Uniretic（口服）

仅接收

整体描述

Uniretic®（盐酸莫西普利/氢氯噻嗪）是血管紧张肽转化酶（ACE）抑制剂，莫昔普利盐酸盐，和利尿剂，氢氯噻嗪的组合。盐酸莫西普利为白色至类白色粉末。在室温下可溶于蒸馏水（约占体积的10％）。它的经验式为C 27 H 34 N 2 O 7 •HCl，分子量为535.04。化学上描述为[3S- [2 [R *（R *）]，3R *]]-2- [2-[[1-（乙氧羰基）-3-苯基-丙基]氨基] -1-氧代丙基] -1,2,3,4-四氢-6,7-二甲氧基-3-异喹啉-羧酸，单盐酸盐。盐酸莫西普利是活性ACE抑制剂莫西普利拉特的不含巯基的前体，其结构式为：

氢氯噻嗪是白色或几乎白色的结晶性粉末。微溶于水，易溶于氢氧化钠溶液，正丁胺和二甲基甲酰胺。氢氯噻嗪的经验式为C 7 H 8 ClN 3 O 4 S 2 ，分子量为297.75。化学上描述为2 H -1,2,4-苯并噻二嗪-7-磺酰胺，6-氯-3,4-二氢-，1,1-二氧化物。氢氯噻嗪是噻嗪类利尿剂，其结构式为：

Uniretic®是三款平板的优势可用于口服给药。所有强度的非活性成分是乳糖，氧化镁，交聚维酮，硬脂酸镁和明胶。所有强度的薄膜包衣均包含羟丙基纤维素，羟丙甲纤维素，聚乙二醇6000，硬脂酸镁和二氧化钛。此外，对于Uniretic®7.5毫克/ 12.5毫克和Uniretic膜包衣®15毫克/ 25毫克含有三氧化二铁。

Uniretic-临床药理学

作用机理

盐酸莫西普利是莫西普利拉特的前药，可抑制人和动物中的ACE。据认为，莫西普利拉特降低血压的机制主要是抑制ACE活性。 ACE是一种肽基二肽酶，可催化无活性的十肽血管紧张素I转化为血管收缩物质血管紧张素II。血管紧张素II是一种有效的外周血管收缩剂，它还可刺激肾上腺皮质的醛固酮分泌，并提供有关肾素分泌的负反馈。 ACE与激肽酶II相同，激肽酶II是一种降解缓激肽的酶，缓激肽是一种内皮依赖性血管舒张剂。 Moexiprilat在抑制ACE和激肽酶II方面的功效是Moexipril的1000倍。 ACE的抑制导致血管紧张素II减少，导致血管收缩减少，血浆肾素活性增加和醛固酮分泌减少。后者导致利尿和利尿，血清钾浓度略有增加（单独使用莫西普利时，平均钾浓度增加约0.25 mEq / L）。

缓激肽（一种有效的血管抑制肽）的水平升高是否在莫西普利的治疗作用中发挥作用尚待阐明。尽管据认为莫西普利降低血压的主要机制是通过肾素-血管紧张素-醛固酮系统，但即使在明显的低肾素高血压中，ACEI抑制剂也对血压有一定作用。但是，与其他ACE抑制剂一样，莫西普利在黑人患者（主要是低肾素人群）中的降压作用比非黑人高血压患者小。尽管莫西普利单一疗法在黑人中的疗效不如非黑人，但联合疗法的疗效似乎与种族无关。

氢氯噻嗪是一种噻嗪类利尿剂和降压药。噻嗪类药物会影响远端肾小管的电解质重吸收机制，直接增加钠和氯的排泄量，大约相等。间接地，氢氯噻嗪的利尿作用减少了血浆量，从而导致血浆肾素活性增加，醛固酮分泌增加，尿钾流失增加以及血清钾减少。肾素-醛固酮链接是由血管紧张素介导的，因此并用ACE抑制剂可逆转与这些利尿剂有关的钾流失。噻嗪类药物降压作用的机制尚不清楚。

药代动力学

继Uniretic口服®时，莫昔血药峰浓度为0.8小时内到达，用药后发生moexiprilat的血药峰浓度1.6小时。达到峰值血浆水平（C max ）后，莫西普利特血浆浓度呈双相下降。 Uniretic给药后®，氢氯噻嗪不变肾脏排泄大约是在24小时内60％。 Uniretic®给药后莫昔和氢氯噻嗪的药代动力学没有不同，分别从莫昔和双氢从速释制剂单药治疗的药代动力学。

Moexipril的抗高血压活性几乎完全归因于其去酯化代谢产物moexiprilat。口服莫西普利的生物利用度与静脉内（IV）莫西普利（均用于测量代谢物莫西普利拉特）相比约为13％，并且受食物的影响显着，这会降低C max和AUC（请参见吸收）。因此，Moexipril应该处于禁食状态。峰血浆浓度的moexiprilat的时间（T max）为约1个半小时和消除半衰期（T 1/2），估计在不同的研究2〜9小时，可变性反映不是简单指数复杂消失模式。像所有ACE抑制剂一样，moexiprilat具有延长的末端消除阶段，大概反映了与ACE结合的药物释放缓慢。重复给药的莫西普利特的累积极少，约为30％，与约12小时的功能消除t 1/2相容。在7.5至30 mg的剂量范围内，药代动力学大致与剂量成比例。

