丁酮

免责声明：FDA尚未发现此药是安全有效的，并且该标签尚未获得FDA的批准。有关未经批准的药物的更多信息，请点击此处。

描述

盐酸安非他酮是氨基酮类的抗抑郁药，在化学上与三环，四环，选择性5-羟色胺再摄取抑制剂或其他已知的抗抑郁药无关。它的结构与二乙基丙酸非常相似。它与苯乙胺有关。它被称为（±）-1-（3-氯苯基）-2-[（（1,1-二甲基乙基）氨基] -1-丙酮盐酸盐。分子量为276.2。分子式为C13H18CINO-HCl。盐酸安非他酮粉末为白色晶体，易溶于水。它具有苦味，并在口腔粘膜上产生局部麻醉的感觉。它具有以下结构式：



每种口服安非他酮盐酸盐片均含有75毫克或100毫克盐酸安非他酮。此外，每个盐酸安非他酮片均包含以下非活性成分：FDandC蓝色2号铝色淀，FDandC红色40号铝色淀，羟丙基甲基纤维素，微晶纤维素，氯化钾，预胶化淀粉，硬脂酸，二氧化钛和柠檬酸三乙酯。

临床药理学

药效学

安非他酮抗抑郁作用的神经化学机制尚不清楚。安非他酮是去甲肾上腺素和多巴胺的神经元摄取的相对较弱的抑制剂，并且不抑制单胺氧化酶或5-羟色胺的再摄取。

安非他酮在动物体内产生剂量相关的中枢神经系统（CNS）刺激作用，运动能力增强，各种时间表控制的操作行为任务的响应率增加以及高剂量诱导轻度刻板行为证明了这一点。安非他酮在啮齿类动物和狗中引起惊厥，其剂量约为推荐的人类抗抑郁剂剂量的十倍。

药代动力学

安非他酮是外消旋混合物。尚未研究单个对映异构体的药理活性和药代动力学。在人类中，口服安非他酮盐酸盐片后，通常在2小时内达到血浆安非他酮峰值浓度，然后双相下降。最终阶段的平均半衰期为14小时，范围为8到24小时。分布阶段的平均半衰期为3-4小时。慢性给药后，安非他酮的平均消除半衰期（±SD）为21（±9）小时，并且在8天内达到稳态的安非他酮血浆浓度。血浆安非他酮浓度按单次剂量100至250毫克剂量成比例；然而，在长期使用中剂量和血浆水平之间的比例是否保持不变尚不知道。

吸收性
盐酸安非他酮片在人体中的绝对生物利用度尚未确定，因为尚无用于人体的静脉内制剂。但是，很可能只有一小部分口服剂量可以完整地到达体循环。

分配
体外测试表明，安非他酮在高达200 mcg / mL的浓度下与人血浆蛋白结合的比例为84％。羟基安非他酮代谢物的蛋白质结合程度与安非他酮相似，而苏糖氢安非他酮代谢物的蛋白质结合程度约为安非他酮所见程度的一半。

代谢
安非他酮在人体中广泛代谢。已显示三种代谢物具有活性：通过安非他酮的叔丁基羟基化形成的羟基安非他酮，以及通过羰基还原形成的氨基醇异构体苏氢安非他酮和赤氢安非他酮。体外研究结果表明，细胞色素P450IIB6（CYP2B6）是参与羟基安非他酮形成的主要同工酶，而细胞色素P450同工酶不涉及苏氢双氢安非他酮的形成。安非他酮侧链的氧化导致形成间氯苯甲酸的甘氨酸偶联物，然后将其作为主要的尿代谢产物排出体外。尚未完全表征代谢产物相对于安非他酮的效力和毒性。然而，在小鼠的抗抑郁筛选试验中已证明，羟基安非他酮的效力是安非他酮的二分之一，而苏氢氢安非他酮和赤氢安非他酮的效力比安非他酮小5倍。这可能具有临床重要性，因为它们的血浆浓度与安非他酮的血浆浓度相同或更高。

