卡波滕说明

Capoten®（卡托普利片，USP）是血管紧张素I转换酶（ACE）的一种特殊竞争性抑制剂，该酶负责将血管紧张素I转化为血管紧张素II。

Capoten在化学上被称为1-[（（2S）-3-巯基-2-甲基丙酰基] -L脯氨酸[MW 217.29]，具有以下结构：

卡托普利是白色至类白色结晶性粉末，可能有轻微的硫磺味。它溶于水（约160 mg / mL），甲醇和乙醇，微溶于氯仿和乙酸乙酯。

Capoten的刻痕片剂口服剂量分别为12.5 mg，25 mg，50 mg和100 mg。

非活性成分：微晶纤维素，玉米淀粉，乳糖和硬脂酸。

Capoten-临床药理学

作用机理

Capoten的作用机理尚未完全阐明。它对高血压和心力衰竭的有益作用似乎主要来自抑制肾素血管紧张素-醛固酮系统。但是，肾素水平与对药物的反应之间没有一致的相关性。肾素，一种由肾脏合成的酶，释放到循环系统中，作用于血浆球蛋白底物上，产生血管紧张素I（一种相对无活性的十肽）。然后，血管紧张素I通过血管紧张素转化酶（ACE）转化为血管紧张素II，血管紧张素II是一种有效的内源性血管收缩物质。血管紧张素II还刺激肾上腺皮质的醛固酮分泌，从而促进钠和液体的滞留。

Capoten通过抑制ACE（一种肽基二肽羧基水解酶）来防止血管紧张素I转化为血管紧张素II。通过显示出由卡托普利减弱或消除了外源性给予血管紧张素I引起的血压升高，已在健康的人类受试者和动物中证明了这种抑制作用。在动物研究中，卡托普利并未改变对其他多种药物（包括血管紧张素II和去甲肾上腺素）的升压反应，表明其作用特异性。

ACE与“缓激肽酶”相同，并且Capoten也可能干扰血管舒缩肽，缓激肽的降解。缓激肽或前列腺素E 2浓度的增加也可能对Capoten的治疗作用起作用。

ACE的抑制导致血浆血管紧张素II减少和血浆肾素活性（PRA）升高，后者是由于血管紧张素II减少引起的肾素释放的负反馈损失所致。血管紧张素II的减少导致醛固酮分泌减少，因此，血清钾的少量增加可能与钠和体液的流失同时发生。

与可证明的循环ACE抑制相比，降压作用持续更长的时间。尚不知道存在于血管内皮中的ACE是否比循环血液中的ACE被抑制的时间更长。

药代动力学

口服给予治疗剂量的Capoten后，在约一小时的峰值血液中迅速吸收。胃肠道中食物的存在使吸收减少了大约30％至40％。因此，卡托普利应在饭前一小时服用。根据碳14标记，平均最小吸收量约为75％。在24小时内，尿液中95％以上的吸收剂量被消除； 40％至50％为不变药物；其余大部分是卡托普利和卡托普利-半胱氨酸二硫键的二硫键二聚体。

大约25％至30％的循环药物与血浆蛋白结合。血液中总放射性的表观消除半衰期可能少于3小时。目前尚无法准确测定未改变的卡托普利的半衰期，但可能少于2小时。然而，在肾功能不全的患者中，卡托普利会发生保留（参见剂量和用法）。

药效学

服用Capoten可使高血压患者的外周动脉阻力降低，而心输出量不变或升高。服用Capoten后肾血流量增加，肾小球滤过率通常保持不变。

口服单独剂量的Capoten后，血压降低通常最多60至90分钟。作用的持续时间与剂量有关。血压的降低可能是逐步的，因此要获得最大的治疗效果，可能需要数周的治疗时间。卡托普利和噻嗪类利尿剂的降血压作用是相加的。相反，卡托普利和β-受体阻滞剂的作用小于加和作用。