吸收性

莫西普利未被完全吸收，其生物利​​用度约为莫西普利特的13％。生物利用度随配方和食物摄入量的不同而变化，摄入低脂早餐后分别降低Moexiprilat的C max和AUC约70％和40％，或摄入高脂早餐后分别降低Cmax和AUC约80％和50％。

分配

Moexipril的清除率（CL）为441 mL / min，moexiprilat的清除率为（CL）232 mL / min， ½的时间分别为1.3小时和9.8小时。 Moexiprilat是约50％的蛋白质结合。莫西普利特的分布量约为2.8 L / kg。

代谢与排泄

莫西普利相对迅速地转化成其活性代谢物moexiprilat，但仍然存在长于某些其它ACE抑制剂的前药，使得其吨½是在一小时内，它有一个显著AUC。莫西普利和莫西普利拉都转化为二酮哌嗪衍生物和未鉴定的代谢物。静脉注射莫西普利后，约40％的剂量以莫西普利特形式出现在尿液中，约26％为莫西普利，其中含有少量代谢物。大约20％的静脉注射剂量出现在粪便中，主要是莫西普利拉特。口服后，尿液中仅约7％的剂量以莫西普利特形式出现，约1％的莫西普利形式，约5％的其他代谢物形式出现。粪便中有52％的剂量以莫西普利特形式恢复，而1％以莫西普利形式恢复。

特殊人群

肾功能减退

既莫昔和moexiprilat的有效消除牛逼½和AUC与减少肾功能的增加。有信息不足可充分表征这种关系，但在10至40毫升/分钟的范围内肌酐清除率，所述吨½moexiprilat的增加的3〜4倍。

肝功能下降

在轻度至中度肝硬化患者中，单次服用15 mg的莫西普利，莫西普利的C max增加约50％，AUC增加约120％，而莫西普利拉的C max下降约50％，AUC增长了近300％。

老年患者

在具有正常肾脏和肝功能的老年男性受试者（65-80岁）中，莫西普利特的AUC和C max比年轻受试者（19-42岁）高约30％。

与其他药物的药代动力学相互作用

当莫西普利与氢氯噻嗪，地高辛或西咪替丁同时给药时，没有发生临床上重要的药代动力学相互作用。

吸收性

口服后，单剂量氢氯噻嗪的60-80％被吸收。食物对氢氯噻嗪吸收影响的报道研究尚无定论。据报道，充血性心力衰竭患者氢氯噻嗪的吸收减少了50％。氢氯噻嗪在12.5至75 mg的剂量范围内显示出剂量比例关系。

分配

已经观察到表观分布体积在1.5-4.2L / kg之间变化。氢氯噻嗪会积聚在红细胞中，因此全血水平高于血浆中的水平。口服后4小时达到全血水平和血浆水平之间的平衡。氢氯噻嗪越过胎盘屏障。氢氯噻嗪的蛋白质结合率为21-24％。

代谢与排泄

氢氯噻嗪不被代谢。氢氯噻嗪可被肾脏迅速清除。超过60％的口服剂量在24小时内保持不变。当跟踪血浆水平至少24小时后，观察到血浆半衰期在5.6和14.8小时之间变化。观察到肾脏清除率在3.1-5.5 mL / min / kg之间变化。

特殊人群

肾功能减退

在一项肾功能不全患者（平均肌酐清除率为19 mL / min）的研究中，氢氯噻嗪的消除半衰期延长至21小时。

与其他药物的药代动力学相互作用

并用苯丙胺或胍基苯可增加对氢氯噻嗪的吸收，而并用胆甾醇胺或考来替泊可降低对氢氯噻嗪的吸收。

药效学和临床疗效

在使用莫昔普利剂量的3.75-30毫克和双氢剂量的3.125-50毫克Uniretic®临床试验中，抗高血压作用是持续至少24小时，并它们随任一组分的剂量增加而增加。相比于各成分的单一疗法与Uniretic®看出血压降低的程度是大约添加剂。 Uniretic的降压作用®治疗长达24个月期间继续进行。 Uniretic®的有效性并没有显著的患者年龄或性别的影响。虽然莫昔单药治疗是黑人比非黑人中的那么有效，Uniretic®的功效似乎是独立的种族。

通过阻断肾素-血管紧张素-醛固酮轴，莫西普利的给药倾向于减少与氢氯噻嗪有关的钾流失。在Uniretic®对照的临床试验，在血清钾的平均变化在谁收到3.75毫克/ 6.25毫克或7.5毫克/ 12.5毫克的受试者是接近零，但谁收到了15毫克/ 12.5毫克或15毫克/ 25毫克受试者经历温和的血清钾水平降低，类似于接受相同剂量氢氯噻嗪单药治疗的受试者的情况。

