氢可酮，氯苯那敏和伪麻黄碱

氢可酮，氯苯那敏和伪麻黄碱的适应症和用法

酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液适用于18岁以上患者的咳嗽和上呼吸道症状的临时缓解，包括鼻充血，变态反应或普通感冒。

重要使用限制

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未指定用于18岁以下的小儿患者[请参见在特定人群中使用（8.4） ]

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小于6岁的小儿患者禁忌[参见禁忌症（4） ]

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由于存在成瘾，滥用和误用阿片类药物的风险，即使按推荐剂量服用[见警告和注意事项（5.1） ]，也应储备酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液，用于咳嗽有益的成年患者预计抑制会胜过风险，并且已经对咳嗽的病因进行了充分的评估。

氢可酮，氯苯那敏和伪麻黄碱的剂量和给药

重要剂量和管理说明

只能通过口服途径施用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液。

服用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液时，请务必使用精确的毫升量度装置，以确保准确计量和给药剂量。家用茶匙不是一个精确的测量装置，可能会导致剂量过大[参见警告和注意事项（5.5） ]。对于未提供测量装置的处方，药剂师可以提供适当的测量装置，并可以提供用于测量正确剂量的说明。不要过量填充。每次使用后请用水冲洗测量设备。

建议患者不要增加酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液的剂量或给药频率，因为过量会导致严重的不良反应，例如呼吸抑制[见警告和注意事项（5.2），过量（10） ]。如果咳嗽没有反应，不应增加酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液的剂量；对于潜在的潜在病理应重新评估无反应的咳嗽[参见剂量和用法（2.3），警告和注意事项（5.4） ]。

推荐剂量

18岁及以上的成年人：根据需要每4至6个小时服用5毫升，在24小时内不要超过4剂（20毫升）。

监测，维护和中止治疗

处方最短持续时间的酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液[与警告和注意事项（5.1）一致] 。

密切监测患者的呼吸抑制，尤其是在开始治疗的最初24-72小时内[请参阅警告和注意事项（5.2） ] 。

在5天或更早的时间内对咳嗽无反应的患者进行重新评估，以了解可能的潜在病理状况，例如异物或下呼吸道疾病[请参阅警告和注意事项（5.4） ]。如果患者需要补充药物，请重新评估咳嗽的原因，并评估是否需要继续使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液进行治疗，不良反应的相对发生率以及成瘾，滥用或滥用的发生[请参阅警告和注意事项（5.1） ]。

请勿在对身体有依赖性的患者中突然停用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液[请参阅药物滥用和依赖性（9.3） ]。当已定期服用酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液的患者并且可能身体依赖时，不再需要用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液治疗，剂量逐渐减少25％至50％每2至4天，同时仔细监测停药的体征和症状。如果患者出现这些症状或体征，可通过增加减小之间的间隔，减小剂量的变化量或两者，将剂量提高到先前的水平并逐渐减量。

剂型和优势

口服溶液：每5毫升包含：酒石酸氢可酮USP，5毫克；马来酸氯苯那敏，USP，4 mg；和伪麻黄碱盐酸盐，USP，60毫克。酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液是透明，无色至浅黄色的葡萄味液体。 [参见说明（11） ]

禁忌症

酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液禁忌：

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所有6岁以下的儿童[参见警告和注意事项（5.2），在特定人群中使用（8.4） ]。

下列患者也禁忌使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液：

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严重的呼吸抑制[请参阅警告和注意事项（5.2） ]。

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在不受监控的环境中或没有复苏设备的情况下进行的急性或重度支气管哮喘[请参阅警告和注意事项（5.4） ]。

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已知或怀疑的胃肠道梗阻，包括麻痹性肠梗阻[请参阅警告和注意事项（5.9） ]。

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窄角型青光眼，尿retention留，严重高血压或严重冠状动脉疾病[参见警告和注意事项（5.11） ]。

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对氢可酮，扑尔敏，伪麻黄碱或ZUTRIPRO中的任何非活性成分过敏[见不良反应（6） ]。