站立姿势和仰卧姿势的血压均降低到相同程度。体位性影响和心动过速很少见，但可能在体量耗尽的患者中发生。卡波滕的突然停药并未与血压的快速升高相关。

在心力衰竭患者中，已证明外周（全身血管）阻力和血压（后负荷）显着降低，肺毛细血管楔压（前负荷）和肺血管阻力降低，心输出量增加以及运动耐力时间（ETT）增加。这些血液动力学和临床效应在首次给药后发生，并且在治疗期间似乎持续存在。对利尿剂和洋地黄没有充分反应的患者进行的为期12周的安慰剂对照研究表明，对ETT的有益作用没有耐受性。在某些情况下暴露长达18个月的开放研究还表明，ETT的益处得以保持。在一些急性血液动力学影响最小的患者中观察到临床改善。

生存和心室扩大（SAVE）研究是一项多中心，随机，双盲，安慰剂对照试验，研究对象是2,231名在心肌梗塞急性期幸存且没有活动性缺血的患者（年龄21至79岁）。患者患有左心功能不全（LVD），定义为静息的左心室射血分数≤40％，但在随机分组时症状不足以要求ACE抑制剂治疗心力衰竭。过去约有一半的患者有心力衰竭症状。患者接受测试剂量为6.25 mg的口服Capoten，并在梗塞后3至16天内随机分组，除常规治疗外，还接受Capoten或安慰剂治疗。 Capoten以6.25 mg或12.5 mg tid的剂量开始，两周后滴定至50 mg tid的目标维持剂量，研究结束时约80％的患者正在接受目标剂量。对患者进行了至少两年至五年的随访，平均随访时间为3.5年。

安慰剂组和Capoten组的基准血压分别为113/70 mmHg和112/70 mmHg。在研究期间，两个治疗组的血压均略有上升，而卡波滕组的血压则稍低（1年时为119/74对125/77 mmHg）。

与安慰剂相比，Capoten疗法可改善长期生存率和临床结局。所有原因死亡的风险降低为19％（P = 0.02），心血管死亡的风险降低为21％（P = 0.014）。卡托普利治疗的受试者因心力衰竭而住院的次数减少了22％（P = 0.034）。与安慰剂相比，接受卡托普利的患者出现明显心力衰竭症状的人数减少了22％。两组之间因所有原因（2056安慰剂； 2036卡托普利）的总住院率之间无显着差异。

在存在其他疗法（例如阿司匹林，β受体阻滞剂，硝酸盐，血管扩张剂，钙拮抗剂和利尿剂）的情况下，卡波滕具有良好的耐受性。

在一项多中心，双盲，安慰剂对照试验中，409例年龄在18至49岁之间的男女，有或没有高血压，伴有I型（青少年型，发病于30岁之前）胰岛素依赖型糖尿病，视网膜病变，蛋白尿≥每天500 mg且血清肌酐≤2.5 mg / dL，随机分配至安慰剂或Capoten（25 mg tid），随访时间长达4.8年（中位数为3年）。为实现血压控制，两组患者均根据需要添加了其他降压药（利尿剂，β受体阻滞剂，中枢性药物或血管扩张药）。

Capoten组的血清肌酐增加一倍的风险降低了51％（P <0.01），而终末期肾脏疾病（透析或移植）或死亡的合并终点的风险降低了51％（P <0.01）。卡波滕治疗导致头3个月尿蛋白排泄减少30％（P <0.05），在整个试验过程中一直保持这种状态。卡波滕组的血压控制效果比安慰剂组好一些，但是卡波滕对肾功能的影响要大于单独降低血压组的预期结果。 Capoten在该患者人群中耐受良好。在两项多中心，双盲，安慰剂对照研究中，将235名血压正常，胰岛素依赖型糖尿病，视网膜病变和微量白蛋白尿（20-200 µg / min）的患者随机分配至安慰剂或卡波坦（50 mg bid），然后随访长达2年。在两项研究中，卡波滕均延迟了向明显的肾病（蛋白尿≥500 mg /天）的进展（风险降低67％至76％； P <0.05）。卡波滕还降低了白蛋白排泄率。然而，降低从微量白蛋白尿发展为蛋白尿的长期临床益处尚未确立。