15毫克或更多单次或多次剂量的moexipril可以持续抑制血浆ACE活性80-90％，从2小时内开始，持续24小时（80％）。

在对照试验中，口服莫西普利的峰值效果在每天一次给药的7.5至60 mg剂量范围内随剂量增加而增加。首次给药后约1小时可检测到降压作用，给药后3至6个小时达到峰值。就在给药前（即在给药谷时），降压作用与剂量的相关性不太明显，并且在每天给药一次的24小时给药间隔中，降压作用趋于减弱。

在每天一次的7.5至30 mg剂量范围内的多剂量研究中，莫西普利比安慰剂使谷中的坐姿血压降低4-11 / 3-6 mmHg，这是高剂量时反应增加的趋势。这些作用是ACE抑制剂的典型作用。没有将莫西普利与其他降压药进行比较的足够规模的试验。

较高剂量的莫西普利通常会在低谷时留下更大的峰值血压效应。在剂量滴定过程中，任何有关给药方案是否适当的决定都应基于低谷血压测量值。如果在给药间隔结束时舒张压控制不充分，则可以增加剂量或采用分次（BID）方案。

在慢性治疗期间，任何剂量的莫西普利的降压作用通常在治疗2周内即可见，在4周后最大程度降低。莫西普利的抗高血压作用已被证明在治疗期间持续长达24个月。

与其他ACE抑制剂一样，Moexipril在降低黑人的低谷血压方面不如在非黑人中有效。在建议的剂量范围内，黑人的安慰剂校正过的低谷组舒张压对血压的影响为+1至-3 mmHg，而非黑人为-4至-6 mmHg。

莫西普利的有效性不受患者年龄，性别或体重的显着影响。已显示莫西普利在参加安慰剂对照临床试验的绝经前和绝经后妇女中均具有降压活性。

Uniretic的适应症和用法

Uniretic®适用于治疗的高血压患者。此固定组合不适用于高血压的初始治疗（请参阅剂量和用法）。

在使用Uniretic®，应考虑这样的事实，另一个ACE抑制剂卡托普利，已经引起粒细胞缺乏症，特别是在患有肾损伤或胶原血管病。现有数据不足以表明Uniretic®没有类似的风险（见警告，中性粒细胞减少/粒细胞缺乏症）。此外，有足够数据的ACE抑制剂可导致黑人的血管性水肿发生率高于非黑人患者（请参阅警告，血管性水肿）。

禁忌症

Uniretic®在病人谁是过敏本产品的任何部件和患者与先前治疗与ACE抑制剂血管神经性水肿的历史禁忌。由于存在氢氯噻嗪成分，对无尿或对其他磺酰胺类药物过敏的患者禁用该产品。有过敏或支气管哮喘病史的患者更容易发生超敏反应。

难道糖尿病患者与Uniretic®不共辖阿利吉仑（见PRECATIONS，药物相互作用）。

警告事项

过敏反应和可能相关的反应

这大概是因为血管紧张素转换酶抑制剂影响的类花生酸和多肽，包括内源性缓激肽，患者接受ACE抑制剂，包括Uniretic®的代谢，可经受各种不良反应，它们中的一些严重的。

头颈部血管性水肿

据报道，用ACE抑制剂（包括moexipril）治疗的患者涉及面部，四肢，嘴唇，舌头，声门和/或喉头的血管性水肿。在安慰剂对照试验中，接受莫西普利治疗的患者中，＜0.5％的患者出现血管性水肿或面部水肿的症状。没有一例被认为会危及生命，所有未经治疗或药物治疗（抗组胺药或糖皮质激素）均可解决。一名仅接受氢氯噻嗪治疗的患者出现喉头水肿。安慰剂治疗的患者没有血管性水肿的报道。

在血管性水肿的情况下，与Uniretic®治疗应及时停药，并直至肿消失病人仔细观察。在肿胀仅限于面部和嘴唇的情况下，尽管抗组胺药可用于缓解症状，但一般情况下无需治疗即可缓解症状。

与舌头，声门或喉部受累相关的血管性水肿可能由于气道阻塞而致死。应立即提供适当的治疗方法，例如皮下肾上腺素溶液1：1000（0.3至0.5 mL）和/或确保通气的措施（请参阅“不良反应” ）。

肠血管性水肿

ACE抑制剂治疗的患者有肠道血管性水肿的报道。这些患者出现腹痛（有或没有恶心或呕吐）；在某些情况下，没有面部血管性水肿的病史，C-1酯酶水平正常。通过腹部CT扫描或超声检查或在手术中诊断出血管性水肿，并在停用ACE抑制剂后症状得以缓解。在出现腹痛的ACE抑制剂患者的鉴别诊断中应包括肠道血管性水肿。

脱敏过程中的类过敏反应

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

膜暴露过程中的类过敏反应

已经报道了用高通量膜透析并同时使用ACE抑制剂治疗的患者发生类过敏反应。在进行低密度脂蛋白单采与硫酸葡聚糖吸收的患者中也有过敏样反应的报道。

低血压

Uniretic®可引起症状性低血压，但是，与其他ACE抑制剂，这与Uniretic®单独治疗无并发症的高血压患者不寻常。有症状的低血压最可能发生在由于长期利尿治疗，饮食限盐，透析，腹泻或呕吐而导致盐和/或容量减少的患者中。体积和/或盐的耗尽应该开始治疗与Uniretic之前被校正®（见不良反应）。