由于安非他酮被广泛代谢，因此存在药物-药物相互作用的潜力，特别是与那些被细胞色素P450IIB6（CYP2B6）同工酶代谢或抑制/诱导的药物，如利托那韦。

在一项健康的志愿者研究中，每天两次两次100 mg的利托那韦可使安非他酮的AUC和Cmax分别降低22％和21％。羟基安非他酮代谢物的暴露减少了23％，苏氢安非他酮减少了38％，而赤氢安非他酮减少了48％。

在第二项健康志愿者研究中，每天两次两次600 mg的利托那韦使安非他酮的AUC和Cmax分别降低66％和62％。羟基安非他酮代谢物的暴露减少了78％，苏氢安非他酮减少了50％，而赤氢安非他酮减少了68％。

在另一项健康的志愿者研究中，KALETRA®*（洛匹那韦400 mg /利托那韦100 mg每天两次）可使安非他酮的AUC和Cmax降低57％。羟基安非他酮的AUC和Cmax分别降低了50％和31％（请参见预防措施：药物相互作用）。

尽管安非他酮不被细胞色素P450IID6（CYP2D6）代谢，但是当安非他酮与被该同工酶代谢的药物共同给药时，仍存在药物-药物相互作用的可能性（请参见注意事项：药物相互作用）。

在人中单次给药后，盐酸安非他酮片给药后约3小时，血浆羟基安非他酮的峰值浓度出现。羟基安非他酮的血浆峰值浓度约为稳态时母体药物峰值水平的10倍。羟基安非他酮的消除半衰期约为20（±5）小时，稳态时的AUC约为安非他酮的17倍。红氢安非他酮和苏氢安非他酮代谢物达到峰值浓度的时间与羟基安非他酮代谢物的峰值时间相似。然而，它们的消除半衰期更长，分别为33（±10）和37（±13）小时，稳态AUC分别是安非他酮的1.5和7倍。

在长期服用300至450 mg /天后，安非他酮及其代谢产物表现出线性动力学。

消除
在人类口服200 mg 14C-安非他酮后，尿液和粪便中分别回收了放射性剂量的87％和10％。然而，盐酸安非他酮片剂的口服剂量不变地排泄的比例仅为0.5％，这一发现与安非他酮的广泛代谢相符。

人口亚组

可能会改变代谢能力的因素或条件（例如，肝病，充血性心力衰竭[CHF]，年龄，伴随用药等）或消除，从而影响安非他酮活性代谢物的累积程度和程度。安非他酮的主要代谢产物的消除可能受到肾或肝功能下降的影响，因为它们是中等极性的化合物，在尿排泄之前可能会在肝脏中进一步代谢或结合。

肝的
肝功能不全对安非他酮的药代动力学的影响在两项单剂量研究中进行了描述，一项研究涉及酒精性肝病患者，一项研究涉及轻度至重度肝硬化患者。第一项研究表明，酒精性肝病患者中羟基安非他酮的半衰期比8名健康志愿者显着更长（分别为32±14小时和21±5小时）。尽管无统计学意义，但是在酒精性肝病志愿者中，用于安非他酮和羟基安非他酮的AUC更具可变性，并且倾向于更大（53％至57％）。在两个患者组中，安非他酮和其他代谢物的半衰期差异很小。

第二项研究表明，与8名健康志愿者相比，在9例轻中度肝硬化患者中，安非他酮及其活性代谢产物的药代动力学无统计学意义差异。然而，在轻度至中度肝硬化患者中，安非他酮的一些药代动力学参数（AUC，Cmax和Tmax）及其活性代谢物（t1 / 2）观察到更多的变异性。此外，在重度肝硬化患者中，与健康志愿者的值相比，安非他酮的Cmax和AUC显着增加（平均差异分别约为70％和3倍），并且变化更大。安非他酮的平均半衰期也更长（重度肝硬化患者为29小时，健康受试者为19小时）。对于代谢物羟基安非他酮，平均Cmax降低约69％。对于组合的氨基醇异构体苏氢安非他酮和赤氢安非他酮，平均Cmax降低约31％。对于羟基安非他酮，平均AUC增加约11/2倍，对于苏/赤氢安非他酮，平均AUC增加约21/2倍。羟基安非他酮在19小时后观察到中值Tmax，苏/赤氢安非他酮在31小时后观察到。与健康志愿者相比，重症肝硬化患者的羟基安非他酮和苏/红氢安非他酮的平均半衰期分别增加了5倍和2倍（请参阅“警告，注意事项以及剂量和给药方法”）。

肾的
关于安非他酮在肾功能不全患者中的药代动力学信息有限。正常受试者与患有终末期肾衰竭的患者之间的研究比较表明，两组母体药物的Cmax和AUC值相当，而羟基安非他酮和苏糖氢安非他酮的代谢物分别增加了2.3倍和2.8倍，在终末期肾衰竭的患者中使用AUC。第二项研究比较了正常受试者和患有中度至重度肾功能不全（GFR 30.9±10.8 mL / min）的患者，发现单剂量150 mg持续释放的安非他酮的暴露量约为受损患者的2倍两组的肾功能和羟基安非他酮和苏/红氢安非他酮（联合）代谢产物的水平相似。肾功能受损可能会减少安非他酮和/或安非他酮的主要代谢产物的消除（请参阅预防措施：肾功能不全）。

左心功能不全
在对14名左心功能不全（CHF病史或X线检查中有心脏扩大史）的抑郁症患者进行的长期剂量研究中，与健康志愿者相比，未发现对安非他酮或其代谢产物的药代动力学有明显影响。

年龄
年龄对安非他酮及其代谢产物的药代动力学的影响尚未完全表征，但通过多次抑郁症研究（涉及剂量为300至750 mg /天的患者）进行了3次探索稳态安非他酮浓度的研究每天的时间表显示，年龄（18至83岁）与安非他酮的血浆浓度之间没有关系。一项单剂量药代动力学研究表明，老年受试者中安非他酮及其代谢产物的分布与年轻受试者相似。这些数据表明年龄对安非他酮浓度没有显着影响。但是，另一项单次和多次剂量的药代动力学研究表明，老年人的安非他酮及其代谢产物蓄积的风险增加（请参阅预防措施：老年用药）。

性别
一项由12位健康的男性和12位健康的女性志愿者进行的单剂量研究表明，安非他酮的药代动力学参数没有性别相关的差异。

烟民
在34名健康的男性和女性志愿者中研究了吸烟对安非他酮药代动力学的影响。 17位是长期吸烟者，17位是不吸烟者。口服给予150 mg安非他酮单剂后，吸烟者和非吸烟者之间的Cmax，半衰期，Tmax，AUC或安非他酮或其活性代谢产物的清除率无统计学差异。

适应症和用途

盐酸安非他酮片适用于治疗重度抑郁症。考虑将盐酸安非他酮片用于治疗患者的首次抑郁症的医生应意识到，该药物可能以剂量依赖的方式引起全身性癫痫发作，其发病率约为0.4％（4 / 1,000）。癫痫发作的发病率可能比其他市售抗抑郁药高出4倍。由于尚未进行任何直接的比较研究，因此该相对风险只是一个大概的估计值（请参阅警告）。

盐酸安非他酮片的功效已在3个安慰剂对照试验中得到证实，其中2个在抑郁症住院患者中持续时间约3周，而2个在抑郁症住院患者中持续时间约6周。所研究患者的抑郁症与APA诊断和统计手册III中的主要抑郁症类别最接近。

重度抑郁症是指突出且相对持续的抑郁或烦躁情绪，通常会干扰日常功能（几乎每天至少持续2周）；它应至少包括以下8种症状中的4种：食欲改变，睡眠改变，精神运动性躁动或发育迟缓，对日常活动失去兴趣或性欲降低，易疲劳性增加，内gui感或无价值感，思维迟钝或受损专心，有自杀念头或企图。

长期使用（即超过6周）盐酸安非他酮片的有效性尚未在对照试验中进行系统评估。因此，选择长时间使用盐酸安非他酮片的医生应定期重新评估该药物对个别患者的长期实用性。

禁忌症

患有癫痫病的患者禁用盐酸安非他酮片。

ZYBAN（盐酸安非他酮）缓释片治疗的患者禁用盐酸安非他酮片； Wellbutrin SR（盐酸安非他酮），缓释制剂； Wellbutrin XL（盐酸安非他酮），缓释制剂；或任何其他含有安非他酮的药物，因为癫痫发作的发生与剂量有关。

在目前或之前诊断为贪食症或神经性厌食症的患者中，禁止使用盐酸安非他酮片，因为在使用盐酸安非他酮片治疗的此类患者中，癫痫发作的发生率较高。

盐酸安非他酮片是禁忌酒精或镇静剂（包括苯二氮卓类）突然停药的患者的药物。

禁止同时使用盐酸安非他酮片和单胺氧化酶（MAO）抑制剂。从停用MAO抑制剂到开始使用盐酸安非他酮片治疗之间应至少间隔14天。

盐酸安非他酮片禁用于对安非他酮或组成盐酸安非他酮片的其他成分有过敏反应的患者。

警告

治疗精神疾病的临床恶化和自杀风险

无论是成人还是儿童，无论是成人还是小儿，患有严重抑郁症（MDD）的患者都可能经历抑郁症的恶化和/或自杀意念和行为（自杀性）的出现或行为的异常变化，无论是否服用抗抑郁药，风险可能会持续到出现重大缓解。自杀是抑郁症和某些其他精神疾病的已知风险，而这些疾病本身是自杀的最强预测因子。但是，长期以来人们一直担心，抗抑郁药可能在治疗的早期阶段在某些患者中引起抑郁症的恶化和自杀倾向的出现。对抗抑郁药（SSRIs和其他药物）的短期安慰剂对照试验的汇总分析表明，这些药物会增加患有严重抑郁症的儿童，青少年和年轻人（18-24岁）的自杀思维和行为（自杀）的风险。疾病（MDD）和其他精神疾病。短期研究并未显示与安慰剂相比，超过24岁的成年人服用抗抑郁药自杀的风险增加。与安慰剂相比，在65岁及以上的成年人中抗抑郁药的含量有所降低。

对患有MDD，强迫症（OCD）或其他精神疾病的儿童和青少年进行的安慰剂对照试验的汇总分析包括对超过4,400名患者的9种抗抑郁药的总共24项短期试验。对患有MDD或其他精神疾病的成人进行的安慰剂对照试验的汇总分析包括对7.7万名患者中的11种抗抑郁药进行的总共295项短期试验（中位持续时间2个月）。药物自杀的风险差异很大，但几乎所有研究的药物，年轻患者的发病率都有增加的趋势。在不同适应症中自杀的绝对风险存在差异，其中MDD的发生率最高。但是，风险差异（药物与安慰剂）在年龄分层内和跨适应症相对稳定。表1列出了这些风险差异（药物-安慰剂治疗的每千名患者中自杀性病例数的差异）。

在任何儿科试验中均未发生自杀。成人试验中有自杀，但数量不足以得出有关自杀药作用的任何结论。

自杀风险是否会扩展到长期使用（即超过数月）尚不清楚。但是，在患有抑郁症的成人中进行的安慰剂对照维持试验的大量证据表明，使用抗抑郁药可以延缓抑郁症的复发。

应适当监测所有接受抗抑郁药治疗的患者的任何适应症，并密切观察其临床恶化，自杀倾向和异常行为变化，尤其是在药物治疗过程的最初几个月中，或在剂量变化时，无论是否增加或减少。

在成年和儿科患者中也有以下症状，焦虑，激动，惊恐发作，失眠，易怒，敌意，攻击性，冲动性，静坐不安（精神运动性躁动不安），躁狂症和躁狂症，也已报告了接受抗抑郁药治疗的重性抑郁症患者至于其他适应症，包括精神病和非精神病。尽管这种症状的出现与抑郁症的恶化和/或自杀性冲动的出现之间的因果关系尚未建立，但令人担忧的是，此类症状可能是自杀倾向的先兆。

对于抑郁持续恶化的患者，或正在经历突然的自杀倾向或可能是抑郁或自杀倾向加剧的症状的患者，应考虑改变治疗方案，包括可能终止用药，尤其是在这些症状严重，突然的情况下发病或不是患者出现症状的一部分。

应提醒正在接受抗抑郁药治疗严重抑郁症或其他精神病和非精神病患者的家属和照顾者注意需要监测患者出现的躁动，烦躁，行为异常变化以及上述其他症状的情况，以及自杀倾向的出现，并立即向医护人员报告此类症状。这种监测应包括家庭和看护者的日常观察。盐酸安非他酮的处方应尽量减少片剂用量，并与患者管理保持一致，以减少用药过量的风险。

戒烟治疗中的神经精神症状和自杀风险

盐酸安非他酮，盐酸安非他酮（缓释制剂）和盐酸安非他酮（缓释剂）未获准戒烟，但已批准将ZYBAN（盐酸安非他酮）缓释片命名为安非他酮。已报告服用安非他酮戒烟的患者出现严重的神经精神症状（见盒装警告，不良反应）。这些包括情绪变化（包括抑郁症和躁狂症），精神病，幻觉，妄想症，妄想，杀人观念，敌意，激动，攻击性，焦虑和恐慌，以及自杀观念，自杀企图和完全自杀。停止吸烟的患者中某些报道的病例可能因尼古丁戒断症状而变得复杂。情绪低落可能是尼古丁戒断的症状。据报道，在没有药物治疗的情况下，尝试戒烟的吸烟者情绪低落，很少有自杀意念。但是，其中一些症状发生在继续吸烟的服用安非他酮的患者中。当出现症状时，大多数是在安非他酮治疗期间，但有些是在停止安非他酮治疗之后。

这些事件发生在有和没有精神疾病的患者中；有些人的精神疾病恶化了。应观察所有接受过安非他酮戒烟治疗的患者的神经精神症状或先前存在的精神疾病恶化。

患有严重精神疾病（例如精神分裂症，双相情感障碍和重度抑郁症）的患者未参加ZYBAN的上市前研究。

告知患者和护理人员，如果观察到躁动，情绪低落，行为或思维改变（对于患者而言不常见）或患者自杀，则应使用安非他酮戒烟的患者应停止服用安非他酮并立即与医疗人员联系。想法或自杀行为。在许多售后案例中，有报道称ZYBAN停用后症状得以缓解，尽管在某些情况下症状仍持续存在，因此，应提供持续的监测和支持治疗，直到症状消失。

使用安非他酮戒烟的风险应与使用它的好处进行权衡。与安慰剂相比，ZYBAN已被证明可以戒烟长达六个月。戒烟对健康的好处是立竿见影的。

筛查双相情感障碍患者

严重的抑郁发作可能是双相情感障碍的最初表现。通常认为（尽管尚未在对照试验中建立），仅用抗抑郁药治疗此类发作可能会增加患有双相情感障碍风险的患者出现混合性/躁狂发作的可能性。上述症状是否代表这种转换尚不清楚。但是，在开始使用抗抑郁药治疗之前，应对具有抑郁症状的患者进行充分筛查，以确定他们是否有患双相情感障碍的风险；此类筛查应包括详细的精神病史，包括自杀，双相情感障碍和抑郁症的家族史。应当指出，盐酸安非他酮片未获批准用于治疗双相抑郁症。

含有安非他酮的产品

应该使患者意识到盐酸安非他酮片含有与ZYBAN中相同的活性成分，可用于戒烟治疗，并且盐酸安非他酮片不应与ZYBAN或任何其他含有安非他酮的药物联合使用，例如包括缓释制剂Wellbutrin SR（盐酸安非他酮）或缓释制剂Wellbutrin XL（盐酸安非他酮）。

癫痫发作

在以最高450毫克/天的剂量治疗的患者中，约有0.4％（4 / 1,000）的患者患有安非他酮。癫痫发作的发病率可能比其他市售抗抑郁药高出4倍。由于尚未进行任何直接的比较研究，因此该相对风险只是一个大概的估计。在450至600 mg /天之间，盐酸安非他酮片的估计癫痫发作率几乎增加了十倍，是通常每日所需剂量（300 mg）的两倍，是最高每日建议剂量（450 mg）的三分之一。鉴于个体之间的广泛差异以及他们代谢和消除药物的能力，这种癫痫发作的发生率与剂量的增加成比例地增加，因此需要谨慎用药。

在最初的开发过程中，约2400例盐酸安非他酮片治疗的患者中有25例发生癫痫发作。癫痫发作时，有7名患者每天接受450 mg或以下的剂量，在推荐剂量范围内的发生率为0.33％（3 / 1,000）。 12名患者以600 mg /天的发作（2.3％的发生率）；另外6名患者的日剂量在600到900 mg之间发生癫痫发作（发生率为2.8％）。

进行了一项单独的前瞻性研究，以确定在约3,200名每天接受剂量最高为450毫克的患者中，在8周的治疗暴露中癫痫发作的发生率。如果有临床指征，则允许患者继续治疗超过8周。在最初的8周治疗期内发生了8次癫痫发作，并且在持续治疗8周以上的患者中报告有5次癫痫发作，导致总癫痫发作发生率为0.4％。

癫痫发作的风险似乎与剂量密切相关。剂量的突然大幅度增加可能会增加风险。尽管许多癫痫发作在治疗过程的早期发生，但在固定剂量数周后确实发生了一些癫痫发作。对于在治疗中出现癫痫发作的患者，应停用盐酸安非他酮片，并且不得重新开始使用。

癫痫发作的风险还与患者因素，临床情况和伴随用药有关，在选择盐酸安非他酮片进行治疗的患者选择中必须考虑这些风险。

-患者因素：使用安非他酮可能增加癫痫发作风险的诱发因素包括头部外伤或先前癫痫发作的历史，中枢神经系统（CNS）肿瘤，严重肝硬化的存在以及降低癫痫发作阈值的伴随药物。
-临床情况：与癫痫发作风险增加相关的情况包括：过度使用酒精或镇静剂（包括苯二氮卓类药物）；对鸦片，可卡因或兴奋剂成瘾；使用非处方兴奋剂和厌食药；以及口服降糖药或胰岛素治疗的糖尿病。
-伴随药物：已知许多药物（例如抗精神病药，抗抑郁药，茶碱，全身性类固醇）可降低癫痫发作阈值。

减少癫痫发作风险的建议
对开发盐酸安非他酮片期间获得的临床经验进行的回顾性分析表明，如果•盐酸安非他酮片的日总剂量不超过450毫克，则可将癫痫发作的风险降至最低。

-每日给药3次，每日剂量每次不超过150 mg，以避免安非他酮和/或其代谢产物的高峰值浓度，和
-剂量增加的速度非常缓慢。
具有癫痫发作，颅外伤或其他易患癫痫病史的患者或接受其他药物治疗的患者（例如抗精神病药，其他抗抑郁药，茶碱，全身性类固醇等）应格外小心地使用盐酸安非他酮片。 ）降低癫痫发作阈值。