在大鼠和猫中进行的研究表明，Capoten不会在任何重大程度上越过血脑屏障。

卡波滕的适应症和用法

高血压： Capoten（卡托普利片，USP）适用于治疗高血压。

在使用Capoten时，应考虑中性粒细胞减少症/粒细胞缺乏症的风险（请参阅警告）。

卡波滕可以用作肾功能正常的患者的初始治疗，这些患者的风险相对较低。对于肾功能受损的患者，尤其是那些患有胶原蛋白血管疾病的患者，应将卡托普利用于那些对其他药物产生不可接受的副作用或对药物组合没有满意的反应的高血压患者。

卡波滕单独或与其他降压药（尤其是噻嗪类利尿剂）联合使用时均有效。卡托普利和噻嗪类的降血压作用近似可加。

心力衰竭： Capoten通常用于利尿药和洋地黄的充血性心力衰竭治疗。卡托普利对心力衰竭的有益作用不需要洋地黄的存在，但是，卡托普利的大多数受控临床试验经验是接受洋地黄以及利尿剂治疗的患者。

心肌梗塞后左心室功能不全： Capoten适用于临床稳定的左心室功能不全患者，其射血分数≤40％，可改善心肌梗塞后的生存率，并减少明显的心力衰竭的发生率以及随后因充血性心力衰竭而住院治疗耐心。

糖尿病肾病： Capoten适用于I型胰岛素依赖型糖尿病和视网膜病患者的糖尿病肾病（蛋白尿> 500 mg /天）的治疗。卡波滕降低了肾功能不全的进展速度和严重的不良临床结局（死亡或需要进行肾移植或透析）。

在考虑使用Capoten时，应该注意的是，在对照试验中，ACEI抑制剂对血压的影响在黑人患者中比在非黑人患者中少。此外，ACE抑制剂（有足够的数据可用）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：头颈部血管性水肿和肠道血管性水肿）。

禁忌症

对本产品或任何其他血管紧张素转化酶抑制剂过敏的患者（例如，在使用任何其他ACE抑制剂治疗期间经历血管性水肿的患者）禁忌服用Capoten。

警告事项

过敏反应和可能相关的反应

据推测，由于血管紧张素转换酶抑制剂会影响类花生酸和多肽（包括内源性缓激肽）的代谢，因此接受ACE抑制剂（包括Capoten）的患者可能会遭受各种不良反应，其中一些反应很严重。

头颈部血管性水肿：在包括卡托普利在内的ACE抑制剂治疗的患者中发现了涉及四肢，面部，嘴唇，粘膜，舌头，声门或喉部的血管性水肿。如果血管性水肿累及舌头，声门或喉部，则可能发生气道阻塞并致命。应立即采取紧急治疗措施，包括但不限于皮下注射1：1000肾上腺素溶液。

止于卡托普利后，肿胀仅限于面部，口腔，嘴唇和四肢的粘膜肿胀。有些病例需要药物治疗。 （请参阅预防措施：有关患者和不良反应的信息。 ）

肠血管性水肿：据报道，接受ACE抑制剂治疗的患者存在肠血管性水肿。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：两名接受膜状动脉膜炎减毒治疗并同时接受ACE抑制剂治疗的患者持续危及生命。在同一例患者中，当暂时停用ACE抑制剂时可避免这些反应，但在无意间再次攻击时会再次出现。

