Tachycardia, Ventricular

药品简介 米氮平由美国Organonk开发，是一种对去肾上腺素能和5-羟色胺具有双重抑制作用的药物，用于抑郁症的治疗。 荷兰上市：1994年首先在荷兰获得批准上市，用于抑郁症的治疗。 美国上市：1996年6月通过FDA的审批。 日本上市：2009年9月，在日获批上市。 中国上市：2004年在国内通过进口的方式批准上市。 医保报销：医保甲类；基药（2018年版）。 基本信息 通用名称：米氮平片 英文名称：Mirtazapine Tablets 汉语拼音：Midanping Pian 成份：本品主要成份为米氮平。 化学名称：1,2,3,4,10,14b-六氢-2-甲基吡嗪基[2,1-a]吡啶并[2,3-c][2]苯并氮杂䓬 化学结构式： 分子式：C17H19N3 分子量：265.35 适应症 用于治疗抑郁症。 用法用量 口服给药。应随水吞服，不应嚼碎。 成人：有效剂量通常为每日15～45mg。治疗起始剂量为15mg或30mg。通常在用药一至二周后起效。当服用药物适量时，二至四周内应有疗效。若效果不够明显，可将剂量增加直至最大剂量。若剂量增加二至四周后仍无作用，应停止使用本品。 肾功能损害患者：中重度肾功能损害（肌酐清除率＜40ml/min）患者对米氮平的清除率下降。中重度肾功能损害患者使用本品时应谨慎选择剂量（见【注意事项】）。 肝功能损害患者：肝功能损害患者对米氮平的清除率下降。肝功能损害患者使用本品时应谨慎选择剂量。由于尚未在重度肝功能损害患者中开展研究，此类人群使用本品时更应特别小心（见【注意事项】）。 米氮平的清除半衰期为20～40小时，因此本品适于每日服用一次（最好在临睡前服用）。本品也可分次服用（如早晚各一次，夜间应服用较高剂量）。 患者应连续服药，充分治疗至少6个月，以维持疗效。 建议逐渐停药，以防止撤药症状发生（见【注意事项】）。 注意事项 临床症状的恶化和自杀风险 患有抑郁症的成年和儿童患者，无论是否服用抗抑郁药，他们的抑郁症都有可能恶化，并有可能出现自杀意念和自杀行为以及行为异常变化，这种风险一直会持续到病情发生明显缓解时为止。已知抑郁和某些精神障碍与自杀风险有关，并且这些精神障碍本身为自杀的最强的预兆。然而，长期以来一直有这些的担忧：在某些患者治疗早期，抗抑郁药可能对诱导抑郁症状恶化，以及产生自杀意念和行为中起着作用。抗抑郁药（SSRIs（5-羟色胺再摄取抑制剂）和其他）短期安慰剂对照研究汇总分析显示，在患有抑郁症和其它精神障碍的儿童、青少年和青年（18-24岁）中，与安慰剂相比，抗抑郁药增加了产生自杀意念和行为的风险。但短期的临床试验没有显示，在年龄大于24岁的成年人中，与安慰剂相比，使用抗抑郁药会增加自杀意念和行为的风险；在65岁及以上的成年人中，使用抗抑郁药后，自杀意念和行为的风险有所降低。 在患有抑郁症、强迫症或其它精神障碍的儿童和青少年中进行的安慰剂对照试验（共计24项短期临床试验，9种抗抑郁药，超过4400例患者）和在患有抑郁症或其它精神障碍的成年患者中进行的安慰剂对照试验（共计295项短期临床试验[中位持续时间为2个月]，11种抗抑郁药，超过77000例患者），各种药物引起的自杀意念和行为的风险有很大的差异，但是大部分的药物研究显现出较年轻患者自杀意念和行为风险增加的趋势。在各个不同的适应症中，自杀意念和行为的绝对风险不同，在抑郁症中的绝对风险最高。虽然在各个适应症中的绝对风险有所不同（药物和安慰剂相比），但是，在不同适应症的年龄层中的风险相对稳定。下表1提供了风险差异（每1000名患者中药物和安慰剂治疗产生的自杀意念和行为风险差异的例数）。 表 1年龄范围每1000名患者中药物和安慰剂治疗产生的自杀意念和行为风险差异的例数 在儿童临床试验中没有自杀事件发生。在成人临床试验中有自杀事件的发生，但是发生的数量不足以对药物在自杀中的影响做出结论。 自杀意念和行为的风险在长期用药过程中（如几个月后）是否会延续尚不可知。但是，从在成年抑郁症患者中进行的安慰剂对照的维持治疗临床试验的证据充分显示，使用抗抑郁药可以延缓抑郁症的复发。 无论治疗哪种适应症，对接受抗抑郁药治疗的所有患者，都应密切观察和监测其临床症状恶化、自杀意念和行为以及行为异常变化的情况。尤其在药物最初治疗的数月内，及增加或减少剂量的时候。 用抗抑郁药治疗患有抑郁症、其它精神病性或非精神病性障碍的成年和儿童患者时，可以出现下列症状：焦虑、激越、惊恐发作、失眠、易激惹、敌意、攻击性、冲动、静坐不能（精神运动性不安）以及轻躁狂和躁狂。虽然尚未建立这些症状的出现与抑郁症的恶化和/或自杀意念和行为的产生之间的因果关系，但注意到了这些症状的出现可能是产生自杀意念和行为的先兆。 当患者的抑郁症状持续恶化，出现自杀意念和行为，或出现可能是抑郁症状恶化或自杀意念和行为的先兆症状时，应当仔细考虑包括中止药物治疗在内的治疗方案调整。如果这些症状是严重的、突发的、或与患者当前症状不符合时更应如此。 如果决定中止治疗，剂量应当尽快递减，但需意识到突然停药可能会引起某些症状（参见【注意事项】和【用法用量】）。 用抗抑郁药治疗患有抑郁症或其它精神病性或非精神病性障碍的患者时，应当提醒家属以及看护者有必要监察患者是否出现激越、易激惹、行为异常变化、其它以上提及的症状以及出现自杀意念和行为的情况，一旦出现，立即向医疗卫生专业人士汇报这些症状。家属以及看护者应当每天对患者进行以上监察。使用米氮平时，处方应当从最小量开始，并配合良好的患者管理，以减少过量用药的危险。 双相情感障碍患者的筛查 抑郁发作可能是双相情感障碍的初期表现。一般认为（虽然未通过对照试验明确），单用抗抑郁药治疗这类发作可能增加具有双相情感障碍风险患者的混合型/躁狂发作的可能性。尚不明确以上提及的症状是否意味着可能出现这种转变。然而，在用抗抑郁药开始治疗之前，应当对有抑郁症状的患者进行充分的筛查，以确定他们是否具有双相情感障碍的风险；该筛查应当包括自杀家族史和双相情感障碍和抑郁症家族史在内的详细的精神病史。米氮平尚未批准用于治疗双相情感障碍。 5-羟色胺综合征 类似其它5-羟色胺能药物，使用米氮平治疗时，可能发生5-羟色胺综合征（一种有潜在生命威胁的情况），尤其是在与其它可能作用于5-羟色胺递质系统的药物合用时（如：曲坦、SSRIs、SNRIs(去甲肾上腺素再摄取抑制剂)、锂盐、西布曲明、安非他明、圣约翰草[金丝桃属植物提取物]、芬太尼及其类似物、曲马多、美沙芬、他喷他多、哌替啶、美沙酮、喷他佐辛、三环类抗抑郁药、色氨酸和丁螺环酮），与损害5-羟色胺代谢的药物合用时（如：MAOIs的亚甲蓝），与5-羟色胺前体物质合用时（如：色氨酸补充剂），与抗精神病药物或与其他多巴胺拮抗剂合用时。 5-羟色胺综合征可能包括精神状态的改变（如：激越、幻觉、谵妄、昏迷）、自主神经不稳定（如：心动过速、血压不稳、体温过高、发汗、潮红和头晕）、神经肌肉系统失调（如：震颤、强直、肌阵挛、反射亢进、动作失调）、癫痫发作和胃肠道症状（如：恶心、呕吐、腹泻）。最严重的5-羟色胺综合征与抗精神病药物恶性综合征的表现相似，包括体温过高、肌肉强直、自主神经不稳定可能伴有生命体征的快速波动，以及精神状态的改变。（见 【药物相互作用】 ）。 禁止米氮平与MAOIs合用。正在接受利奈唑胺或静脉用亚甲蓝等 MAOIs 治疗的患者也不应使用米氮平。所有报告中亚甲蓝的给药途径均为1 mg/kg 至 8 mg/kg 剂量范围内的静脉给药。没有报告采用其他途径（例如口服片剂或局部组织注射）或较低剂量给予亚甲蓝。在某些情况下，正在服用米氮平的患者可能必须接受利奈唑胺或静脉用亚甲蓝等 MAOIs治疗。在开始 MAOIs治疗之前应先停用米氮平（见【禁忌】）。 如果临床上有合理需要，要合并使用米氮平和某种SSRIs、SNRIs或其他5-羟色胺能药物（如：曲普坦类药、三环类抗抑郁药、芬太尼、锂盐、曲马多、丁螺环酮、色氨酸和圣约翰草），建议密切观察患者情况，尤其在治疗初期和增加剂量时（见【药物相互作用】）。 不推荐合并使用米氮平和5-羟色胺前体物质（如：色氨酸补充剂）。 当上述事件发生时，必须立即停用米氮平及任何合并使用的5-羟色胺能药物，并开始对症支持治疗。 闭角型青光眼 对于解剖结构中房角狭窄的、未进行明确的虹膜切除术的患者，使用多种抗抑郁药（包括米氮平）后出现的瞳孔扩大可能会引起房角关闭所致的青光眼发作。 骨髓抑制、粒细胞缺乏症 米氮平治疗过程中已有骨髓抑制的报道，其表现通常为粒细胞减少或粒细胞缺乏症。在米氮平临床试验中罕见可逆性的粒细胞缺乏症。在上市前临床试验中，2796名接受米氮平治疗的患者有2人出现粒细胞缺乏症[中性粒细胞绝对计数（ANC）＜500/mm3并伴有体征和症状，例如发热、感染等]，其中一人为Sjögren综合征，还有一名患者出现了重度的中性粒细胞减少症（ANC ＜500/mm3无相关症状）。这三名患者分别在治疗的第61天、第9天和第14天发生重度中性粒细胞减少，均在停用米氮平后恢复。基于这三个病例得出重度中性粒细胞减少（伴有或不伴有相关感染）的发生率约为1.1/1000，95%置信区间非常宽，即2.2/10,000～3.1/1000。如果患者出现咽喉痛、发热、口腔炎或其他感染迹象，并伴有白细胞（WBC）计数降低，应中断米氮平治疗并对患者进行密切监测。 上市后使用米氮平出现粒细胞缺乏症的报道很少，大多数是可逆性的，但是有几例是致命的。致命个例中，大部分患者年龄为65岁以上。因此医生在治疗过程中应注意，一旦发现患者有发热、喉痛、口炎或其他感染症状应立即停止用药并作血细胞计数检查。 一般注意事项： 中断治疗的症状：已有中断（特别是突然中断）米氮平片后即出现不良反应的报告，包括但不仅限于以下反应：头晕、梦异常、感觉紊乱（包括感觉异常和电休克感）、激动、焦虑、疲劳、意识错乱、头痛、震颤、恶心、呕吐、出汗或其它可能具有临床意义的症状。报告的大多数病例为轻度并呈自限性。尽管如此，以上这些被当作不良反应报告，但应明确这些症状可能与基础疾病有关。 鉴于存在出现中断治疗症状的风险，目前正服用米氮平的患者不能突然中断治疗。当出于医学考虑需中断米氮平治疗时，推荐逐步减量而非骤然停用。 静坐不能/精神运动性坐立不安：抗抑郁药的使用与静坐不能的发生相关，表现为主观不悦或烦恼不安，需要经常走动，并伴有不能静坐或静止站立，最可能发生于治疗的最初几周内。调高剂量对于发生这些症状的患者是有害的。 低钠血症：因使用米氮平出现低钠血症的报告非常罕见。对于存在相应风险的患者，比如老年患者或合并使用已知可致低钠血症的其它药物的患者，应谨慎用药。 嗜睡：在美国进行的对照试验中，有54%接受米氮平治疗的患者出现嗜睡，安慰剂组为18%，阿米替林组为60%。这些试验中，嗜睡造成10.4%接受米氮平治疗的患者中断治疗，安慰剂组为2.2%。尚不清楚是否会对米氮平的嗜睡作用产生耐受。由于米氮平可能会显著损害行为能力，患者在从事需要警觉性的活动时应谨慎，直到他们能评估药物对自身精神运动能力所产生的影响。 头晕：在美国进行的对照试验中，7%接受米氮平治疗的患者报告头晕，安慰剂组为3%，阿米替林组为14%。尚不清楚是否会对米氮平使用有关的头晕产生耐受。 食欲/体重增加：在美国进行的对照试验中，17%接受米氮平治疗的患者报告食欲增加，安慰剂组为2%，阿米替林组为6%。在这些相同的试验中，7.5%米氮平治疗的患者体重增加≥7%，安慰剂组为0%，阿米替林组为5.9%。在美国进行的上市前临床试验，包括许多长期、开放标签治疗的患者，有8%接受米氮平治疗的患者因体重增加而停药。在一项为期8周的儿童和青少年临床试验中，每日给药剂量为15～45mg，49%接受米氮平治疗的患者体重增加至少7%，安慰剂治疗患者为5.7%。 胆固醇/甘油三酯：在美国进行的对照试验中，15%接受米氮平治疗的患者观察到非空腹胆固醇比正常值上限升高≥20% ，安慰剂组为7%，阿米替林组为8%。在这些相同的试验中，6%接受米氮平治疗的患者非空腹甘油三酯升高至≥500 mg/dL，安慰剂组为3%，阿米替林组为3%。 转氨酶升高：在美国进行的短期对照试验，2.0%接受米氮平治疗的患者（8/424）观察到临床显著的转氨酶（ALT）升高（≥3倍正常范围上限），安慰剂治疗患者为0.3%（1/328），阿米替林治疗患者为2.0%（3/181）。这些ALT升高的患者中大多数没有出现与肝功能受损有关的体征或症状。一些患者因ALT升高而停药，另一些患者尽管继续米氮平治疗，但肝酶水平恢复正常。肝功能受损患者应慎用米氮平。 黄疸：一旦出现黄疸，应停止用药。 诱发躁狂/轻度躁狂：在美国进行的研究中，约有0.2%接受米氮平治疗的患者（3/1299患者）出现躁狂/轻度躁狂。虽然躁狂/轻度躁狂的发生率在米氮平治疗期间非常低，但有躁狂/轻度躁狂病史的患者应慎用。 癫痫发作：在上市前临床试验中，2796名接受米氮平治疗的美国和非美国患者中只报告了1例癫痫发作。但是，尚未对有癫痫发作病史的患者进行对照试验。因此这些患者使用米氮平时应谨慎。 在有伴随疾病患者中的使用：在有伴随全身疾病的患者中使用米氮平的临床经验有限。因此，对伴随影响代谢或血液动力学应答的疾病或状况的患者，开具米氮平处方应谨慎。 对近期有心肌梗死或其他显著心脏疾病病史的患者未进行米氮平的系统评价或未使用米氮平至可评估的剂量。在健康志愿者中进行的早期临床药理学试验中，米氮平用药伴有显著的体位性低血压。在抑郁症患者的临床试验中少见体位性低血压。对已知在低血压情况下症状可能恶化的心血管或脑血管疾病患者（心肌梗死、心绞痛或缺血性脑卒中发作病史），以及易出现低血压状况的患者（脱水、血容量减少以及降血压药物治疗），应慎用米氮平。  中度[肾小球滤过率（GFR）=11～39 ml/min/1.73m2]和重度[GFR ＜10 ml/min/1.73 m2]肾功能损害患者的米氮平清除率降低，肝功能损害患者也是如此。这些患者应慎用米氮平（见【用法用量】）。 需要监护的情况： 对以下病症患者，应注意用药剂量并定期作仔细检查： • 癫痫和器质性脑综合征，尽管临床经验表明与其他抗抑郁药一样，服用米氮平时极少有癫痫发作，但是对于有发作史的患者使用米氮平应慎重。当患者出现癫痫或者癫痫发作频率增加应该停止使用。 • 肝功能损害患者：单剂量口服15mg米氮平后，轻中度肝功能损害患者的米氮平清除率相比肝功能正常的受试者下降约35％。米氮平的平均血浆浓度升高约55％。 • 肾功能损害患者：单剂量口服15mg米氮平后，中度（肌酐清除率＜40ml/min）和重度（肌酐清除率≤10ml/min）肾功能损害患者的米氮平清除率与正常受试者相比分别下降30％和50％。米氮平的平均血浆浓度分别升高约55％和115％。轻度肾功能损害患者（肌酐清除率＜80ml/min）与对照组相比没有显著差异。 • 心脏病如传导障碍，心绞痛和近期发作的心肌梗塞。对这类病症应采取常规预防措施并谨慎服用其他药物。 • 低血压。 • 糖尿病：糖尿病患者，抗抑郁药可能会改变血糖控制水平。可能需要调整胰岛素和/或口服降血糖药的剂量，并推荐做密切监护。 与服用其他抗抑郁药物一样，以下患者服用米氮平时应予注意： • 伴精神分裂症及其他精神病的患者服用抗抑郁药后精神病性症状会恶化，妄想可能加重。 • 处于抑郁期的双相情感障碍患者使用抗抑郁药后，患者有可能转变为躁狂相。应密切监护有躁狂症/轻度躁狂症病史的患者。任何进入躁狂期的患者，应停止使用米氮平。 • 尽管米氮平没有成瘾性，上市后用药经验显示，在长期给药后突然停止治疗有时会引起停药症状。大部分停药反应较弱且具有自限性。在各种报道的停药症状中，头晕、焦虑、激越、头疼和恶心最为常见。尽管这些都被报道为停药症状，需要注意的是，这些症状可能与基础疾病有关。如同【用法用量】，建议逐渐停止使用米氮平。 • 排尿困难（如前列腺肥大患者）、急性窄角性青光眼和眼内压增高的患者服药期间需注意观察（尽管米氮平仅有很弱的抗胆碱作用且其发生问题的机会很小）。 • 在一项54名健康受试者参加的随机、安慰剂、莫西沙星对照的临床试验中使用暴露反应分析评估了米氮平对QTc间期的影响。试验结果表明米氮平45mg剂量（治疗）和75mg剂量（超治疗）均未对QTc间期有临床意义的影响。米氮平上市后使用过程中曾报告QT延长、尖端扭转型室性心动过速、室性心动过速和猝死病例。大多数报告与过量相关或发生在有QT延长的其它风险因素的患者中，包括伴随使用延长QTc的药物。在已知有心血管疾病或QT延长家族史的患者中处方米氮平时，以及与延长QTc间期的其它药品伴随用药时，应当谨慎。 酒精：已知米氮平能叠加酒精对认知或运动技能造成损害。因此，患者在服用米氮平期间不得饮酒。 乳糖：此药物含有乳糖，伴有罕见的遗传性半乳糖不耐症，乳糖分解酵素酶缺乏或葡萄糖-半乳糖吸收障碍的患者不应服用此药。 干扰认知和运动行为：因为米氮平显著的镇静作用，可能对判断、思维，特别是运动技能造成损伤。使用米氮平造成的困倦可能会损害患者驾驶，操作机器，或完成需要警觉性任务的能力。因此，患者在参与危险活动时应谨慎，直到他们有理由确定米氮平治疗不会对他们参与这些活动的能力造成不良影响。 患者用药信息：处方医师或其他健康从业人员应告知患者、患者家属和他们的护理人员有关米氮平治疗的风险和益处，并且应提供合理用药的咨询。处方药，放于儿童不能触及的地方。 18岁以下儿童和青少年：本品不能用于18岁以下儿童和青少年患者。 在儿童和青少年服用抗抑郁药物的临床试验中，自杀相关行为（自杀企图和自杀想法）和敌对行为（主要为攻击、对立行为和愤怒）比服用安慰剂者更常见。此外，目前尚缺乏儿童和青少年服用此药对于他们的成长、发育、认知和行为的发展的长期安全数据。 完成治疗疗程：在患者采用米氮平治疗1～4周可能出现病情改善的情况下，建议他们应遵医嘱继续治疗。 合并用药：如果患者正在服用或准备服用任何处方药或非处方药，应告知医生，因为米氮平有可能会与其他药物产生相互作用。 特殊人群 孕妇及哺乳期妇女用药 如果患者怀孕或在米氮平治疗期间准备怀孕，应告知医生。 妊娠妇女使用米氮平的数据有限，未显示先天畸形的风险升高。动物试验未显示任何与临床相关的致畸作用，但是观察到了发育毒性（见【药理毒理】）。 流行病学资料表明，怀孕期使用SSRIs，特别是妊娠晚期，可能会增加新生儿持续性肺动脉高压的风险（PPHN）。虽然没有研究过PPHN与米氮平治疗之间的关系，但考虑到有关作用机制（5-羟色胺浓度的增加），不能排除这种潜在的风险。 给妊娠妇女开具米氮平处方时应谨慎，除非明确需要，米氮平不得在妊娠期间使用。如果直到分娩或分娩前不久才停用米氮平，建议对新生儿进行出生后可能的停药效应的监测。 如果患者在哺乳婴儿，应告知医生。 由于米氮平可能部分分泌至乳汁中，因此哺乳期妇女应慎用米氮平。 动物实验以及有限的临床数据表明，只有极少量的米氮平经乳汁分泌。是否中断哺乳或者中断米氮平的治疗，应该充分权衡母乳喂养对幼儿的益处以及米氮平对母亲治疗的益处，再作决定。 儿童用药 18岁以下儿童及青少年患者用药的安全性和有效性尚未确立。（见【注意事项】）。 老年用药 老年患者慎用本品。 约有190名老年人（年龄≥65岁）参与米氮平的临床试验。已知米氮平主要通过肾脏排泄（75%），在肾功能受损患者中米氮平清除率下降的风险升高。由于老年人更容易出现肾功能下降，剂量选择时应谨慎。镇静药可能造成老年人意识混乱和过度镇静。该组人群未发现异常的与年龄有关的不良现象。药代动力学试验显示老年人药物清除率下降。 药物相互作用 药效学相互作用 米氮平不应与单胺氧化酶（MAO）抑制剂合并使用或者在停用MAO抑制剂治疗的两周内使用。反之，接受米氮平治疗的患者如果需要使用MAO抑制剂治疗，之间应间隔约两周（见【禁忌】）。另外，与SSRIs一样，米氮平与其他5-羟色胺活性物质（L-色氨酸、曲坦类、曲马多、利奈唑胺、亚甲蓝、SSRIs、文拉法辛、锂和贯叶连翘（Hypericum perforatum）制剂）合并给药可能会导致发生5-羟色胺相关反应（5-羟色胺综合征，见【注意事项】）。 米氮平可能加重苯二氮卓类和其他镇静剂（特别是大多数抗精神病药、组胺H1拮抗剂、阿片类）的镇静作用。当这类药物与米氮平合用时应予以注意。12名健康受试者合并使用地西泮（15mg）对米氮平（15mg）的血浆浓度水平影响甚微。但是米氮平产生的运动技能损伤与地西泮产生的影响有叠加作用。因此，应建议患者在服用米氮平期间避免使用地西泮以及其他类似药物。 米氮平可增加酒精对中枢神经系统抑制作用，因此，治疗期间应建议患者不要饮用含酒精的饮料。 同时服用华法林的受试者每日服用米氮平30mg会引起小幅但有统计学意义的国际标准化比值（INR）增高。当增加米氮平的服用剂量时，不能排除更显著的作用，建议在米氮平和华法林同时使用时，监测INR水平。 QT延长和/或室性心律失常（例如尖端扭转型室性心动过速）风险可能随着延长QTc间期的伴随用药（例如某些抗精神病药和抗生素）和米氮平过量而增加。 药代动力学相互作用 影响肝代谢的药物：米氮平的代谢和药代动力学可能受到药物代谢酶诱导剂或抑制剂的影响。由细胞色素酶P450代谢的药物以及/或抑制细胞色素酶P450的药物： CYP酶诱导剂（以下均为稳态情况下的研究）： 苯妥英：健康男性受试者（n=18）中，苯妥英（200mg/天）使米氮平（30mg/天）的清除率增加约2倍，导致米氮平的平均血浆浓度降低45%。米氮平对苯妥英的药代动力学影响不明显。 卡马西平：健康男性受试者（n=24）中，卡马西平（400mg，2次/天）使米氮平（15mg，2次/天）的清除率增加约2倍，导致米氮平的平均血浆浓度降低60%。当苯妥英，卡马西平或其他的肝代谢诱导剂（如利福平）与米氮平同用时，米氮平的剂量可能需要增加。如果停用此类药品，米氮平的剂量可能需要降低。 CYP酶抑制剂： 西咪替丁：健康男性受试者（n=12）接受西咪替丁，一种弱CYP1A2、CYP2D6、CYP3A4抑制剂（800mg，2次/天），达稳态后与稳态下的米氮平（30mg/天）合用，米氮平曲线下面积（AUC）增加超过50％。米氮平不改变西咪替丁的药代动力学特征。当开始合用西咪替丁时，米氮平可能需要减量，当停用西咪替丁时则应增加米氮平剂量。 酮康唑：健康男性白种人中（n=24）合用强CYP3A4抑制剂酮康唑（200mg ，2次/天，连续6.5天），可使单剂量30mg米氮平的血浆峰浓度和AUC分别升高约40％和50％。 当米氮平与强CYP3A4抑制剂、HIV蛋白酶抑制剂、唑类抗真菌剂、红霉素或奈法唑酮合用时应谨慎。 帕罗西汀：一项在健康、强CYP2D6代谢受试者（n=24）体内相互作用研究显示，稳态下的米氮平（30mg/天）不改变稳态下帕罗西汀（40mg/天），一种CYP2D6抑制剂的药代动力学特征。 其它药物－药物相互作用 阿米替林：在健康、强CYP2D6代谢受试者（n=32）中，稳态下阿米替林（75mg/天）不改变稳态下米氮平（30mg/天）的药代动力学特征；米氮平也不改变阿米替林的药代动力学特征。 锂：未发现健康男性受试者稳态下的亚治疗剂量锂（600mg/天，连续10天）对单剂量30mg米氮平产生临床效应或明显的药代动力学改变。尚不清楚较高剂量的锂对米氮平药代动力学的作用。 利培酮：一项在需要抗精神病药和抗抑郁药治疗的受试者（n=6）中的非随机化、相互作用的体内研究显示，米氮平（30mg/天）稳态下不影响利培酮（最高达3mg，2次/天）的药代动力学。 药理作用 米氮平具有四环结构，属于哌嗪-氮卓类化合物。本品治疗严重抑郁症的作用机制尚不清楚，临床前试验显示米氮平可增强中枢去甲肾上腺素和5-羟色胺活性，这可能与米氮平为中枢突触前抑制性α2肾上腺素受体拮抗剂相关。 