Uniretic®的噻嗪类组分可以增强的其它抗高血压药物，特别是神经节或外周肾上腺素能阻断药物的作用。交感神经切除术后患者中噻嗪类成分的抗高血压作用也可能得到增强。

在充血性心力衰竭患者中，伴有或不伴有肾功能不全，ACE抑制剂治疗可能会导致过度的低血压，这可能与少尿或进行性氮质血症有关，很少发生急性肾衰竭和死亡。在这些患者中，Uniretic®治疗应密切医疗监督下启动，并且患者应该密切观察前两个星期的治疗和每当Uniretic®的剂量增加之后。患有缺血性心脏病，主动脉瓣狭窄或脑血管疾病的患者也应注意避免低血压，在这些患者中，血压过度下降可能会导致心肌梗塞或脑血管意外。

如果发生低血压，应将患者仰卧，必要时可通过静脉输注生理盐水进行治疗。 Uniretic®治疗通常可以继续以下血压和体积的恢复。

肾功能受损

Uniretic®应慎用于患有严重肾脏疾病中使用。噻嗪类利尿剂可能会使这类患者发生氮质血症，重复给药的效果可能会累积。

由于抑制了肾素-血管紧张素-醛固酮系统，因此易感人群的肾功能可能会发生变化。有高血压的治疗肾功能衰竭患者Uniretic®没有临床经验。

一些没有明显先前存在的肾血管疾病的高血压患者的血尿素氮和血清肌酐水平升高，通常是轻微和短暂的升高，尤其是当莫西普利与噻嗪类利尿剂同时使用时。既往有肾功能不全的患者更容易发生这种情况。可能有必要Uniretic®的剂量调整。对高血压患者的评估应始终包括对肾功能的评估（参见剂量和用法）。

在严重充血性心力衰竭的高血压患者中，其肾功能可能取决于肾素-血管紧张素-醛固酮系统的活性，ACE抑制剂（包括莫西普利）的治疗可能与少尿和/或进行性氮质血症有关，而急性肾功能不全失败和/或死亡。

在患有单侧或双侧肾动脉狭窄的高血压患者中，在接受ACE抑制剂治疗后，一些患者的血尿素氮和血清肌酐升高。停用ACE抑制剂和/或利尿剂治疗后，这些增加几乎总是可逆的。在此类患者中，应在治疗的最初几周内监测肾功能。

中性粒细胞减少/粒细胞缺乏症

已显示另一种ACE抑制剂卡托普利可引起粒细胞缺乏症和骨髓抑制，在没有并发症的高血压患者中很少见，但在肾功能不全的高血压患者中更常见，特别是如果他们还患有胶原性血管疾病，例如系统性红斑狼疮或硬皮病。尽管接受莫西普利治疗的患者没有发生严重的中性粒细胞减少症（绝对嗜中性白血球计数<500 / mm 3 ）的情况，与其他ACE抑制剂一样，对于胶原蛋白血管疾病的患者，应考虑监测白细胞计数，尤其是在该疾病与肾功能受损有关。 Moexipril临床试验的可用数据不足以显示Moexipril不会以与卡托普利相似的速率引起粒细胞缺乏症。

胎儿毒性

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。导致的羊水过少可能与胎儿肺发育不全和骨骼变形有关。潜在的新生儿不良事件包括颅骨发育不全，无尿，低血压，肾衰竭和死亡。当检测到怀孕，停止Uniretic®尽快。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。孕妇在孕期进行适当的高血压治疗对于优化母亲和胎儿的结局非常重要。

在特殊情况下，除了针对特定患者的影响肾素-血管紧张素系统的药物治疗之外，没有其他适当的替代方法，请告知母亲母亲对胎儿的潜在风险。进行连续超声检查以评估羊膜内环境。如果发现羊水过少，请停止Uniretic，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。密切与在子宫内暴露于Uniretic®低血压，少尿，和高钾血症的历史观察婴儿。 （请参阅预防措施，儿科使用）

宫内暴露于噻嗪类利尿剂与胎儿或新生儿黄疸，血小板减少症以及成人中可能发生的其他不良反应有关。

盐酸莫西普利和氢氯噻嗪的组合（比率7.5：12.5）的生殖研究表明，该组合在大鼠中的致死剂量为800 mg / kg / day，对中毒剂量为160 mg / kg / day时，没有致畸性。在兔子的一天。

肝功能衰竭

很少有ACE抑制剂与以胆汁淤积性黄疸开始并发展为暴发性肝坏死甚至死亡的综合征相关。该综合征的机制尚不清楚。接受ACE抑制剂而出现黄疸或肝酶显着升高的患者应停用ACE抑制剂并接受适当的医学随访。

肝功能受损

Uniretic®应谨慎患者受损肝功能或进行性肝脏疾病中使用，因为液体和电解质平衡的较小改变可以沉淀肝昏迷。在轻度至中度肝硬化患者中，单次服用15 mg的莫西普利，莫西普利的C max增加约50％，AUC增加约120％，而莫西普利拉的C max下降约50％，AUC增长了近300％。没有正式的药代动力学研究已经在高血压患者的肝功能受损与Uniretic®进行。