膜暴露过程中的类过敏反应：据报道，在高通量膜透析并同时使用ACE抑制剂治疗的患者中出现类过敏反应。低密度脂蛋白单采与硫酸右旋糖酐吸收的患者也有过敏样反应的报道。

中性粒细胞减少/粒细胞缺乏症

卡托普利的使用导致中性粒细胞减少（<1000 / mm3）伴有髓样增生。大约一半的中性粒细胞减少症患者出现全身性或口腔感染或粒细胞缺乏症候群的其他特征。

中性粒细胞减少症的风险取决于患者的临床状况：

在具有正常肾功能（血清肌酐低于1.6 mg / dL，无胶原血管疾病）的高血压患者的临床试验中，在超过8,600例暴露的患者中发现中性粒细胞减少。

在某些程度的肾衰竭（血清肌酐至少为1.6 mg / dL）但没有胶原血管疾病的患者中，临床试验中中性粒细胞减少的风险约为每500人1例，其频率是单纯性高血压的15倍以上。这些患者的卡托普利的每日剂量相对较高，尤其是考虑到他们的肾功能减弱。在国外针对肾衰竭患者的营销经验中，将别嘌醇与卡托普利同时使用已与中性粒细胞减少有关，但这种关联在美国报道中并未出现。

在患有胶原蛋白血管疾病（例如系统性红斑狼疮，硬皮病）和肾功能受损的患者中，临床试验中3.7％的患者发生中性粒细胞减少。

在正式的心力衰竭临床试验中，超过750名患者中没有一个发生中性粒细胞减少症，但在随后的临床经验中却发生了中性粒细胞减少症。报告的病例中约有一半的血清肌酐≥1.6mg / dL，并且超过75％的患者也在接受普鲁卡因胺治疗。在心力衰竭中，似乎存在相同的中性粒细胞减少症危险因素。

通常在卡托普利启动后三个月内发现中性粒细胞减少症。中性粒细胞减少症患者的骨髓检查始终显示出髓质发育不全，经常伴有红系发育不全和巨核细胞数量减少（例如，发育不良的骨髓和全血细胞减少症）；有时会出现贫血和血小板减少症。

通常，停用卡托普利后约两周，中性粒细胞恢复正常，严重感染仅限于临床复杂的患者。约13％的中性粒细胞减少症死亡已经死亡，但几乎所有死亡都是在患有严重疾病，患有胶原蛋白血管疾病，肾功能衰竭，心力衰竭或免疫抑制剂治疗或这些复杂因素的综合症的患者中。

对高血压或心力衰竭患者的评估应始终包括对肾功能的评估。

如果将卡托普利用于肾功能不全的患者，则应在开始治疗前以约两周的间隔（约三个月）评估白细胞和差异计数，然后定期进行评估。

对于患有胶原蛋白血管疾病的患者或暴露于已知会影响白细胞或免疫反应的其他药物的患者，尤其是在肾功能受损的患者中，应在评估获益和风险后谨慎使用卡托普利。

应该告知所有接受卡托普利治疗的患者报告任何感染迹象（例如，喉咙痛，发烧）。如果怀疑感染，应立即进行白细胞计数。

由于卡托普利和其他药物的停用通常会导致白色计数迅速恢复正常，因此在确认中性粒细胞减少（中性粒细胞计数<1000 / mm 3 ）后，医生应撤出卡托普利并密切注意患者的病情。

蛋白尿

在接受卡托普利的患者中，每天约有1％的尿蛋白总量大于1 g。大约90％的患病患者有先前肾脏疾病的证据或接受了相对较高剂量的卡托普利（超过150毫克/天），或两者都有。大约五分之一的蛋白尿患者发生肾病综合征。在大多数情况下，无论卡托普利是否持续使用，蛋白尿均会在六个月内消退或清除。蛋白尿患者很少改变肾功能参数，例如BUN和肌酐。

低血压

在高血压患者中很少见到过低的血压，但这是卡托普利在盐/容量不足的人群（例如用利尿剂治疗的患者），心力衰竭患者或接受肾透析的患者中使用的可能结果。 （请参阅预防措施：药物相互作用。 ）

在心力衰竭中，血压为正常或低，大约一半的患者记录到平均血压短暂下降超过20％。这种短暂性低血压很可能在前几剂中的任何一种之后发生，并且通常被很好地耐受，既没有症状也没有短暂的轻度头晕，尽管在极少数情况下，它与心律不齐或传导缺陷有关。低血压是3.6％的心力衰竭患者停药的原因。

由于这些患者的血压可能下降，因此应在非常严格的医疗监督下开始进行治疗。起始剂量为6.25或12.5 mg tid可能会使降压作用最小化。在治疗的前两周以及卡托普利和/或利尿剂的剂量增加时，应密切随访患者。对于患有心力衰竭的患者，如果可行，减少利尿剂的剂量可最大程度地降低血压下降。

低血压本身并不是停用卡托普利的原因。在心力衰竭开始服用卡波汀（卡托普利片，USP）治疗后，全身血压的一些降低是常见且理想的观察结果。在治疗过程的早期，减少的幅度最大。这种效果在一两个星期内稳定下来，并且通常会在两个月内恢复到治疗前的水平，而不会降低治疗效果。

胎儿/新生儿发病率和死亡率

向孕妇服用时，ACEI抑制剂可导致胎儿和新生儿发病及死亡。世界文献中已经报道了数十起病例。当检测到怀孕时，应尽快停用ACE抑制剂。

妊娠中期和中期使用ACE抑制剂与胎儿和新生儿损伤有关，包括低血压，新生儿颅骨发育不全，无尿，可逆性或不可逆性肾衰竭和死亡。羊水过少也有报道，可能是由于胎儿肾功能下降引起的。羊水过少与胎儿肢体挛缩，颅面变形和肺发育不良有关。尽管尚不清楚这些事件是否是由于ACE抑制剂的暴露，但早产，子宫内发育迟缓和动脉导管未闭也有报道。

这些不良反应似乎不是由于宫内ACE抑制剂暴露所致，而宫内ACE抑制剂的暴露仅限于孕早期。应当仅告知其胚胎和胎儿仅在妊娠前三个月才接触ACE抑制剂的母亲。但是，当患者怀孕时，医生应尽一切努力尽快停止使用卡托普利。

很少（可能少于每千次怀孕一次），没有找到ACE抑制剂的替代品。在这些罕见的情况下，应告知母亲其胎儿的潜在危害，并应进行连续超声检查以评估羊膜内环境。

如果发现羊水过少，除非认为卡托普利可以挽救母亲的生命，否则应停用卡托普利。根据怀孕的一周，可以进行收缩压力测试（CST），非压力测试（NST）或生物物理轮廓（BPP）。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。

有子宫内暴露于ACE抑制剂史的婴儿应密切观察其低血压，少尿和高钾血症。如果发生少尿，应注意支持血压和肾灌注。可能需要进行交换输血或透析，以逆转低血压和/或替代功能紊乱的肾功能。尽管卡托普利可通过血液透析从成人循环系统中清除，但有关血液透析从新生儿或儿童循环系统中清除血液透析的有效性的数据不足。腹膜透析对去除卡托普利无效。没有关于从全身循环中去除卡托普利的交换输血的信息。

当卡托普利以最大推荐人剂量的约0.8到70倍（以mg / kg为基础）给予兔子时，发现颅面部畸形的发生率较低。在怀孕大鼠和仓鼠的研究中未观察到卡托普利的致畸作用。以mg / kg为基础，所用剂量最高为建议最大人类剂量的150倍（仓鼠）和625倍（大鼠）。

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和（有时）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。

预防措施

一般

肾功能受损

高血压-一些患有肾脏疾病的患者，尤其是那些患有严重肾动脉狭窄的患者，在用卡托普利降低血压后，BUN和血清肌酐升高。可能需要降低卡托普利的剂量和/或停用利尿剂。对于其中一些患者，可能无法使血压正常化并维持足够的肾脏灌注。

心力衰竭-长期用卡托普利治疗后，约有20％的患者BUN稳定升高，血清肌酐比正常或基线高20％以上。少于5％的患者（通常患有严重的既往有肾脏疾病的患者）由于肌酐的逐渐增加而需要中止治疗；随后的改善可能取决于潜在的肾脏疾病的严重程度。

参见临床药理学，剂量和管理，不良反应：改变的实验室检查结果。

高钾血症：在一些使用ACE抑制剂（包括卡托普利）治疗的患者中，血钾升高。当使用ACE抑制剂治疗时，有发生高钾血症风险的患者包括：肾功能不全；糖尿病以及那些同时使用保钾利尿剂，补钾剂或含钾盐替代品的人；在I型糖尿病蛋白尿患者的试验中，使用氯吡格雷或其他与血清钾增加相关的药物时，停用卡托普利治疗高钾血症的发生率为2％（4/207）。在两项降血压的I型糖尿病微蛋白尿患者的试验中，无卡托普利组受试者发生高钾血症（0/116）。 （请参阅预防措施：有关患者和药物相互作用的信息；不良反应：更改的实验室发现。）

咳嗽：据推测由于抑制内源性缓激肽的降解，所有ACE抑制剂均出现持续的非生产性咳嗽，在治疗中断后始终可以缓解。在咳嗽的鉴别诊断中应考虑ACE抑制剂引起的咳嗽。

瓣膜狭窄：从理论上讲，主动脉瓣狭窄的患者在接受血管扩张药治疗时可能特别有降低冠状动脉血流灌注的风险，因为它们的后负荷减少不如其他人那么多。

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，卡托普利将阻断继发性肾素释放后血管紧张素II的形成。如果发生低血压并且被认为是由于这种机制引起的，则可以通过体积扩张予以纠正。

血液透析

最近的临床观察表明，接受ACE抑制剂的患者在血液透析过程中的超敏反应（类过敏反应）与高通量透析膜（例如AN69）相关。在这些患者中，应考虑使用不同类型的透析膜或不同种类的药物。 （请参阅警告：膜暴露期间的类过敏反应。）

给患者的信息

建议患者立即向医师报告任何提示血管水肿的体征或症状（例如，面部，眼睛，嘴唇，舌头，喉头和四肢肿胀；吞咽或呼吸困难；声音嘶哑），并停止治疗。 （请参阅警告：头颈部血管性水肿和肠道血管性水肿。 ）

应告知患者及时报告任何感染迹象（例如，喉咙痛，发烧），这可能是嗜中性白血球减少症或进行性水肿的迹象，可能与蛋白尿和肾病综合征有关。

所有患者均应注意，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；建议患者咨询医师。

不建议患者在未咨询医生的情况下不要使用保钾利尿剂，补钾剂或含钾盐替代品。 （请参阅预防措施：一般和药物相互作用；不良反应。 ）

除非医生指示，否则应警告患者不要中断或终止用药。

应注意使用卡托普利治疗的心力衰竭患者，避免身体活动迅速增加。

应告知患者饭前一小时服用卡波滕（参见剂量和用法）。

怀孕：应告知育龄女性患者孕中期和孕晚期接触ACE抑制剂的后果，还应告知她们这些后果似乎并非因宫内ACE抑制剂暴露受限所致到头三个月应要求这些患者尽快向医生报告怀孕情况。

药物相互作用

非甾体类抗炎药，包括选择性环氧合酶– 2种抑制剂（COX-2抑制剂）

对于年老，体量减少（包括利尿剂治疗）或肾功能不全的患者，将NSAIDs（包括选择性COX-2抑制剂）与ACE抑制剂（包括卡托普利）并用可能会导致肾功能恶化包括可能的急性肾衰竭。这些影响通常是可逆的。定期监测接受卡托普利和非甾体抗炎药治疗的患者的肾功能。非甾体抗炎药可能会削弱包括卡托普利在内的ACE抑制剂的降压作用