米氮平是5-HT2和5-HT3受体的强拮抗剂，但对5-HT1A和5-HT1B受体没有明显的亲和力。同时，米氮平是H1受体的强效拮抗剂，这种属性可解释其明显的镇静作用；米氮平对α1肾上腺素受体具有中等强度的拮抗作用，这种属性可解释其使用中报道的偶发性体位性低血压；米氮平对M受体具有中等强度拮抗作用，这种属性可解释其相对低的抗胆碱副作用发生率。 毒理研究 遗传毒性：Ames试验、体外中国仓鼠V79细胞基因突变试验、体外培养家兔淋巴细胞姊妹染色体交换试验、大鼠骨髓微核试验和HeLa细胞程序外DNA合成试验结果均为阴性。 生殖毒性：大鼠给予米氮平达100mg/kg剂量（以mg/m2计，为人最大推荐剂量的20倍），未发现对交配、妊娠的影响，但剂量为人最大推荐剂量的3倍或以上剂量时，动物的动情期中断，20倍剂量时，发生着床前丢失。 妊娠大鼠和家孕兔剂量分别达100mg/kg和40mg/kg（以mg/m2计，分别为人最大推荐剂量的20和17倍）时未发现有致畸作用。但给予米氮平的妊娠大鼠的着床后丢失增加，哺乳期前3天幼仔死亡增加（死亡的原因尚不清楚），幼仔出生体重降低，这些作用发生在人最大推荐剂量20倍剂量时，3倍剂量时未出现。 致癌性：采用掺食法进行了大鼠给药2、20和60mg/kg/天、小鼠2、20和200mg/kg/天的致癌性研究（以mg/m2计，大、小鼠最大剂量分别约为人推荐最大剂量的12和20倍）。结果显示，高剂量组雄性小鼠的肝细胞腺瘤和癌的发生率增加；中、高剂量组雌性大鼠肝细胞腺瘤，及高剂量组雄性大鼠肝细胞腺瘤和甲状腺滤泡腺瘤/囊腺瘤及癌的发生率增加。这些资料提示上述作用可能是由非基因毒性机制介导，其与人的相关性尚不清楚。 小鼠研究中给药剂量可能不足够高，没有充分反映出米氮平潜在致癌性特点。 药代动力学 口服米氮平片后其活性成份米氮平很快被吸收（生物利用度约为50%）。约二小时后血浆浓度达到高峰。米氮平约85%与血浆蛋白结合。平均半衰期为20～40小时；偶见长达65小时的半衰期；在年轻人中也偶见较短的半衰期。清除半衰期的大小适于将服用方式定为每日一次。血药浓度在服药3～4天后达到稳态，此后将无体内聚积现象。在所推荐的剂量范围内，米氮平呈线性药代动力学。与食物同服不会影响米氮平的药代动力学特征。 米氮平在服药后几天内大多被代谢并通过尿液和粪便排出体外。其主要生物转化方式为脱甲基及氧化反应，其次为结合反应。对人类肝脏微粒体生物体外的研究表明细胞色素P450酶CYP2D6和CYP1A2参与米氮平的8-羟基代谢物的形成。CYP3A4被认为负责N-去甲基和N-氧化物代谢物的形成。脱甲后的代谢产物仍具有药理学活性，并和原化合物具有一样的药代动力学特性。 肾功能不全：米氮平的清除与肌酐清除率相关。与正常受试者相比，米氮平的总体清除率在中度肾功能损害患者（肌酐清除率（Clcr）=11～39ml/min/1.73 m2）下降约30％，在重度肾功能损害患者（Clcr = <10 ml/min/1.73 m2）下降约50%。肾功能损害患者应慎用米氮平（见【注意事项】和【用法用量】）。 肝功能不全：与正常肝功能受试者相比，单次口服15mg米氮平片后，肝功能损害患者的米氮平清除率下降约30%。肝功能损害患者应慎用米氮平（见【注意事项】和【用法用量】）。 药品中标价格 （数据来源：国家第八批集采、戊戌数据整理） END ★ 点击下方卡片，发现更多精彩

Medical education in Asia may be headed to a future where institutions are not only training students but also training AI models. In the HIMSS24 APAC session, "Implementing AI in Healthcare," Dr Hyung-Chul Lee, deputy CIO of Seoul National University Hospital (SNUH), shared how their hospital develops, validates, and implements AI technologies. "For more than 100 years, our hospital has been educating medical students and residents. But now we also have to train LLMs (large language models)." When LLMs eventually made their way to healthcare recently, researchers at SNUH quickly validated their potential application. While LLMs scored high in one of the world's toughest medical examinations and outperformed existing predictive AI models in such use cases as predicting in-hospital mortality and real-time admissions, their ability remains limited. "Our research shows that no LLMs have yet scored higher than 60 [in the Korean Medical License Exam], especially in medical law." "Also, these LLMs have limited ability [in performing] multimodal tasks. For example, if I uploaded images related to ventricular tachycardia – a condition requiring emergency resuscitation – from VitalDB (a multi-parameter vital signs database), even the [latest] ChatGPT-4o [wrongly] answers that it's a normal ECG and no resuscitation is required." Acknowledging the need for LLMs to get fed with more diverse data, Dr Lee and his team built a vector database and a model for fine-tuning search. "We are currently working on vector embedding of all data in our hospital and loading it into the VectorDB." This initiative led to the development of SNUH's in-house LLM platform to safely develop AI models for their clinicians. The LLM service, Dr Lee said, required 40 H100 GPUs and six petabytes of storage. "VectorDB will be our textbook and fine-tuning it will be [in] our curriculum." "I look forward to seeing AI models trained at our hospital and [how these] will change our practice and improve patient outcomes."

October 9, 2024 6:45 am ET Merck Underscores Continued Commitment to Fighting Infectious Diseases with More than 40 Data Presentations Across Vaccines, Antibacterials and Antivirals, Including Respiratory Syncytial Virus, Pneumococcal Disease and HIV For the First Time, Full Results will be Highlighted from the Phase 2b/3 Trial of Clesrovimab (MK-1654), an Investigational Respiratory Syncytial Virus Preventative Monoclonal Antibody for Infants RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced its plans to present new research findings demonstrating the continued impact of its increasingly broad and diverse vaccines and infectious disease portfolio and the potential of its innovative pipeline at IDWeek 2024 in Los Angeles, CA, from October 16-19. Data to be presented include a late-breaker oral presentation of positive detailed results from the Phase 2b/3 trial evaluating clesrovimab (MK-1654), an investigational prophylactic monoclonal antibody designed to protect infants from respiratory syncytial virus (RSV) disease; data from the Phase 3 STRIDE-8 trial evaluating CAPVAXIVE™ (Pneumococcal 21-valent Conjugate Vaccine) in adults 18-64 years of age at increased risk of pneumococcal disease; as well as a late-breaker oral presentation of Week 48 data from the Phase 2 study evaluating an investigational once-weekly oral combination regimen of islatravir, the company’s nucleoside reverse transcriptase translocation inhibitor (NRTTI), and Gilead’s lenacapavir, a first-in-class capsid inhibitor, for treatment of people with HIV-1 infection. “The breadth of innovative research we will showcase during IDWeek 2024 is a testament to our ongoing commitment to advancing science with the pursuit of addressing persisting global health needs, such as RSV,” said Dr. Paula Annunziato, senior vice president, infectious diseases and vaccines, Global Clinical Development, Merck Research Laboratories. “We are proud of our company’s longstanding legacy and continued momentum in helping to treat and prevent a variety of potentially serious infectious diseases for individuals around the world and across all stages of life – from birth through older adulthood – and we look forward to sharing these data.” Key data from Merck’s portfolio and pipeline to be presented during IDWeek 2024: First time data from the Phase 2b/3 study evaluating a single dose of clesrovimab (MK-1654) administered to pre-term and full-term infants (Abstract #166, Late Breaker Oral Abstract Session: Respiratory Viruses Across All Ages); First presentation of results from the interim analysis of the Phase 3 trial evaluating the safety and efficacy of clesrovimab versus palivizumab in infants and children at increased risk for severe RSV disease (Abstract #167, Late Breaker Oral Abstract Session: Respiratory Viruses Across All Ages); First presentation of data from the Phase 3 STRIDE-8 trial evaluating CAPVAXIVE in vaccine-naïve adults 18-64 years of age at increased risk of pneumococcal disease (Abstract #45, Poster Session: Adult Vaccines); Week 48 data from the Phase 2 study evaluating once-weekly oral islatravir plus lenacapavir (Abstract #577, Late Breaker Oral Abstract Session: What's Going Viral); Data from the SPECTRA (Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam [C/T] Real-world Analysis) study (multiple abstracts) and updates from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance program (multiple abstracts). Details on abstracts listed above and additional key abstracts for Merck: RSV A Phase 2b/3 Study to Evaluate the Efficacy and Safety of an Investigational Respiratory Syncytial Virus (RSV) Antibody, Clesrovimab, in Healthy Preterm and Full-Term Infants. A. Sinha. Abstract #166, Oral Abstract, Late Breaker Abstract Session: Respiratory Viruses Across All Ages Phase 3, Randomized, Controlled Trial Evaluating Safety, Efficacy, and Pharmacokinetics (PK) of Clesrovimab in Infants and Children at Increased Risk for Severe Respiratory Syncytial Virus (RSV) Disease. O. Ramilo. Abstract #167, Oral Abstract, Late Breaker Abstract Session: Respiratory Viruses Across All Ages Pneumococcal A Phase 3, Randomized Trial Investigating the Safety, Tolerability, and Immunogenicity of V116, an Investigational Adult-Specific Pneumococcal Conjugate Vaccine, in Pneumococcal Vaccine-Naïve Adults 18–64 Years of Age with Increased Risk for Pneumococcal Disease. P. Scott. Abstract #45, Poster Session: Adult Vaccines Disparities and Inequities in the Burden of Pneumococcal Disease in US Adults. N. Cossrow. Abstract #242, Poster Session: HAIs: Device-Associated (CLABSI, CAUTI, VAP) Quantifying the Impact of Introducing a New Adult-Focused PCV in the United States. O. Sharomi. Abstract #58, Poster Session: Adult Vaccines HIV Week 48 Results of a Phase 2 Study Evaluating Once-weekly Oral Islatravir Plus Lenacapavir. A. Colson. Abstract #577, Oral Abstract, Late Breaker Abstract Session: What's Going Viral Undesired Weight Gain and Associated Healthcare Outcomes Among People with HIV on Antiretroviral Treatment. B.K. Tadese. Abstract #540, Poster Session: HIV: Treatment Antivirals Drug-Drug Interactions (DDIs) with Letermovir (LET) for Cytomegalovirus (CMV) Prophylaxis in Pediatric (Birth to <18 Years of Age) Hematopoietic Cell Transplant (HCT) Recipients. L. Danziger-Isakov. Abstract #1196, Poster Session: Pediatric Viral Studies A SFGM-TC Real-world Study to Characterize Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) and Identify Both the Cytomegalovirus (CMV) Serology Status of Both Recipients and Their Donors. X. Bourge. Abstract #2356, Poster Session: Virology: Epidemiology of Viral Infections Virologic and Clinical Outcomes Among Participants Hospitalized in a Phase 3 Trial Comparing Molnupiravir with Placebo for Treating Mild-to-Moderate COVID-19. M. Johnson. Abstract #1928, Poster Session: COVID-19: Complications, Coinfections and Clinical Outcomes Antibiotics Treatment Patterns Among Hospitalized Patients with Gram-Negative Infection Treated with Imipenem/Cilastatin/Relebactam (I/R): Retrospective US-Based EHR Medical Chart Review. E. Yucel. Abstract #1075, Poster Session: Novel Agents Effectiveness of Imipenem-Relebactam for Multidrug-resistant Pseudomonas AeruGinosa in PnEumonia and Bloodstream Infections in the United States (MIRAGE): Preliminary Results. R. Shields. Abstract #1105, Poster Session: Novel Agents Comparative Effectiveness of Early Treatment with Ceftolozane/Tazobactam (C/T) Relative to Polymyxin (PB)-based Therapy for Non-COVID-19 Patients (pts) with Pneumonia (PNA) due to Multi-drug Resistant Pseudomonas Aeruginosa (MDR-PSA) Across US Hospitals. T. Lodise. Abstract #1537, Poster Session: Treatment of Antimicrobial Resistant Infections Clinical Outcomes in Patients Hospitalized with Exacerbation of Chronic Respiratory Infections Treated with Ceftolozane/Tazobactam: Results from SPECTRA. E. Yucel. Abstract #1074, Poster Session: Novel Agents Describing the Clinical Characteristics, Treatment Patterns and Outcomes in Hospitalized Pneumonia Patients Treated with Ceftolozane/Tazobactam (C/T): Insights from the SPECTRA Study. E. Yucel. Abstract #1076, Poster Session: Novel Agents Treatment Patterns and Clinical Outcomes in Hospitalized Patients with Febrile Neutropenia Treated with Ceftolozane/Tazobactam: A Subgroup Analysis of the SPECTRA Study. E. Yucel. Abstract #1113, Poster Session: Novel Agents Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam [C/T) Real-world Analysis Results (SPECTRA): Results of Immunocompromised Patients. E. Yucel. Abstract #2305, Poster Session: Transplant: Studies of Empiric and Preemptive Therapy Study of Prescribing patterns and Effectiveness of Ceftolozane/Tazobactam (C/T) Real-world Analysis (SPECTRA): Clinical Outcomes and Treatment Patterns from Mexico. E. Yucel. Abstract #1077, Poster Session: Novel Agents Antimicrobial Epidemiology/Surveillance Susceptibility of Clinical Non-Morganellaceae Enterobacterales Isolates from Bloodstream and Respiratory Tract Infections to Imipenem/Relebactam and Comparators: SMART United States 2020-2022. M. Wise. Abstract #1519, Poster Session: Treatment of Antimicrobial Resistant Infections Activity of Ceftolozane/Tazobactam, Imipenem/Relebactam and Comparators Against Clinical MDR and DTR non-Morganellaceae Enterobacterales and Pseudomonas Aeruginosa Stratified by Patient Age and Hospital Ward: SMART United States 2020-2022. M. Wise. Abstract #1518, Poster Session: Treatment of Antimicrobial Resistant Infections About Clesrovimab (MK-1654) Clesrovimab (MK-1654) is an investigational, extended half-life monoclonal antibody (mAb) developed as a passive immunization for the prevention of RSV. Clesrovimab is designed to be administered as the same single dose, regardless of birth weight, and is being studied in healthy pre-term, full-term and at-risk infants to provide direct, rapid and durable protection through their first RSV season against mild, moderate and severe RSV. About CAPVAXIVE CAPVAXIVE is Merck’s approved 21-valent pneumococcal conjugate vaccine indicated for active immunization for the prevention of invasive disease and pneumonia in adults 18 years of age and older. CAPVAXIVE is specifically designed to help address Streptococcus pneumoniae serotypes predominantly responsible for adult invasive pneumococcal disease (IPD), including eight unique serotypes, 15A, 15C, 16F, 23A, 23B, 24F, 31, and 35B compared to other pneumococcal vaccines. CAPVAXIVE is administered as a single dose. Select Safety Information for CAPVAXIVE Do not administer CAPVAXIVE to individuals with a history of a severe allergic reaction (eg, anaphylaxis) to any component of CAPVAXIVE or to diphtheria toxoid. Individuals with altered immunocompetence, including those receiving immunosuppressive therapy, may have a reduced immune response to CAPVAXIVE. The most commonly reported (>10%) solicited adverse reactions in individuals 18 through 49 years of age who received CAPVAXIVE were: injection-site pain (73.1%), fatigue (36.0%), headache (27.5%), myalgia (16.4%), injection-site erythema (13.8%), and injection-site swelling (13.3%). The most commonly reported (>10%) solicited adverse reactions in individuals 50 years of age and older who received CAPVAXIVE were: injection-site pain (41.2%), fatigue (19.7%), and headache (11.0%). Vaccination with CAPVAXIVE may not protect all vaccine recipients. Authorized Use of LAGEVRIO™ (molnupiravir) in the U.S. LAGEVRIO (molnupiravir) is authorized for use under an Emergency Use Authorization (EUA) for the treatment of adults with mild-to-moderate coronavirus disease 2019 (COVID-19): who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. LAGEVRIO is not approved for any use, including the treatment of COVID-19, but is authorized for emergency use by the FDA under an Emergency Use Authorization (EUA). The emergency use of LAGEVRIO is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 360bbb-3(b)(1) unless the declaration is terminated or authorization revoked sooner. Limitations of Authorized Use LAGEVRIO is not authorized: for use in patients who are less than 18 years of age for initiation of treatment in patients hospitalized due to COVID-19. Benefit of treatment with LAGEVRIO has not been observed in subjects when treatment was initiated after hospitalization due to COVID-19 for use for longer than 5 consecutive days for pre-exposure or post-exposure prophylaxis for prevention of COVID-19 LAGEVRIO may only be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs in the therapeutic class to which LAGEVRIO belongs (ie, anti-infectives). Selected Safety Information for LAGEVRIO Contraindications No contraindications have been identified based on the limited available data on the emergency use of LAGEVRIO authorized under this EUA. Warnings and Precautions There are limited clinical data available for LAGEVRIO. Serious and unexpected adverse events may occur that have not been previously reported with LAGEVRIO use. LAGEVRIO is not recommended for use during pregnancy. Based on findings from animal reproduction studies, LAGEVRIO may cause fetal harm when administered to pregnant individuals. There are no available human data on the use of LAGEVRIO in pregnant individuals to evaluate the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. LAGEVRIO is authorized to be prescribed to a pregnant individual only after the healthcare provider has determined that the benefits would outweigh the risks for that individual patient. If the decision is made to use LAGEVRIO during pregnancy, the prescribing healthcare provider must document that the known and potential benefits and the potential risks of using LAGEVRIO during pregnancy were communicated to the pregnant individual. There is a pregnancy registry that monitors pregnancy outcomes in individuals exposed to LAGEVRIO during pregnancy. The prescribing healthcare provider must document that a pregnant individual was made aware of the pregnancy registry at https://covid-pr.pregistry.com or 1-800-616-3791. Pregnant individuals exposed to LAGEVRIO or their healthcare providers can also report the exposure by contacting Merck Sharp & Dohme LLC, Rahway, NJ, USA at 1-877-888-4231. Advise individuals of childbearing potential of the potential risk to a fetus and to use an effective method of contraception correctly and consistently during treatment with LAGEVRIO and for 4 days after the final dose. Prior to initiating treatment with LAGEVRIO, assess whether an individual of childbearing potential is pregnant or not, if clinically indicated. Hypersensitivity reactions, including anaphylaxis, have been reported with LAGEVRIO. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue LAGEVRIO and initiate appropriate medications and/or supportive care. LAGEVRIO is not authorized for use in patients less than 18 years of age because it may affect bone and cartilage growth. The safety and efficacy of LAGEVRIO have not been established in pediatric patients. Adverse Reactions The most common adverse reactions occurring in ≥1% of subjects in the LAGEVRIO treatment group in the Phase 3 double-blind MOVe-OUT study were diarrhea (2% versus placebo at 2%), nausea (1% versus placebo at 1%), and dizziness (1% versus placebo at 1%) all of which were Grade 1 (mild) or Grade 2 (moderate). Serious adverse events occurred in 7% of subjects receiving LAGEVRIO and 10% receiving placebo; most serious adverse events were COVID-19 related. Adverse events leading to death occurred in 2 (<1%) of the subjects receiving LAGEVRIO and 12 (2%) of subjects receiving placebo. Drug Interactions No drug interactions have been identified based on the limited available data on the emergency use of LAGEVRIO. No clinical drug-drug interaction trials of LAGEVRIO with concomitant medications, including other treatments for mild-to-moderate COVID-19, have been conducted. Pregnancy/Breastfeeding There are no data on the presence of molnupiravir or its metabolites in human milk. It is unknown whether molnupiravir has an effect on the breastfed infant or effects on milk production. Based on the potential for adverse reactions in the infant from LAGEVRIO, breastfeeding is not recommended during treatment with LAGEVRIO and for 4 days after the final dose. A lactating individual may consider interrupting breastfeeding and may consider pumping and discarding breast milk during treatment and for 4 days after the last dose of LAGEVRIO. Males of Reproductive Potential While the risk is regarded as low, there is a theoretical risk for LAGEVRIO to affect offspring of treated males based on its mechanism of action. Advise sexually active individuals with partners of childbearing potential to use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose of LAGEVRIO. The risk beyond three months after the last dose of LAGEVRIO is unknown. Required Reporting for Serious Adverse Events and Medication Errors The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events and medication errors potentially related to LAGEVRIO within 7 calendar days from the healthcare provider’s awareness of the event. Submit adverse event and medication error reports, using FDA Form 3500, to FDA MedWatch using one of the following methods: Complete and submit the report online: www.fda.gov/medwatch/report.htm Complete and submit a postage-paid FDA Form 3500 ( https://www.fda.gov/media/76299/download ) and return by: Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or Fax to 1-800-FDA-0178, or Call 1-800-FDA-1088 to request a reporting form In addition, please provide a copy of all FDA MedWatch forms to: Merck Sharp & Dohme LLC, Rahway, NJ, USA by: Fax: 215-616-5677 Email: dpoc.usa@merck.com Indications for PREVYMIS® (letermovir) PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]). Selected Safety Information for PREVYMIS Contraindications PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis. Warnings and Precautions The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks. In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels. Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. The active ingredient, letermovir, is not known to be associated with ototoxicity. Adverse Reactions The rate of adverse events occurring in at least 10% of adult HSCT recipients treated with PREVYMIS and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one adult HSCT recipient following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation. The most common adverse event occurring in at least 10% of adult kidney transplant recipients treated with PREVYMIS and at a frequency greater than valganciclovir was diarrhea (32% vs 29%). The safety profile of PREVYMIS in pediatric subjects was consistent with the safety profile observed in clinical trials of PREVYMIS in adults. Drug Interactions If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older. If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required. Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full Prescribing Information prior to and during treatment for potential drug interactions. Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment. Use in Specific Populations The safety and effectiveness of PREVYMIS have not been established for: HSCT recipients less than 6 months of age or weighing less than 6 kg, or Kidney transplant recipients less than 12 years of age or weighing less than 40 kg. For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown. Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. Indications and usage for RECARBRIO™ (imipenem, cilastatin, and relebactam) RECARBRIO is indicated for the treatment of patients 18 years of age and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible gram-negative microorganisms: Acinetobacter calcoaceticus-baumannii complex, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens . RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae , and Pseudomonas aeruginosa . RECARBRIO is indicated in patients 18 years of age and older who have limited or no alternative treatment options for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible gram-negative microorganisms: Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Parabacteroides distasonis , and Pseudomonas aeruginosa . Approval of the cUTI and cIAI indications is based on limited clinical safety and efficacy data for RECARBRIO. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of RECARBRIO and other antibacterial drugs, RECARBRIO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Selected Safety Information for RECARBRIO Hypersensitivity Reactions : RECARBRIO is contraindicated in patients with a history of known severe hypersensitivity (severe systemic allergic reaction such as anaphylaxis) to any component of RECARBRIO. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with RECARBRIO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta-lactams, and other allergens. If a hypersensitivity reaction to RECARBRIO occurs, discontinue the therapy immediately. Seizures and Other Central Nervous System (CNS) Adverse Reactions : CNS adverse reactions, such as seizures, confusional states, and myoclonic activity, have been reported during treatment with imipenem/cilastatin, a component of RECARBRIO, especially when recommended dosages of imipenem were exceeded. These have been reported most commonly in patients with CNS disorders (eg, brain lesions or history of seizures) and/or compromised renal function. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether RECARBRIO should be discontinued. Increased Seizure Potential Due to Interaction with Valproic Acid : Concomitant use of RECARBRIO, with valproic acid or divalproex sodium may increase the risk of breakthrough seizures. Avoid concomitant use of RECARBRIO with valproic acid or divalproex sodium or consider alternative antibacterial drugs other than carbapenems. Clostridioides difficile –Associated Diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including RECARBRIO, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C difficile may need to be discontinued. Development of Drug-Resistant Bacteria : Prescribing RECARBRIO in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Adverse Reactions : The most frequently reported adverse reactions occurring in ≥5% of HABP/VABP patients treated with RECARBRIO were aspartate aminotransferase increased (11.7%), anemia (10.5%), alanine aminotransferase increased (9.8%), diarrhea (7.9%), hypokalemia (7.9%), and hyponatremia (6.4%). The most frequently reported adverse reactions occurring in ≥2% of cUTI and cIAI patients treated with RECARBRIO were diarrhea (6%), nausea (6%), headache (4%), vomiting (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), phlebitis/infusion site reactions (2%), pyrexia (2%), and hypertension (2%). Indications and usage for ZERBAXA® (ceftolozane and tazobactam) ZERBAXA is indicated for the treatment of adult patients (18 years and older) with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa , and Serratia marcescens . ZERBAXA is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) with complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis , and Pseudomonas aeruginosa . ZERBAXA used in combination with metronidazole is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) with complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus , and Streptococcus salivarius . Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Important Safety Information for ZERBAXA Patients with renal impairment : Decreased efficacy of ZERBAXA has been observed in patients with baseline CrCl of 30 to <50 mL/min. In a clinical trial of adult patients, patients with cIAIs with CrCl >50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA plus metronidazole vs 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to <50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Dose adjustment is required for adult patients with CrCl 50 mL/min or less. All doses of ZERBAXA are administered over 1 hour. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly. Hypersensitivity : ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane/tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy. Clostridioides difficile -associated diarrhea (CDAD) , ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible. Development of drug-resistant bacteria : Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria. Adverse reactions in adult patients with HABP/VABP : The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the HABP/VABP trial were hepatic transaminase increased (11.9%), renal impairment/renal failure (8.9%), and diarrhea (6.4%). Adverse reactions in adult patients with cIAI or cUTI : The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the cUTI and cIAI trials were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial. Adverse reactions in pediatric patients with cIAI or cUTI : The most common adverse reactions occurring in ≥7% of pediatric patients receiving ZERBAXA in the cIAI trial were diarrhea (17%), thrombocytosis (16%), pyrexia (13%), abdominal pain (11%), vomiting (10%), increased aspartate aminotransferase (7%), and anemia (7%). The most common adverse reactions occurring in ≥7% of pediatric patients receiving ZERBAXA in the cUTI trial were thrombocytosis (9%), leukopenia (8%), diarrhea (7%), and pyrexia (7%). Pediatric Use : There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m2 or less. ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m2 or less. Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m2 or greater at birth or within the first few months of life. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site ( www.sec.gov ). Please see Prescribing Information for CAPVAXIVE (Pneumococcal 21-valent Conjugate Vaccine) at https://www.merck.com/product/usa/pi_circulars/c/capvaxive/capvaxive_pi.pdf and Patient Information/Medication Guide for CAPVAXIVE at https://www.merck.com/product/usa/pi_circulars/c/capvaxive/capvaxive_ppi.pdf Before prescribing LAGEVRIO (molnupiravir) please read the Fact Sheet for Healthcare Providers, including Mandatory Requirements for Administration of Molnupiravir under Emergency Use Authorization, at https://www.merck.com/eua/molnupiravir-hcp-fact-sheet.pdf and Fact Sheet for Patients and Caregivers at https://www.merck.com/eua/molnupiravir-patient-fact-sheet-english.pdf Please see Prescribing Information for PREVYMIS (letermovir) at https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_pi.pdf , Patient Information/Medication Guide for PREVYMIS at https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_ppi.pdf and Instructions for Use for PREVYMIS at https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_ifu.pdf Please see Prescribing Information for RECARBRIO (imipenem, cilastatin, and relebactam) at https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf Please see Prescribing Information for ZERBAXA (ceftolozane and tazobactam) at https://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf Media Contacts: Julie Cunningham (617) 519-6264 Courtney Ronaldo (908) 442-5695 Investor Contacts: Peter Dannenbaum (732) 594-1579 Alexis Constantine (732) 594-1578 Source: Merck & Co., Inc.