警告和注意事项

上瘾，滥用和滥用

酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液均含有氢可酮，是附表二管制物质。作为阿片类药物，酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液使使用者面临上瘾，滥用和误用的风险[请参阅药物滥用和依赖性（9） ] ，这可能导致用药过量和死亡[请参见药物过量（10）] ] 。储备的酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液供成年患者使用，成年患者预期抑制咳嗽的益处大于危险，并且已对咳嗽的病因进行了充分评估。在开处方酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液之前，应评估每个患者的风险，在与个体患者治疗目标相符的最短时间内开出酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液，并定期监测所有患者的病情发展上瘾或虐待，并且只有在重新评估是否需要继续治疗后才能重新装药。

尽管任何人上瘾的风险尚不明确，但在适当处方酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液的患者中可能会发生。如果滥用或滥用药物，则可能以推荐剂量上瘾。具有个人或家庭药物滥用史（包括吸毒或酗酒或成瘾）或精神疾病（例如严重抑郁症）的患者的风险增加。

阿片类药物是吸毒者和成瘾性疾病患者所寻求的，并且会被转用于刑事犯罪。处方或分配酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液时，请考虑这些风险。减少这些风险的策略包括开出最小剂量的适当药物，并建议患者正确处置未使用的药物[参见患者咨询信息（17） ]。请与当地的州专业许可委员会或州控制的物质管理局联系，以获取有关如何预防和检测此产品的滥用或转移的信息。

危及生命的呼吸抑制

使用阿片类药物（包括氢可酮，酒石酸氢可酮中的有效成分之一），马来酸氯苯那敏和盐酸伪麻黄碱口服液等阿片类药物的使用已引起严重，威胁生命或致命的呼吸抑制。氢可酮通过直接作用于控制呼吸节律的脑干呼吸中枢而产生与剂量有关的呼吸抑制，并可能产生不规则的周期性呼吸。如果不立即识别和治疗呼吸抑制，可能会导致呼吸停止和死亡。呼吸抑制的管理包括停用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液，密切观察，支持措施以及根据患者的临床状况使用阿片类药物拮抗剂（例如纳洛酮）[见剂量过量（10） ]。阿片类药物引起的呼吸抑制导致的二氧化碳（CO 2 ）滞留会加剧阿片类药物的镇静作用。

虽然在使用酒石酸氢可待因酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液的任何时间都可能发生严重的，危及生命的生命或致命的呼吸抑制，但在开始治疗时，当酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱的风险最大。口服溶液与其他可能引起呼吸抑制的药物同时使用[请参阅警告和注意事项（5.7） ]，患有慢性肺部疾病或呼吸储备下降的患者以及药代动力学或清除率发生改变的患者（例如，老年人，恶病质或虚弱的患者）[请参阅警告和注意事项（5.3） ]。

为了降低呼吸抑制的风险，必不可少的是要适当剂量的酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液[见剂量和用法（2.1），警告和注意事项（5.5） ]。密切监视患者，尤其是在开始治疗的最初24-72小时内或在高风险患者中使用时。

成人过量使用氢可酮会导致致命的呼吸抑制，建议使用时，六岁以下儿童使用氢可酮会导致致命的呼吸抑制。意外摄入什至一剂酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液，尤其是儿童，可能导致呼吸抑制和死亡。

在儿科人群中使用的风险

儿童对氢可酮的呼吸抑制作用特别敏感[见警告和注意事项（5.2） ]。由于存在危及生命的呼吸抑制和死亡的危险，所以6岁以下的儿童禁忌使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液[参见禁忌症（4） ]。

在儿童中使用酒石酸氢可待因酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液，也使他们面临成瘾，虐待和滥用的风险[见药物滥用和依赖性（9） ] ，这可能导致剂量过量和死亡[见警告和注意事项]。 （5.1），过量（10） ] 。由于对症治疗与变态反应或普通感冒相关的咳嗽的益处并未超过小儿患者使用氢可酮的风险，因此不建议将氢可酮酒石酸氢盐，马来酸氯苯那敏和盐酸伪麻黄碱口服液用于18岁以下的患者。年龄[参见适应症（1），在特定人群中使用（8.4） ]。

在其他风险人群中使用的风险

无反应的咳嗽

如果咳嗽没有反应，不应增加酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液的剂量；对于无反应的咳嗽，应在5天内或更早重新评估可能的潜在病理状况，例如异物或下呼吸道疾病[参见剂量和用法（2.3） ]。

哮喘和其他肺部疾病

禁止在不受监测的情况下或在没有复苏设备的情况下，在急性或重度支气管哮喘患者中使用酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液[见禁忌症（4） ]。

阿片类镇痛药和镇咳药，包括氢可酮，酒石酸氢可酮中的有效成分之一，马来酸氯苯那敏和盐酸伪麻黄碱口服液，不适用于伴有生产性咳嗽的急性发热性疾病或慢性呼吸道疾病而影响能力的患者清除气管支气管分泌物树会对患者的呼吸功能产生有害影响。

氢可酮酒石酸氢盐，马来酸氯苯那敏和盐酸伪麻黄碱口服液治疗的患有严重慢性阻塞性肺疾病或肺心病的患者，以及呼吸储备，低氧血症，高碳酸血症或先前存在呼吸抑制的患者，其呼吸驱动降低的风险增加甚至包括呼吸暂停，甚至以推荐剂量的酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液也是如此[参见警告和注意事项（5.2） ] 。

老人，恶病质，或体弱者：危及生命的呼吸抑制更可能发生在老年人，恶病质或虚弱的病人发生，因为他们可能已经改变的药代动力学或改变间隙相比，更年轻，更健康的患者[见警告和注意事项（5.2）] 。

由于存在呼吸抑制的风险，对于呼吸功能受损的患者，有呼吸衰竭风险的患者以及年长，恶病质或虚弱的患者，避免使用阿片类镇咳药，包括酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液。如果开了酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液，应密切监视这些患者，特别是在开始使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液时，以及同时给予酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液并用会抑制呼吸[请参阅警告和注意事项（5.8） ]。

服药错误导致的意外用药过量和死亡风险

计量错误可能导致意外的服药过量和死亡。为了减少用药过量和呼吸抑制的风险，请确保传达和准确分配氢可酮酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液的剂量[参见剂量和用法（2.1） ]。

建议患者在测量和给药酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液时，始终使用精确的毫升测量装置。告知患者家用茶匙不是一种精确的测量设备，这种使用可能会导致剂量过大和严重的不良反应[参见剂量（10） ]。对于未提供测量装置的处方，药剂师可以提供适当的校准测量装置，并可以提供用于测量正确剂量的说明。

需要精神警觉的活动：驾驶和操作机器的风险

氢可酮酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液中的两种有效成分氢可酮和氯苯那敏可能会产生明显的嗜睡现象，并损害执行潜在危险任务（如驾驶汽车或操作机器）所需的精神和/或身体能力。劝告患者避免在摄入酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液后进行需要精神警觉和运动协调的危险工作。避免与酒精或其他中枢神经系统抑制剂同时使用酒石酸氢可待因酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液，因为中枢神经系统的性能可能会进一步受损[请参阅警告和注意事项（5.8） ] 。

同时使用或停用细胞色素P450 3A4抑制剂和诱导剂的风险

酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液与CYP3A4抑制剂（如大环内酯类抗生素（如红霉素），唑类抗真菌药（如酮康唑）和蛋白酶抑制剂（如利托那韦））同时使用可能会增加血浆浓度的氢可待因酮和延长的阿片类药物不良反应，可能会导致致命的呼吸抑制[见警告和注意事项（5.2） ]，尤其是在达到稳定剂量的酒石酸氢可酮，酒石酸氯苯那敏和盐酸伪麻黄碱口服液后添加抑制剂时。类似地，在酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液治疗的患者中停用CYP3A4诱导剂，如利福平，卡马西平和苯妥英钠，可能会增加氢可酮的血浆浓度并延长阿片类药物的不良反应。

将对氢可酮物理依赖的患者同时使用氢可酮酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液与CYP3A4诱导剂同时使用或停止使用CYP3A4抑制剂可降低氢可酮血浆浓度，降低阿片类药物疗效或可能导致戒断综合征。

服用CYP3A4抑制剂或诱导剂的患者，避免使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液。如果需要同时使用酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液与CYP3A4抑制剂或诱导剂同时使用，请监测患者的体征和症状，以反映阿片类药物的毒性和阿片类药物的戒断[见药物相互作用（7.2，7.3） ]。

与苯二氮卓类或其他中枢神经系统抑制剂同时使用的风险

阿片类药物（包括酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液）与苯二氮卓类或其他中枢神经系统抑制剂（包括酒精）并用可能会导致严重的镇静，呼吸抑制，昏迷和死亡。由于这些风险，请避免在服用苯二氮卓类，其他中枢神经系统抑制剂或酒精的患者中使用阿片类止咳药[参见药物相互作用（7.5） ]。

观察性研究表明，与单独使用阿片类药物相比，同时使用阿片类镇痛药和苯并二氮杂类会增加与药物相关的死亡风险。由于具有相似的药理特性，可以合理预期同时使用阿片类止咳药和苯二氮卓类药物，其他中枢神经系统抑制剂或酒精会带来类似的风险。

如果将酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液与苯二氮卓类，酒精或其他中枢神经系统抑制剂一起使用，请告知患者和护理人员有关呼吸抑制和镇静的风险[请参阅患者咨询信息（17） ] 。

患者不得在酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液疗法中饮用含酒精的饮料，含酒精的处方或非处方产品。酒精与酒石酸氢可待因酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液的共同摄入可能导致血浆水平升高和氢可酮的潜在致命过量[见药物相互作用（7.1，7.5） ]

胃肠道疾病患者的使用风险

已知或疑似胃肠道梗阻（包括麻痹性肠梗阻）的患者禁用禁忌酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液[见禁忌证（4） ]。在酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液中使用氢可酮可能会掩盖急性腹部疾病患者的诊断或临床病程。

将抗胆碱药与酒石酸氢可待酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液同时使用可能产生麻痹性肠梗阻[见药物相互作用（7.10） ]。

酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液中的氢可酮可能会导致便秘或肠梗阻，特别是在有潜在肠动力障碍的患者中。潜在的肠道动力障碍患者慎用。

酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液中的氢可酮可能会引起奥迪括约肌痉挛，导致胆道压力升高。阿片类药物可能导致血清淀粉酶升高[参见警告和注意事项（5.16） ]。监测包括急性胰腺炎在内的胆道疾病患者的症状是否恶化。

头部受伤，意识受损，颅内压增高或脑肿瘤的患者使用的风险

对于头部受伤，颅内病变或颅内压已有升高的患者，避免使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液。对于可能易受颅内CO 2滞留影响的患者（例如，有颅内压升高或脑肿瘤的证据的患者），酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液可能会减少呼吸驱动，并导致CO 2滞留可以进一步增加颅内压。此外，阿片类药物会产生不良反应，可能使头部受伤患者的临床病程难以理解。

心血管和中枢神经系统的影响

酒石酸氢可待因酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液中所含的伪麻黄碱可在某些患者中产生心血管和中枢神经系统作用，例如失眠，头晕，虚弱，震颤，血压短暂升高或心律不齐。此外，据报道有惊厥引起的中枢神经系统刺激或伴有低血压的心血管衰竭。因此，重度高血压或冠心病患者忌用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液[见禁忌症（4） ]，其他心血管疾病患者应谨慎使用。

癫痫病患者的癫痫发作风险增加

酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液中的氢可待酮和氯苯那敏可能会增加癫痫发作患者的癫痫发作频率，并可能增加在与癫痫发作相关的其他临床情况下发生癫痫发作的风险。监测有癫痫病史的患者，以在酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液治疗期间癫痫发作控制恶化。

严重低血压

氢可酮酒石酸氢盐，马来酸氯苯那敏和盐酸伪麻黄碱口服液可能会引起非卧床患者的严重低血压，包括体位性低血压和晕厥。降低血压或同时服用某些中枢神经系统抑制药（例如吩噻嗪或全身麻醉剂）已使维持血压的能力受到损害的患者风险增加[见药物相互作用（7.5） ] 。在开始使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液后，监测这些患者的低血压迹象。

在循环休克患者中，酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液可能引起血管舒张，从而进一步降低心输出量和血压。循环休克患者应避免使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液。

新生儿阿片类药物戒断综合征

不建议孕妇使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服溶液。怀孕期间长时间使用酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液可导致新生儿停药。与成人类鸦片戒断综合征不同，新生儿类鸦片戒断综合征如果不得到认可和治疗，可能会危及生命，并且需要根据新生儿科专家制定的方案进行管理。观察新生儿的新生儿阿片戒断综合征的征兆，并据此进行处理。建议孕妇长时间使用阿片类药物有新生儿阿片戒断综合征的风险，并确保可获得适当的治疗。 [参见“在特定人群中使用（8.1），患者咨询信息（17）]”

肾上腺功能不全

据报道，使用阿片类药物导致肾上腺皮质功能不全的病例，多于使用一个月以上。肾上腺功能不全的表现可能包括非特异性症状和体征，包括恶心，呕吐，厌食，疲劳，虚弱，头晕和低血压。如果怀疑肾上腺功能不全，请尽快通过诊断测试确认诊断。如果诊断出肾上腺功能不全，请使用生理替代剂量的皮质类固醇治疗。使患者断奶，以使肾上腺功能恢复，并继续皮质类固醇治疗直至肾上腺功能恢复。可以尝试使用其他阿片类药物，因为有些病例报道使用了其他阿片类药物，但没有肾上腺功能不全的复发。可用信息未确定任何特定的阿片类药物更可能与肾上腺功能不全有关

药物/实验室测试的相互作用

由于阿片类激动剂可能会增加胆道压力，从而导致血浆淀粉酶或脂肪酶水平升高，因此在服用一定剂量的酒石酸氢可酮，马来酸氯苯那敏和盐酸伪麻黄碱口服液后24小时，对这些酶水平的测定可能是不可靠的。

不良反应

在其他部分中描述或更详细地描述了以下严重不良反应：

•

上瘾，滥用和误用[请参阅警告和注意事项（5.1），药物滥用和依赖性（9.3） ]

•

Life-threatening respiratory depression [ see Warnings and Precautions (5.2, 5.3, 5.4, 5.8), Overdosage (10) ]

•

Accidental overdose and death due to medication errors [ see Warnings and Precautions (5.5) ]

•

Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions (5.6) ]

•

Interactions with benzodiazepines and other CNS depressants [ see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.5) ]

•

Paralytic ileus, gastrointestinal adverse reactions [ see Warnings and Precautions (5.9) ]

•

Increased intracranial pressure [ see Warnings and Precautions (5.10) ]

•

Obscured clinical course in patients with head injuries [ see Warnings and Precautions (5.10) ]

•

Cardiovascular and CNS effects [ see Warnings and Precautions (5.11) ]

•

Seizures [ see Warnings and Precautions (5.12) ]

•

Severe hypotension [ see Warnings and Precautions (5.13) ]

•

Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.14) ]

•

Adrenal insufficiency [ see Warnings and Precautions (5.15) ]

The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone, chlorpheniramine, and/or pseudoephedrine. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most common adverse reactions to hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation tachycardia, arrhythmias including premature ventricular contractions, CNS stimulation including anxiety, restlessness, nervousness, tremor, and irritability.

其他反应包括：

Anaphylaxis: Anaphylaxis has been reported with hydrocodone, one of the ingredients in hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution.

Body as a whole : Coma, death, fatigue, falling injuries, lethargy, weakness, hyperthermia, ataxia, vertigo.

Cardiovascular : Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush, atrial fibrillation, myocardial infarction.

Central Nervous System : Facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tremor.

Dermatologic : Flushing, hyperhidrosis, pruritus, rash. Cases of severe skin reactions such as acute generalized exanthematous pustulosis (AGEP) have been reported with pseudoephedrine-containing products.

Endocrine/Metabolic : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology (12.2) ].

Gastrointestinal : Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi), dysgeusia, ischemic colitis.

Genitourinary : Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention.

Hematologic : Agranulocytosis, aplastic anemia, and thrombocytopenia have been reported.

Laboratory : Increases in serum amylase.

Musculoskeletal : Arthralgia, backache, muscle spasm.

Ophthalmic : Miosis (constricted pupils), visual disturbances, mydriasis (dilated pupils), blurred vision, diplopia.

Psychiatric : Agitation, anxiety, confusion, fear, dysphoria, depression, hyperactivity, ataxia, confusion, hallucinations, hyperexcitability.

Reproductive : Hypogonadism, infertility.

Respiratory : Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection, thickening of bronchial secretions, tightness of chest and wheezing, dry nose, dry throat, tinnitus.

Other : Drug abuse, drug dependence, opioid withdrawal syndrome.

药物相互作用

No specific drug interaction studies have been conducted with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution.

醇

Concomitant use of alcohol with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution therapy [ see Warnings and Precautions (5.8), Clinical Pharmacology (12.3) ] .

Inhibitors of CYP3A4 and CYP2D6

The concomitant use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution and CYP3A4 inhibitors, such as macrolide antibiotics (eg, erythromycin), azole-antifungal agents (eg ketoconazole), or protease inhibitors (eg, ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution is achieved [ see Warnings and Precautions (5.7) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [ see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.

Avoid the use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

CYP3A4 Inducers

The concomitant use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [ see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [ see Warnings and Precautions (5.7) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [ see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Avoid the use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

苯妥英

Adverse event reports in the literature suggest a possible drug interaction involving increased serum phenytoin levels and phenytoin toxicity when chlorpheniramine and phenytoin are co-administered. The exact mechanism for this interaction is not known, however it is believed that chlorpheniramine may inhibit the hepatic metabolism of phenytoin. Avoid the use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution in patients who are taking phenytoin.

Benzodiazepines, and Other CNS Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution in patients who are taking benzodiazepines or other CNS depressants [ see Warnings and Precautions (5.8) ], and instruct patients to avoid consumption of alcohol while on hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution [ see Drug Interactions (7.1), Patient Counseling Information (17) ].

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

Avoid the use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (eg, respiratory depression, coma) . An increase in blood pressure or hypertensive crisis may also occur when pseudoephedrine containing preparations are used with MAOIs.

Muscle Relaxants

Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

利尿剂

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [ see Warnings and Precautions (5.9) ]. Monitor patients for signs of urinary retention or reduced gastric motility when hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution is used concomitantly with anticholinergic drugs.

Additive adverse effects resulting from cholinergic blockade (eg, xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine.

Antihypertensive Drugs

Due to the antagonistic pharmacologic effects of pseudoephedrine, one of the active ingredients in hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution, the concomitant use of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution with antihypertensive drugs which interfere with sympathetic activity (eg, methyldopa, mecamylamine, and reserpine) may reduce their antihypertensive effects. Use hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution with caution in patients who are taking antihypertensive drugs.

洋地黄

Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Use hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution with caution in patients who are taking digitalis.

在特定人群中的使用

怀孕

风险摘要

Hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution is not recommended for use in pregnant women, including during or immediately prior to labor.

Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [ see Warnings and Precautions (5.13), Clinical Considerations ].

There are no available data with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Published studies with hydrocodone have reported inconsistent findings and have important methodological limitations ( see Data ).

Reproductive toxicity studies have not been conducted with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution; however, studies are available with individual active ingredients or related active ingredients ( see Data ).

In animal reproduction studies, hydrocodone administered by the subcutaneous route to pregnant hamsters during the period of organogenesis produced a teratogenic effect at a dose approximately 70 times the maximum recommended human dose (MRHD) ( see Data ).

Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryolethal at a dose approximately 9 times the MRHD and decreased postnatal survival when dosing was continued after parturition. Chlorpheniramine administered by the oral route to male and female rats prior to mating produced embryolethality at a dose approximately 9 times the MRHD ( see Data ).

Based on the animal data, advise pregnant women of the potential risk to a fetus.

对于指定人群，估计的主要先天缺陷和流产的背景风险尚不清楚。所有怀孕都有出生缺陷，流产或其他不良后果的背景风险。 In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Consideration

胎儿/新生儿不良反应

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [ see Warnings and Precautions (5.14) ].

Maternal use of pseudoephedrine can cause fetal tachycardia.

人工或分娩

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression.

数据

人数据

Hydrocodone

A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing hydrocodone use during pregnancy. However, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size and lack of details regarding dose, duration and timing of exposure.

Chlorpheniramine

The majority of studies examining the use of chlorpheniramine in pregnancy did not find an association with an increased risk of congenital anomalies. In the few studies reporting an association, there was no consistent pattern of malformations noted.