低血压—利尿剂治疗的患者：利尿剂的患者，特别是最近开始使用利尿剂治疗的患者，以及饮食中严格限制食盐或透析的患者，通常在接受降压药后的第一小时内可能会突然血压急剧下降。卡托普利的初始剂量。

卡托普利降压作用的可能性可以通过在开始用卡波滕（卡托普利片，USP）治疗或开始小剂量（6.25或12.5毫克）治疗前约一周停用利尿剂或增加盐摄入量来最小化。或者，在初始剂量后至少一小时提供医疗监督。如果发生低血压，应将患者仰卧，必要时可静脉输注生理盐水。这种短暂的降压反应不是进一步剂量的禁忌症，一旦在体积膨胀后血压升高，就可以毫无困难地给予更多剂量。

Agents Having Vasodilator Activity : Data on the effect of concomitant use of other vasodilators in patients receiving Capoten for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting Capoten. If resumed during Capoten therapy, such agents should be administered cautiously, and perhaps at lower dosage.

Agents Causing Renin Release : Captopril's effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (eg, thiazides) may activate the renin-angiotensin-aldosterone system.

Agents Affecting Sympathetic Activity : The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving captopril alone or with diuretics. Therefore, agents affecting sympathetic activity (eg, ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to captopril, but the overall response is less than additive.

Agents Increasing Serum Potassium : Since captopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution.

Lithium : Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.

Cardiac Glycosides: In a study of young healthy male subjects no evidence ofa direct pharmacokinetic captopril-digoxin interaction could be found.

Loop Diuretics : Furosemide administered concurrently with captopril does not alter the pharmacokinetics of captopril in renally impaired hypertensive patients.

Allopurinol: In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when captopril and allopurinol were administered concomitantly for 6 days.

Drug and/or Laboratory Test Interactions

Captopril may cause a false-positive urine test for acetone.

致癌，致突变和生育力受损

Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to show any evidence of carcinogenic potential. The high dose in these studies is 150 times the maximum recommended human dose of 450 mg, assuming a 50-kg subject. On a body-surface-area basis, the high doses for mice and rats are 13 and 26 times the maximum recommended human dose, respectively.

Studies in rats have revealed no impairment of fertility.

Animal Toxicology

Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels.

Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a 50 kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum recommended dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration.

Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis).

Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on surface-area basis) for only 5 to 7 days.

In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing.

Pregnancy Categories C (first trimester) and D (second and third trimesters) See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

护理母亲

Concentrations of captopril in human milk are approximately one percent of those in maternal blood. Because of the potential for serious adverse reactions in nursing infants from captopril, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of Capoten to the mother. (See PRECAUTIONS: Pediatric Use .)

Pediatric Use

儿科患者的安全性和有效性尚未确定。 There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults.

Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported.

Capoten should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.

Adverse Reactions

Reported incidences are based on clinical trials involving approximately 7000 patients.

Renal : About one of 100 patients developed proteinuria (see WARNINGS ).

Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency.

Hematologic : Neutropenia/agranulocytosis has occurred (see WARNINGS ). Cases of anemia, thrombocytopenia, and pancytopenia have been reported.

Dermatologic : Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.

Flushing or pallor has been reported in 2 to 5 of 1000 patients.

Cardiovascular : Hypotension may occur; see WARNINGS and PRECAUTIONS [Drug Interactions] for discussion of hypotension with captopril therapy.

Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients.

Angina pectoris, myocardial infarction, Raynaud's syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients.

Dysgeusia : Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste.

Angioedema : Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction. (See WARNINGS: Head and Neck Angioedema, Intestinal Angioedema and PRECAUTIONS: Information for Patients. )

Cough: Cough has been reported in 0.5–2% of patients treated with captopril in clinical trials (see PRECAUTIONS: General, Cough).

The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias.

Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.

Body as a whole : Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible related reactions and PRECAUTIONS: Hemodialysis ).

General: Asthenia, gynecomastia .

Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope .

Dermatologic : Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis.

Gastrointestinal : Pancreatitis, glossitis, dyspepsia.

Hematologic : Anemia, including aplastic and hemolytic.

Hepatobiliary : Jaundice, hepatitis, including rare cases of necrosis, cholestasis.

Metabolic : Symptomatic hyponatremia.

Musculoskeletal : Myalgia, myasthenia.

Nervous/Psychiatric : Ataxia, confusion, depression, nervousness, somnolence.

Respiratory : Bronchospasm, eosinophilic pneumonitis, rhinitis.

Special Senses : Blurred vision.

Urogenital : Impotence.

As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR.

Fetal/Neonatal Morbidity and Mortality

See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Altered Laboratory findings

Serum Electrolytes: Hyperkalemia: small increases in serum potassium,especially in patients with renal impairment (see PRECAUTIONS ).

Hyponatremia : particularly in patients receiving a low sodium diet or concomitant diuretics.

BUN/Serum Creatinine : Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine.

Hematologic : A positive ANA has been reported.

Liver Function Tests : Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred.

Overdosage

Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure.

While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril from the general circulation.

Capoten Dosage and Administration

Capoten should be taken one hour before meals. Dosage must be individualized.

Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient's previous antihypertensive drug regimen for one week before starting Capoten.

The initial dose of Capoten (captopril tablets, USP) is 25 mg bid or tid If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg bid or tid Concomitant sodium restriction may be beneficial when Capoten is used alone.

The dose of Capoten in hypertension usually does not exceed 50 mg tid Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (eg, hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one- to two-week intervals until its highest usual antihypertensive dose is reached.

If Capoten is being started in a patient already receiving a diuretic, Capoten therapy should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension), with dosage and titration of Capoten as noted above.

If further blood pressure reduction is required, the dose of Capoten may be increased to 100 mg bid or tid and then, if necessary, to 150 mg bid or tid (while continuing the diuretic). The usual dose range is 25 to 150 mg bid or tid A maximum daily dose of 450 mg Capoten should not be exceeded.

For patients with severe hypertension (eg, accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and Capoten dosage promptly initiated at 25 mg bid or tid, under close medical supervision.

When necessitated by the patient's clinical condition, the daily dose of Capoten may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of Capoten is reached. In this regimen, addition of a more potent diuretic, eg, furosemide, may also be indicated.

Beta-blockers may also be used in conjunction with Capoten therapy (see PRECAUTIONS: Drug Interactions ), but the effects of the two drugs are less than additive.

Heart Failure: Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg tid may minimize the magnitude or duration of the hypotensive effect (see WARNINGS: Hypotension ); for these patients, titration to the usual daily dosage can then occur within the next several days.

For most patients the usual initial daily dosage is 25 mg tid After a dose of 50 mg tid is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg tid A maximum daily dose of 450 mg of Capoten should not be exceeded.

Capoten should generally be used in conjunction with a diuretic and digitalis.

Capoten therapy must be initiated under very close medical supervision.

Left Ventricular Dysfunction After Myocardial Infarction: The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg tid

Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, Capoten therapy should be initiated at 12.5 mg tid Capoten should then be increased to 25 mg tid during the next several days and to a target dose of 50 mg tid over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY ).

Capoten may be used in patients treated with other post-myocardial infarction therapies, eg, thrombolytics, aspirin, beta blockers.

Diabetic Nephropathy: The recommended dose of Capoten for long term use to treat diabetic nephropathy is 25 mg tid

Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with Capoten if additional therapy is required to further lower blood pressure.

Dosage Adjustment in Renal Impairment: Because Capoten is excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses.

Accordingly, for patients with significant renal impairment, initial daily dosage of Capoten should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (eg, furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment. (See WARNINGS: Anaphylactoid reactions during membrane exposure and PRECAUTIONS: Hemodialysis. )