肝功能不全

严重肝硬化患者应谨慎使用盐酸安非他酮片。在这些患者中，由于安非他酮峰以及AUC的水平显着增加，因此需要减少剂量和/或频率，并且这种患者中的蓄积可能比平时更大。这些患者每天的剂量不应超过75毫克（请参阅临床药理学，注意事项以及剂量和给药方法）。

潜在的肝毒性

长期接受大剂量安非他酮的大鼠中，肝增生性结节和肝细胞肥大的发生率增加。长期接受大剂量安非他酮的狗在肝脏中观察到各种组织学变化，并且实验室检查表明有轻度肝细胞损伤。

预防措施

一般

躁动和失眠
盐酸安非他酮片治疗的患者中，相当一部分患者会出现某种程度的躁动，躁动，焦虑和失眠，特别是在开始治疗后不久。在临床研究中，这些症状有时足以引起镇静/催眠药的治疗。在大约2％的患者中，症状严重到需要停止使用盐酸安非他酮片的治疗。

精神病，精神错乱和其他神经精神病现象据报道，用盐酸安非他酮片治疗的抑郁症患者表现出多种神经精神病症状和体征，包括妄想，幻觉，精神病，注意力不集中，妄想症和精神错乱。由于许多研究的不受控制的性质，无法准确估计盐酸安非他酮片治疗带来的风险程度。在一些情况下，减少剂量和/或停止治疗会减轻神经精神现象。

激活精神病和/或躁狂症

抗抑郁药可在躁郁症患者的抑郁症发作期间使其躁狂发作，并可能激活其他易感患者的潜在精神病。盐酸安非他酮片预计会带来类似的风险。

食欲和体重改变
在接受盐酸安非他酮片治疗的患者中，有28％的患者体重减轻了5磅以上。该发病率大约是三环类药物或安慰剂治疗患者的两倍。此外，虽然接受三环类抗抑郁药的患者中35％体重增加，但仅9.4％的安非他酮治疗的患者体重增加。因此，如果体重减轻是患者抑郁症的主要表现，应考虑盐酸安非他酮片的厌食和/或减轻体重的潜力。

过敏反应
Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking bupropion hydrochloride tablets and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (eg, skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment. Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

心血管作用
In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy.在有和没有高血压先兆的患者中都观察到了这些事件。

Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and one patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with ZYBAN or placebo.建议对接受安非他酮和尼古丁替代治疗的患者进行血压监测。

There is no clinical experience establishing the safety of bupropion hydrochloride tablets in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.

肝功能不全
Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced dose and frequency is required. Bupropion hydrochloride tablets should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis. All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY, WARNINGS, and DOSAGE AND ADMINISTRATION).

肾功能不全
There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150 mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. Bupropion hydrochloride tablets should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered as bupropion and the metabolites of bupropion may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects that could indicate high drug or metabolite levels.

给患者的信息

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Bupropion Hydrochloride Tablets?” is available for bupropion hydrochloride tablets.开处方者或卫生专业人员应指导患者，其家人和护理人员阅读《用药指南》，并应帮助他们了解其内容。患者应有机会讨论《用药指南》的内容并获得对他们可能遇到的任何问题的解答。本文末尾会重印《用药指南》的全文。 Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking bupropion hydrochloride.

Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.应建议患者的家属和照顾者每天寻找此类症状的出现，因为变化可能会突然发生。此类症状应报告给患者的开药者或卫生专业人员，特别是如果症状严重，起病突然或不属于患者出现的症状时。诸如此类的症状可能与自杀思维和行为的风险增加有关，并表明需要非常密切的监控，并可能需要更换药物。

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation TreatmentAlthough bupropion hydrochloride tablets are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN which is approved for this use. Patients should be informed that quitting smoking, with or without ZYBAN, may be associated with nicotine withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing psychiatric illness. Furthermore, some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Bupropion-Containing Products
Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient found in ZYBAN, used as an aid to smoking cessation, and that bupropion hydrochloride tablets should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as Wellbutrin SR, the sustained-release formulation and Wellbutrin XL, the extended-release formulation).

Patients should be instructed to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day to minimize the risk of seizure. Patients should be told that bupropion hydrochloride tablets should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be told that any CNS-active drug like bupropion hydrochloride tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion hydrochloride tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.

Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with bupropion hydrochloride tablets.

Patients should be advised that the consumption of alcohol should be minimized or avoided. Patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because bupropion hydrochloride tablets and other drugs may affect each other's metabolism.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.

实验室测试

There are no specific laboratory tests recommended.

药物相互作用

Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between bupropion hydrochloride tablets and drugs that are substrates or inhibitors/inducers of the CYP2B6 isoenzyme (eg, orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150 mg sustained-release tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism).

While not systematically studied, certain drugs may induce the metabolism of bupropion (eg, carbamazepine, phenobarbital, phenytoin).

Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.

Drugs Metabolized by Cytochrome P450IID6 (CYP2D6)

Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19 to 35 years) who were
extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (eg, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (eg, haloperidol, risperidone, thioridazine), beta-blockers (eg, metoprolol), and Type 1C antiarrhythmics (eg, propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.

Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its 3 metabolites.

MAO Inhibitors
Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).

Levodopa and Amantadine
Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine. Administration of bupropion hydrochloride tablets to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and small gradual dose increases.

Drugs that Lower Seizure Threshold

Concurrent administration of bupropion hydrochloride tablets and agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution (see WARNINGS). Low initial dosing and small gradual dose increases should be employed.

Nicotine Transdermal System
(See PRECAUTIONS: Cardiovascular Effects)

醇
In post-marketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion hydrochloride tablets. The consumption of alcohol during treatment with bupropion hydrochloride tablets should be minimized or avoided (also see CONTRAINDICATIONS).

致癌，诱变，生育力受损

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not 100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance of these results in estimating the risk of human exposure to therapeutic doses is unknown.

A fertility study was performed in rats; no evidence of impairment of fertility was encountered at oral doses up to 300 mg/kg/day.

怀孕

致畸作用

怀孕类别C
In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively, on a mg/m2 basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.

When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

One study has been conducted in pregnant women. This retrospective, managed-care database study assessed the risk of congenital malformations overall and cardiovascular malformations specifically, following exposure to bupropion in the first trimester compared to the risk of these malformations following exposure to other antidepressants in the first trimester and bupropion outside of the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study showed no greater risk for congenital malformations overall or cardiovascular malformations specifically, following first trimester bupropion exposure compared to exposure to all other antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this study have not been corroborated. Bupropion hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

人工与分娩

The effect of bupropion hydrochloride tablets on labor and delivery in humans is unknown.

护理母亲

Like many other drugs, bupropion hydrochloride tablets and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from bupropion, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

儿科用

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders). Anyone considering the use of bupropion hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need.

老人用

Of the approximately 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies).在这些受试者与较年轻的受试者之间未观察到安全性或有效性的总体差异，其他报告的临床经验也未发现老年与较年轻患者之间的反应差异，但是不能排除某些老年患者的敏感性更高。

A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).

Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction 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 PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).

不良反应

(See also WARNINGS and PRECAUTIONS)

Adverse events commonly encountered in patients treated with bupropion hydrochloride tablets are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.

Adverse events were sufficiently troublesome to cause discontinuation of treatment with bupropion hydrochloride tablets in approximately 10% of the 2,400 patients and volunteers who participated in clinical trials during the product's initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.

Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. Consequently, Table 2 is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of bupropion hydrochloride tablets under relatively similar conditions of daily dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors must differ from those which prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions.

Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion hydrochloride tablets is provided in WARNINGS and PRECAUTIONS.