Budeprion SR（口服）

处方信息

仅Rx

Budeprion SR平板电脑说明

BUDEPRION SR®（安非他酮盐酸盐），氨基酮类的抗抑郁剂，在化学上是不相关的三环，四环，选择性血清素再摄取抑制剂，或其它已知的抗抑郁剂。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C 13 H 18 ClNO·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。结构式为：

BUDEPRION SR®用于口服给药为100毫克和150毫克，薄膜包衣，缓释片剂提供。每片含有标记量的盐酸安非他酮和非活性成分：胶体二氧化硅，羟丙基纤维素，硬脂酸镁和微晶纤维素。 100毫克片剂还包含FD＆C红色40号，FD＆C黄色5号，羟丙甲纤维素，氧化铁黄，聚乙二醇，聚葡萄糖，二氧化钛和三醋精。 150毫克片剂还含有羟丙甲纤维素，氧化铁黄，聚乙二醇，聚葡萄糖，二氧化钛和三醋精。

该产品符合USP药物释放测试＃3。

Budeprion SR片剂-临床药理学

药效学

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。虽然与其他抗抑郁药一样，安非他酮的作用机理尚不清楚，但推测该作用是由去甲肾上腺素能和/或多巴胺能机制介导的。

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。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。在一项将150毫克盐酸安非他酮缓释片的慢性给药与每天100毫克安非他酮速释制剂，每天3次进行长期给药的比较中，盐酸安非他酮缓释片的稳态血浆血浆浓度最高（SR）约为速释制剂的85％。安非他酮的AUC值相等，所有3种可检测的安非他酮代谢物的血浆峰浓度和AUC值均相等。因此，在稳态下，每天两次给予的盐酸安非他酮缓释片（SR）和每天给予3次的安非他酮速释制剂对于安非他酮和3种在定量上重要的代谢物基本上是生物等效的。

吸收性

与食物一起服用盐酸安非他酮缓释片（SR）可能会增加对安非他酮的暴露。在健康志愿者中进行的三项研究表明，与食物一起服用时，安非他酮的血浆峰值浓度（C max ）增加了11％至35％，而安非他酮的总体暴露量（AUC）增加了16％至19％。认为食物的作用没有临床意义，可以与食物一起或不与食物一起服用盐酸安非他酮缓释片（SR）。

分配

体外试验表明，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间氯苯甲酸的甘氨酸共轭物的形成，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，因为代谢产物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，如利托那韦或依非韦伦。在一项健康的志愿者研究中，每天两次100 mg的利托那韦可使安非他酮的AUC和C max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600 mg利托那韦使安非他酮的AUC和C max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％。

在另一个健康志愿者的研究中，KALETRA®（洛匹那韦400毫克/利托那韦100毫克，每天两次）由57％减少安非他酮AUC和Cmax。羟基安非他酮的AUC和C max分别降低了50％和31％（请参见预防措施：药物相互作用）。

在一项针对健康志愿者的研究中，依非韦伦600 mg每天一次，持续2周，可使安非他酮的AUC和C max分别降低约55％和34％。羟基安非他酮的AUC不变，而羟基安非他酮的C max增加了50％。

尽管安非他酮不被细胞色素P450IID6（CYP2D6）代谢，但当安非他酮与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）。

在人类中单次给药后，盐酸安非他酮缓释片（SR）给药约6小时后，羟基安非他酮的血浆峰值浓度出现。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，其稳态下的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

在人体内口服200 mg 14 C-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，安非他酮口服剂量的排泄比例仅为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，但酒精性肝病患者的安非他酮和羟基安非他酮的AUC更具可变性，并且往往更大（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。

第二项研究显示，与8名健康志愿者相比，在9例轻度至中度肝硬化患者中，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，C max和T max ）及其活性代谢物（t 1/2 ）存在更大的变异性。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C max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C max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C max降低约31％。对于羟基安非他酮，平均AUC增加约1.5倍，对于苏/赤氢安非他酮，平均AUC增加约2.5倍。在19小时后观察到羟基安非他酮的中值T max ，在苏/赤氢安非他酮后31小时观察到。与健康志愿者相比，重度肝硬化患者中羟基安非他酮和苏/赤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，两组的母体药物C max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2.3倍和2.8倍，在AUC中用于晚期肾功能衰竭的患者。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水平约为2倍。肾功能受损，而两组中的羟基安非他酮和苏/红氢安非他酮（合并）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（请参见预防措施：肾功能不全）。