系统性红斑狼疮

据报道，噻嗪类利尿剂可导致全身性红斑狼疮恶化或活化。

急性近视和继发性闭角型青光眼

氢氯噻嗪（一种磺酰胺）可引起特发性反应，导致急性短暂性近视和急性闭角型青光眼。症状包括视力下降或眼痛的急性发作，通常在药物启动后数小时至数周内发生。未经治疗的急性闭角型青光眼可导致永久性视力丧失。主要治疗方法是尽快终止氢氯噻嗪。如果眼内压保持不受控制，可能需要考虑及时的医学或外科治疗。发生急性闭角型青光眼的危险因素可能包括磺酰胺或青霉素过敏史。

预防措施

一般

血清电解质失衡

在莫西普利单药治疗的临床试验中，约1.3％接受莫西普利的高血压患者发生持续性高钾血症（血清钾高于5.4 mEq / L）。使用ACE抑制剂引起高钾血症的危险因素包括肾功能不全，糖尿病以及与同时使用保钾利尿剂，钾补充剂和/或含钾盐替代品。

噻嗪类利尿剂的治疗与低血钾，低血钠和低氯性碱中毒有关。这些障碍有时表现为以下一种或多种：口干，口渴，无力，嗜睡，嗜睡，躁动，肌肉疼痛或抽筋，肌肉疲劳，低血压，少尿，心动过速，恶心和呕吐。低钾血症也有报道使心脏对洋地黄的毒性作用敏感或夸大。低钾血症的风险在肝硬化患者，利尿快的患者，口服电解质摄入不足的患者以及接受糖皮质激素或ACTH联合治疗的患者中最大。

莫西普利和氢氯噻嗪对血清钾的相反作用将在许多患者中相互抵消，因此几乎看不到对血清钾的净作用。应当以适当的间隔对血清电解质进行初始和定期测定，以检测可能的电解质失衡。

氯化物缺乏症通常是轻微的，仅在特殊情况下（例如，在肝脏疾病或肾脏疾病中）需要特殊治疗。水肿患者可能发生稀释性低钠血症；适当的疗法是用水限制而不是撒盐，除非在少数情况下低钠血症会危及生命。在实际的盐消耗中，适当的替代疗法是选择的治疗方法。

噻嗪可减少钙排泄。在少数接受噻嗪类药物长期治疗的患者中，已观察到甲状旁腺的病理改变，伴有高钙血症和低磷血症。还没有发现甲状旁腺功能亢进症的更严重的并发症（肾结石，骨吸收和消化性溃疡）。噻嗪类药物可促进镁的尿排泄，可能导致低镁血症。

其他代谢紊乱

噻嗪类利尿剂可能会降低葡萄糖耐量，并可能提高血清中的胆固醇，甘油三酸酯和尿酸水平。这些影响通常很小，但易感患者可能会诱发坦率的痛风或明显的糖尿病。

手术/麻醉

在进行大手术或在麻醉过程中使用产生低血压药物的患者，莫西普利可能会阻断代偿性肾素释放的作用。如果在这种情况下发生低血压并被认为是由于这种机制引起的，则可以通过扩大体积进行纠正。

咳嗽

据推测，由于抑制了内源性缓激肽的降解，所有ACEI抑制剂均出现持续性非生产性咳嗽，在治疗中断后总能缓解。在咳嗽的鉴别诊断中应考虑ACE抑制剂引起的咳嗽。与Uniretic安慰剂对照试验®，咳嗽存在于Uniretic®患者的3％，并且给定的安慰剂患者1％。

给患者的信息

餐饮

应建议患者采取Uniretic®一小时餐前（见临床药理学和剂量和用法）。

血管性水肿

使用ACE抑制剂治疗可能会发生血管性水肿，包括喉头水肿，通常发生在治疗初期（第一个月内）。应该这样建议患者，并告知患者应立即报告任何提示血管水肿的迹象或症状（面部肿胀，四肢，眼睛，嘴唇，舌头，呼吸困难），并且在与处方医生协商之前不再服用药物。

有症状的低血压

患者应提醒说，头昏可以Uniretic®发生，特别是在治疗的最初几天。如果发生昏厥，患者应停止服用Uniretic®和咨询处方医生。

所有患者应注意，由于体液减少，过度排汗和脱水可能导致血压过度下降。其他引起体力消耗的原因，例如呕吐或腹泻，也可能导致血压下降；如果患者出现这些情况，应建议他们咨询医生。

高钾血症

应告知患者在未咨询医生的情况下不要使用钾补充剂或含钾盐替代品。

中性粒细胞减少

应告知患者及时报告可能是中性粒细胞减少症迹象的任何感染迹象（例如，喉咙痛，发烧）。

怀孕

育龄女性患者应被告知暴露于Uniretic®怀孕期间的后果。与计划怀孕的妇女讨论治疗方案。应要求患者尽快向医生报告怀孕情况。

药物相互作用

补钾和省钾利尿剂

如上述（血清电解质失衡）指出，Uniretic®的净效应可以是提升患者的血清钾，以降低它，或者把它留不变。保钾利尿剂（螺内酯，阿米洛利，氨苯蝶啶）或钾补充剂会增加高钾血症的风险。如果指示同时使用此类药物，则应谨慎使用，并应监测患者的血清钾。

口服抗凝剂

与华法林的相互作用研究未能确定莫西普利单药治疗对抗凝剂的血清浓度或其抗凝剂的任何临床重要影响。

锂

据报道在用锂治疗期间接受ACE抑制剂的患者血清锂水平升高和锂中毒症状。 Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with Uniretic ® , a thiazide diuretic is coadministered with the ACE inhibitor. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

Gold

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

Alcohol, Barbiturates, or Narcotics

Potentiation of orthostatic hypotension may occur in patients on thiazide diuretic therapy with concomitant use of alcohol, barbiturates, or narcotics.

Antidiabetic Agents

Use of thiazide diuretics concomitantly with antidiabetic agents (oral agents and insulin) may require dosage adjustment of the antidiabetic agent. Moexipril has been used in clinical trials concomitantly with oral hypoglycemic agents and there was no evidence of any clinically important adverse interactions.

Cholestyramine and Colestipol Resins

在阴离子交换树脂的存在下，氢氯噻嗪的吸收受到损害。单剂量的胆甾胺或胆甾醇树脂结合氢氯噻嗪，并减少其从胃肠道的吸收，分别最多达85％和43％。

Corticosteroids, ACTH

Use of thiazide diuretics concomitantly with corticosteroids or ACTH may intensify electrolyte depletion, particularly hypokalemia.

Pressor Amines

Thiazide diuretics may decrease arterial responsiveness to pressor amines
(eg norepinephrine), but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Skeletal Muscle Relaxants, Nondepolarizing

Thiazide diuretics may increase the responsiveness to tubocurarine.

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

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

The antihypertensive effect of ACE inhibitors and hydrochlorothiazide, as well as the diuretic and natriuretic effects of hydrochlorothiazide, may be attenuated by NSAIDS.

肾素-血管紧张素系统（RAS）的双重阻断

与单一疗法相比，用血管紧张素受体阻滞剂，ACEI抑制剂或阿利吉仑双重阻断RAS与低血压，高钾血症和肾功能变化（包括急性肾功能衰竭）的风险增加有关。 Closely monitor blood pressure, renal function and electrolytes in patients on Uniretic ® and other agents that affect the RAS.

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

Other Agents

No clinically important pharmacokinetic interactions occurred when moexipril was administered concomitantly with digoxin or cimetidine.

Moexipril has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H 2 blockers, digoxin, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. In general, ACE inhibitors have less than additive effects with beta-adrenergic blockers, presumably because both work by inhibiting the renin-angiotensin system.

Coadministration of propantheline or guanabenz increased the absorption of hydrochlorothiazide.

致癌，诱变，生育力受损

No evidence of carcinogenicity was detected in long-term studies when moexipril was administered to mice and rats at doses up to 14 or 27.3 times the Maximum Recommended Human Dose (MRHD) on a mg/m 2 basis. No mutagenicity was detected in the Ames test and microbial reverse mutation assay, with and without metabolic activation, or in an in vivo nucleus anomaly test. However, increased chromosomal aberration frequency in Chinese hamster ovary (CHO) cells was detected under metabolic activation conditions at a 20-hour harvest time. Reproduction studies have been performed in rabbits at oral doses up to 0.7 times the MRHD on a mg/m 2 basis, and in rats up to 90.9 times the MRHD on a mg/m 2 basis. No indication of impaired fertility, reproductive toxicity, or teratogenicity was observed.

Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide in their feed for two years, at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the Ames test); in the CHO test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes; and the Drosophila sex-Iinked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diets, to doses up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

护理母亲

It is not known whether moexipril or moexiprilat is excreted in human milk. Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of moexipril or moexiprilat in infants, a decision should be made whether to discontinue nursing or to discontinue Uniretic ® , taking into account the importance of the drug to the mother.

儿科用

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

Safety and effectiveness of Uniretic ® in pediatric patients have not been established.

老人用

Of the patients who received Uniretic ® in controlled clinical studies, 24% were 65 years of age or older. No overall differences in effectiveness or safety were observed between these patients and younger patients. In elderly patients receiving moexipril, plasma levels of drug are slightly higher and renal clearance is reduced when compared to younger patients, but these effects did not have detectable consequences. Hydrochlorothiazide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

不良反应

Uniretic ® has been evaluated for safety in more than 1140 patients with hypertension with more than 120 treated for more than one year. Uniretic ® has not demonstrated a potential for causing adverse experiences different from those previously associated with other ACE inhibitor/diuretic combinations. The overall incidence of reported adverse events was slightly less in patients treated with Uniretic ® than patients treated with placebo.

Adverse experiences were usually mild and transient, and there was no relationship between adverse experiences and gender, race, age, or total daily dosage (except for serum potassium decreases at 50 mg hydrochlorothiazide) within the moexipril/hydrochlorothiazide dosage range of 3.75 mg / 3.125 mg to 30 mg / 50 mg. Discontinuation of therapy due to adverse experiences was required in 5.3% of patients treated with Uniretic ® and in 8.4% of patients treated with placebo. The most common reasons for discontinuation of therapy with Uniretic ® were cough (0.5%) and dizziness (0.5%).

All adverse experiences considered at least possibly related to treatment that occurred at any dose in placebo-controlled trials of once-daily dosing in more than 1% of patients treated with Uniretic ® and that were at least as frequent in the Uniretic ® group as in the placebo group are shown in the following table.

Other adverse experiences occurring in more than 1% of patients treated with Uniretic ® in controlled or uncontrolled trials, some of which were of uncertain drug relationship, listed in decreasing frequency include: upper respiratory infection, headache, pain, flu syndrome, pharyngitis, hyperuricemia, diarrhea, back pain, rhinitis, sinusitis, abnormal ECG, infection, abdominal pain, chest pain, dyspepsia, hyperglycemia, hypokalemia, rash, vertigo, nausea, hypertonia, increased SGPT, urinary tract infection, impotence, peripheral edema, pyuria, bronchitis, and fever. See WARNINGS and PRECAUTIONS for discussion of anaphylactoid reactions, angioedema, hypotension, neutropenia/agranulocytosis, fetal/neonatal morbidity and mortality, serum electrolyte imbalances, and cough.

The following adverse experiences, some of which are of uncertain drug relationship, were reported in Uniretic ® controlled or uncontrolled clinical trials in less than 1% of patients or have been attributed to other ACE inhibitors. Within each organ system, adverse experiences are listed in decreasing frequency.

Cardiovascular: palpitation, flushing, syncope, tachycardia, myocardial infarct, hypotension, postural hypotension, arrhythmia, first degree AV block, ventricular extrasystoles, atrial fibrillation, migraine, hemorrhage, sinus bradycardia, bigeminy, bradycardia, bundle branch block, heart arrest, myocardial ischemia, peripheral vascular disorder, prolonged QT interval, inverted T wave, ventricular fibrillation

Dermatologic: eczema, pruritus, sweating, acne, dry skin, herpes simplex, contact dermatitis, herpes zoster, psoriasis, alopecia, angioedema, erythema nodosum, fungal dermatitis, furunculosis, maculopapular rash, purpuric rash, skin carcinoma, subcutaneous nodule, urticaria, pemphigus

Gastrointestinal: vomiting, constipation, gastroenteritis, periodontal abscess, cholelithiasis, gastritis, gingivitis, esophagitis, flatulence, anorexia, colitis, dysphagia, tooth caries, cheilitis, enteritis, eructation, gastrointestinal carcinoma, gastrointestinal hemorrhage, glossitis, increased appetite, jaundice, melena, rectal hemorrhage, stomatitis, tongue discoloration, tongue edema

Hematologic: anemia, hypochromic anemia, leukopenia, abnormal erythrocytes, ecchymosis, lymphocytosis, hemolysis, lymphadenopathy, eosinophilia, petechia, abnormal WBC, hemolytic anemia

Metabolic: hyperlipemia, increased SGOT, gout, bilirubinemia, increased creatinine, hypercholesterolemia, increased BUN, increased CPK, diabetes mellitus, hyponatremia, thirst, edema, increased alkaline phosphatase, increased amylase, dehydration, decreased glucose tolerance, goiter, hypercalcemia, hyperkalemia, hypocalcemia, hypochloremia, hypoproteinemia, weight gain

Neurologic/Psychiatric: insomnia, postural dizziness, somnolence, dry mouth, anxiety, nervousness, paresthesia, depression, neuritis, hypesthesia, decreased libido, neuralgia, amnesia, ataxia, cerebral infarct, emotional lability, facial paralysis, hypokinesia, neurosis, vocal cord paralysis

Renal: albuminuria, urinary frequency, hematuria, glycosuria, cystitis, dysuria, nocturia, polyuria, kidney calculus, pyelonephritis, urate crystalluria, urinary casts, urinary retention

Respiratory: epistaxis, pneumonia, dyspnea, asthma, lung carcinoma, hemoptysis, laryngitis, voice alteration, eosinophilic pneumonitis

Urogenital: vaginal hemorrhage, breast carcinoma, scrotal edema, vaginitis, breast enlargement, breast pain, dysmenorrhea, leukorrhea

Other: asthenia, conjunctivitis, myalgia, arthralgia, arthrosis, hernia, neck pain, cyst, tenosynovitis, abnormal vision, allergic reaction, arthritis, cataract, cellulitis, moniliasis, otitis media, eye hemorrhage, chills, abscess, bursitis, deafness, ear pain, glaucoma, iritis, neck rigidity, photosensitivity, retinal degeneration, tinnitus

Monotherapy with moexipril has been evaluated for safety in over 3000 patients. In clinical trials, the observed adverse experiences with moexipril were similar to those seen in the Uniretic ® trials.

氢氯噻嗪

The following adverse reactions have been reported with hydrochlorothiazide and, within each organ system, are listed by decreasing severity.

Cardiovascular: orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics)

Gastrointestinal: pancreatitis, jaundice (intrahepatic cholestatic, see WARNINGS ), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia

Neurologic/Psychiatric: vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness

Musculoskeletal: muscle spasm

Hematologic: aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia

Metabolic: hyperglycemia, glycosuria, hyperuricemia

Hypersensitivity: necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity

Clinical Laboratory Test Findings

See PRECAUTIONS, General .

As with other ACE inhibitors, minor increases in blood urea nitrogen or serum creatinine, reversible upon discontinuation of therapy, were observed in less than 1% of patients with essential hypertension who were treated with Uniretic ® . Increases are more likely to occur in patients with compromised renal function (see PRECAUTIONS, General ).

Clinically important changes in standard laboratory tests were rarely associated with Uniretic ® administration.

过量

No specific information is available on the treatment of overdosage with Uniretic ® . Treatment should be symptomatic and supportive. Therapy with Uniretic ® should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Single oral doses of 2 g/kg moexipril were associated with significant lethality in mice. Rats, however, tolerated single oral doses of up to 3 g/kg. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in mice and rats. For the combination of moexipril hydrochloride and hydrochlorothiazide (ratio 7.5:12.5), the approximate LD 50 was around 10 g/kg for mice and above 10 g/kg for rats. Addition of hydrochlorothiazide to moexipril hydrochloride did not increase the acute toxicity due to moexipril hydrochloride.

Human overdoses of moexipril have not been reported. In case reports of overdoses with other ACE inhibitors, hypotension has been the principal adverse effect noted. The most common signs and symptoms observed with an overdose of hydrochlorothiazide have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

No data are available to suggest that physiological maneuvers (eg, maneuvers to change the pH of the urine) would accelerate elimination of moexipril and its metabolites. The dialyzability of moexipril is not known.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of moexipril overdose, but angiotensin II is essentially unavailable outside of research facilities. Because the hypotensive effect of moexipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat moexipril overdose by infusion of normal saline solution. In addition, renal function and serum potassium should be monitored.

Uniretic Dosage and Administration

Moexipril and hydrochlorothiazide are effective treatments for hypertension. The recommended dosage range of moexipril is 7.5 to 30 mg daily, administered in a single or two divided doses one hour before meals, while hydrochlorothiazide is effective in a dosage of 12.5 to 50 mg daily.

The side effects (see WARNINGS ) of moexipril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. Therapy with any combination of moexipril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens in which moexipril is combined with low doses of hydrochlorothiazide produce minimal effects on serum potassium. In Uniretic ® controlled clinical trials, the average change in serum potassium was near zero in subjects who received 3.75 mg / 6.25 mg or 7.5 mg / 12.5 mg, but subjects who received 15 mg / 12.5 mg or 15 mg / 25 mg experienced a mild decrease in serum potassium, similar to that experienced by subjects who received the same dose of hydrochlorothiazide monotherapy.为了使剂量无关的副作用降到最低，通常只有在患者单药治疗未能达到预期效果后才开始联合治疗。

Dose Titration Guided by Clinical Effect

A patient whose blood pressure is not adequately controlled with either moexipril or hydrochlorothiazide monotherapy may be given Uniretic ® 7.5 mg / 12.5 mg, Uniretic ® 15 mg / 12.5 mg or Uniretic ® 15 mg / 25 mg one hour before a meal. Further increases of moexipril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed.

Total daily doses above 30 mg / 50 mg a day have not been studied in hypertensive patients. Patients whose blood pressures are adequately controlled with 25 mg of hydrochlorothiazide daily, but who experience significant potassium loss with this regimen, may achieve blood pressure control without electrolyte disturbance if they are switched to moexipril 3.75 mg/hydrochlorothiazide 6.25 mg (one-half of the Uniretic ® 7.5 mg / 12.5 tablet). For patients who experience an excessive reduction in blood pressure with Uniretic ® 7.5 mg / 12.5 mg, the physician may consider prescribing moexipril 3.75 mg/hydrochlorothiazide 6.25 mg.

Replacement Therapy

The combination may be substituted for the titrated individual active ingredients.

用于肾功能不全

The usual dosage regimen of Uniretic ® does not need to be adjusted as long as the patient's creatinine clearance is > 40 mL/min/1.73 m 2 (serum creatinine approximately ≤ 3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Uniretic ® is not recommended (see PRECAUTIONS, General ).

How is Uniretic Supplied

Uniretic ® (moexipril hydrochloride/hydrochlorothiazide) 7.5 mg / 12.5 mg tablets are yellow, oval, film-coated and scored with engraved code 712 on the unscored side and S and P on either side of the score. They are supplied as follows:

Uniretic ® (moexipril hydrochloride/hydrochlorothiazide) 15 mg / 12.5 mg tablets are white, oval, film-coated and scored with engraved code 720 on the unscored side and S and P on either side of the score. They are supplied as follows:

Uniretic ® (moexipril hydrochloride/hydrochlorothiazide) 15 mg / 25 mg tablets are yellow, oval, film-coated and scored with engraved code 725 on the unscored side and S and P on either side of the score. They are supplied as follows: