【临床应用】
1.用于高血压。本药作为一线用药，可单独或与其它降压药联合应用。
2.心律失常。用于纠正快速室上性心律失常、室性心律失常，特别是与循环儿茶酚胺水平增高或心脏对儿茶酚胺的敏感性增高有关的心律失常，如运动、情绪紧张、焦虑、心肌梗死早期、洋地黄中毒等引起的心律失常。
3.用于心绞痛、心肌梗死。
4.用于甲状腺功能亢进。
5.用于嗜铬细胞瘤。
6.用于梗阻性肥厚型心肌病，可减轻心悸、晕厥等症状。
7.近年来尚用于心力衰竭的治疗。研究表明，与洋地黄、利尿药和血管紧张素转换酶抑制剂等药物合理联合应用，对提高生存率和降低病死率有一定疗效，但应谨慎使用，从低剂量开始。

【药理】
1.药效学 本药为选择性β1-肾上腺素受体阻断药，膜稳定作用较弱，无内在拟交感活性，脂溶性中等。较大剂量时心脏选择性逐渐消失，对血管及支气管平滑肌的β2受体也有作用。
抗高血压的机制目前尚未完全阐明，可能通过以下几个方面发挥降压作用：(1)阻断心脏β1受体，降低心排血量。(2)抑制肾素释放，降低血浆肾素浓度。(3)阻断中枢β受体，降低外周交感神经活性。(4)减少去甲肾上腺素释放以及促进前列环素生成。
本药能阻止儿茶酚胺对窦房结、心房起搏点及浦肯野纤维4期自发除极，从而降低自律性。还能通过增加K+外流、抑制Na+内流而发挥膜稳定作用，减慢房室结及浦肯野纤维的传导速度，因而临床可用于治疗心律失常。
本药通过阻滞β受体，使心肌收缩力下降、收缩速度减慢；并通过减慢传导速度，使心脏对运动或应激的反应减弱，从而降低心肌氧耗、增加患者的运动耐量，有效治疗心绞痛。
本药能拮抗儿茶酚胺的效应，也用于治疗嗜铬细胞瘤及甲状腺功能亢进。甲亢的许多症状是由β肾上腺素受体活性过高引起，应用本药后，甲亢症状可得到控制，甲状腺激素的分泌并不减少，但外周组织中甲状腺素(T4)、三碘甲状腺原氨酸(T3)的转变减少，β1和β2受体的活动均处于抑制状态。
2.药动学 口服吸收迅速完全，吸收率大于95%，生物利用度约50%。口服1.5小时血药浓度达峰值，最大作用时间为1-2小时。血压的降低与血药浓度不平行，而心率的减慢则与血药浓度呈直线关系。本药吸收后迅速进入细胞外组织，能透过血-脑脊液屏障及胎盘屏障。在肝脏广泛代谢，其代谢呈基因多态型。蛋白结合率低(约12%)。半衰期为3-7小时，肾功能不全时半衰期无明显改变。主要以代谢物形式经肾随尿液排出，原形不足5%。能少量分泌入乳汁。本药不能经透析清除。
缓释片峰浓度明显降低，达峰时间延长，谷峰浓度波动减小。口服1-2小时达有效血药浓度，3-4日后达稳态，生物利用度为普通片的96%。

【注意事项】
1.禁忌症 (1)对本药过敏者。(2)心源性休克。(3)急性或难治性心力衰竭。(4)严重窦性心动过缓。(5)Ⅱ-Ⅲ度房室传导阻滞。(6)末梢循环灌注不良。(7)严重的周围血管疾病。(8)急性心肌梗死患者出现以下任何一项时禁用：心率低于45次、PR间期大于或等于0.24秒、收缩压低于13.33kPa(100mmHg)、中至重度心力衰竭(国外资料)。
2.慎用 (1)对本药有过敏史者。(2)充血性心力衰竭。(3)Ⅰ度房室传导阻滞。(4)糖尿病。(5)肺气肿或非过敏性支气管炎。(6)肝、肾功能减退。(7)甲状腺功能低下。(8)雷诺综合征或其它周围血管疾病。(9)麻醉或手术患者(国外资料)。
3.药物对儿童的影响 安全性和有效性尚未明确。
4.药物对老人的影响 老年人对本药代谢与排泄能力低，应适当调整剂量。
5.药物对妊娠的影响 本药可通过胎盘进入胎儿体内，有报道妊娠高血压患者用后可致宫内胎儿发育迟缓，分娩时无力造成难产。新生儿可出现低血压、低血糖、呼吸抑制及心率减慢。尽管也有报告对母亲及胎儿均无影响，但必须慎用，不宜作为在妊娠过程中治疗高血压的首选药物，只在其它药物无效或无其它药物可供选择时才使用。美国药品和食品管理局(FDA)对本药的妊娠安全性分级为C级。
6.药物对哺乳的影响 本药可少量分泌入乳汁，哺乳期妇女慎用。
7.药物对检验值或诊断的影响 (1)可使血尿素氮、肌酸酐、钾、脂蛋白、三酰甘油、尿酸等增高。(2)可使血糖降低，但糖尿病患者可能出现血糖增高。(3)肾功能不全时，代谢产物可蓄积血中，使血清胆红素的重氮反应测试出现假阳性。
8.用药前后及用药时应当检查或监测 用药期间应定期检查血常规、血压、心肝肾功能。糖尿病患者应定期检查血糖。

【不良反应】
患者对本药常能较好耐受，多数不良反应与受体阻滞有关，理论上讲选择性β1受体抑制所致不良反应较轻。
1.中枢神经系统 因本药具脂溶性而较易透入中枢神经系统，故该系统不良反应较多见，特别是在治疗初期，继续服药可减少或消失。常见中枢神经系统不良反应为疲乏和眩晕，其次是抑郁，其它还可引起头痛、失眠或多梦。
2.心血管系统 可见气短和心动过缓，还可出现肢端发冷、雷诺现象，少见心力衰竭。
3.消化系统 可见腹泻、轻微上腹部不适，少见恶心、胃痛、便秘。
4.其它 还可引起肺内哮鸣、皮肤瘙痒、腹膜后腔纤维变性、耳聋、眼痛等。
[国外不良反应参考]
1.心血管系统 可引起充血性心力衰竭、心悸、外周水肿、低血压、晕厥。也可出现气短和心动过缓。静脉给药更容易出现低血压、心动过缓、各种房室传导阻滞、心力衰竭。也可引起血管神经性水肿。无症状外周动脉病患者使用本药偶可诱发间歇性跛行。心绞痛患者突然停用β-肾上腺素受体阻断药可能引起心绞痛发作频率和严重性显著增加，甚至导致严重的心血管事件，如心肌梗死、心律失常或猝死。高血压患者突然停药也可出现高血压反跳。
2.精神神经系统 可引起疲乏、眩晕。其它还可引起头痛、梦魇、失眠、嗜睡、意识混浊、短期记忆丧失、幻觉、感觉异常、抑郁。长期给药可引起腕管综合征。
3.代谢/内分泌系统 (1)对血糖调节的影响：选择性β1-肾上腺素受体阻断药较少影响糖尿病患者的血糖、胰岛素或胰高血糖素。(2)对脂肪代谢的影响：心脏选择性或有内在拟交感活性的β-肾上腺素受体阻断药对血脂代谢的影响较小。但也有报道，可使血脂正常患者出现明显的总胆固醇、三酰甘油、低密度脂蛋白水平升高。而血脂代谢紊乱患者的总胆固醇、三酰甘油无明显改变，但可使高密度脂蛋白水平显著降低。(3)可轻度升高血钾，但体内总钾量不变。
4.消化系统 可引起口干、恶心、胃痛、胃肠胀气、腹泻、便秘、烧心感。也有引起肝炎的报道，停药后可恢复。罕见腹膜后纤维性变。
5.泌尿生殖系统 可引起阳萎。
6.呼吸系统 可引起支气管痉挛、喘鸣、呼吸困难。大剂量时心脏选择性消失，更易出现上述不良反应。其它β-肾上腺素受体阻断药还可引起哮喘、鼻炎、鼻窦炎、咽炎等。
7.眼 可引起眼痛、眼干、视物模糊等眼部不适等。
8.皮肤 可引起瘙痒、皮疹、指甲松离。可使银屑病加重。罕见脱发，为可逆性。其它β-肾上腺素受体阻断药还可引起出汗、湿疹、痤疮、皮肤刺激、面色潮红、剥脱性皮炎等。
9.肌肉骨骼系统 可引起关节痛，常累及膝关节和肩关节，也可累及多个关节。

【药物相互作用】
•药物-药物相互作用
1.与单胺氧化酶抑制药合用，可致极度低血压，应禁止合用。
2.奎尼丁可使本药的清除下降，导致心动过缓、疲乏、气短等。如必须合用，应密切监测心功能，必要时调整两者的用量。
3.普罗帕酮可增加本药浓度，引起卧位血压明显降低。如必须合用，应仔细监测心功能，特别是血压，必要时调整本药用量。
4.与胺碘酮合用，可出现明显的心动过缓和窦性停搏。
5.与二氢吡啶类钙通道阻滞药合用治疗心绞痛或高血压有效，但也可引起严重的低血压或心力储备降低。合用时应仔细监测心功能，尤其是左室功能受损、心律失常或主动脉瓣狭窄的患者。
6.地尔硫卓可增强β-肾上腺素受体阻断药的药理作用，对心功能正常的患者有利。但合用后也有引起低血压、左室衰竭和房室传导阻滞的报道。如合用应密切监测患者的心脏功能，尤其是老年、左室衰竭、主动脉瓣狭窄及两种药物的用量都较大时。
7.维拉帕米与本药均有直接的负性肌力和负性传导作用，可能引起低血压、心动过缓、充血性心力衰竭和传导障碍。在左室功能不全、主动脉瓣狭窄或两药用量均大时危险性增加。两药合用时，应密切监测心功能。
8.与咪贝地尔合用可引起低血压、心动过缓或心力储备降低。在开始β-肾上腺素受体阻断药治疗前应停用咪贝地尔7-14日。如必须合用，应监测心功能，特别是老年、左室功能下降、心脏传导功能下降或主动脉瓣狭窄的患者。
9.肼屈嗪可增加本药的生物利用度，空腹服药时易发生，而对本药缓释制剂无影响。如需合用，应在进食时服用，或换用缓释制剂。
10.与苯乙肼合用，可引起心率下降。如需合用应仔细监测。
11.与利舍平合用，两者作用相加，β受体阻滞作用增强，可能出现心动过缓及低血压。
12.与右丙氧芬合用，可增加低血压和心动过缓的危险。合用时应注意监测。
13.与奥洛福林合用，可引起低血压或高血压伴心动过缓。合用时应密切监测患者的血压和心率。
14.芬太尼麻醉时，使用本药可引起严重的低血压。
15.西咪替丁可增加本药的血药浓度。合用时应密切监测心功能，必要时应调整剂量。
16.环丙沙星可增加本药的浓度，导致低血压和心动过缓。合用应监测血压和心功能。
17.苯海拉明、帕罗西汀、羟氯喹等可改变本药的药动学，增强药效，增加不良反应发生的危险。如合用，本药应减量，并监测有无本药毒性反应症状(如心动过缓)和心脏选择性消失的征象。
18.氟西汀可引起本药的血药浓度升高，毒性增大，故应注意监测，必要时减少本药的用量。
19.利托那韦可增加本药的血药浓度及毒性反应。如合用，应减小本药的用量。
20.氟伏沙明可抑制本药代谢，导致心动过缓和(或)低血压。如合用，建议本药开始剂量宜小，小心调整剂量，并监测心率及血压。
21.安非拉酮可增加本药的血药浓度，两者合用应慎重，开始剂量宜小。
22.当归提取物可抑制本药经肝脏细胞色素P450酶的代谢，如合用，应注意监测血压。
23.虽然目前还没有苄普地尔、氟桂利嗪、利多氟嗪、加洛帕米、哌克昔林与本药发生相互作用的报道，但这些药均能减弱心肌收缩、减慢房室结传导，从而引起血压降低、心动过缓或心力储备下降，因此如必须合用，应监测心功能，特别是左室功能下降、心脏传导功能下降或主动脉瓣狭窄的患者。
24.虽然目前还没有氯丙嗪、氯普噻吨或三氟丙嗪与本药发生相互作用的报道，但吩噻嗪类药物与β-肾上腺素受体阻断药合用可相互增强作用，引起低血压和吩噻嗪中毒。合用时应监测两种药物效应，必要时减少剂量。
25.齐留通可使本药血药浓度明显升高。虽然目前没有关于齐留通与本药发生相互作用的报道，但合用时仍应当谨慎，并密切监护。
26.本药可加重α1肾上腺素受体阻滞药的首剂反应。除哌唑嗪外其它α1肾上腺素受体阻滞药虽然较少出现，但与本药合用时仍需注意。
27.本药可增加利多卡因的血药浓度。合用时应密切监测利多卡因的血药浓度，相应调整剂量。
28.与地高辛合用可导致房室传导时间延长，且本药可使地高辛血药浓度升高，合用时应仔细监测心电图和地高辛血药浓度，并相应调整剂量。
29.本药可使非去极化肌松药(如氯化筒箭毒碱、戈拉碘铵等)药效增强，作用时间延长。
30.与肾上腺素合用时，可引起高血压和心动过缓。虽然本药为心脏选择性的β-肾上腺素受体阻断药，对肾上腺素引起的加压反应较小，但仍应尽量避免合用。如合用，应仔细监测血压。
31.本药与可乐定联合治疗时，突然撤去可乐定可使高血压加重。因此要撤可乐定时，应先撤本药，密切监测血压，数天后再逐步减停可乐定。与莫索尼定合用时，如突然撤去莫索尼定也可引起高血压反跳，应予注意。
32.与甲基多巴合用时，极少数患者对内源性或外源性儿茶酚胺可出现异常的反应，如高血压、心动过速或心律失常。
33.与非甾体类抗炎药合用，可使血压升高。如合用，应监测患者的血压，相应调整本药剂量。
34.利福平、利福布汀可诱导肝脏细胞色素酶，加快本药代谢，降低疗效。如合用，应增加本药剂量。
35.苯巴比妥或戊巴比妥对肝脏微粒体酶系统有诱导作用，可降低本药的血药浓度、生物利用度和疗效。必须合用时应监测疗效，必要时调整剂量，或换用其它不依赖肝脏代谢的β-肾上腺素受体阻断药，如阿替洛尔、噻吗洛尔。
36.本药可拮抗去甲肾上腺素吸入产生的支气管扩张作用。
37.β-肾上腺素受体阻断药可拮抗利托君的作用，因此应避免本药与利托君合用。
38.本药可减弱异丙肾上腺素或恩丙茶碱的疗效。
39.阿布他明有β受体激动作用，如本药与其合用则该作用减弱。故在使用阿布他明前，本药应停用至少48小时。
40.心脏选择性β-肾上腺素受体阻断药较少引起2型糖尿病患者的葡萄糖耐量降低，但糖尿病患者在联用本药与降糖药时仍应注意。
41.麻黄含有麻黄碱和伪麻黄碱，可降低抗高血压药的疗效。使用本药治疗的高血压患者应避免使用含麻黄的制剂。
42.本药与醋硝香豆素、苯丙香豆素、普鲁卡因胺、乙酰胆碱、抗酸药、溴西泮、劳拉西泮、可莱塞兰、单硝酸异山梨酯、尼扎替丁、泮托拉唑、奥美拉唑、利扎曲坦、司维拉姆等无明显相互作用。
•药物-食物相互作用
进食可增加本药血药浓度和曲线下面积。

【给药说明】
1.本药个体差异较大，用量宜个体化。
2.大剂量时，本药的β1受体选择性逐渐消失。支气管痉挛患者需慎用，一般仅用小量，并及时加用β2受体激动药。
3.既往无心力衰竭史患者在长期使用本药期间可能出现心力衰竭征象，宜加用强心药和(或)利尿药，如心衰症状继续应停药。
4.静脉给药能快速控制心率及心肌收缩力。研究表明，在心肌梗死症状发作几小时内静脉给药效果优于口服。而心肌梗死后先静脉给药，然后改口服维持治疗比单用一种方法更好。
5.对于外科手术前应否停药尚无统一意见，β受体阻滞后心脏对反射性交感兴奋的反应降低，使全麻和手术的危险性增加，但可用多巴酚丁胺或异丙肾上腺素逆转。而停药可引起心绞痛和(或)高血压反跳，其危险性可能比手术本身产生的心脏抑制更大。
6.用于心力衰竭时，对于纽约心脏病学会(NYHA)心功能为Ⅱ、Ⅲ级、病情稳定且左室射血分数(LVEF)低于40%者，应尽早使用β-肾上腺素受体阻断药，有望降低病死率；对于NYHA心功能Ⅳ级的心力衰竭患者，需待病情稳定(4日内未静脉用药，已无液体潴留，体重稳定)后，在严格监护下方可使用β-肾上腺素受体阻断药。
7.避免突然停药。本药在撤药时，应逐渐减量以避免发生严重的心血管事件，如心肌梗死、心律失常、猝死等。体力活动是心绞痛的重要诱因，故在停药期间以及停药后2-3周应尽量限制活动量。
8.甲状腺功能亢进时应用本药，可使某些症状(如心动过速)被掩盖，疑有甲亢可能时应避免骤然停用，以免发生甲状腺危象。
9.用药过量的表现：本药过量可导致严重低血压、窦性心动过缓、房室传导阻滞、心衰、心源性休克、心脏停搏、支气管痉挛、昏迷、恶心、呕吐和紫绀。药物过量最初的临床表现会在药物摄入后20分钟至2小时出现。
10.用药过量的处理：可给予活性炭，必要时洗胃，还可采取支持疗法和对症治疗。(1)心动过缓时给予阿托品或异丙肾上腺素，必要时安置人工起搏器。(2)室性期前收缩时给予利多卡因或苯妥英钠。(3)心力衰竭时给予吸氧、洋地黄糖苷类药或利尿药。(4)低血压时输液并给予升压药。(5)抽搐时给予地西泮或苯妥英钠。(6)支气管痉挛时给予异丙肾上腺素。
11.本药注射液浓度为1mg/ml，最大剂量可用至40mg，可加入1000ml下列注射液中静脉滴注：0.9%氯化钠、10%葡萄糖、5%葡萄糖、林格注射液、林格-葡萄糖液和乙酸化林格液。注射液稀释后应在12小时内使用。本药不应加入右旋糖酐70血浆代用品中滴注。经静脉给药时应仔细监测患者的血压和心电图，并备有复苏抢救设施。

【用法与用量】
成人
•常规剂量
•口服给药
1.高血压：一般用量为一次25-50mg，一日2-3次；或一次100mg，一日2次。在血流动力学稳定后立即使用。治疗高血压时，一次100-200mg、一日2次的疗效与使用阿替洛尔一次100mg、一日1次的疗效相当。
2.心律失常、肥厚型心肌病、甲状腺功能亢进：一般用量为一次25-50mg，一日2-3次；或一次100mg，一日2次。
3.急性心肌梗死：主张在早期(即最初的几小时内)使用。因为早期使用，在未能溶栓的患者中可减小梗死范围、降低短期(15日)死亡率(此作用在用药后24小时即出现)；在已经溶栓的患者中可降低再梗死与再缺血发生率，若在2小时内用药还可以降低死亡率。一般用法为：可先静脉注射本药一次2.5-5mg(2分钟内)，每5分钟1次，共3次(10-15mg)；15分钟之后开始口服，一次25-50mg，每6-12小时1次，共24-48小时；然后口服一次50-100mg，一日2次。心肌梗死后若无禁忌症应长期服用，已经证实长期服用可以降低心性死亡率(包括猝死)，一般为一次50-100mg，一日2次。
4.心绞痛：一般用量为一次25-50mg，一日2-3次；或一次100mg，一日2次。不稳定性心绞痛也主张早期使用，用法与用量可参照"急性心肌梗死"。
5.心力衰竭：应在使用洋地黄和(或)利尿药等抗心衰治疗的基础上使用本药。起初一次6.25mg，一日2-3次，以后视临床情况每数日至1周增加6.25-12.5mg，一日2-3次，可用至一次50-100mg，一日2次。最大剂量不应超过一日300-400mg。
•静脉注射
1.室上性快速型心律失常：开始时以1-2mg/min的速度静脉注射，用量可达5mg(5ml)；如病情需要，可间隔5分钟重复注射，总剂量为10-15mg。静脉注射后4-6小时，心律失常已经控制，改用口服制剂维持，一次剂量不超过50mg，一日2-3次。
2.预防和治疗已确诊或可疑急性心肌梗死患者的心肌缺血、快速性心律失常和胸痛：参见"急性心肌梗死"的口服给药项。
[国外用法用量参考]
成人
•常规剂量
•口服给药
1.心绞痛：(1)起始剂量为一日100mg，分2次服(缓释片为一日1次)，进餐时或餐后立即服用。常用剂量为一日100-400mg。剂量必须个体化，以1周为间隔逐渐加量直至达到最佳控制或出现心率减慢。随着剂量增加，本药的β1受体选择性逐渐消失。(2)不稳定型心绞痛及无ST段升高的心肌梗死，应先静脉给药，然后改口服维持治疗。静脉给药的具体用法与用量参见静脉给药项。对于可耐受15mg静脉剂量的患者，在最后一次注射后15分钟开始口服本药，一次25-50mg，每6小时1次，共用48小时。然后给予维持剂量一次100mg，一日2次。(3)从速释剂转为缓释剂时，缓释剂开始剂量与速释剂总量相同，以后再逐渐调整以达到个体化剂量。
2.心律失常：常用剂量尚不明确。
3.充血性心力衰竭：治疗充血性心力衰竭的常用剂量范围尚不明确。研究表明，除常规治疗外，本药控释(缓释)剂对稳定的慢性心力衰竭患者有效。起始剂量为一次12.5mg或25mg，一日1次，心功能Ⅲ-Ⅳ级患者的起始剂量宜小。如患者能够耐受，则每1-2周将剂量加倍，直至达到目标剂量一次150-200mg，一日1次。
4.高血压：起始剂量为一日50-100mg，1次或分次口服(缓释片为一日1次)，进餐时或餐后立即服用。常用剂量为一日100-450mg。剂量必须个体化，以1周为间隔逐渐加量直至达到理想的血压控制或出现心率明显减慢。随着剂量增加，本药的β1受体选择性逐渐消失。每日1次服用可维持降压作用24小时，但服用较小剂量时，可能在24小时的后期不能满意降压，故需加量或增加服药次数。
5.心肌梗死：心肌梗死后先静脉给药，然后改口服维持治疗。对于可耐受15mg静脉剂量的患者，应在最后一次注射15分钟后口服一次50mg，每6小时1次，持续48小时。然后改为维持剂量一次100mg，一日2次，疗程至少3个月。不能耐受15mg静脉剂量的患者，应在最后一次注射15分钟后口服，一次25-50mg，每6小时1次。未静脉给药的患者，其口服治疗方案为一次100mg，一日2次，疗程至少3个月。也有研究建议口服治疗应持续1-3年。
6.偏头痛：每日50-200mg可减少典型及普通型偏头痛的发作次数，缩短持续时间以及减轻严重程度。
•静脉给药
1.心绞痛：不稳定型心绞痛及无ST段升高的心肌梗死，一次5mg，缓慢(1-2分钟)静脉注射，隔5分钟重复1次直至总量达15mg。静脉给药后应改为口服，具体用法与用量参见口服给药项。
2.心律失常：(1)常用剂量为一次2-20mg。(2)室上性多源性心动过速(如阵发性房性心动过速、心房扑动或心房颤动)给予5-15mg有很好的疗效。给药方法为：在2.5分钟内静脉注射5mg，每隔7.5分钟注射1次。
3.心肌梗死后早期治疗：(1)急性心肌梗死后立即静脉注射5mg，2分钟后可重复1次，共可用3次(15mg)，注射同时应严密监护患者的心率、血压和心电图。在最后一次注射15分钟后改为口服治疗，相关用法用量见口服给药项。
•肾功能不全时剂量
肾衰竭患者无需调整剂量。
•肝功能不全时剂量
本药在肝脏广泛代谢，肝功能不全患者应调整剂量。
•老年人剂量
研究显示，老年高血压患者每日使用本药100mg，必要时加小剂量氢氯噻嗪是安全有效的，优于单用氢氯噻嗪治疗。
•透析时剂量
透析后患者应给予维持剂量。

【制剂与规格】
酒石酸美托洛尔片 (1)25mg。(2)50mg。(3)100mg。
贮法：遮光，密封保存。
酒石酸美托洛尔胶囊 50mg。
酒石酸美托洛尔缓释片 (1)50mg。(2)100mg。(3)200mg。
贮法：遮光，密封保存。
酒石酸美托洛尔注射液 (1)2ml:2mg(另含氯化钠18mg)。(2)5ml:5mg(另含氯化钠45mg)。F7y胸部肿瘤防治工作组
贮法：遮光，密封保存。
注射用酒石酸美托洛尔 5mg。
贮法：遮光，密闭保存。

【原产地英文商品名】LOPRESSOR HCT (50/25)mg/tab 100tabs/bottle
【原产地英文药品名】METOPROLOL TARTRATE/HYDROCHLOROTHIAZIDE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请以电话咨询为准！
·LOPRESSOR HCT (50/25)毫克/片 100片/瓶
·LOPRESSOR HCT (100/50)毫克/片 100片/瓶
·LOPRESSOR HCT (100/25)毫克/片 100片/瓶
【中文参考药品译名】酒石酸美托洛尔/氢氯噻嗪
【生产厂家中文参考译名】诺华
【生产厂家英文名】NOVARTIS
-------------------------------------------------------------------------
【原产地英文商品名】METOPROLOL-HCTZ(LOPRESSOR-HCT GENERIC) (100/50)mg/tab 100tabs/bottle
【原产地英文药品名】METOPROLOL TARTRATE/HYDROCHLOROTHIAZIDE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请以电话咨询为准！
·美托洛尔-氢氯噻嗪(LOPRESSOR-HCT仿制药) (100/50)毫克/片 100片/瓶
·美托洛尔-氢氯噻嗪(LOPRESSOR-HCT仿制药) (100/25)毫克/片 100片/瓶
【中文参考药品译名】酒石酸美托洛尔/氢氯噻嗪

Lopressor HCT®

metoprolol tartrate USP and hydrochlorothiazide USP

50/25 Tablets

100/25 Tablets

100/50 Tablets

Beta Blocker/Diuretic Antihypertensive

Rx only

Prescribing Information

DESCRIPTION
 Lopressor HCT has the antihypertensive effect of Lopressor®, metoprolol tartrate, a selective beta1-adrenoreceptor blocking agent, and the antihypertensive and diuretic actions of hydrochlorothiazide. It is available as tablets for oral administration. The 50/25 tablets contain 50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; the 100/25 tablets contain 100 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; and the 100/50 tablets contain 100 mg of metoprolol tartrate USP and 50 mg of hydrochlorothiazide USP. Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is

Metoprolol tartrate USP is a white, crystalline powder. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. Its molecular weight is 684.82.

Hydrochlorothiazide is 6-chloro-3, 4-dihydro-2 H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide, and its structural formula is

Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.73.

Inactive Ingredients: Cellulose compounds, colloidal silicon dioxide, D&C Yellow No. 10 (100/50-mg tablets), FD&C Blue No. 1 (50/25-mg tablets), FD&C Red No. 40 and FD&C Yellow No. 6 (100/25-mg tablets), lactose, magnesium stearate, povidone, sodium starch glycolate, corn starch, stearic acid, and sucrose.

CLINICAL PHARMACOLOGY

Lopressor

Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, Lopressor also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.

Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.

Relative beta1 selectivity has been confirmed by the following: (1) In normal subjects, Lopressor is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC significantly less than a nonselective beta blocker, propranolol at equivalent beta1-receptor blocking doses.

Lopressor has no intrinsic sympathomimetic activity and only weak membrane-stabilizing activity. Lopressor crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.

In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100-450 mg daily. In controlled, comparative, clinical studies, Lopressor has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing positions.

The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.

Pharmacokinetics

In man, absorption of Lopressor is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.

Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of Lopressor is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of Lopressor in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.

In elderly subjects with clinically normal renal function, there are no significant differences in Lopressor pharmacokinetics compared to young subjects.

Lopressor is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of Lopressor is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.

Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Lopressor than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of Lopressor seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of Lopressor contribute significantly to its beta-blocking effect.

Pharmacodynamics

Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.

There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.

Hydrochlorothiazide

Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.

Pharmacokinetics

Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1-2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6-1.8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25- to 100-mg doses, 72-97% of the dose is excreted in the urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10-17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg.

Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.

Pharmacodynamics

The onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action persists for approximately 6-12 hours.

INDICATIONS AND USAGE

Lopressor HCT is indicated for the management of hypertension.

This fixed-combination drug is not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient’s needs, therapy with the fixed combination may be more convenient than with the separate components.

CONTRAINDICATIONS

Lopressor

Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS).

Hypersensitivity to Lopressor and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur).

Sick-sinus syndrome.

Severe peripheral arterial circulatory disorders.

Hydrochlorothiazide

Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs (see WARNINGS).

WARNINGS

Lopressor

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive patients who have congestive heart failure controlled by digitalis and diuretics, Lopressor should be administered cautiously.

In Patients Without a History of Cardiac Failure: Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, Lopressor should be withdrawn.

Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Even in the absence of overt angina pectoris, when discontinuing therapy, Lopressor should not be withdrawn abruptly, and patients should be cautioned against interruption of therapy without the physician’s advice (see PRECAUTIONS, Information for Patients).

Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor HCT. Because of its relative beta1 selectivity, however, Lopressor may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 selectivity is not absolute, a beta2-stimulating agent should be administered concomitantly, and the lowest possible dose of Lopressor should be used. In these circumstances it would be prudent initially to administer Lopressor in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).

Major Surgery: The necessity or desirability of withdrawing beta-blocking therapy, including Lopressor HCT, prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Lopressor, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta blockers.

Diabetes and Hypoglycemia: Lopressor should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers, including Lopressor HCT, may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. Selective beta blockers do not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, do not delay recovery of blood glucose to normal levels.

Pheochromocytoma: If Lopressor is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.

Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) or hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.

Hydrochlorothiazide

Thiazides should be used with caution in patients with severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.

Sensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

General

Lopressor: Lopressor should be used with caution in patients with impaired hepatic function.

Hydrochlorothiazide: All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia (see Laboratory Tests and Drug/Drug Interactions). Warning signs are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance, such as nausea or vomiting.

Hypokalemia may develop, especially in cases of brisk diuresis or severe cirrhosis.

Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia may be avoided or treated by the use of potassium supplements or foods with high potassium content.

Any chloride deficit is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In cases of actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Latent diabetes may become manifest during thiazide administration (see Drug/Drug Interactions).

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, withholding or discontinuing diuretic therapy should be considered.

Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen.

Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Information for Patients

Patients should be advised to take Lopressor HCT regularly and continuously, as directed, with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue Lopressor HCT without consulting the physician.

Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with Lopressor HCT has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking Lopressor HCT.

Laboratory Tests

Lopressor: Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

Hydrochlorothiazide: Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.

Drug/Drug Interactions

Lopressor: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with Lopressor plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

General Anesthetics

Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see WARNINGS; Lopressor; Major Surgery).

CYP2D6 Inhibitors

Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer. Caution should therefore be exercised when administering potent CYP2D6 inhibitors with Lopressor. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.

Clonidine

If a patient is treated with clonidine and Lopressor concurrently, and clonidine treatment is to be discontinued, Lopressor should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta blocker treatment.

Hydrochlorothiazide: Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Hypokalemia may develop during concomitant use of steroids or ACTH.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Thiazides may increase the responsiveness to tubocurarine.

Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.

There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa.

Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.

Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Drug/Laboratory Test Interactions

Hydrochlorothiazide: Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid function are made. (see General, Hydrochlorothiazide, Calcium excretion).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lopressor HCT: Carcinogenicity and mutagenicity studies have not been conducted with Lopressor HCT. Lopressor HCT produced no evidence of impaired fertility in male or female rats administered gavaged doses up to 200/50 mg/kg (100/50 times the maximum recommended daily human dose) prior to mating and throughout gestation and rearing of young.

Lopressor: Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.

All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were negative.

No evidence of impaired fertility due to Lopressor was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.

Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for 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 (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

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

Pregnancy: Teratogenic Effects. Pregnancy Category C

Lopressor HCT: No evidence of adverse effects on pregnancy or the fetus were observed in rats when dams were administered gavaged doses up to 200/50 mg/kg of Lopressor HCT (100/50 times the maximum recommended daily human dose) during the period of organogenesis. Increased postimplantation loss and decreased postnatal survival were observed with these doses when administered later in pregnancy (gestation days 15-21). In rabbits, increased fetal loss was observed with oral doses of 25/6.25 mg/kg of Lopressor HCT (12/6 times the maximum recommended daily human dose), but not with lower doses. There are no adequate and well-controlled studies of Lopressor HCT in pregnant women. Lopressor HCT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lopressor: Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in mice confirm exposure of the fetus when Lopressor is administered to the pregnant animal. These studies have revealed no evidence of teratogenicity.

Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.

Nonteratogenic Effects

Hydrochlorothiazide: Thiazides cross the placental barrier and appear in cord blood, and there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Nursing Mothers

Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of breast milk daily would receive a dose of metoprolol of less than 1 mg. Thiazides are also excreted in breast milk. If the use of Lopressor HCT is deemed essential, the patient should stop nursing.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Lopressor HCT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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 (see WARNINGS). 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 concomitant disease or other drug therapy.

ADVERSE REACTIONS

Lopressor HCT

The following adverse reactions were reported in controlled clinical studies of the combination of Lopressor and hydrochlorothiazide.

Body as a Whole: Fatigue or lethargy and flu syndrome have each been reported in about 10 in 100 patients.

Nervous System: Dizziness or vertigo, drowsiness or somnolence, and headache have each occurred in about 10 in 100 patients. Nightmare has occurred in 1 in 100 patients.

Cardiovascular: Bradycardia has occurred in about 6 in 100 patients. Decreased exercise tolerance and dyspnea have each occurred in about 1 of 100 patients.

Digestive: Diarrhea, digestive disorder, dry mouth, nausea or vomiting, and constipation have each occurred in about 1 in 100 patients.

Metabolic and Nutritional: Hypokalemia has occurred in fewer than 10 in 100 patients. Edema, gout, and anorexia have each occurred in 1 in 100 patients.

Special Senses: Blurred vision, tinnitus, and earache have each been reported in 1 in 100 patients.

Skin: Sweating and purpura have each occurred in 1 in 100 patients.

Urogenital: Impotence has occurred in 1 in 100 patients.

Musculoskeletal: Muscle pain has occurred in 1 in 100 patients.

Lopressor

Most adverse effects have been mild and transient.

Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported, but a drug relationship is not clear.

Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; and congestive heart failure have been reported. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Respiratory: Wheezing (bronchospasm) has been reported in fewer than 1 of 100 patients (see WARNINGS). Rhinitis has also been reported.

Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, gastric pain, constipation, flatulence, and heartburn have been reported in 1 of 100, or fewer, patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.

Hypersensitive Reactions: Pruritus has occurred in fewer than 1 of 100 patients. Rash has been reported. Very rarely, photosensitivity and worsening of psoriasis has been reported.

Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Alopecia has been reported. There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to Lopressor has not been definitely established).

The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with Lopressor.

Potential Adverse Reactions

A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Lopressor.

Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.

Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress.

Postmarketing Experience

The following adverse reactions have been reported during postapproval use of Lopressor: confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

Hydrochlorothiazide

The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ systems and are listed in decreasing order of severity and not frequency.

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia.

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

Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness.

Musculoskeletal: Muscle spasm.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Metabolic: Hyperglycemia, glycosuria, hyperuricemia.

Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.

OVERDOSAGE

Acute Toxicity

Several cases of overdosage with Lopressor have been reported, some leading to death. No deaths have been reported with hydrochlorothiazide.

Oral LD 50’s (mg/kg): mice, 1158 (Lopressor); rats, 3090 (Lopressor), 2750 (hydrochlorothiazide).

Signs and Symptoms

Lopressor: Potential signs and symptoms associated with overdosage with Lopressor are bradycardia, hypotension, bronchospasm, and cardiac failure.

Hydrochlorothiazide: The most prominent feature of poisoning is acute loss of fluid and electrolytes.

Cardiovascular: Tachycardia, hypotension, shock.

Neuromuscular: Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness.

Digestive: Nausea, vomiting, thirst.

Renal: Polyuria, oliguria, or anuria (due to hemoconcentration).

Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN (especially in patients with renal insufficiency).

Combined Poisoning: Signs and symptoms may be aggravated or modified by concomitant intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia), corticosteroids, narcotics, or alcohol.

Treatment

There is no specific antidote.

On the basis of the pharmacologic actions of Lopressor and hydrochlorothiazide, the following general measures should be employed:

Elimination of the Drug: Inducement of vomiting, gastric lavage, and activated charcoal.

Bradycardia: Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously.

Hypotension: The patient’s legs should be elevated and lost fluid and electrolytes (potassium, sodium) should be replaced. A vasopressor should be administered, e.g., levarterenol or dopamine.

Bronchospasm: A beta2-stimulating agent and/or a theophylline derivative should be administered.

Cardiac Failure: A digitalis glycoside and diuretic should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon may be considered.

Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until conditions become normal.

DOSAGE AND ADMINISTRATION

Dosage should be determined by individual titration (see INDICATIONS AND USAGE).

Hydrochlorothiazide is usually given at a dosage of 12.5 to 50 mg per day. The usual initial dosage of Lopressor is 100 mg daily in single or divided doses. Dosage may be increased gradually until optimum blood pressure control is achieved. The effective dosage range is 100 to 450 mg per day. While once-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. Beta1 selectivity diminishes as dosage of Lopressor is increased.

The following dosage schedule may be used to administer from 100 to 200 mg of Lopressor per day and from 25 to 50 mg of hydrochlorothiazide per day:

Lopressor HCT	Dosage
Tablets of 50/25	2 tablets per day in single or divided doses
Tablets of 100/25	1 to 2 tablets per day in single or divided doses
Tablets of 100/50	1 tablet per day in single or divided doses

Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended. When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid an excessive fall in blood pressure.

HOW SUPPLIED

Tablets 50/25 -       capsule-shaped, white and mottled-blue, scored (imprinted Geigy on one side and 35 twice on the scored side), 50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide

Bottles of 100……………………………………NDC 0078-0460-05

Tablets 100/25 -       capsule-shaped, white and mottled-pink, scored (imprinted Geigy on one side and 53 twice on the scored side), 100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide

Bottles of 100……………………………………NDC 0078-0461-05

Tablets 100/50 -       capsule- shaped, white and mottled-yellow, scored (imprinted Geigy on one side and 73 twice on the scored side), 100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazide

Bottles of 100……………………………………NDC 0078-0462-05

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in tight, light-resistant container (USP).