左心功能不全

在对14名左心功能不全的抑郁患者（CHF病史或X线检查中有心脏增大的病史）进行的慢性安非他酮剂量研究中，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（请参见预防措施：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C max ，半衰期，T max ，AUC或安非他酮或其活性代谢产物的清除率无统计学差异。

临床试验

在两项针对成人抑郁症住院患者的4周安慰剂对照试验和一项针对成年人抑郁症成人患者进行的6周安慰剂对照试验中，建立了安非他酮速释制剂治疗抑郁症的功效。在第一个研究中，安非他酮剂量范围为300至600毫克/天，每天3次，进行滴定。 78％的患者接受的最大剂量为450毫克/天或更低。该试验在汉密尔顿抑郁量表（HDRS）总评分，该量表中的抑郁情绪项（项目1）和临床总体印象（CGI）严重程度评分中证明了安非他酮速释制剂的有效性。第二项研究包括2个固定剂量的安非他酮速释制剂（300和450 mg /天）和安慰剂。该试验证明了安非他酮速释制剂的有效性，但仅在450 mg /天的剂量下有效。结果对HDRS总分和CGI严重度得分均为阳性，但对HDRS第1项结果却不为阳性。在第三项研究中，门诊患者每天服用300毫克安非他酮速释制剂。这项研究证明了安非他酮速释制剂对HDRS总评分，HDRS第1项，蒙哥马利-阿斯伯格抑郁量表，CGI严重程度评分和CGI改善评分的有效性。

尽管目前尚无独立的试验证明安非他酮缓释制剂的抗抑郁作用，但研究表明，稳态状态下安非他酮的即释和持续释放形式即安非他酮缓释具有生物等效性。就母体药物和代谢产物的吸收速率和吸收程度而言，每天两次两次服用150毫克与安非他酮速释制剂每天三次100毫克具有生物等效性。

在一项长期研究中，符合DSM-IV标准的重度抑郁症（复发型）的门诊患者在一项为期8周的盐酸安非他酮缓释片（SR）（150 mg每天两次）的公开试验中有反应，被随机分配至持续服用相同剂量的盐酸安非他酮缓释片（SR）或安慰剂，长达44周的复发观察。开放阶段的反应被定义为在最后3周中的每一个CGI改善得分为1（大大改善）或2（大大改善）。双盲阶段的复发被定义为研究者认为需要药物治疗来使抑郁症状恶化。与接受安慰剂的患者相比，接受盐酸安非他酮缓释片（SR）持续治疗的患者在随后的44周内复发率显着降低。

Budeprion SR片的适应症和用法

盐酸安非他酮缓释片（SR）适用于治疗重度抑郁症。

在两项抑郁症住院患者的4周对照试验和一项抑郁症门诊患者6周对照试验中确立了安非他酮在治疗重度抑郁发作中的疗效，该试验的诊断与APA诊断和治疗的重度抑郁症最接近统计手册（DSM）（请参阅临床药理学）。

严重的抑郁发作（DSM-IV）表示存在1）情绪低落或2）失去兴趣或愉悦；此外，在相同的2周内，至少出现以下5种症状，这些症状与以前的功能有所不同：情绪低落，对日常活动的兴趣或愉悦感明显降低，体重和/或食欲显着变化，失眠或失眠，精神运动性躁动或发育迟缓，疲劳加剧，内感或无价值感，思维减慢或注意力不集中，自杀企图或自杀意念。

在安慰剂对照试验中，证实了盐酸丙酸安非他酮缓释片（SR）在急性治疗8周后维持抗抑郁应答长达44周的功效（请参阅临床药理学）。但是，选择长时间使用盐酸安非他酮缓释片（SR）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

癫痫发作患者禁用盐酸安非他酮缓释片（SR）。

安非他酮盐酸盐缓释片剂（SR）与ZYBAN治疗的患者是禁忌®[盐酸安非他酮缓释片剂（SR）]; WELLBUTRIN®（安非他酮盐酸盐的片剂），所述速释制剂; WELLBUTRIN XL®[盐酸安非他酮缓释片剂（XL）]时，延长释放制剂;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。

