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药品名称：

【通用名称】 奥美沙坦酯氨氯地平片

【商品名称】 思卫平

【英文名称】 Olmesartan Medoxomil and Amlodipine Besylate Tablets

警示语：

一旦发现妊娠应尽快停止使用本品。
直接作用于肾素-血管紧张素系统的药物，可导致发育中的胎儿损伤和死亡。

成份：

本品为复方制剂，其组份为：每片含奥美沙坦酯20mg和苯磺酸氨氯地平5mg(以氨氯地平计)。
（1）奥美沙坦酯
化学名称：2,3-二羟基-2-丁烯基 4-(1-羟基-1-甲乙基)-2-丙基-1-[对-(邻-1H-四唑-5-苯基)苄基]咪唑-5-羧酸酯, 环 2,3-碳酸
化学结构式：
分子式：C29H30N6O6
分子量：558.59
（2）苯磺酸氨氯地平
化学名称：（±）-2-[（2-氨基乙氧基）甲基]-4-（2-氯苯基）-1,4-二氢-6-甲基-3,5-吡啶二羧酸-5-甲酯，3-乙酯苯磺酸盐
化学结构式：
分子式：C20H25ClN2O5·C6H6O3S
分子量：567.05

性状：

本品为薄膜衣片，除去包衣后显白色。

作用类别：

血管紧张素受体拮抗剂（ARB）+钙离子拮抗剂（CCB）的单片复方药物。

适应症：

用于治疗原发性高血压。本固定剂量复方适用于单用奥美沙坦酯或单用氨氯地平治疗血压控制效果不佳的成人患者。
血压的下降可降低致命及非致命的心血管事件风险，主要包括卒中和心肌梗死。包括本品所属类别在内的多种药理学分类的抗高血压药物的对照临床试验中均可见上述获益。
尚未有本品降低心血管风险的对照临床试验证据。
高血压的控制是心血管风险综合管理的一部分，综合管理措施可能需要包括：血脂控制、糖尿病管理、抗血栓治疗、戒烟、体育锻炼和限制钠盐摄入。
来自多种药理学分类、具不同作用机制的众多抗高血压药物在随机对照临床试验中已显示出降低心血管发病率和死亡率的作用，这可以判定这些获益主要归因于血压降低的作用，而非药物的其它药理学属性。最主要且最一致的心血管获益是卒中风险的减少，但心肌梗死发生率和心血管死亡率的下降也较常见。
收缩压或舒张压的升高均增高心血管风险。在更高的基础血压水平上，每毫米汞柱血压的升高所带来的绝对风险增加会更高。严重高血压患者，略微降低血压就能带来较大的临床获益。降低血压获得风险降低的相对程度，在有不同心血管绝对风险的人群中是相似的。

规格：

每片含奥美沙坦酯20mg和苯磺酸氨氯地平5mg(以氨氯地平计)

用法用量：

用法：
药片应用足够量的水吞服（如，一杯水），药片不能咀嚼，应在每日同一时间服用。
成年人
本品推荐剂量是每日 1 次，每次 1 片。
本品可用于单用奥美沙坦酯 20mg 或单用氨氯地平 5mg 治疗血压控制效果不佳的患者。
在换用固定剂量复方药片之前，建议先逐步调整单一成分的用药剂量。根据临床情况，也可以考虑从单药治疗直接换用固定剂量复方药片治疗。
服用 2 周内，可达最大降压效果。服用 2 周后可以根据需要增加剂量。本品最大推荐剂量为每日不超过 2 片（即，奥美沙坦酯 40 mg/氨氯地平 10 mg）。
为方便起见，服用奥美沙坦酯和氨氯地平两种药片的患者可以换用含有相同剂量的本品。
本品可与或不与食物同服。
老年人（≥65 岁）
老年人用药推荐剂量一般无需调整，若要增加剂量应慎重。老年患者的氨氯地平清除率下降。年龄≥75 岁的患者应以氨氯地平 2.5 mg 的剂量开始单药服用或添加服用氨氯地平。
如果奥美沙坦酯的用药剂量需要逐步调整到每日的最大剂量 40 mg，则应当密切监测血压变化。
肾功能损伤的患者
轻度到中度肾功能损伤（肌酐清除率 20-60 mL/min）的患者，奥美沙坦酯的最大推荐用药剂量是 20 mg，每日 1 次，因为该患者人群中使用更大剂量治疗的经验有限。重度肾功能损伤（肌酐清除率<20 mL/min）的患者，不宜使用本品。
中度肾功能损伤患者，治疗时应监测血钾和肌酐水平。
肝功能损伤的患者
轻度到中度肝功能损伤的患者应慎用本品。
中度肝功能损伤的患者，推荐奥美沙坦酯的起始剂量为 10 mg 每日 1 次，最大剂量不能超过 20 mg 每日 1 次。已经用利尿剂和/或其他降压药治疗并且有肝功能损伤的患者，要密切监测血压和肾功能变化。尚无奥美沙坦酯治疗重度肝功能损伤患者的经验。
和所有钙拮抗剂一样，氨氯地平在肝功能损伤的患者中的半衰期延长，尚未确定推荐的用药剂量。所以这些患者应当慎用 Sevikar。尚未在重度肝损伤患者中研究氨氯地平的药代动力学。肝损伤患者应以氨氯地平的最低剂量开始治疗，之后逐步增加剂量。重度肝损伤患者禁用本品。
儿童人群
尚未确定本品在 18 岁以下儿童和青少年中的安全性和疗效。目前无可用的数据。

不良反应：

通常奥美沙坦酯的不良反应是轻微、一过性的，且无剂量相关性。水肿是氨氯地平已知具有剂量相关性的不良反应。
[临床试验经验和上市后经验]
治疗期间最常见的不良反应包括外周水肿（11.3%）、头痛（5.3%）和头晕（4.5%）。
临床试验、上市后安全性研究和自发报告中 Sevikar 的不良反应总结见下表，并包括单个成分奥美沙坦酯和氨氯地平的不良反应（基于二者的已知安全性特征）。
为了区分不良反应的发生频率高低，采用了下列术语：
十分常见（≥1/10）
常见（≥1/100 到<1/10）
偶见（≥1/1000 到<1/100）
罕见（≥1/10000 到<1/1000）
十分罕见（<1/10000），不明（根据现有数据无法估计）




报告有 1 例横纹肌溶解病例，发生时间与摄入血管紧张素Ⅱ受体阻滞剂有关。氨氯地平治疗患者中报告有 1 例锥体束外综合征病例。
与使用单组份相比，本品更大程度地降低了血红蛋白和血细胞比容。
疑似不良反应报告
药品上市批准后报告疑似不良反应十分重要，其有助于继续监测药品的风险/获益性。要求专业医护人员报告任何疑似不良反应。

禁忌：

对本品所含成份及二氢吡啶类衍生物过敏者禁用。
不可将本品与阿利吉仑联合用于糖尿病患者或肾功能损伤患者（GFR < 60 mL/min）。
妊娠期（见【孕妇及哺乳期妇女用药】）。
重度肝功能不全和胆道梗阻（见【注意事项】）。
由于含有氨氯地平成分，所以本品也禁用于有下列情况的患者：
- 重度低血压。
- 休克（包括心源性休克）。
- 左心室流出道阻塞（如高度主动脉瓣狭窄）。
- 急性心肌梗死后血流动力学不稳定型心脏衰竭。

注意事项：

1. 胎儿毒性
在妊娠的中、晚期，使用直接作用于肾素-血管紧张素系统的药物可降低胎儿肾功能，增加胎儿和新生儿的发病率和死亡率。由此产生的羊水过少可以与胎儿肺发育不全与骨骼变形相关。潜在的新生儿不良反应包括颅骨发育不全、无尿症、低血压、肾衰竭和死亡。一旦发现妊娠，应尽快停止使用本品。（见【孕妇及哺乳期妇女用药】
2. 血容量不足或者低钠患者的低血压
奥美沙坦酯
首次服用奥美沙坦酯后可能出现症状性低血压。肾素-血管紧张素系统受激的患者，如
血容量不足和/或低钠患者（例如，使用高剂量利尿剂治疗、膳食性盐摄入限制、腹泻或呕吐的患者），特别容易发生上述反应。因此必须在周密的医疗监护下开始使用本品治疗。如果发生低血压，患者应仰卧，必要时静脉滴注生理盐水。一过性的低血压反应并非进一步治疗的禁忌，一旦血压稳定，可继续用本品治疗。
3. 血管扩张
氨氯地平
因本品组份氨氯地平扩张血管的作用是逐渐产生的，罕有口服氨氯地平后发生急性低血压的报道。尽管如此，和其它任何外周血管扩张剂类似，应用奥美沙坦酯氨氯地平时应谨慎，尤其是在严重主动脉瓣或二尖瓣狭窄，梗阻性肥厚型心肌病的患者。
4. 严重冠状动脉阻塞性疾病的患者
氨氯地平
患者，特别是伴有严重冠状动脉阻塞性疾病的患者，在开始使用钙离子拮抗剂治疗或增加剂量时，可能出现心绞痛或急性心肌梗死发生频率增加、持续时间延长、程度加重。其作用机制尚不明确。
5. 充血性心衰患者
氨氯地平
心衰患者治疗时应慎重。在一项氨氯地平治疗重度心衰（NYHA III 级和 IV 级）患者的长期、安慰剂对照试验中，氨氯地平治疗组报告的肺水肿发生率高于安慰剂组。充血性心力衰竭患者应慎用钙通道抑制剂，包括氨氯地平，因为可能会增加未来发生心血管事件或死亡的风险。
6. 肾功能损伤患者
奥美沙坦酯/氨氯地平
尚无本品用于肾功能不全患者的资料。
尚无本品用于近期肾移植的患者或终末期肾功能损伤（即，肌酐清除率<12mL/min）患者的经验。
轻度到中度肾功能损伤（肌酐清除率 20-60 mL/min）的患者，奥美沙坦酯的最大推荐用药剂量是 20 mg，每日 1 次，因为该患者人群中使用更大剂量治疗的经验有限。重度肾功能损伤（肌酐清除率<20 mL/min）的患者，不宜使用本品。
肾功能损伤患者，建议治疗时监测血钾和肌酐水平。
奥美沙坦酯
由于对肾素-血管紧张素-醛固酮系统的抑制作用，预期敏感性患者服用奥美沙坦酯治疗后，肾功能可能发生变化。在那些肾功能依赖于肾素-血管紧张素-醛固酮系统活性的患者（如严重的充血性心力衰竭患者）中使用 ACE 抑制剂和血管紧张素受体拮抗剂，可能出现少尿和/或进行性氮质血症、急性肾功能衰竭和/或死亡（罕见）。由于本品含有奥美沙坦酯，在此类患者中使用本品预期也可能出现类似的结果。有报道称：ACE 抑制剂可能使单侧或者双侧肾动脉狭窄患者的血肌酐或者血尿素氮（BUN）升高。目前还没有在此类患者中长期使用奥美沙坦酯的经验，但可以预计奥美沙坦酯与本品可能导致类似的结果。
氨氯地平
肾功能损伤对氨氯地平药代动力学不产生显著影响。因此，肾衰患者可以接受常规起始剂量。
7. 肝功能损伤患者
尚无本品用于肝功能不全患者的资料，但是氨氯地平和奥美沙坦酯在肝功能不全患者体内的暴露量均有上升。其中，氨氯地平主要通过肝脏广泛代谢，其在重度肝功能不全患者中的血浆消除半衰期（t 1/2） 为 56 小时。对于中度肝功能损伤的患者，奥美沙坦酯的剂量不能超过 20mg。因此，轻度到中度肝功能损伤的患者应慎用本品，重度肝功能损伤的患者应禁用本品。
肝功能损伤患者的氨氯地平清除率下降。肝功能损伤的患者应以 2.5 mg 的剂量开始单药服用或添加服用氨氯地平。本品的最低剂量为奥美沙坦酯 20mg/氨氯地平 5mg；因此，对肝功能受损的患者应慎用本品。
8. 口炎性腹泻样肠病
在服用奥美沙坦数月至数年的患者中，报道有严重的慢性腹泻，并伴随明显的体重减轻，可能是局部迟发型超敏反应所致。患者的肠活检常显示有绒毛萎缩。如果患者在服用奥美沙坦期间出现上述状况，应排除其他病因。在未发现其他病因的情况下，考虑停止服用本品。
如果腹泻在停药一周内未好转，需进一步就医（如胃肠病学家）检查。
9. 肾动脉狭窄患者
双侧肾动脉狭窄的患者或者单侧存在肾脏动脉狭窄的患者，用影响肾素-血管紧张素-醛固酮系统的药品治疗时，发生重度低血压和肾功能不全的风险升高。
10. 高钾血症
和其他血管紧张素 II 受体拮抗剂和 ACE 抑制剂一样，治疗期间可能会发生高钾血症，特别是在患者伴有肾功能损伤和/或心衰的情况下。有发生高血钾风险的患者，建议密切监测血钾水平。
同时进行补钾治疗、合用保钾利尿剂、使用含钾的补液盐或其他可能增加血钾水平的药品（肝素等）时，要特别慎重，应当密切监测血钾水平。
11. 对驾驶和机械操作能力的影响
本品对驾驶和操作机器能力产生微弱影响或中等影响。
接受抗高血压药治疗患者偶尔发生头晕、头痛、恶心或疲乏，可能会损害反应能力。建议治疗需谨慎，尤其是治疗初期。
12. 其它
和所有抗高血压药物一样，缺血性心脏病或缺血性脑血管病患者血压过分降低，可导致心肌梗死或脑卒中。

孕妇及哺乳期妇女用药：

孕妇
未进行本复方制剂在孕妇中用药的安全有效性试验，无相关数据。尚未对本品开展动物生殖毒性研究。
作用于肾素-血管紧张素系统的药物
奥美沙坦酯为作用于肾素-血管紧张素系统的药物。
孕妇服用本品时，可能导致胎儿伤害。在妊娠早期必须禁用本品。在计划受孕前，患者应变更到合适的可选的治疗方式。如果在治疗过程中发现妊娠，必须尽快停用本品。
在妊娠的中、晚期，使用直接作用于肾素-血管紧张素系统的药物可降低胎儿肾功能，增加胎儿和新生儿的发病率和死亡率。由此产生的羊水过少可以与胎儿肺发育不全与骨骼变形相关。潜在的新生儿不良反应包括颅骨发育不全、无尿症、低血压、肾衰竭和死亡。一旦发现妊娠，应尽快停止使用本品。这些不良结果通常与妊娠的中、晚期使用这些药物有关。
针对妊娠早期暴露于抗高血压药后出现的胎儿异常的大多数流行病学研究并没有把作用于肾素-血管紧张素系统的药物和其他抗高血压药物区分开来。在孕期适当控制母体的血压对于优化母亲和胎儿的结果都很重要。
极少情况下，无法找到适当的替代作用于肾素-血管紧张素系统的药物，应当告知孕妇药物对胎儿的潜在危害，并进行系列超声波检查来评估羊膜内的情况。当发现羊水过少，除非为了挽救孕妇的生命，应停止使用本品，并基于孕周进行胎儿检测。然而，患者和医生应该注意，出现羊水过少时，胎儿可能已出现持续的、不可逆的损伤。应密切监测曾在子宫内暴露于本品的婴儿的低血压、少尿和高血钾的情况。

氨氯地平
妊娠期暴露的孕妇人数有限，根据这些孕妇的数据，未显示氨氯地平或其他钙受体拮抗剂对胎儿的健康有害。但是，可能有分娩时间延长的危险。
哺乳期妇女
目前尚不清楚本品的奥美沙坦酯或氨氯地平是否可以经人体母乳分泌，但奥美沙坦在哺乳大鼠的乳汁中有少量分泌。尚不了解氨氯地平是否会分泌到人体母乳中。但有类似的二氢
吡啶类钙通道阻滞剂可分泌到母乳中。
由于尚无有关哺乳期间使用奥美沙坦和氨氯地平的信息，故不建议哺乳期妇女使用本品，应首选在哺乳期间使用比较安全的替代治疗，尤其是在哺乳新生儿或早产儿期间。
生育力
据报道，部分患者经钙通道阻滞剂治疗后，精细胞头部发生可逆性生化变化。缺乏有关氨氯地平对生育力影响的临床数据。在一项大鼠研究中，发现其对雄鼠生育力产生影响。

儿童用药：

奥美沙坦酯/氨氯地平
曾在子宫内暴露于本品的新生儿：如出现少尿或低血压，则治疗应关注维持血压和肾灌注。可使用换血疗法或透析来逆转低血压和/或作为肾功能障碍的替代疗法。
尚未建立 18 岁以下儿童和青少年应用本品的安全性和有效性数据。
奥美沙坦酯
尚未建立儿童用药的安全性和有效性数据。
氨氯地平
尚不清楚对 6 岁以下患者血压的影响。

老年用药：

奥美沙坦酯/氨氯地平
本品的双盲临床试验中，65岁及以上占20% （384/1940），75岁及以上占3%（62/1940）。
未见老年患者（65岁及以上）与年轻患者间在安全性或有效性方面存在总体差异。
老年患者的氨氯地平清除率下降。年龄≥75岁的患者应以2.5 mg的剂量开始单药服用或添加服用氨氯地平。本品的最低剂量为奥美沙坦酯20mg/氨氯地平5mg，因此，对年龄≥75岁的患者应在逐步调整好两单药联合用药的剂量后采用相同剂量下的本品治疗。
奥美沙坦酯
临床试验奥美沙坦酯组的高血压患者中，超过 20%为 65 岁及以上，超过 5%为 75 岁及以上。未见老年患者和年轻患者间在有效性或安全性方面存在总体差异。其它报道的临床经验也未确定老年患者和年轻患者用药的反应差异，但不排除个别老年患者敏感性较高。
氨氯地平
报道的临床经验未确定老年患者和年轻患者用药的反应差异。通常，老年患者肝、肾、心功能衰退的发生率较高，合并症或使用其它药物治疗的情况较多，因此老年患者的剂量选择应谨慎，通常由最低剂量开始用药。老年患者的氨氯地平清除率下降，导致药时曲线下面积 AUC 增加约 40%-60%，因此宜采用较低的起始剂量。

药物相互作用：

奥美沙坦酯/氨氯地平
奥美沙坦酯和氨氯地平合并给药时，两者的药代动力学均未发生改变。
未进行本品与其它药物的相互作用研究，但对本品单一组份奥美沙坦酯和氨氯地平分别进行了研究。具体如下：
奥美沙坦酯
在健康受试者中合并应用地高辛或华法林未见明显的药物相互作用。
合并应用抗酸剂[Al(OH)3/Mg(OH)2]，奥美沙坦酯的生物利用度无明显改变。
非甾体抗炎药（NSAIDs），包括选择性环氧合酶-2 抑制剂（COX-2 抑制剂）：
在老年患者、血容量不足（包括接受利尿剂治疗）患者或肾功能损伤患者中，将 NSAIDs（包括选择性 COX-2 抑制剂）与血管紧张素Ⅱ受体拮抗剂（包括奥美沙坦酯）联合给药，可能导致肾功能的恶化，甚至可能出现急性肾衰竭。这些影响通常是可逆的。同时使用奥美沙坦酯和非甾体抗炎药的患者应定期监测肾功能。
NSAIDs（包括选择性 COX-2 抑制剂）可能会降低血管紧张素Ⅱ受体拮抗剂（包括奥美沙坦酯）的抗高血压作用。
肾素-血管紧张素系统（RAS）的双重抑制：
与单药治疗相比，应用血管紧张素受体抑制剂、ACE 抑制剂或阿利吉仑的组合对 RAS进行双重抑制，会增加低血压、高钾血症和肾功能改变（包括急性肾衰竭）的风险。与使用单药相比，大部分联合使用两种 RAS 抑制剂的患者并没有获得额外的疗效。一般情况下，要避免 RAS 抑制剂的联合用药。对服用本品和其他影响 RAS 的药物的患者，应密切监测其血压、肾功能和电解质。
本品不得与阿利吉仑合用于糖尿病患者。避免在肾功能损伤患者（肾小球滤过率<60mL/分钟）中合用本品和阿利吉仑。
与盐酸考来维仑合用：
与胆汁酸螯合剂盐酸考来维仑同时服用，会降低奥美沙坦的系统暴露量和血药浓度峰值。
奥美沙坦酯提前于考来维仑至少 4 小时服用，可降低药物相互作用。考虑在服用盐酸考来维仑前至少 4 小时服用奥美沙坦。
锂
据报道，锂制剂与血管紧张素 II 受体拮抗剂（包括本品）合用时，血清锂浓度和毒性可逆性增加。合用期间监测血清锂浓度。
氨氯地平
其它药物对氨氯地平的作用

西米替丁：与西米替丁合用不改变氨氯地平的药代动力学。
葡萄柚汁：20 名健康志愿者口服单剂量 10 mg氨氯地平并同时服用 240 mL葡萄柚汁，未见对氨氯地平的药代动力学有明显影响。
[Al(OH)3/Mg(OH)2]（抗酸剂）：同时服用单剂量氨氯地平和[Al(OH)3/Mg(OH)2]抗酸剂，未见对氨氯地平的药代动力学有明显影响。
西地那非：单剂量 100mg 西地那非不影响原发性高血压患者氨氯地平的药代动力学。
二药合用，每种药品独立发挥其降压效应。
CYP3A4 抑制剂：氨氯地平和强或中效 CYP3A4 抑制剂（蛋白酶抑制剂，唑类抗真菌药，大环内酯类如红霉素或克拉霉素，维拉帕米或地尔硫卓）联合使用可能导致氨氯地平的暴露量显著增加。这些药代动力学改变在老年人可能更显著。因此可能需要进行临
床监测和剂量调整。
CYP3A4 诱导剂：关于 CYP3A4 诱导剂对氨氯地平的作用尚无数据。氨氯地平和CYP3A4 诱导剂（例如利福平，惯叶金丝桃）可能导致氨氯地平血浆浓度降低。氨氯地平和 CYP3A4 诱导剂应谨慎联用。
氨氯地平对其它药物的作用
阿托伐他汀：10 mg 氨氯地平合并 80 mg 阿托伐他汀多次给药，阿托伐他汀的稳态药代动力学参数未见明显改变。
地高辛：氨氯地平与地高辛合用，正常志愿者血清地高辛水平或其肾清除率未见改变。
乙醇（酒精）：10 mg 氨氯地平单次或多次给药，未见对乙醇的药代动力学产生明显影响。
华法林：氨氯地平和华法林合用，不改变华法林凝血酶原反应时间。
辛伐他汀：10mg 氨氯地平合并 80mg 辛伐他汀多次给药，与单独使用辛伐他汀相比，辛伐他汀的暴露量增加 77%。若辛伐他汀与氨氯地平联合使用，辛伐他汀剂量不得超过每日 20mg。
他克莫司：氨氯地平与他克莫司联合使用可能增加他克莫司的暴露量。本品含有氨氯地平，与他克莫司联合使用时应监测他克莫司的血药浓度。
环孢霉素：在肾移植患者的一项前瞻性研究中，在使用氨氯地平的情况下，观察到环孢霉素的谷浓度的水平平均增加 40%。氨氯地平与环孢霉素联合使用可能增加环孢霉素的暴露量。本品含有氨氯地平，与环孢菌素联合使用时应监测环
孢霉素的浓度。

药物过量：

奥美沙坦酯/氨氯地平
尚无本品在人体的药物过量信息。本品各组份的药物过量信息如下：
奥美沙坦酯
人体药物过量的资料有限。药物过量最可能的表现是低血压和心动过速。如果副交感神经系统（迷走神经）兴奋可能会出现心动过缓。如果出现症状性低血压，应该给予适当支持治疗。奥美沙坦是否可以通过血液透析清除尚未知。

氨氯地平
对小鼠和大鼠单次经口给予马来酸氨氯地平，剂量分别相当于 40 mg 氨氯地平/kg 和100 mg 氨氯地平/kg，导致实验动物死亡。对犬单次经口给予马来酸氨氯地平，剂量相当于4 mg 氨氯地平/kg 或更高剂量（以 mg/m2计，相当于人体最大推荐剂量的 11 倍或更多），导致显著外周血管扩张和低血压。
预期药物过量可能导致外周血管过度扩张，伴随显著的低血压，并可能引起反射性心动过速。有报道，药物过量可能导致长时间、显著的低血压，甚至导致致命性休克。氨氯地平在人体刻意过量使用的经验有限。
如果发生严重的药物过量，应采取积极的心肺监护，并经常测量血压。一旦发生低血压，应给予心血管支持，包括抬高肢体、慎重补液。如果上述保守治疗对低血压无效，应考虑使用升压药物（如苯肾上腺素），同时注意循环血容量和尿量。静脉注射葡萄糖酸钙对逆转钙通道阻滞剂的效应可能有益。由于氨氯地平与血浆蛋白结合率高，透析治疗是无益的。

临床试验：

国外临床试验结果
奥美沙坦酯/氨氯地平
在一项为期 8 周的多中心、随机、双盲、安慰剂对照、平行析因试验中，1940 例轻度至重度高血压患者被随机进入 12 组：安慰剂组、氨氯地平单方治疗组（5 mg 和 10 mg）、奥美沙坦酯单方治疗组（10 mg、20 mg 和 40 mg）、奥美沙坦酯/氨氯地平联合治疗组（10/5mg, 20/5 mg, 40/5 mg, 10/10 mg, 20/10 mg 和 40/10mg）。患者停止原先的高血压治疗。受试人群平均基线血压为 164/102mmHg。所有受试人群中有 970 名患者以复方制剂作为初始治疗。与本品各组份的单方治疗效果相比，奥美沙坦酯/氨氯地平联合给药能够更大程度地降低收缩压和舒张压。剂量调整后 2 周内，可达最大降压效果。
下表可见奥美沙坦酯/氨氯地平联合给药 8 周后，对坐位收缩压和舒张压的降压效果，随着奥美沙坦酯和氨氯地平剂量的增加，降压幅度逐步增加。
双盲治疗期间坐位收缩压/舒张压的降幅（mmHg）：联合治疗对比各组份单方治疗

8周双盲、安慰剂对照试验结束后，有1684例患者接着进入44周开放的延长试验，
接受奥美沙坦酯 40mg/氨氯地平 5 mg 的联合治疗。期间，如果患者用药后血压未得到充分控制（即血压未能控制在140/90mmHg以下，糖尿病患者血压未控制在130/80mmHg以下），
则增加剂量至奥美沙坦酯 40mg/氨氯地平 10 mg；若血压仍未能得到充分控制，增加给予氢氯噻嗪 12.5mg 或必要时给予 25 mg。
试验结果显示，每日一次服用本品，降压效果可维持 24 小时，收缩压和舒张压相应的谷-峰比值为 71%～82%。无论有无抗高血压药物治疗史、是否伴有糖尿病、不同年龄、性别，均不影响本品的抗高血压效果。≥75 岁患者应用本品的数据有限。本品对黑人患者（通常为低肾素人群）有效，且其降压强度接近于非黑人患者。
一项双盲、随机、安慰剂对照试验评价了用奥美沙坦酯 20 mg 单药治疗 8 周血压控制效果不佳的白人患者加用氨氯地平联合治疗的有效性。
继续单用 20 mg 奥美沙坦酯治疗的患者，再治疗 8 周后收缩压/舒张压降低了 10.6/7.8mmHg，加用 5 mg 氨氯地平治疗 8 周后，收缩压/舒张压降低了 16.2/10.6 mmHg（p=0.0006）。
20 mg/5 mg 联合治疗组的血压达标率（非糖尿病患者达到<140/90 mmHg，糖尿病患者达到<130/80 mmHg）为 44.5%，单用 20 mg 奥美沙坦酯治疗组的达标率为 28.5%。
一项试验评价了单用 5 mg 氨氯地平单药治疗 8 周血压控制效果不佳的白人患者加用不同剂量奥美沙坦酯治疗的附加效果。继续单用 5 mg 氨氯地平治疗的患者，再治疗 8 周后收缩压/舒张压降低 9.9/5.7 mmHg，而加用奥美沙坦酯 20 mg 治疗后，收缩压/舒张压降低15.3/9.3 mmHg，加用奥美沙坦酯 40 mg 治疗后，收缩压/舒张压降低 16.7/9.5 mmHg（p<0.0001）。继续单用 5 mg 氨氯地平治疗的患者血压达标率（非糖尿病患者达到<140/90mmHg，糖尿病患者达到<130/80 mmHg）为 29.9%，而 Sevikar 20 mg/5 mg 治疗组的达标率为 53.5%，Sevikar 40 mg/5 mg 治疗组的达标率为 50.5%。
未得到控制的高血压患者中，尚没有中等剂量 Sevikar 复方与单用最大剂量氨氯地平或奥美沙坦治疗进行比较的随机化试验数据。
有 3 个试验都证明，Sevikar 每日用药 1 次可以保持 24 小时的降压作用，收缩压和舒张压的谷峰比值为 71%到 82%，通过动态血压监测证实本品具有 24 小时降压效果。
无论多大年龄，也不管是男性和女性，Sevikar 的降压作用都相似。无论患者有无糖尿病，Sevikar 的降压作用也相似。
两项开放性的、非随机、长期试验中，Sevikar 40 mg/5 mg 治疗 1 年，49-67%的患者持续有效。
奥美沙坦酯
7 项安慰剂对照、给药剂量范围为 2.5～80 mg、疗程为 6～12 周的临床试验，总共研究了 2693 例原发性高血压患者（2145 例服用奥美沙坦酯，548 例服用安慰剂），证实每日一次服用奥美沙坦酯，血压峰值和血压谷值都有统计学意义的显著降低。降压作用与剂量呈相关性，降压效果可维持 24 小时。期间，收缩压和舒张压下降的谷-峰比值在 60%～80%。
氨氯地平
共 15 项随机、双盲、安慰剂对照临床试验对氨氯地平抗高血压的有效性进行了研究，其中氨氯地平组 800 例患者，安慰剂组 538 例患者。轻度到中度高血压患者每日口服一次，经安慰剂校正的 24 小时卧位和立位血压均有显著统计学意义的降低，卧位血压平均降低约13/7 mmHg ，立位血压平均降低约 12/6 mmHg 。在 24 小时的服药间隔内，可维持降压效果，血压峰值和血压谷值差异小。
在中国进行的注册临床试验
在中国进行了两项随机、双盲、双模拟、平行分组、阳性对照、多中心注册临床研究。
第一项研究中，原发性轻、中度中国高血压患者在服用奥美沙坦酯 20mg 4 周后，将血压控制效果不佳者随机分配入组，分别接受奥美沙坦酯氨氯地平 20/5mg 或者奥美沙坦酯40mg 的治疗。来自 18 个研究中心的 281 名患者接受了 8 周的双盲治疗。疗效评价显示，治疗 8 周后，两组平均 SeSBP/SeDBP 谷值较基线的降幅在奥美沙坦酯氨氯地平 20/5mg
组和奥美沙坦酯 40mg 组分别为 13.8mmHg/11.6mmHg 和 10.5mmHg/9.6mmHg。
第二项研究中，原发性轻、中度中国高血压患者在服用氨氯地平 5mg 4 周后，将血压控制效果不佳者随机分配入组，分别接受奥美沙坦酯氨氯地平 20/5mg 或者氨氯地平 5mg
的治疗。来自 14 个研究中心的 292 名患者接受了 8 周的双盲治疗。疗效评价显示，治疗 8周后，两组平均 SeSBP/SeDBP 谷值较基线的降幅在奥美沙坦酯氨氯地平 20/5mg 组和氨氯地平 5mg 组分别为 14.6mmHg/11.9mmHg 和 9.1mmHg/7.7mmHg。

药理毒理：

药理作用
奥美沙坦酯氨氯地平片是由奥美沙坦酯和氨氯地平组成的复方制剂，其药理作用来自单方和二者联合的协同。
毒理研究
遗传毒性：
奥美沙坦酯：
奥美沙坦、奥美沙坦酯的体外叙利亚仓鼠胚胎细胞转换试验、Ames 试验均未显示基因毒性的证据。奥美沙坦、奥美沙坦酯均可导致体外培养的中国仓鼠肺细胞的染色体断裂；在体外进行的小鼠淋巴瘤胸腺核苷激酶突变试验中，奥美沙坦酯呈阳性反应（奥美沙坦未进行该项试验）。经口给予突变小鼠（MutaMouse）奥美沙坦酯（未对奥美沙坦进行试验），最高剂量达 2000 mg/kg，肠和肾脏的体内基因突变试验和体内小鼠骨髓染色体诱裂试验（微核试验）的结果均呈阴性。
氨氯地平：
Ames 试验，小鼠淋巴瘤试验、染色体畸变试验、小鼠微核试验结果为阴性。
生殖毒性：
奥美沙坦酯：
雌性和雄性大鼠分别在交配前 2 周、9 周开始给予奥美沙坦酯，在剂量达 1000mg/kg/日（约为人体最大日推荐剂量 MRHD 的 120 倍）时未见生育毒性。
氨氯地平：

大鼠于交配前、交配、妊娠和哺乳期间，经口给药达 10mg/kg/d，连续 14 天。结果母体动物平均体重降低、分娩困难、妊娠期延长。F1 代骨骼、内脏或外观未见明显异常，窝仔数减少（约降 50%），平均宫内死亡数增加（5 倍左右）。大鼠妊娠第 6 天-15 天经口给药达 10mg/kg/d，兔妊娠第 7 天-第 18 天经口给药达 10mg/kg/d，结果均未见明显的母体毒性和胚胎胎仔生长发育毒性。
致癌性：
奥美沙坦酯：
大鼠经口给予奥美沙坦酯给药 2 年，最大剂量为 2000mg/kg/日，按体表面积计算大约为最大推荐人用剂量（MRHD）40mg/日的 480 倍，未见致癌性。在小鼠进行了两个 6 个月的致癌性研究：p53knockout 小鼠灌胃给药研究，Hras2 转基因小鼠经食物给药研究，最高给药剂量为 1000mg/kg/日（约为 MRHD 的 120 倍），未见致癌作用。
氨氯地平：
大鼠和小鼠致癌性试验周期 2 年，给药剂量均达 2.5mg/kg/d，未见致癌性。

药代动力学：

国外药代动力学研究结果
本品中奥美沙坦酯和氨氯地平的药代动力学与两者单独使用时的药代动力学一致。两者的生物利用度均小于 100%，但均不受食物影响。氨氯地平的有效半衰期为 45±11 小时，奥美沙坦的有效半衰期为 7±1 小时，因此每日一次给药后，氨氯地平有 2-3 倍的蓄积，奥美沙坦的蓄积可忽略不计。
[吸收]
奥美沙坦酯：奥美沙坦酯口服后经胃肠道吸收，迅速、完全地去酯化水解为奥美沙坦，绝对生物利用度约为 26%。口服给药 1～2 小时后即达血药峰值浓度。进食不影响奥美沙坦酯的生物利用度。
氨氯地平 ： 口服治疗剂量的氨氯地平后，6-12 小时血药浓度达峰值。绝对生物利用度约为 64%-90%。
[分布]
奥美沙坦酯：奥美沙坦的血浆蛋白结合率高达 99%，不穿透红细胞，稳态分布容积约为17 升。血药浓度高于推荐剂量下的浓度范围时，蛋白结合率保持恒定。
大鼠实验中，奥美沙坦不易通过血脑屏障，但可通过胎盘屏障并分布到胎鼠中，也可少量分布于大鼠乳汁中。
氨氯地平 ：体 外 试 验 中 ，高血压患者体循环中的氨氯地平血浆蛋白结合率约为 93%。
每日一次，连续给药 7-8 天后血药浓度达到稳态。
[代谢和排泄]
奥美沙坦酯：奥美沙坦酯迅速、完全地转化为奥美沙坦后，不再进一步代谢。奥美沙坦按双相方式被消除，终末消除半衰期约为 13 小时，总血浆清除率是 1.3 L/小时，肾清除率是 0.6 L/小时。大约有 35%～50%吸收的药物从尿液中排出，
其余经胆汁从粪便中排出。
无论单次口服给药（最大剂量至 320 mg）或多次口服给药（最大剂量可至80 mg/次），奥美沙坦均呈线性药代动力学特征。在 3-5 天之内可达到稳态血药浓度，每日一次给药血浆内无蓄积。
氨氯地平 ：氨氯地平通过肝脏广泛代谢为无活性的代谢物（约 90%）。氨氯地平以双相方式从血浆中消除，终末消除半衰期约为 30-50 小时。10%的原药和 60%的代谢物由尿液排出。
[特殊人群药代动力学]
儿 童 奥美沙坦酯：尚未在 18 岁以下人群中进行奥美沙坦酯药代动力学研究。
氨氯地平 ：62名6-17岁高血压患者接受氨氯地平治疗，剂量为1.25 mg-20mg。剔除体重因素的影响，儿童患者的氨氯地平清除率和分布体积与成人相似。
老 年 人 奥美沙坦酯 /氨氯地平 ：在老年患者中的药代动力学特征与其成份单独用药时相似。
奥美沙坦酯：奥美沙坦的最大血浆浓度在年轻成人和老年人（≥ 65 岁）中相似。在多次用药的老年人中观察到了奥美沙坦的轻度蓄积；平均稳态药时曲线下面积（AUCss）在老年人中要高 33%，相应的肾清除率（CLR）则减少 30%。
氨氯地平 ： 老年患者氨氯地平清除率降低，药时曲线下面积（AUC）增加约 40%-60%。因此，老年患者宜采用较低起始剂量。
性 别 奥美沙坦酯：男性和女性间，奥美沙坦酯药代动力学可见轻微差异，女性患者的药时曲线下面积（AUC）和最大血药浓度（Cmax）比男性高 10%-15%，相应的清除率则减少 15%。
氨氯地平 ：性别对氨氯地平清除率没有影响。
肾功能不全 奥美沙坦酯：与肾功能正常的受试者相比，肾功能不全患者的奥美沙坦血清浓度上升。严重肾功能损伤（肌酐清除率＜20 mL/分钟）的患者多次给药后的药时曲线下面积（AUC）约为肾功能正常人的 3 倍。未对接受血液透析的患者进行研究。
氨氯地平 ：肾功能损伤对氨氯地平药代动力学不产生显著影响。因此肾衰患者可以接受常规起始剂量。
肝功能不全 奥美沙坦酯：对中度肝功能损伤患者，药物从零点时间至全部消除的药时曲线下面积（AUC0→∞）和最大血药浓度（Cmax）都增高，药时曲线下面积（AUC）增加了约 60%。
氨氯地平 ：肝功能不全患者清除率下降，药时曲线下面积（AUC）增加约40%-60%。
心 衰 氨氯地平 ： 心衰患者清除率下降，药时曲线下面积（AUC）增加约40%-60%。
药物相互作用
胆汁酸螯合剂盐酸考来维仑：
在健康受试者中同时服用奥美沙坦酯 40mg 与盐酸考来维仑 3750mg，导致奥美沙坦的 Cmax降低 28%、AUC 降低 39%。当奥美沙坦酯提前于考来维仑 4 小时服用，产生较小的影响，Cmax和 AUC 分别降低 4%和 15%。
在中国健康志愿者中进行的药代动力学研究
单次给药后，奥美沙坦酯被迅速吸收并转化为奥美沙坦，血浆达峰时间（Tmax）的中位数（范围）是 2（1-3）小时，消除半衰期（t1/2）的平均值（标准差）是 15.2（4.27）小时。
相比之下，氨氯地平的吸收较慢，给药后血浆达峰时间中位数（范围）是 6（3-8）小时，消除半衰期（t1/2）的平均值（标准差）是 41.4（8.95）小时。多次口服奥美沙坦酯氨氯地平 20/5mg 片后 8 天达到稳态。多次给药后，奥美沙坦在血浆中没有蓄积，氨氯地平的血浆水平呈现与其半衰期和给药间隔相匹配的中等程度蓄积。

贮藏：

遮光，密封保存。

 

 

 

 

 

 

 

 

 

1. Name of the medicinal product
Sevikar 20 mg/5 mg film-coated tablets
Sevikar 40 mg/5 mg film-coated tablets
Sevikar 40 mg/10 mg film-coated tablets
2. Qualitative and quantitative composition
Sevikar 20 mg/5 mg film-coated tablets: 
Each film-coated tablet of Sevikar contains 20 mg of olmesartan medoxomil and 5 mg of amlodipine (as amlodipine besilate).
Sevikar 40 mg/5 mg film-coated tablets:
Each film-coated tablet of Sevikar contains 40 mg of olmesartan medoxomil and 5 mg of amlodipine (as amlodipine besilate).
Sevikar 40 mg/10 mg film-coated tablets: 
Each film-coated tablet of Sevikar contains 40 mg of olmesartan medoxomil and 10 mg of amlodipine (as amlodipine besilate).
Excipients with known effect
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet
Sevikar 20 mg/5 mg film-coated tablets: 
White, round, film-coated tablet of 6 mm with C73 debossed on one side.
Sevikar 40 mg/5 mg film-coated tablets: 
Cream, round, film-coated tablet of 8 mm with C75 debossed on one side.
Sevikar 40 mg/10 mg film-coated tablets: 
Brownish-red, round, film-coated tablet of 8 mm with C77 debossed on one side
4. Clinical particulars
4.1 Therapeutic indications
Treatment of essential hypertension.
Sevikar is indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil or amlodipine monotherapy (see section 4.2 and section 5.1).
4.2 Posology and method of administration
Posology
Adults
The recommended dosage of Sevikar is 1 tablet per day. 
Sevikar 20 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil or 5 mg amlodipine alone.
Sevikar 40 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled by Sevikar 20 mg/5 mg.
Sevikar 40 mg/10 mg may be administered in patients whose blood pressure is not adequately controlled by Sevikar 40 mg/5 mg.
A step-wise titration of the dosage of the individual components is recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered. 
For convenience, patients receiving olmesartan medoxomil and amlodipine from separate tablets may be switched to Sevikar tablets containing the same component doses.
Sevikar can be taken with or without food.
Elderly (age 65 years or over)
No adjustment of the recommended dose is generally required for elderly people but increase of the dosage should take place with care (see sections 4.4 and 5.2).
If up-titration to the maximum dose of 40 mg olmesartan medoxomil daily is required, blood pressure should be closely monitored.
Renal impairment
The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 20 – 60 mL/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group. The use of Sevikar in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended (see 4.4, 5.2). 
Monitoring of potassium levels and creatinine is advised in patients with moderate renal impairment.
Hepatic impairment
Sevikar should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.4, 5.2). 
In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment.
As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Sevikar should therefore be administered with caution in these patients. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with impaired liver function. Use of Sevikar in patients with severe hepatic impairment is contraindicated (see section 4.3).
Paediatric population
The safety and efficacy of Sevikar in children and adolescents below 18 years has not been established. No data are available.
Method of administration:
The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.
4.3 Contraindications
Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients listed in section 6.1.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Severe hepatic insufficiency and biliary obstruction (see section 5.2).
The concomitant use of Sevikar with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.5 and 5.1).
Due to the component amlodipine Sevikar is also contraindicated in patients with:
- severe hypotension.
- shock (including cardiogenic shock).
- obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).
- haemodynamically unstable heart failure after acute myocardial infarction
4.4 Special warnings and precautions for use
Patients with hypovolaemia or sodium depletion:
Symptomatic hypotension may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Sevikar or close medical supervision at the start of the treatment is recommended.
Other conditions with stimulation of the renin-angiotensin-aldosterone system:
In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system, such as angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. 
Renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation:
When Sevikar is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Sevikar is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections 4.2, 5.2). There is no experience of the administration of Sevikar in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 mL/min).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Hepatic impairment:
Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2). Care should be taken when Sevikar is administered in patients with mild to moderate hepatic impairment. In moderately impaired patients, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2). In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Use of Sevikar in patients with severe hepatic impairment is contraindicated (see section 4.3).
Hyperkalaemia:
As with other angiotensin II antagonists and ACE inhibitors, hyperkalaemia may occur during treatment, especially in the presence of renal impairment and/or heart failure (see section 4.5). Close monitoring of serum potassium levels in at-risk patients is recommended.
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.
Lithium:
As with other angiotensin II receptor antagonists, the concomitant use of Sevikar and lithium is not recommended (see section 4.5).
Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:
Due to the amlodipine component of Sevikar, as with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism:
Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Sevikar is not recommended in such patients.
Heart failure:
As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. 
Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Sprue-like enteropathy:
In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.
Ethnic differences:
As with all other angiotensin II antagonists, the blood pressure lowering effect of Sevikar can be somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.
Elderly
In the elderly, increase of the dosage should take place with care (see section 5.2).
Pregnancy:
Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Other:
As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.
4.5 Interaction with other medicinal products and other forms of interaction
Potential interactions related to the Sevikar combination:
To be taken into account with concomitant use
Other antihypertensive agents: 
The blood pressure lowering effect of Sevikar can be increased by concomitant use of other antihypertensive medicinal products (e.g. alpha blockers, diuretics).
Potential interactions related to the olmesartan medoxomil component of Sevikar:
Concomitant use not recommended
ACE-inhibitors, angiotensin II receptor blockers or aliskiren:
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Medicinal products affecting potassium levels:
Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with Sevikar, monitoring of serum potassium levels is recommended.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II antagonists. Therefore concomitant use of Sevikar and lithium is not recommended (see section 4.4). If concomitant use of Sevikar and lithium proves necessary, careful monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs:
When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening of renal function and may lead to an increase in serum potassium. Therefore monitoring of renal function at the beginning of such concomitant therapy is recommended, as well as adequate hydration of the patient.
Bile acid sequestering agent colesevelam:
Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered (see section 5.2).
Additional information
After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.
Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.
Potential interactions related to the amlodipine component of Sevikar:
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors:
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers:
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (i.e. rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Effects of amlodipine on other medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.
Simvastatin: Co-administration 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. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate. 
Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed when used concomitantly with amlodipine. The co-administration of Sevikar with cyclosporine may increase exposure to cyclosporine. Monitor trough cyclosporine levels during concomitant use and cyclosporine dose reductions should be made as necessary.
4.6 Fertility, pregnancy and lactation
Pregnancy (see section 4.3)
There are no data about the use of Sevikar in pregnant patients. Animal reproductive toxicity studies with Sevikar have not been performed. 
Olmesartan medoxomil (active ingredient of Sevikar)
The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II antagonists therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to angiotensin II antagonists have occurred from the second trimester on, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).
Amlodipine (active ingredient of Sevikar)
Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.
As a consequence, Sevikar is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
Breastfeeding
Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk. It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine type are excreted in breast milk. 
Because no information is available regarding the use of olmesartan and amlodipine during breast-feeding, Sevikar is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Fertility
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Sevikar can have minor or moderate influence on the ability to drive and use machines.
Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react. Caution is recommended especially at the start of treatment.
4.8 Undesirable effects
Sevikar:
The most commonly reported adverse reactions during treatment with Sevikar are peripheral oedema (11.3%), headache (5.3%) and dizziness (4.5%).
Adverse reactions from Sevikar in clinical trials, post-authorisation safety studies and spontaneous reporting are summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and amlodipine based on the known safety profile of these substances.
The following terminologies have been used in order to classify the occurrence of adverse reactions:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000), not known (cannot be estimated from the available data)
MedDRA System Organ Class Adverse reactions Frequency 
Olmesartan/Amlodipine combination Olmesartan Amlodipine
Blood and lymphatic system disorders Leukocytopenia Very rare
Thrombocytopenia Uncommon Very rare
Immune system disorders Allergic reaction /Drug hypersensitivity Rare Very rare
Anaphylactic reaction Uncommon 
Metabolism and nutrition disorders Hyperglycaemia Very rare
Hyperkalaemia Uncommon Rare 
Hypertriglyceridaemia Common 
Hyperuricaemia Common 
Psychiatric disorders Confusion Rare
Depression Uncommon
Insomnia Uncommon
Irritability Uncommon
Libido decreased Uncommon 
Mood changes (including anxiety) Uncommon
Nervous system disorders Dizziness Common Common Common
Dysgeusia Uncommon
Headache Common Common Common (especially at the beginning of treatment)
Hypertonia Very rare
Hypoaesthesia Uncommon Uncommon
Lethargy Uncommon 
Paraesthesia Uncommon Uncommon
Peripheral neuropathy Very rare
Postural dizziness Uncommon 
Sleep disorder Uncommon
Somnolence Common 
Syncope Rare Uncommon
Tremor Uncommon
Eye disorders Visual disturbance (including diplopia) Common
Ear and labyrinth disorders Tinnitus Uncommon
Vertigo Uncommon Uncommon 
Cardiac disorders Angina pectoris Uncommon Uncommon (incl. aggravation of angina pectoris)
Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) Uncommon
Myocardial infarction Very rare
Palpitations Uncommon Common
Tachycardia Uncommon 
Vascular disorders Hypotension Uncommon Rare Uncommon
Orthostatic hypotension Uncommon 
Flushing Rare Common
Vasculitis Very rare
Respiratory, thoracic and mediastinal disorders Bronchitis Common 
Cough Uncommon Common Uncommon
Dyspnoea Uncommon Common
Pharyngitis Common 
Rhinitis Common Uncommon
Gastrointestinal disorders Abdominal pain Common Common
Altered bowel habits (including diarrhoea and constipation) Common
Constipation Uncommon 
Diarrhoea Uncommon Common 
Dry mouth Uncommon Uncommon
Dyspepsia Uncommon Common Common
Gastritis Very rare
Gastroenteritis Common 
Gingival hyperplasia Very rare
Nausea Uncommon Common Common
Pancreatitis Very rare
Upper abdominal pain Uncommon 
Vomiting Uncommon Uncommon Uncommon
Sprue-like enteropathy (see section 4.4) Very rare 
Hepato-biliary disorders Hepatic enzymes increased Common Very rare (mostly consistent with cholestasis)
Hepatitis Very rare
Jaundice Very rare
Skin and subcutaneous tissue disorders Alopecia Uncommon
Angioneurotic oedema Rare Very rare
Allergic dermatitis Uncommon 
Erythema multiforme Very rare
Exanthema Uncommon Uncommon
Exfoliative dermatitis Very rare
Hyperhydrosis Uncommon
Photosensitivity Very rare
Pruritus Uncommon Uncommon
Purpura Uncommon
Quincke oedema Very rare
Rash Uncommon Uncommon Uncommon
Skin discoloration Uncommon
Stevens-Johnson syndrome Very rare
Urticaria Rare Uncommon Uncommon
Musculoskeletal and connective tissue disorders Ankle swelling Common
Arthralgia Uncommon
Arthritis Common 
Back pain Uncommon Common Uncommon
Muscle spasm Uncommon Rare Common
Myalgia Uncommon Uncommon
Pain in extremity Uncommon 
Skeletal pain Common 
Renal and urinary disorders Acute renal failure Rare 
Haematuria Common 
Increased urinary frequency Uncommon
Micturition disorder Uncommon
Nocturia Uncommon
Pollakiuria Uncommon 
Renal insufficiency Rare 
Urinary tract infection Common 
Reproductive system and breast disorders Erectile dysfunction/impotence Uncommon Uncommon
Gynecomastia Uncommon
General disorders and administration site conditions Asthenia Uncommon Uncommon Common
Chest pain Common Uncommon
Face oedema Rare Uncommon 
Fatigue Common Common Common
Influenza-like symptoms Common 
Lethargy Rare 
Malaise Uncommon Uncommon
Oedema Common Very common
Pain Common Uncommon
Peripheral oedema Common Common 
Pitting oedema Common 
Investigations Blood creatinine increased Uncommon Rare 
Blood creatine phosphokinase increased Common 
Blood potassium decreased Uncommon 
Blood urea increased Common 
Blood uric acid increased Uncommon 
Gamma glutamyl transferase increased Uncommon 
Weight decrease Uncommon
Weight increase Uncommon
Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers. Single cases of extrapyramidal syndrome have been reported in patients treated with amlodipine. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms:
There is no experience of overdose with Sevikar. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported.
Treatment:
If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.
Clinically significant hypotension due to an overdose of Sevikar requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan is unknown.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists and calcium channel blockers, ATC code C09DB02.
Mechanism of action
Sevikar is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a calcium channel blocker, amlodipine besilate. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Clinical efficacy and safety
Sevikar
In an 8-week, double-blind, randomised, placebo-controlled factorial design study in 1940 patients (71% Caucasian and 29% non-Caucasian patients), treatment with each combination dose of Sevikar resulted in significantly greater reductions in diastolic and systolic blood pressures than the respective monotherapy components. The mean change in systolic/diastolic blood pressure was dose-dependent: -24/-14 mmHg (20 mg/5 mg combination), -25/-16 mmHg (40 mg/5 mg combination) and -30/-19 mmHg (40 mg/10 mg combination). 
Sevikar 40 mg/5 mg reduced seated systolic/diastolic blood pressure by an additional 2.5/1.7 mmHg over Sevikar 20 mg/5 mg. Similarly Sevikar 40 mg/10 mg reduced seated systolic/diastolic blood pressure by an additional 4.7/3.5 mmHg over Sevikar 40 mg/5 mg.
The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) were 42.5%, 51.0% and 49.1% for Sevikar 20 mg/5 mg, 40 mg/5 mg and 40 mg/10 mg respectively.
The majority of the antihypertensive effect of Sevikar was generally achieved within the first 2 weeks of therapy.
A second double-blind, randomised, placebo-controlled study evaluated the effectiveness of adding amlodipine to the treatment in Caucasian patients whose blood pressure was inadequately controlled by 8 weeks of monotherapy with 20 mg olmesartan medoxomil. 
In patients who continued to receive only 20 mg olmesartan medoxomil, systolic/diastolic blood pressure was reduced by -10.6/ -7.8 mmHg after a further 8 weeks. The addition of 5 mg amlodipine for 8 weeks resulted in a reduction in systolic/diastolic blood pressure of -16.2/-10.6 mmHg (p = 0.0006). 
The proportion of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) was 44.5% for the 20 mg/5 mg combination compared to 28.5% for 20 mg olmesartan medoxomil.
A further study evaluated the addition of various doses of olmesartan medoxomil in Caucasian patients whose blood pressure was not adequately controlled by 8 weeks of monotherapy with 5 mg amlodipine. 
In patients who continued to receive only 5 mg amlodipine, systolic/diastolic blood pressure was reduced by -9.9/ -5.7 mmHg after a further 8 weeks. The addition of 20 mg olmesartan medoxomil resulted in a reduction in systolic/diastolic blood pressure of -15.3/-9.3 mmHg and the addition of 40 mg olmesartan medoxomil resulted in a reduction in systolic/diastolic blood pressure of -16.7/-9.5 mmHg (p < 0.0001). 
The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) was 29.9% for the group who continued to receive 5 mg amlodipine alone, 53.5% for Sevikar 20 mg/5 mg and 50.5% for Sevikar 40 mg/5 mg.
Randomised data in uncontrolled hypertensive patients, comparing the use of medium dose Sevikar combination therapy versus escalation to top dose monotherapy of amlodipine or olmesartan, are not available.
The three studies performed confirmed that the blood pressure lowering effect of Sevikar once daily was maintained throughout the 24-hour dose interval, with trough-to-peak ratios of 71% to 82% for systolic and diastolic response and with 24-hour effectiveness being confirmed by ambulatory blood pressure monitoring. 
The antihypertensive effect of Sevikar was similar irrespective of age and gender, and was similar in patients with and without diabetes. 
In two open-label, non-randomised extension studies, sustained efficacy using Sevikar 40 mg/5 mg was demonstrated at one year for 49 - 67% of patients. 
Olmesartan medoxomil (active ingredient of Sevikar)
The olmesartan medoxomil component of Sevikar is a selective angiotensin II type 1 (AT1) receptor antagonist. Olmesartan medoxomil is rapidly converted to the pharmacologically active metabolite, olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations. 
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Following once daily administration to patients with hypertension, olmesartan medoxomil produces an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.
With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. 
The effect of olmesartan medoxomil on mortality and morbidity is not yet known. 
The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.
For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.
For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates for non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality with olmesartan was numerically increased (26 patients (1.2%) vs. 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events.
The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.
The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all-cause death) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p=0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan versus 3 (1.1%) receiving placebo, overall mortality 19 (6.7%) versus 20 (7.0%), non-fatal stroke 8 (2.8%) versus 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) versus 7 (2.5%), respectively.
Amlodipine (active ingredient of Sevikar)
The amlodipine component of Sevikar is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of blood pressure. 
In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy. 
Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria. 
In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms.
A placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity in patients with heart failure.
In a follow-up, long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total or cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Treatment to prevent heart attack trial (ALLHAT)
A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension.”
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial infarction or stroke (> 6 months prior to enrollment) or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%). 
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy (RR 0.96 95% CI [0.89-1.02] p=0.20).
Other information:
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
5.2 Pharmacokinetic properties
Sevikar
Following oral intake of Sevikar, peak plasma concentrations of olmesartan and amlodipine are reached at 1.5 – 2 h and 6 – 8 hours, respectively. The rate and extent of absorption of the two active substances from Sevikar are equivalent to the rate and extent of absorption following intake of the two components as separate tablets. Food does not affect the bioavailability of olmesartan and amlodipine from Sevikar.
Olmesartan medoxomil (active ingredient of Sevikar)
Absorption and distribution:
Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg. 
Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food. 
No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L).
Biotransformation and elimination:
Total plasma clearance of olmesartan was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10% – 16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated (see section 4.3).
The terminal elimination half life of olmesartan is between 10 and 15 hours after multiple oral dosing. Steady state is reached after the first few doses and no further accumulation is evident after 14 days of repeated dosing. Renal clearance is approximately 0.5 – 0.7 L/h and is independent of dose.
Drug interactions
Bile acid sequestering agent colesevelam:
Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride (see section 4.5).
Amlodipine (active ingredient of Sevikar)
Absorption and distribution:
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The absorption of amlodipine is unaffected by the concomitant intake of food.
Biotransformation and elimination:
The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Olmesartan medoxomil and amlodipine (active ingredients of Sevikar)
Special populations
Paediatric population (age below 18 years):
No pharmacokinetic data in paediatric patients are available.
Elderly (age 65 years or over):
In hypertensive patients, the olmesartan AUC at steady state is increased by ca 35% in elderly people (65 – 75 years old) and by ca 44% in very elderly people (≥ 75 years old) compared with the younger age group (see section 4.2). This may be at least in part related to a mean decrease in renal function in this group of patients. The recommended dosage regimen for elderly people is, however, the same, although caution should be exercised when increasing the dosage.
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half life in elderly people. Increases in AUC and elimination half life in patients with congestive heart failure were as expected for the patient age group in this study (see section 4.4).
Renal impairment:
In renally impaired patients, the olmesartan AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls (see sections 4.2, 4.4).
Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.
Hepatic impairment:
After single oral administration, olmesartan AUC values are 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment is 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC is again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values are similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections 4.2, 4.4).
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. The clearance of amlodipine is decreased and the half-life is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40% – 60% (see sections 4.2, 4.4).
5.3 Preclinical safety data
Based on the non-clinical toxicity profile of each substance, no exacerbation of toxicities for the combination is expected, because each substance has different targets, i.e. the kidneys for olmesartan medoxomil and the heart for amlodipine.
In a 3-month, repeat-dose toxicity study of orally administered olmesartan medoxomil/amlodipine in combination in rats the following alterations were observed: decreases in red blood cell count-related parameters and kidney changes both of which might be induced by the olmesartan medoxomil component; alterations in the intestines (luminal dilatation and diffuse mucosal thickening of the ileum and colon), the adrenals (hypertrophy of the glomerular cortical cells and vacuolation of the fascicular cortical cells), and hypertrophy of the ducts in the mammary glands which might be induced by the amlodipine component. These alterations neither augmented any of the previously reported and existing toxicity of the individual agents nor induced any new toxicity, and no toxicologically synergistic effects were observed.
Olmesartan medoxomil (active ingredient of Sevikar)
In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine; reduction in heart weight; reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride. In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.
Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing program suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.
Olmesartan medoxomil was not carcinogenic, in a 2-year study in rats nor in two 6-month carcinogenicity studies in transgenic mice.
In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.
Amlodipine (active ingredient of Sevikar)
Reproductive toxicology 
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg. 
Impairment of fertility 
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells. 
Carcinogenesis, mutagenesis 
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats. 
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels. 
*Based on patient weight of 50 kg
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core:
Starch, pregelatinised maize
Silicified microcrystalline cellulose (microcrystalline cellulose with colloidal silicon dioxide)
Croscarmellose sodium
Magnesium stearate
Tablet coat:
Polyvinyl alcohol
Macrogol 3350
Talc
Titanium dioxide (E171) 
Iron (III) oxide yellow (E172) (Sevikar 40 mg/ 5 mg and 40 mg/10 mg film-coated tablets only)
Iron (III) oxide red (E172) (Sevikar 40 mg/ 10 mg film-coated tablets only)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
OPA / Aluminium / PVC / Aluminium blister.
Pack sizes: 14, 28, 30, 56, 90, 98, 10 x 28 and 10 x 30 film-coated tablets.
Pack sizes with perforated unit dose blisters: 10, 50 and 500 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
DAIICHI SANKYO UK Limited 
Chalfont Park 
Gerrards Cross 
England 
SL9 0GA 
UK 
8. Marketing authorisation number(s)
Sevikar 20 mg/5 mg film-coated tablet:
Sevikar 40 mg/5 mg film-coated tablet:
Sevikar 40 mg/10 mg film-coated tablet: PL 08265/0026
PL 08265/0027
PL 08265/0028
9. Date of first authorisation/renewal of the authorisation
29 October 2008/12 July 2013
10. Date of revision of the text
07/2017