Pseudoephedrine

The majority of studies examining the use of pseudoephedrine in pregnancy did not find an association with an increased risk of congenital anomalies. Some studies reported an association with an increased risk of gastroschisis. However, several similar studies did not find a statistically significant association. Methodological limitations of these studies included small sample size, recall bias and lack of information regarding dose and timing of exposure.

动物资料

Reproductive toxicity studies have not been conducted with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution; however, studies are available with individual active ingredients or related active ingredients.

Hydrocodone

In an embryofetal development study in pregnant hamsters dosed on gestation day 8 during the period of organogenesis, hydrocodone induced cranioschisis, a malformation, at approximately 70 times the MRHD (on a mg/m 2 basis with a maternal subcutaneous dose of 102 mg/kg). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone. In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, codeine increased resorptions and decreased fetal weights at a dose approximately 95 times the MRHD of hydrocodone (on a mg/m 2 basis with a maternal oral dose of codeine at 120 mg/kg/day); however, these effects occurred in the presence of maternal toxicity. In embryofetal development studies with pregnant rabbits and mice dosed throughout the period of organogenesis, codeine produced no adverse developmental effects at doses approximately 50 and 240 times, respectively, the MRHD of hydrocodone (on a mg/m 2 basis with maternal oral doses of codeine at 30 mg/kg/day in rabbits and 600 mg/kg/day in mice).

Chlorpheniramine

In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, chlorpheniramine produced no adverse developmental effects at oral doses up to approximately 35 and 45 times, respectively, the MRHD on a mg/m 2 basis. However, in a reproduction study with pregnant mice dosed throughout pregnancy, chlorpheniramine produced embryolethality at a dose approximately 9 times the MRHD (on a mg/m 2 basis with a maternal oral dose of 20 mg/kg/day) and decreased postnatal survival when dosing was continued after parturition. In a fertility and reproduction study with male and female rats dosed prior to mating, chlorpheniramine produced embryolethality at a dose approximately 9 times the MRHD (on a mg/m 2 basis with an oral parental dose of 10 mg/kg/day).

Pseudoephedrine

Animal studies with pseudoephedrine are not available.

哺乳期

风险摘要

Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution.

There are no data on the presence of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution in human milk, the effects of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution on the breastfed infant, or the effects of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution on milk production; however, data are available with hydrocodone, chlorpheniramine, and pseudoephedrine.

Hydrocodone

Hydrocodone is present in breast milk. Published cases report variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period with relative infant doses of hydrocodone ranging between 1.4 and 3.7%. There are case reports of excessive sedation and respiratory depression in breastfed infants exposed to hydrocodone. No information is available on the effects of hydrocodone on milk production.

Chlorpheniramine

Chlorpheniramine is present in human milk. Chlorpheniramine has not been reported to cause effects on the breastfed infant. The published literature suggests that chlorpheniramine may decrease milk production based on its anticholinergic effects. ( see Clinical Considerations )

Pseudoephedrine

Pseudoephedrine is present in human milk. Pseudoephedrine has been reported to decrease milk production ( see Data ). Pseudoephedrine has been reported to cause “irritability” in a breastfed infant ( see Clinical Considerations and Data ) .

临床注意事项

Infants exposed to hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution through breast milk should be monitored for excess sedation, respiratory depression, and irritability. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped.

数据

Pseudoephedrine

In a study of eight lactating women, who were 8 to 76 weeks postpartum and received a single dose of 60 mg of pseudoephedrine, the mean 24-hour milk production was reduced by 24%. In the same study, the estimated mean relative infant dose from breast milk (assuming mean milk consumption of 150 ml/kg/day and a maternal dosing regimen of 60 mg pseudoephedrine four times per day) was calculated to be 4.3% of the weight-adjusted maternal dose.

Females and Males of Reproductive Potential

不孕症

Chronic use of opioids, such as hydrocodone, a component of hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [ see Adverse Reactions (6), Clinical Pharmacology (12.2) ] .

儿科用

Hydrocodone bitartrate, chlorpheniramine maleate and pseudoephedrine hydrochloride oral solution is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients [