莱克塞尔

Lexxel说明

Lexxel（马来酸依那普利-非洛地平ER）是一种组合产品，由马来酸依那普利的外层围绕缓释非洛地平制剂的核心片剂组成。

马来酸依那普利是依那普利的马来酸盐，依那普利是长效血管紧张素转化酶抑制剂依那普利拉的乙酯。马来酸依那普利被化学描述为（S）-1- [N- [1-（乙氧基羰基）-3-苯基丙基] -L-丙氨酰基] -L-脯氨酸，（Z）-2-丁烯二酸盐（1：1）。其经验公式为C 20 H 28 N 2 O 5 •C 4 H 4 O 4 ，其结构式为：

马来酸依那普利是白色至类白色结晶性粉末，分子量为492.53。微溶于水，溶于乙醇，易溶于甲醇。

非洛地平是一种钙通道阻滞剂，是一种二氢吡啶衍生物，在化学上被描述为4-（2,3-二氯苯基）-1,4-二氢-2,6-二甲基-3,5-吡啶二甲酸±乙基甲基酯。其经验公式为C 18 H 19 C l2 NO 4 ，其结构公式为：

非洛地平是一种略带黄色的结晶性粉末，分子量为384.26。它不溶于水，可自由溶于二氯甲烷和乙醇。非洛地平是一种外消旋混合物。然而，S-非洛地平是具有更高生物活性的对映异构体。

Lexxel可以口服使用，片剂中含有5 mg马来酸依那普利和5 mg非洛地平作为缓释制剂。

非活性成分包括：没食子酸丙酯，聚氧乙烯40氢化蓖麻油，纤维素化合物，乳糖，硅酸铝，硬脂富马酸钠，巴西棕榈蜡和黑色氧化铁。片剂上印有合成的黑色氧化铁墨水，其中包含SD-45中的药用釉，正丁醇，丙二醇，异丙醇，氢氧化铵和甲醇。

Lexxel-临床药理学

作用机理

Lexxel的两个成分具有互补的降压作用。依那普利是一种前药。口服后，它通过将乙酯水解为依那普利拉而被生物激活，依那普利拉是一种活性血管紧张素转化酶（ACE）抑制剂。依那普利拉抑制人和动物中的血管紧张素转化酶。 ACE是一种肽基二肽酶，可催化血管紧张素I转化为血管收缩物质血管紧张素II。血管紧张素II还刺激肾上腺皮质的醛固酮分泌。依那普利对高血压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。

抑制ACE会导致血浆血管紧张素II降低，从而导致血管升压活性降低和醛固酮分泌降低。尽管后者的减少很小，但导致血清钾的增加很少。在仅接受马来酸依那普利治疗长达48周的高血压患者中，观察到血清钾平均升高约0.2 mEq / L。在接受马来酸依那普利联合噻嗪类利尿剂治疗的患者中，血清钾基本没有变化。 （请参阅注意事项。）去除血管紧张素II对肾素分泌的负面反馈会导致血浆肾素活性增加。

ACE与激肽酶相同，激肽酶可降解缓激肽。缓激肽（一种有效的血管压迫肽）的水平升高是否在马来酸依那普利的治疗作用中发挥作用尚待阐明。

虽然依那普利降低血压的机制被认为主要是抑制肾素-血管紧张素-醛固酮系统，但依那普利即使在低肾素高血压患者中也具有降压作用。尽管在所有研究的种族中，依那普利均具有降压作用，但黑人高血压患者（通常为低肾素高血压人群）对依那普利单一疗法的平均反应较非黑人患者小。

非洛地平是一种二氢吡啶类钙离子通道阻滞剂，可通过影响血管平滑肌和培养的兔心房细胞中依赖电压的L通道来减少Ca ++的流入，并阻断钾诱导的大鼠门静脉挛缩。

药理研究表明，非洛地平对收缩过程的作用是选择性的，对血管平滑肌的作用大于对心肌的作用。可以在体外检测到负性肌力作用，但在完整的动物中尚未见到这种作用。

非洛地平产生的血管舒张作用的后果包括心率的适度，短暂的反射增加。在几种动物和人类中都观察到了轻度的利尿作用，但是非洛地平对周围血管阻力的作用可以解释为大多数作用。

药代动力学与代谢

依那普利和非洛地平作为缓释制剂的同时给药对这两种化合物的生物利用度几乎没有影响。 Lexxel对依那普利的吸收速率和吸收程度与VASOTEC1（马来酸依那普利）中的依那普利吸收率无明显差异。尚未直接将Lexxel中非洛地平的吸收速率和吸收程度与PLENDIL2（非洛地平）中非洛地平的缓释制剂进行比较。

口服Lexxel后，依那普利的峰值浓度在约一小时内出现。依那普利被水解成依那普利，这是一种比依那普利更有效的血管紧张素转化酶抑制剂。口服Lexxel约三小时后，出现依那普利拉峰的最高血清浓度。基于尿液恢复，依那普利的吸收程度约为60％。

非洛地平异构体的峰值浓度通常在服用Lexxel后3-6小时见到。口服后，非洛地平几乎被完全吸收，并经历大量的首过代谢。非洛地平ER的全身生物利用度约为20％。

当Lexxel与食物一起食用（基本餐点为650 kcal或更高）时，其成分的某些药代动力学会发生变化。尽管非洛地平的AUC （0-48 hr）不变，但其异构体的峰浓度几乎翻了一番，谷浓度约减了一半。依那普利的生物利用度（通过依那普利拉的总尿回收率来衡量）略有降低。与其他二氢吡啶类钙通道阻滞剂相比，与水或橙汁相比，与葡萄汁一起服用时，非洛地平的生物利用度增加。

年轻健康受试者中非洛地平的全身血浆清除率约为0.8 L / min，表观分布体积为10 L / kg。约99％的非洛地平与血浆蛋白结合。

在人体内施用14 C标记的静脉内或即释非洛地平口服液后，尿液中回收了约70％的放射性，粪便中回收了约10％的放射性。在尿液和粪便中回收到的微不足道的完整非洛地平（<0.5％）。已经鉴定出六种代谢物，它们占口服剂量的23％。没有一个具有明显的血管舒张活性。口服施用速释制剂后，非洛地平的血浆水平呈指数倍下降，平均终末半衰期为11至16小时。

依那普利拉和依那普利的排泄主要是肾脏。大约94％的剂量以依那普利拉或依那普利从尿液和粪便中回收。尿液中的主要成分是依那普利拉，约占剂量的40％，而依那普利则完整。除依那普利拉外，没有任何依那普利代谢产物的证据。依那普利拉的血清浓度曲线显示出延长的终末期，显然代表已与ACE结合的一小部分给药剂量。结合的量不随剂量增加，表明结合的饱和位点。多次服用马来酸依那普利后，依那普利累积的有效半衰期为11小时。

肾功能不全患者的依那普利和依那普利拉的治疗与肾功能正常的患者相似，直到肾小球滤过率降低至30 mL / min或更低。肾小球滤过率≤30 mL / min时，依那普利拉峰和谷水平增加，到达峰浓度的时间增加，到达稳态的时间可能延迟。在此肾功能不全水平下，多次服用马来酸依那普利后，依那普利拉的有效半衰期得以延长。依那普利拉可以62 mL / min的速度透析。

单次服用并处于稳定状态后，非洛地平的血浆浓度随年龄增长而增加。老年高血压患者（平均年龄74岁）中非洛地平的平均清除率仅为年轻志愿者（平均年龄26岁）中非洛地平的平均清除率的45％。在稳定状态下，年轻患者的平均AUC是老年人的39％。中等年龄段的数据表明，AUC介于年轻人和老年人之间。

在患有肝病的患者中，非洛地平的清除率降低至正常年轻志愿者所见者的60％。

血脑屏障和血胎盘屏障-动物研究表明，非洛地平穿过血脑屏障。非洛地平的血浆与大脑浓度之比约为20：1。非洛地平穿过胎盘。非洛地平的胎儿血浆水平与孕妇血浆水平相似。对狗的研究表明，依那普利很难穿过血脑屏障，即使有的话。依那普利拉不能进入大脑。大鼠多剂量马来酸依那普利不会导致任何组织中的积累。哺乳期大鼠的乳汁在服用14 C马来酸依那普利后具有放射性。在给怀孕的仓鼠服用标记药物后，发现放射性穿过胎盘。

1个

Biovail Laboratories Incorporated的注册商标。

2

阿斯利康集团的商标

药效学

严重程度从轻到重的高血压患者服用马来酸依那普利可使平卧位和站立时血压均降低，通常无立位成分。单独使用依那普利的患者很少有症状性体位性低血压，尽管在容量减少的患者中可能会出现这种情况。 （请参阅警告。）在大多数接受研究的患者中，口服单剂量的依那普利后，一小时即可出现抗高血压活性，并在4至6小时内达到血压峰值降低。在推荐剂量下，降压作用已维持至少24小时。在某些患者中，作用可能会在给药间隔结束时减弱。

在大多数患者中，要达到最佳的血压降低可能需要数周的治疗。依那普利的抗高血压作用在长期治疗期间一直持续。依那普利的突然停药并未与血压的快速升高相关。在针对原发性高血压患者的血液动力学研究中，血压降低伴随着外周动脉阻力的降低，心输出量增加，心率变化很小或没有变化。服用马来酸依那普利后，肾血流量增加；肾小球滤过率通常不变。肾血管性高血压患者的作用似乎相似。

在临床药理学研究中，将吲哚美辛或舒林酸给予接受依那普利的高血压患者。在这项研究中，没有证据表明依那普利的降压作用减弱。 （请参阅预防措施，药物相互作用。）

非洛地平对血压的影响主要是剂量相关的外周血管阻力降低的结果。向高血压患者服用非洛地平ER后的血压反应与非洛地平的剂量和血浆浓度相关。血压降低通常在2到5个小时内发生。在长期给药期间，基本的血压控制持续24小时，而舒张压的谷值下降约为峰值下降值的40-50％。在治疗的第一周内，心率反射常增加。随着时间的推移，这种增加会减弱。在长期服药期间，心率每分钟可增加5-10次。这种增加受到β受体阻滞剂的抑制。

非洛地平对心脏传导（PR，PQ和HV间隔）无明显影响。在没有左室功能障碍临床证据的高血压患者的临床试验中，未发现提示负性肌力作用的症状。但是，在这个人群中没有人期望。

在为期8周的固定剂量平行分组双盲研究中，将707例高血压患者随机分为依那普利（0、5或20 mg）和缓释非洛地平（0，2.5， 5或10毫克），均每天服用一次。每种非安慰剂组合在降低高峰期（给药后3至5小时）和谷底（给药后24小时）时的坐姿收缩压和舒张压显着优于安慰剂。依那普利和非洛地平对这种作用有加成作用，因此每种活性-活性组合均比其任何一种成分单一疗法有效。在高峰期看到的大多数药物作用仍然存在于谷底。相对于单一疗法，联合疗法的疗效不受种族，性别或年龄的影响。

在长期服用Lexxel的过程中，通常在一到两周后血压可以最大程度地降低。 Lexxel的抗高血压作用在慢性治疗期间至少持续了一年。

Lexxel的适应症和用法

Lexxel适用于治疗高血压。

这种固定的联合用药未用于高血压的初始治疗。 （请参阅剂量和管理。）

在使用Lexxel时，应考虑以下事实：另一种血管紧张素转化酶抑制剂卡托普利引起粒细胞缺乏症，特别是在肾功能不全或胶原血管疾病患者中，可用数据不足以表明依那普利（Lexxel的成分） ）没有类似的风险。 （请参阅警告，中性粒细胞减少/粒细胞缺乏症。）

在考虑使用Lexxel时，应该指出，据报道接受ACE抑制剂的黑人患者与非黑人相比，血管性水肿的发生率更高。 （请参阅警告，血管性水肿。）

禁忌症

对本产品任何成分过敏的患者禁用Lexxel。由于依那普利成分的原因，Lexxel在既往有与先前使用血管紧张素转化酶抑制剂治疗相关的血管性水肿病史的患者以及遗传性或特发性血管性水肿患者中禁用。

警告事项

过敏反应和可能相关的反应-可能是由于血管紧张素转换酶抑制剂影响类花生酸和多肽（包括内源缓激肽）的代谢，接受ACE抑制剂（包括Lexxel）的患者可能会发生多种不良反应，其中一些反应很严重。

血管性水肿：据报道，接受血管紧张素转化酶抑制剂（包括依那普利）治疗的患者面部，四肢，嘴唇，舌头，声门和/或喉部血管性水肿。这可能在治疗期间的任何时间发生。在这种情况下，应立即停用Lexxel，并应提供适当的治疗和监测，直到完全和持续解决体征和症状。在某些情况下，肿胀仅限于脸部和嘴唇，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。与喉头水肿相关的血管性水肿可能是致命的。如果舌，声门或喉部受累，可能导致气道阻塞，应及时采取适当的治疗措施，例如皮下肾上腺素溶液1：1000（0.3 mL至0.5 mL）和/或确保通气的必要措施提供。 （请参阅不良反应。）

具有与ACE抑制剂治疗无关的血管性水肿病史的患者在接受ACE抑制剂时可能会增加血管性水肿的风险（另请参见适应症，用法和禁忌症）。

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，但在无意中再次出现时会再次出现。

膜暴露过程中的类过敏反应：据报道，在用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。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-Lexxel有时会导致症状性低血压。

在单纯接受依那普利治疗的无并发症高血压患者中，过度低血压很少见。处于低血压风险的患者，有时与少尿和/或进行性氮质血症相关，很少有急性肾衰竭和/或死亡，包括以下情况或特征的患者：心力衰竭，低钠血症，高剂量利尿剂治疗，近期密集利尿或任何病因的利尿剂量增加，肾透析或严重的体液和/或盐耗增加。对于能够耐受这种调整的高血压低危患者，在开始使用依那普利马来酸盐治疗之前，建议先利尿剂消除（心力衰竭患者除外），谨慎地减少利尿剂剂量或增加食盐摄入量。 （请参阅预防措施，药物相互作用和不良反应。）对于有过度低血压风险的患者，应在非常严格的医学监督下开始治疗，并且应在治疗的前2周以及每次使用依那普利和/或剂量时密切随访这些患者。或利尿剂增加。对于患有缺血性心脏病或脑血管疾病的患者，可能会考虑类似的考虑，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。

如果发生过度的低血压，应将患者仰卧，并在必要时接受生理盐水的静脉输注。短暂的降压反应并不是马来酸依那普利进一步剂量的禁忌症，一旦血压稳定，通常可以毫无困难地给予马来酸依那普利。如果出现症状性低血压，可能需要降低依那普利或利尿剂的剂量或停用。

像其他钙通道阻滞剂一样，非洛地平可能偶尔引起明显的低血压，很少发生晕厥。它可能导致反射性心动过速，在易感人群中可能会诱发心绞痛。 （请参阅不良反应。）

中性粒细胞减少症/粒细胞缺乏症—另一种血管紧张素转化酶抑制剂卡托普利已显示出粒细胞缺乏症和骨髓抑制，在简单的患者中很少见，但在肾功能不全的患者中更常见，尤其是如果他们也患有胶原蛋白血管疾病。依那普利的临床试验数据不足以表明依那普利不会以相似的速率引起粒细胞缺乏症。市场经验表明，中性粒细胞减少或粒细胞缺乏症的病例不能排除与依那普利的因果关系。应该考虑对胶原血管疾病和肾脏疾病患者进行白细胞计数的定期监测。

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。

胎儿/新生儿发病率和死亡率— ACE抑制剂对孕妇的使用可导致胎儿和新生儿发病率和死亡。世界文献中已经报道了数十起病例。当发现怀孕时，应尽快停用Lexxel。

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。在这种情况下羊水过少与胎儿肢体挛缩，颅面变形和肺发育不良有关。早产，子宫内发育迟缓和动脉导管未闭也有报道，尽管尚不清楚这些事件是否是由于ACE抑制剂暴露引起的。

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Lexxel。

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，除非认为它可以挽救母亲的生命，否则应停止使用Lexxel。取决于怀孕一周，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。作为逆转低血压和/或替代功能紊乱的肾功能的手段，可能需要进行换血或透析。穿过胎盘的依那普利已通过腹膜透析从新生儿循环系统中移除，具有一定的临床意义，尽管在后一种方法上没有经验，但理论上可以通过换血法移除。

在妊娠大鼠和兔子的研究中未观察到依那普利的致畸作用。以人体表面积为基础，所用剂量分别是最大推荐人类每日剂量（MRHDD）的57倍和12倍。

在服用依那普利和非洛地平联合用药的大鼠（依那普利[E] = 1.9-非洛地平[F] = 2.5 mg / kg /天），观察到肾盂/输尿管扩张的胎儿发生率增加。但是，在断奶后代中没有这种作用的证据。在E = 23，F = 30 mg / kg /天或更高剂量的小鼠中，子宫内早期和晚期死亡的发生率均增加。除了第一代后代的体重增加短暂且轻微下降外，后代在性成熟，行为发展，生育力或生殖力方面均无不利影响。

给予怀孕小鼠（依那普利20.8，非洛地平27 mg / kg /天）和大鼠（依那普利= 17.3，非洛地平= 22.5 mg / kg /天）的依那普利-非洛地平产生的依那普利/依那普利拉的血浆水平（C max和AUC值）在人用剂量下，非洛地平的血药浓度比人（非怀孕）的血脂浓度高76至418倍，非洛地平的血浆水平比人的预期血脂水平高151至433倍。

预防措施

一般：

主动脉瓣狭窄/肥厚型心肌病-与所有血管扩张剂一样，依那普利对左心室流出道梗阻的患者应谨慎使用。

肾功能受损-由于抑制了肾素-血管紧张素-醛固酮系统，在接受依那普利治疗的易感人群中，肾功能可能会发生变化。在严重心力衰竭的患者中，其肾功能可能取决于肾素-血管紧张素-醛固酮系统的活性，使用血管紧张素转化酶抑制剂（包括依那普利）治疗可能与少尿和/或进行性氮质血症有关，很少发生急性肾衰竭和/或死亡。

在针对患有单侧或双侧肾动脉狭窄的高血压患者的临床研究中，在接受依那普利治疗的患者中，有20％的患者血尿素氮和血清肌酐升高。停用依那普利和/或利尿剂治疗后，这些增加几乎总是可逆的。在此类患者中，应在治疗的最初几周内监测肾功能。

一些接受依那普利治疗的高血压或心力衰竭患者，没有明显的既往存在的肾血管疾病，血液中尿素和血肌酐的升高，通常是轻微和短暂的，尤其是当依那普利与利尿剂同时使用时。既往有肾功能不全的患者更容易发生这种情况。可能需要减少依那普利的剂量或停用利尿剂。

对高血压患者的评估应始终包括对肾功能的评估。

高血钾症-在仅接受依那普利治疗的临床试验中，约有1％的高血压患者血钾升高（大于5.7 mEq / L）。在大多数情况下，这些是孤立的值，尽管继续治疗仍然可以解决。高钾血症是0.28％高血压患者中止治疗的原因。在心力衰竭的临床试验中，在3.8％的患者中观察到高钾血症，但这并不是停药的原因。

高钾血症发生的危险因素包括肾功能不全，糖尿病和同时使用保钾利尿剂，钾补充剂和/或含钾盐替代品，如果使用依那普利，应谨慎使用。 （请参阅药物相互作用。）

老年患者或肝功能受损的患者— 65岁以上的患者或肝功能受损的患者的非洛地平血浆浓度可能升高。 （请参阅剂量和管理。）

咳嗽—据推测是由于抑制内源性缓激肽的降解，据报道所有ACE抑制剂均会持续产生非生产性咳嗽，并在停药后始终缓解。诊断咳嗽时应考虑ACE抑制剂引起的咳嗽。

手术/麻醉-在进行大手术或在麻醉过程中使用会产生低血压的药物的患者，依那普利可能会在代偿性肾素释放后阻断血管紧张素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。

周围性水肿—在非洛地平临床试验中，最常见的不良事件是周围性水肿，通常为轻度且与全身性液体retention留无关。周围水肿的发生率与剂量和年龄有关。这种不良事件通常在治疗开始后的2-3周内发生。

给患者的信息

应指导患者整顿Lexxel，不要分开，压碎或咀嚼药片。

如果出现以下任何情况，应建议所有患者咨询医生：

血管性水肿—用血管紧张素转化酶抑制剂（包括依那普利）治疗期间的任何时候都可能发生血管性水肿，包括喉头水肿。应该这样建议患者，并告知患者应立即报告任何提示血管性水肿的症状或体征（面部，四肢，眼睛，嘴唇，舌头，吞咽或呼吸困难），并且不要再服用药物，直到他们与处方医生协商。

低血压-应特别提醒患者在治疗的头几天要头晕。如果发生实际晕厥，应告知患者停用Lexxel，直到他们与开药医生协商为止。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。

高钾血症—应告知患者不要在未咨询医生的情况下使用含钾盐替代品。

中性粒细胞减少症-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妊娠中，晚期妊娠接触ACE抑制剂的后果，还应告知这些后果似乎并非因宫内ACE抑制剂暴露受限而导致到头三个月应要求这些患者尽快向医生报告怀孕情况。

牙龈增生—应告知患者已报告了轻度的牙龈增生（牙龈肿胀）。良好的牙齿卫生可降低其发生率和严重性。

注意：与许多其他药物一样，向使用Lexxel治疗的患者提供某些建议是必要的。该信息旨在帮助安全有效地使用该药物。这不是所有可能的不利影响或预期影响的披露。

药物相互作用

低血压-利尿剂治疗的患者：利尿剂的患者，尤其是最近开始使用利尿剂治疗的患者，在开始使用依那普利治疗后可能偶尔会出现血压过度降低的情况。在开始使用依那普利治疗之前，可通过停用利尿剂或增加盐的摄入量来最大程度地降低依那普利产生降压作用的可能性。如果有必要继续使用利尿剂，则在初始剂量后至少两个小时，直到血压稳定至少一个小时，再提供密切的医疗监督。 （请参阅警告和用法用量。）

Agents Causing Renin Release — The antihypertensive effect of enalapril is augmented by antihypertensive agents that cause renin release (eg, diuretics).

Non-steroidal Anti-inflammatory Agents — In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the coadministration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.

In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving VASOTEC (enalapril maleate). In this study there was no evidence of a blunting of the antihypertensive action of VASOTEC (enalapril maleate). However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Agents Increasing Serum Potassium — Enalapril attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.

Lithium — Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.

CYP3A4 Inhibitors —Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or due to a decrease in metabolism. These increases in concentration may lead to increased effects, (lower blood pressure and increased heart rate). These effects have been observed with co-administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be taken. The following specific interactions have been reported:

Itraconazole —Co-administration of another extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the C max , and 2-fold prolongation in the half-life of felodipine.

Erythromycin —Co-administration of felodipine (PLENDIL) with erythromycin resulted in approximately 2.5-fold increase in the AUC and C max , and about 2-fold prolongation in the half-life of felodipine.

Grapefruit juice —Co-administration of felodipine with grapefruit juice resulted in more than 2-fold increase in the AUC and C max , but no prolongation in the half-life of felodipine.

Cimetidine —Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the C max , of felodipine.

Beta-Blocking Agents — Enalapril has been used concomitantly with beta adrenergic-blocking agents without evidence of clinically significant adverse interactions.

A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and C max of metoprolol, however, were increased approximately 31% and 38%, respectively. In controlled clinical trials, however, beta blockers including metoprolol were concurrently administered with felodipine and were well tolerated.

Digoxin — Enalapril has been used concomitantly with digoxin without evidence of clinically significant adverse interactions.

When given concomitantly with felodipine ER, the pharmacokinetics of digoxin in patients with heart failure were not significantly altered.

Anticonvulsants — In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, phenytoin, carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients.

Tacrolimus — Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, the tacrolimus blood concentration should be followed and the tacrolimus dose may need to be adjusted.

Other Concomitant Therapy — In healthy subjects, there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone.

Enalapril has been used concomitantly with methyldopa, nitrates, hydralazine, and prazosin without evidence of clinically significant adverse interactions.

致癌，诱变，生育力受损

No long-term carcinogenicity tests have been performed with the combination. Enalapril-felodipine was not mutagenic with or without metabolic activation in vitro in the Ames microbial mutation assay, the V-79 mammalian cell forward mutation assay, the alkaline elution assay with rat hepatocytes or the CHO mammalian cell cytogenetics assay. An in vivo mouse bone marrow cytogenetics assay was also negative.

In rats given enalapril-felodipine, there was no effect on fertility in males at doses up to 6.9/9 mg/kg/day, and in females at doses up to 17.3/22.5 mg/kg/day.

There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.

Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli , sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.

There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).

In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61 times3 the maximum recommended human dose on a mg/m 2 basis), a dose-related increase in the incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61 times3 the maximum recommended human dose on a mg/m 2 basis). Felodipine, at the doses employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly secondary to these hormonal effects which have not been observed in man.

In this same rat study, a dose-related increase in the incidence of focal squamous cell hyperplasia, compared to control, was observed in the esophageal groove of male and female rats in all dose groups. No other drug-related esophageal or gastric pathology was observed in the rats or with chronic administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to the esophageal groove.

Felodipine was not carcinogenic when fed to mice at doses of up to 138.6 mg/kg/day (61 times3 the maximum recommended human dose on a mg/m 2 basis) for periods of up to 80 weeks in males and 99 weeks in females.

Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times3 the maximum recommended human dose on a mg/m 2 basis) or in vitro in a human lymphocyte chromosome aberration assay.

A fertility study in which male and female rats were administered doses of 3.8, 9.6, or 26.9 mg/kg/day (up to 24 times3 the maximum recommended human dose on a mg/m 2 basis) showed no significant effect of felodipine on reproductive performance.

3

Based on patient weight of 50 kg

怀孕

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

Teratogenic Effects – Studies in pregnant rabbits administered doses of felodipine 0.46, 1.2, 2.3, and 4.6 mg/kg/day (from 0.8 to 8 times3 the maximum recommended human dose on a mg/m 2 basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose-related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not observed in rats given felodipine.

In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.

Nonteratogenic Effects – A prolongation of parturition with difficult labor and an increased frequency of fetal and early postnatal deaths were observed in rats administered felodipine doses of 9.6 mg/kg/day (8 times3 the maximum human dose on a mg/m 2 basis) and above.

Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m 2 basis). This effect occurred only in pregnant rabbits and regressed during lactation. Similar changes in the mammary glands were not observed in rats or monkeys.

There are no adequate and well-controlled studies with felodipine in pregnant women. If felodipine is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery, and on the mammary glands of pregnant females.

护理母亲

Enalapril and enalaprilat are detected in human breast milk. It is not known whether felodipine administered as monotherapy is secreted in human milk; studies of the combination of enalapril and felodipine in rats indicate that felodipine concentrates in milk to a level almost ten-fold that found in plasma.

Because of the potential for serious adverse reactions from enalapril and felodipine in the infant, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Therefore, caution should be exercised when Lexxel is given to a nursing mother.

儿科用

儿科患者的安全性和有效性尚未确定。

老人用

Clinical studies of Lexxel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.其他报告的临床经验尚未发现老年患者和年轻患者在反应方面的差异。 Elderly patients may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION for information on the individual components of Lexxel).

已知该药物基本上被肾脏排泄，并且在肾功能受损的患者中对该药物产生毒性反应的风险可能更大。 Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function (see CLINICAL PHARMACOLOGY).

不良反应

In a factorial study, combinations of enalapril at doses of 0, 5, and 20 mg and felodipine ER at doses of 0, 2.5, 5, and 10 mg were evaluated for safety in more than 700 patients with hypertension. In addition more than 500 patients received various combinations of enalapril (5 or 10 mg) and felodipine ER (2.5, 5, or 10 mg) with or without hydrochlorothiazide (12.5 mg) in an open-labeled study up to 52 weeks (mean 33 weeks). Adverse events were similar to those described with the individual components.

In general, treatment with enalapril maleate-felodipine ER was well tolerated and adverse events were mild and transient in nature. In the placebo-controlled, double-blind trial, discontinuation of therapy due to adverse events considered related (possibly, probably or definitely) occurred in 2.8% vs 1.3% of patients treated with the combination or placebo, respectively. The most frequently observed clinical adverse events considered related to treatment with the combination were headache, edema or swelling, and dizziness.

Clinical adverse events considered related (possibly, probably, or definitely) to treatment with enalapril-felodipine ER that occurred with an incidence of 1% or greater with the combination during the placebo-controlled, double-blind trial are compared to individual components and placebo in the table below:

Other clinical adverse events considered related (possibly, probably, or definitely) to treatment with enalapril-felodipine ER that occurred with an incidence of less than 1% in the placebo-controlled, double-blind trial are listed below. These events are listed in order of decreasing frequency within each category. Body as a Whole : Syncope, facial edema, orthostatic effects, chest pain; Cardiovascular : Palpitation, hypotension, bradycardia, premature ventricular contraction, increased blood pressure; Digestive : Dry mouth, constipation, dyspepsia, flatulence, acid regurgitation, vomiting, diarrhea, nausea, anal/rectal pain; Metabolic : Gout; Musculoskeletal : Neck pain, joint swelling; Nervous/Psychiatric : Insomnia, nervousness, somnolence, ataxia, agitation, paresthesia, tremor; Respiratory : Dyspnea, respiratory congestion, pharyngeal discomfort, dry throat; Skin : Rash, angioedema, pruritus, alopecia, dry skin; Special Senses : Increased intraocular pressure; Urogenital : Impotence, hot flashes.

Other infrequently reported adverse events were seen in clinical trials with enalapril-felodipine ER (causal relationship unknown). These included: Body as a Whole : Abdominal pain, fever; Digestive : Dental pain; Metabolic : Increased ALT and AST, hyperglycemia; Musculoskeletal : Back pain, myalgia, foot pain, knee pain, shoulder pain, tendinitis; Respiratory : Upper respiratory infection, sinusitis, pharyngitis, bronchitis, nasal congestion, influenza, sinus disorder; Special Senses : Conjunctivitis; Urogenital : Proteinuria, pyuria, urinary tract infection.

马来酸依那普利

Other adverse events that have been reported with enalapril, without regard to causality, are listed (in decreasing severity) below:

Angioedema — Angioedema has been reported in patients receiving enalapril maleate, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with Lexxel should be discontinued and appropriate therapy instituted immediately. (See WARNINGS.)

Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions); Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension), orthostatic hypotension, pulmonary embolism and infarction, pulmonary edema, rhythm disturbances including atrial tachycardia and bradycardia, atrial fibrillation, angina pectoris; Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, glossitis, stomatitis; Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression; Musculoskeletal: Muscle cramps; Nervous/Psychiatric: Depression, confusion, peripheral neuropathy (eg paresthesia, dysesthesia), vertigo; Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, pneumonia, pulmonary infiltrates, eosinophilic pneumonitis; Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, diaphoresis, photosensitivity; Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, dry eyes, tearing; Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS), flank pain, gynecomastia; Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity rash and other dermatologic manifestations; Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Felodipine as an Extended-Release Formulation

Other adverse events that have been reported with felodipine ER, without regard to causality, are listed (in decreasing severity) below:

Body as a Whole: Flu-like illness; Cardiovascular: Myocardial infarction, angina pectoris, arrhythmia, tachycardia, premature beats; Digestive: Gingival hyperplasia; Endocrine: Gynecomastia; Hematologic: Anemia; Musculoskeletal: Arthralgia, leg pain, muscle cramps, arm pain, hip pain; Nervous/Psychiatric: Depression, anxiety disorders, irritability, decreased libido; Respiratory: Upper respiratory infection, rhinorrhea, sneezing, pharyngitis, influenza, epistaxis, respiratory infection; Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis; Special Senses: Visual disturbances; Urogenital: Urinary frequency, urinary urgency, dysuria, polyuria.

实验室测试结果

In controlled clinical trials with enalapril-felodipine ER, clinically important changes in standard laboratory parameters associated with administration of Lexxel were rare. No changes peculiar to the combination treatment were observed.

Serum Electrolytes — See PRECAUTIONS.

Creatinine — Minor reversible increases in serum creatinine were observed in patients treated with Lexxel. Increases in creatinine are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see PRECAUTIONS).

Other — Minor reversible increases or decreases in serum potassium were infrequently observed in patients treated with Lexxel; rarely were these measurements outside the normal range.

过量

Limited data are available in regard to enalapril overdosage in humans. In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on admission to hospital; he subsequently recovered without significant sequelae.

Human overdoses with any combination of enalapril and felodipine ER have not been reported.

Single oral doses of enalapril above 1000 mg/kg and ≥1775 mg/kg were associated with lethality in mice and rats, respectively. Oral doses of felodipine at 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and 2250 mg/kg in male and female rats, respectively, caused significant lethality.

In interaction studies on the acute oral toxicity of the combination in mice, pretreatment with felodipine (50 mg/kg) for one hour led to an increase in mortality at doses of enalapril maleate that exceeded 1000 mg/kg. Significant lethality with felodipine was not increased by pretreatment of mice for one hour with 100 mg/kg of enalapril maleate.

Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians' Desk Reference (PDR) . In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

The most likely effect of overdose with Lexxel is vasodilation, with consequent hypotension and tachycardia. Repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required.

Enalaprilat may be removed from general circulation by hemodialysis at a rate of 62 mL/min and has been removed from neonatal circulation by peritoneal dialysis. (See WARNINGS, Anaphylactoid reactions during membrane exposure.) It has not been

注意：本文档包含有关依那普利/非洛地平的副作用信息。此页面上列出的某些剂型可能不适用于Lexxel品牌。

适用于依那普利/非洛地平：口服片剂延长释放

一般

通常，与该组合药物相关的副作用类似于与每种成分相关的副作用。似乎没有联合药物特有的副作用。副作用通常是轻度和短暂的。 ^[参考]

神经系统

神经系统的副作用包括3％至7％（比安慰剂少）的头痛，约3％的头晕和约3％的患者的乏力/疲劳。据报道，在不到1％的患者中，有抑郁症，睡眠问题（失眠或失眠），共济失调，意识模糊，周围神经病变，味觉改变，耳鸣，流泪，弱视，眼睛刺激，视网膜病和眩晕。 ^[参考]

心血管的

心血管副作用可能与任何一种成分有关，包括3％的水肿或肿胀和0.5％至1.6％的胸痛（与可疑药物的关系）。钙通道阻滞很少会导致心动过缓，房室传导阻滞（一级，二级甚至三级房室传导阻滞），心力衰竭和低血压。与依那普利或非洛地平相关的过度低血压很少导致心绞痛，心肌梗塞或中风。心pit的报道很少。 ^[参考]

与使用ACE抑制剂相关的血管性水肿可能是变态反应的征兆，并且可能是终止使用该药物或任何其他ACE抑制剂治疗的指征。涉及面部，喉部或颈部的血管性水肿绝对是治疗的禁忌症。黑人的血管性水肿的发生率似乎比非黑人患者高。 ^[参考]

呼吸道

大约3％的患者出现包括咳嗽在内的呼吸道副作用。很少有鼻塞，咽炎，肺浸润和支气管炎的报道。 ^[参考]

新陈代谢

较不常见的代谢问题（与非洛地平有关）包括高血糖，高尿酸血症（伴有痛风的罕见病例），低钾血症和肌酸激酶升高。 ^[参考]

代谢副作用与依那普利有关。通过抑制血管紧张素II介导的醛固酮分泌，ACEI抑制剂可引起轻度高钾血症，特别是在肾功能不全的患者中。 ^[参考]

肾的

ACE抑制剂与包括新的或恶化的肾功能不全在内的肾脏副作用有关。高危患者包括心力衰竭，肾功能不全和肾动脉狭窄的患者。 ^[参考]

过敏症

据报道，至少有一名服用依那普利三年未发生任何事件的患者，迟发了依那普利引起的血管性水肿（超过三个月）。肠道血管性水肿患者通常会出现腹痛（有或没有恶心或呕吐），在某些情况下，既无面部血管性水肿病史，C-1酯酶水平也正常。停止使用ACE抑制剂后，这些症状会缓解。 ^[参考]

与其他一些血管紧张素转化酶（ACE）抑制剂一样，对依那普利的超敏反应可能会危及生命。接受ACE抑制剂的患者很少有面部，四肢，嘴唇，舌头，声门和/或咽部血管性水肿的报道。依那普利引起的阻塞性喉和舌状血管性水肿很少见，但可能致命。另外，已经报道了用ACE抑制剂治疗的患者的肠血管性水肿。建议任何呼吸困难，吞咽困难或明显的面部血管性水肿的患者立即停止治疗，并通常避免使用ACE抑制剂治疗。不推荐将Enalapril用于有特发性血管水肿病史的患者。

与依那普利有关的其他超敏反应包括0.1％的光敏反应或0.3％的荨麻疹。还报告了一例过敏性紫癜。 ^[参考]

皮肤科

皮肤病副作用通常较轻。据报道有2％的患者出现皮疹。单独使用以下一种或两种药物，很少有以下副作用：脱发，发汗，多形性红斑，剥脱性皮炎，天疱疮，光敏性，瘙痒，史蒂文斯-约翰逊综合征，中毒性表皮坏死症和荨麻疹。对ACE抑制剂的超敏反应可表现为血管性水肿和严重皮疹。 ^[参考]

胃肠道

据报道，多达2％的患者患有胃肠道问题，例如恶心和腹泻。在对照试验中，这些副作用在安慰剂治疗的患者中普遍存在。 ^[参考]

依那普利或非洛地平的使用与罕见的便秘，厌食，口干，消化不良，舌炎，胆汁淤积性黄疸/肝炎，胰腺炎，肠梗阻，口腔炎，呕吐，牙龈增生（与某些钙通道阻滞剂有关）有关。 。 ^[参考]

肌肉骨骼

据报道，多达1％的患者出现肌肉骨骼不适。 ^[参考]

血液学

血液学副作用很少见，对于服用ACE抑制剂的罕见粒细胞缺乏症患者，血液副作用也很明显。在临床试验中，只有不到0.1％的患者因贫血而中止治疗。血小板减少症也鲜有报道。 ^[参考]

服用依那普利的患者，尤其是G6PD缺乏症的患者，罕见溶血性贫血。 ^[参考]

免疫学的

依那普利的使用几乎没有免疫学上的副作用。该复合物可包括阳性ANA，升高的红细胞沉降率，关节痛/关节炎，肌痛/肌炎，发烧，浆膜炎，血管炎，白细胞增多，嗜酸性粒细胞增多，光敏性，皮疹和其他皮肤病学表现。 ^[参考]

泌尿生殖

男性患者中包括阳including在内的泌尿生殖系统疾病极少发生。 ^[参考]

肝的

与使用ACE抑制剂相关的肝副作用包括一种罕见的综合征，其始于胆汁淤积性黄疸，然后发展为暴发性肝坏死和（有时）死亡。专家建议，如果出现黄疸或肝血清酶明显升高，应停止使用该药治疗。 ^[参考]

某些副作用可能没有报道。您可以将其报告给FDA。