研究的信息，该研究评估了阿利吉仑与ARB或ACEI的联合使用[请参阅禁忌症（4），警告和注意事项（5.2）和临床研究（14.2）] 。

在临床研究中报告了2例具有呼吸道症状的血管性水肿，并使用了阿利吉仑。据报道另外两例无呼吸道症状的眶周水肿可能是血管性水肿，导致停药。在完成的研究中，这些血管性水肿病例的发生率为0.06％。

此外，据报道有26例其他水肿病例涉及面部，手或全身，使用了阿利吉仑，其中4例导致停药。

然而，在安慰剂对照研究中，阿利吉仑对面部，手部或全身的水肿发生率为0.4％，而安慰剂为0.5％。在一项对阿利吉仑和HCTZ手臂进行的长期主动对照研究中，两个治疗手臂中涉及面部，手部或全身的水肿发生率均为0.4％。

Aliskiren会产生剂量相关的胃肠道（GI）不良反应。 300 mg的患者中有2.3％出现腹泻，而安慰剂患者为1.2％。在女性和老年人（65岁及以上）中，腹泻率从每天150 mg开始明显增加，这些亚组的剂量为150 mg，与男性或年轻患者300 mg的情况相似（所有比率约2％）。其他胃肠道症状包括腹痛，消化不良和胃食管反流，尽管仅每天600 mg与安慰剂有区别，腹痛和消化不良的发生率增加。腹泻和其他胃肠道症状通常较轻，很少导致停药。

在安慰剂对照研究中，阿利吉仑与咳嗽的轻微增加相关（任何阿利吉仑使用量为1.1％，而安慰剂为0.6％）。在使用ACE抑制剂（雷米普利，赖诺普利）治疗组的主动对照试验中，阿利吉仑治疗组的咳嗽率约为ACE抑制剂治疗组的三分之一至二分之一。

阿利吉仑相比安慰剂发生率增加的其他不良反应包括皮疹（1％比0.3％），尿酸升高（0.4％比0.1％），痛风（0.2％比0.1％）和肾结石（0.2％比0％） ）。

在临床试验中，有2名接受阿利吉仑治疗的患者据报道出现单发性强直阵挛性癫痫发作并失去意识。 1例患者有诱发癫痫的诱因，癫痫发作后脑电图（EEG）和脑影像学均为阴性。对于其他患者，未报告脑电图和影像学结果。 Aliskiren已停产，在两种情况下都没有挑战。

在使用阿利吉仑治疗的患者中，未观察到生命体征或ECG（包括QTc间隔）的临床有意义变化。

苯磺酸氨氯地平

氨氯地平（络活喜®）已超过11000例患者在美国和国外的临床试验进行评估以保证安全。在对照临床试验中或在因果关系不确定的情况下进行的公开试验或市场经验条件下，报告的其他不良事件少于1％但大于0.1％：

心血管：心律失常（包括室性心动过速和心房颤动），心动过缓，胸痛，外周缺血，晕厥，心动过速，血管炎

中枢和周围神经系统：感觉不足，周围神经病变，感觉异常，震颤，眩晕

胃肠道：厌食，便秘，吞咽困难，腹泻，肠胃气胀，胰腺炎，呕吐，牙龈增生

一般：过敏反应，乏力，**背痛，潮红，不适，疼痛，僵硬，体重增加，体重减轻

肌肉骨骼系统：关节痛，关节病，肌肉痉挛，**肌痛

精神病：性功能障碍（男性**和女性），失眠，神经质，抑郁，梦境异常，焦虑，人格解体

呼吸系统：呼吸困难，鼻**

皮肤和附件：血管性水肿，多形性红斑，瘙痒，**皮疹，**皮疹红斑，斑丘疹

**这些事件在安慰剂对照试验中的发生率不到1％，但在所有多剂量研究中，这些副作用的发生率在1％至2％之间。

特殊感觉：视力异常，结膜炎，复视，眼痛，耳鸣

泌尿系统：排尿频率，排尿障碍，夜尿

自主神经系统：口干，出汗增多

代谢和营养：高血糖，口渴

造血：白细胞减少症，紫癜，血小板减少症

氨氯地平报道的其他频率小于或等于0.1％的患者包括：心力衰竭，脉搏不规则，收缩期，皮肤变色，荨麻疹，皮肤干燥，脱发，皮炎，肌肉无力，抽搐，共济失调，肌张力亢进，偏头痛，皮肤寒冷，湿润，冷漠，躁动，健忘症，胃炎，食欲增加，大便稀疏，鼻炎，排尿困难，多尿，妄想症，味觉变态，视觉调节异常和干眼症。其他反应偶发发生，无法与药物或并发疾病如心肌梗塞和心绞痛区分开。

临床实验室测试异常

RBC计数，血红蛋白和血细胞比容：使用Tekamlo和阿利吉仑单药治疗的患者，RBC计数，血红蛋白和血细胞比容与基线相比有较小的平均变化。在作用于肾素-血管紧张素系统的其他药物上也可以看到这种作用。在阿利吉仑单药试验中，与安慰剂相比，这些降低导致贫血率略有增加（任何阿利吉仑使用量为0.1％，阿利吉仑每天600 mg用量为0.3％，而安慰剂为0％）。没有患者因贫血而停药。

血尿素氮（BUN）/肌酐：在未同时用ARB或ACEI治疗的高血压患者中，用Tekamlo治疗的患者的BUN（大于40 mg / dL）和肌酐（大于2.0 mg / dL）升高较少高于1.0％。

血清钾：在未同时接受ARB或ACEI治疗的高血压患者中，血清钾的升高不超过5.5 mEq / L（0.9％，而安慰剂为0.6％） [见禁忌症（4）和警告和注意事项（5.8） ）] 。

上市后经验

在阿利吉仑或氨氯地平的批准后使用过程中，已确认出现以下不良反应。由于这些反应是由不确定大小的人群自愿报告的，因此并非总是可能估计其发生频率或建立与药物暴露的因果关系：

Aliskiren ：周围水肿，严重的皮肤不良反应，包括Stevens-Johnson综合征和中毒性表皮坏死溶解，荨麻疹，肝酶升高，并伴有肝功能障碍，瘙痒，红斑，恶心，呕吐的临床症状

超敏反应：过敏反应和血管性水肿需要气道管理和住院

氨氯地平：在因果关系不确定的情况下，很少有以下上市后事件的报道：男性乳房发育症。在上市后的经验中，据报道与氨氯地平的使用有关，黄疸和肝酶升高（多数与胆汁淤积或肝炎一致），在某些情况下严重到需要住院治疗。

药物相互作用

尽管以下描述了与单独的阿利吉仑和苯磺酸氨氯地平成分的研究，但尚未与Tekamlo和其他药物进行药物相互作用研究。

阿里斯基伦

环孢菌素：避免将环孢菌素与阿利吉仑同时使用[见警告和注意事项（5.7）和临床药理学（12.3）] 。

伊曲康唑：避免将伊曲康唑与阿利吉仑同时使用[见警告和注意事项（5.7）和临床药理学（12.3）] 。

非甾体类抗炎药（NSAIDs），包括选择性的环氧合酶2抑制剂（COX-2抑制剂）：在年老，体量减少（包括利尿剂治疗）或肾功能受损的患者中，NSAID联合给药包括选择性COX-2抑制剂与影响肾素-血管紧张素-醛固酮系统的药物（包括阿利吉仑）可能导致肾功能恶化，包括可能的急性肾衰竭。这些影响通常是可逆的。定期监测接受阿利吉仑和NSAID治疗的患者的肾功能。

非甾体抗炎药可能会减轻阿利吉仑的降压作用。

肾素-血管紧张素-醛固酮系统（RAAS）的双重阻断：将阿利吉仑与其他作用于RAAS的药物（例如ACEIs或ARBs）同时使用会增加低血压，高钾血症和肾功能变化（包括急性）的风险肾功能衰竭）与单一疗法相比，大多数接受两种抑制肾素-血管紧张素系统药物组合的患者没有获得任何其他益处。通常，避免将阿利吉仑与ACE抑制剂或ARB并用，尤其是在CrCl低于60 mL / min的患者中。

监测使用阿利吉仑和其他会影响RAAS的药物的患者的血压，肾功能和电解质[参见警告和注意事项（5.4，5.6，5.8）] 。

禁忌在糖尿病患者中同时使用阿利吉仑和ARB或ACEI [见禁忌症（4）] 。

速尿：口服联合阿利吉仑和速尿可减少速尿的暴露。当呋塞米与阿利吉仑合用时，监测利尿作用。

苯磺酸氨氯地平

辛伐他汀：辛伐他汀与氨氯地平合用会增加辛伐他汀的全身暴露。将氨氯地平患者的辛伐他汀剂量限制为每天20 mg。

CYP3A4抑制剂：与CYP3A抑制剂（中度和强烈）共同给药会导致氨氯地平的全身暴露增加，从而有必要降低剂量。氨氯地平与CYP3A4抑制剂合用时应监测低血压和水肿症状，以确定需要调整剂量。

CYP3A4诱导剂：没有关于CYP3A4诱导剂对氨氯地平的定量作用的信息。氨氯地平与CYP3A4诱导剂合用时应监测血压。

在特定人群中的使用

怀孕

怀孕类别D [请参阅警告和注意事项（5.1）]

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Tekamlo。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，请停用Tekamlo，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。密切观察有子宫内暴露于Tekamlo的低血压，少尿和高钾血症病史的婴儿[见在特定人群中使用（8.4）] 。

动物资料

尚未与阿利吉仑和苯磺酸氨氯地平合用进行生殖毒性研究。但是，仅对阿利吉仑和苯磺酸氨氯地平进行了这些研究。

阿里斯基伦

在发育毒性研究中，怀孕的大鼠和兔子在器官发生期间口服阿利吉仑半富马酸盐口服液的剂量分别是大鼠和兔子基于人体表面积（mg / m 2 ）的最大推荐人剂量（MRHD）的20倍和7倍。大鼠的实际动物剂量最高为600 mg / kg /天，兔子的最高动物剂量为100 mg / kg /天。没有观察到致畸性。然而，以体表面积（mg / m 2 ）为基础，MRHD的3.2倍剂量可使兔的胎儿出生体重降低。 Aliskiren存在于妊娠兔的胎盘，羊水和胎儿中。

氨氯地平

当妊娠大鼠和家兔在其主要器官发生的相应时期内口服马来酸氨氯地平的剂量最高为10 mg氨氯地平/ kg /天时，未发现致畸或胚胎/胎儿毒性的证据。但是，产仔数显着减少（约50％），宫内死亡数量显着增加（约5倍）。氨氯地平已显示在该剂量下可延长大鼠的妊娠期和分娩时间。

护理母亲

尚不知道阿利吉仑或氨氯地平是否会从人乳中排出。阿利吉仑和氨氯地平均在泌乳大鼠的乳汁中分泌。由于来自Tekamlo的母乳喂养婴儿可能会出现严重的不良反应，因此应考虑该药物对母亲的重要性，决定是否停止护理或停止Tekamlo。

儿科用

尚未确定Tekamlo在儿科患者中的安全性和有效性。

临床前研究表明，小儿患者暴露于阿利吉仑的可能性可能会大大增加[见非临床毒理学（13.2）] 。

有子宫内暴露于Tekamlo病史的新生儿

如果发生少尿或低血压，请直接注意支持血压和肾灌注。作为逆转低血压和/或替代功能紊乱的肾功能的手段，可能需要进行换血或透析。

老人用

65岁及以上的患者增加了阿利吉仑和氨氯地平的暴露。考虑从氨氯地平的最低可用剂量开始。最低强度的Tekamlo含有5 mg氨氯地平[请参阅临床药理学（12.3）] 。

在Tekamlo的短期对照临床试验中，接受Tekamlo治疗的患者中有17％年龄在65岁及以上。在这些受试者和较年轻的受试者之间未观察到安全性或有效性的总体差异。其他报告的临床经验尚未发现老年患者和年轻患者之间反应的差异，但是不能排除某些老年患者的敏感性更高。

肝功能不全

肝功能不全的患者氨氯地平的暴露量增加，因此考虑使用较低剂量的Tekamlo [见临床药理学（12.3）] 。

肾功能不全

肾功能对阿利吉仑和氨氯地平的药代动力学没有影响。但是，尚未确定Tekamlo在严重肾功能不全（肌酐清除率（CrCl）低于30 mL / min）患者中的安全性和有效性，因为这些患者已被排除在临床试验之外[请参阅警告和注意事项（5.6），临床药理学（ 12.3）和临床研究（14）] 。

过量

阿里斯基伦

关于人类过量的可用数据有限。药物过量的最可能的表现是低血压。如果出现症状性低血压，请提供支持治疗。

Aliskiren的透析能力很差。因此，血液透析不足以治疗阿利吉仑过度暴露[见临床药理学（12.3）] 。

苯磺酸氨氯地平

服用过量可能会导致过度的外周血管扩张，并伴有明显的低血压和反射性心动过速。据报道，系统性低血压明显升高，甚至可能延长，直至休克并导致致命后果。在人类中，氨氯地平故意过量服用的经验有限。

分别在小鼠和大鼠中单次口服马来酸氨氯地平相当于40 mg氨氯地平/ kg和100 mg氨氯地平/ kg导致死亡。在狗中单次口服氨氯地平马来酸氨氯地平的剂量等于或大于4 mg氨氯地平/ kg或更高（以mg / m 2为基础，是MRHD的11倍或更多倍）会引起明显的外周血管舒张和低血压。

如果发生大量用药过量，请开始积极的心脏和呼吸监测。经常进行血压测量至关重要。如果发生低血压，请提供心血管支持，包括四肢抬高和明智地输液。如果低血压对这些保守措施仍然无反应，请考虑给予血管加压药（如去氧肾上腺素），并注意循环量和尿量。由于氨氯地平具有高度的蛋白结合性，因此血液透析不太可能受益。已证明对健康志愿者立即或在摄入氨氯地平后最多2小时内给予活性炭可显着降低氨氯地平的吸收。

描述

Tekamlo是单片片剂，用于口服给药阿利吉仑半富马酸盐（口服活性，非肽，有效的直接肾素抑制剂）和苯磺酸氨氯地平（一种二氢吡啶钙通道阻滞剂）。

一个liskiren 半富马酸盐

阿利吉仑半富马酸酯在化学上被描述为（2 S ，4 S ，5 S ，7 S ）-N-（2-氨基甲酰基-2-甲基丙基）-5-氨基-4-羟基-2,7-二异丙基-8- [4 -甲氧基-3-（3-甲氧基丙氧基）苯基]-辛酰胺半富马酸酯，其结构式为：

分子式：C 30 H 53 N 3 O 6 •0.5 C 4 H 4 O 4

阿利吉仑半富马酸盐为白色至微黄色粉末，分子量为609.8（游离碱551.8）。它高度溶于水，并易溶于甲醇，乙醇和异丙醇。

苯磺酸氨氯地平

苯磺酸氨氯地平USP在化学上被描述为3-乙基5-甲基（±）-2-[（（2-氨基乙氧基）甲基] -4-（邻氯苯基）-1,4-二氢-6-甲基-3,5 -吡啶二羧酸盐，单苯磺酸盐，其结构式为：

分子式：C 20 H 25 CIN 2 O 5 •C 6 H 6 O 3 S

苯磺酸氨氯地平为白色至浅黄色结晶粉末，分子量为567.1。微溶于水，微溶于乙醇。

Tekamlo片剂经配制用于口服给药，其中包含阿利吉仑半富马酸盐和苯磺酸氨氯地平，提供以下可用组合：150 mg / 5 mg，150 mg / 10 mg，300 mg / 5 mg和300 mg / 10 mg阿利吉仑/氨氯地平。片剂所有强度的非活性成分可能包含胶体二氧化硅，交聚维酮，羟丙甲纤维素，氧化铁红，氧化铁黄，硬脂酸镁，微晶纤维素，聚乙二醇，聚维酮，滑石粉和二氧化钛。

临床药理学

作用机理

阿里斯基伦

肾素响应于血容量的减少和肾脏灌注而由肾脏分泌。肾素裂解血管紧张素原形成无活性的十肽血管紧张素I（Ang I）。 Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, eg, ACE or non-ACE pathways, is not known.

All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACEIs and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.

Amlodipine besylate

Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Tekamlo

The effects of combined treatment of aliskiren and amlodipine arise from the actions of these 2 agents on different, but complementary mechanisms that regulate blood pressure, calcium channel-mediated vasoconstriction and RAAS-mediated effects on vascular tone and sodium excretion.

药效学

Aliskiren

PRA reductions in clinical trials ranged from approximately 50% to 80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.

Amlodipine besylate

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 mmHg to 114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90 mmHg to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter AH and HV conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Amlodipine has indications other than hypertension which can be found in the Norvasc ® package insert.

Tekamlo

In a placebo-controlled study in hypertensive patients, amlodipine was associated with an increase in PRA (59% to 73% increase) whereas aliskiren monotherapy was associated with a 61% to 68% reduction in PRA. Aliskiren in combination with amlodipine reduced PRA (55% to 68% reduction).

药代动力学

吸收与分布

Tekamlo

Following oral administration of the aliskiren/amlodipine combination tablets, the median peak plasma concentration times are within 3 hours for aliskiren and 8 hours for amlodipine. The rate and extent of absorption of aliskiren and amlodipine from Tekamlo are the same as when administered as individual tablets. When taken with food, mean AUC and C max of aliskiren are decreased by 79% and 90%, respectively, while there is no impact of food on the AUC and C max of amlodipine.

Aliskiren

Aliskiren is poorly absorbed (bioavailability about 2.5%) with an accumulation half-life of about 24 hours. Steady state blood levels are reached in about 7 to 8 days. Following oral administration, peak plasma concentrations of aliskiren are reached within 1 to 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials, aliskiren was administered without a fixed relation to meals.

Amlodipine besylate

Peak plasma concentrations of amlodipine are reached 6 to 12 hours after an oral administration of amlodipine. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.

The apparent volume of distribution of amlodipine is about 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

代谢与消除

Aliskiren

About one-fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP3A4.

Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.

Drug Interactions: The effect of coadministered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 5 (impact of coadministered drugs on aliskiren) and Figure 6 (impact of aliskiren on coadministered drugs).

Figure 5: The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren

*Ketoconazole : A 400 mg once daily dose was not studied, but would be expected to increase aliskiren blood levels further.

**Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions (7)] .

Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.

Figure 6: The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs

*Furosemide: Patients receiving furosemide may find its effects diminished after starting aliskiren. In patients with heart failure, coadministration of aliskiren (300 mg/day) reduced plasma AUC and C max of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was coadministered with aliskiren 300 mg/day.

**Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions (7)] .

Amlodipine besylate

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels are reached after once-daily dosing for 7 to 8 days.

药物相互作用：

Aliskiren exposure is increased slightly (AUC increased 29%) when aliskiren is coadministered with amlodipine, while amlodipine exposure remains unchanged when coadministered with aliskiren. The slight exposure increase of aliskiren in the presence of amlodipine is not clinically relevant.

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit juice: Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Maalox ® (antacid): Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin: Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Simvastatin: Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

CYP3A inhibitors: Coadministration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent.

特殊人群

小儿患者

The pharmacokinetics of Tekamlo have not been investigated in patients younger than 18 years of age.

老年患者

Impact of aging on aliskiren pharmacokinetics has been assessed. When compared to young adults (18 to 40 years), aliskiren mean AUC and C max in elderly subjects (older than 65 years) are increased by 57% and 28%, respectively. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve [see Use in Specific Populations (8.5)] .

种族

With Tekamlo, pharmacokinetic differences due to race have not been studied. The pharmacokinetic differences among blacks, Caucasians, and Japanese are minimal with aliskiren therapy.

肝功能不全

The pharmacokinetics of aliskiren is not significantly affected in patients with mild-to-severe liver disease. Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60% [see Use in Specific Populations (8.6)] .

肾功能不全

The pharmacokinetics of aliskiren was evaluated in patients with varying degrees of renal impairment. Rate and extent of exposure (AUC and C max ) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment.

The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis were not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients.

The pharmacokinetics of amlodipine is not significantly influenced by renal impairment [see Warnings and Precautions (5.6) and Use in Specific Populations (8.7)] .

非临床毒理学

致癌，诱变，生育力受损

Studies with Aliskiren hemifumarate and Amlodipine besylate

No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of aliskiren hemifumarate and amlodipine besylate. However, these studies have been conducted for aliskiren hemifumarate and amlodipine besylate alone.

Studies with Aliskiren hemifumarate

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of 750 or more mg/kg/day in both species, with a colonic adenoma identified in 1 rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC 0-24hr ) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the MRHD (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies.

Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli , the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo rat bone marrow micronucleus assay.

Fertility of male and female rats was unaffected at doses of up to aliskiren 250 mg/kg/day (8 times the MRHD of aliskiren 300 mg/60 kg on a mg/m 2 basis).

Studies with Amlodipine besylate

Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m 2 basis, similar to the MRHD of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m 2 basis, about twice the MRHD.

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 8 times the MRHD of 10 mg/day on a mg/m 2 basis).

动物毒理学和/或药理学

Preclinical safety studies have demonstrated that the combination of aliskiren hemifumarate and amlodipine besylate was well tolerated in rats. The findings from the 2- and 13-week oral toxicity studies in rats were consistent with those of aliskiren hemifumarate and amlodipine besylate when both drugs were administered alone. There were no new toxicities or increased severity of the toxicities which were associated with either component.

Animal reproductive and developmental toxicology findings are described elsewhere [see Use in Specific Populations (8.1)] .

Juvenile toxicity studies indicated increased systemic exposure to aliskiren 85- to 385-fold in 14 day and 8 day old rats respectively, compared with adult rats. The mdr1 gene expression in juvenile rats was also significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be mainly attributed to lack of maturation of P-gp. The overexposure in juvenile rats was associated with high mortality [see Use in Specific Populations (8.4)] .

CLINICAL STUDIES

Tekamlo

Tekamlo was studied in a total of 5549 patients with mild to moderate hypertension (diastolic blood pressure between 90 mmHg and 109 mmHg).

Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, randomized, double-blind, placebo-controlled, multifactorial study comparing the combinations 150 mg/5 mg, 150 mg/10 mg, 300 mg/5 mg and 300 mg/10 mg of aliskiren and amlodipine with their components and placebo. The combination of aliskiren and amlodipine resulted in placebo-adjusted decreases in systolic/diastolic blood pressure at trough of 14–17/9–11 mmHg compared to 4–9/3–5 mmHg for aliskiren alone and 9–14/6–8 mmHg for amlodipine alone.

Treatment with Tekamlo resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components.

The antihypertensive effect of Tekamlo was similar in patients with and without diabetes, obese and non-obese patients, in patients 65 years of age or older and under 65 years of age, and in women and men.

A subgroup of 819 patients was studied with ambulatory blood pressure monitoring. The blood pressure lowering effect in the aliskiren/amlodipine group was maintained throughout the 24-hour period (see Figure 7 and Figure 8).

Figure 7: Mean Ambulatory Diastolic Blood Pressure (DBP) at Endpoint by Treatment and Hour

Figure 8: Mean Ambulatory Systolic Blood Pressure (SBP) at Endpoint by Treatment and Hour

Two additional double-blind, active-controlled studies of similar design were conducted in which Tekamlo was administered as initial therapy in patients with moderate to severe hypertension (SBP 160 mmHg to 200 mmHg). Patients were randomized to receive either combination aliskiren/amlodipine or amlodipine monotherapy. The initial dose of aliskiren/amlodipine was 150 mg/5 mg for 1 week with forced titration to 300 mg/10 mg for 7 weeks. The initial dose of amlodipine was 5 mg for 1 week with forced titration to 10 mg for 7 weeks. In one study of 443 black patients, at the primary endpoint of 8 weeks, the treatment difference between aliskiren/amlodipine and amlodipine was 5.2/3.8 mmHg. In the other study of 484 patients, at the primary endpoint of 8 weeks, the treatment differe