在目前或先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缓释片（SR），因为在以速食安非他酮速释制剂治疗贪食症的患者中，癫痫发作的发生率较高。

盐酸安非他酮缓释片（SR）禁止突然停用酒精或镇静剂（包括苯二氮卓类）的患者。

禁止将单胺氧化酶抑制剂或MAOI（旨在治疗精神疾病）与盐酸安非他酮缓释片（SR）同时使用，或在停止使用盐酸安非他酮缓释片（SR）治疗后的14天内使用。当安非他酮与其他抑制多巴胺或去甲肾上腺素再摄取或抑制其代谢的药物（例如，MAOI）同时使用时，发生高血压反应的风险增加。也禁止在停止使用MAOI治疗后的14天内使用盐酸安非他酮缓释片（SR）。禁忌在使用可逆性MAOI（如利奈唑胺或静脉注射亚甲蓝）治疗的患者中使用盐酸安非他酮缓释片（SR）（请参阅“剂量与管理和药物相互作用” ）。

盐酸安非他酮缓释片（SR）禁用于对安非他酮或组成盐酸安非他酮缓释片（SR）的其他成分有过敏反应的患者。

警告事项

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至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岁的成年人使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下降。

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例患者的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-安慰剂在每1,000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。

对于抑郁持续恶化或正在出现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，包括可能中止用药，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。盐酸安非他酮缓释片（SR）的处方应尽量减少片剂用量，与患者的良好管理保持一致，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

WELLBUTRIN®，盐酸安非他酮缓释片（SR），和WELLBUTRIN XL®没有批准用于戒烟治疗，但名称ZYBAN®下安非他酮被批准用于这种用途。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。

患有严重的精神疾病如精神分裂症，双相情感障碍和重度抑郁症没有参加ZYBAN®的前期市场调查。

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。在许多情况下，上市后的ZYBAN®停药后症状缓解报道，虽然在某些情况下，症状持续，因此，持续监测和支持治疗，应直到症状缓解提供。

使用安非他酮戒烟的风险应与使用它的好处进行权衡。 ZYBAN®已经证明，以增加从吸烟长达六个月相比，与安慰剂治疗戒酒的可能性。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。 It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder;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。 It should be noted that bupropion hydrochloride extended-release tablets (SR) are not approved for use in treating bipolar depression.

Bupropion-Containing Products

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in ZYBAN ® , used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN ® , or any other medications that contain bupropion, such as WELLBUTRIN ® (bupropion hydrochloride), the immediate-release formulation or WELLBUTRIN XL ® (bupropion hydrochloride), the extended-release formulation.

癫痫发作

Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride extended-release tablets (SR).

Bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment.

• Dose: At doses of bupropion hydrochloride extended-release tablets (SR) up to a dose of 300 mg/day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg/day.
  
  Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (ie, 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of this dose range is close to the currently recommended maximum dose of 400 mg/day for bupropion hydrochloride extended-release tablets (SR).
  
  This seizure incidence (0.4%) may exceed that of other marketed antidepressants and bupropion hydrochloride extended-release tablets (SR) up to 300 mg/day by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted.
  
  Additional data accumulated for the immediate-release formulation of bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day, which is twice the usual adult dose and one and one-half the maximum recommended daily dose (400 mg) of bupropion hydrochloride extended-release tablets (SR). This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
  
  Data for bupropion hydrochloride extended-release tablets (SR) revealed a seizure incidence of approximately 0.1% (ie, 3 of 3,100 patients followed prospectively) in patients treated at doses in a range of 100 to 300 mg/day. It is not possible to know if the lower seizure incidence observed in this study involving the sustained-release formulation of bupropion resulted from the different formulation or the lower dose used. However, as noted above, the immediate-release and sustained-release formulations are bioequivalent with regard to both rate and extent of absorption during steady state (the most pertinent condition to estimating seizure incidence), since most observed seizures occur under steady-state conditions.
• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (eg, antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.

Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if

• the total daily dose of bupropion hydrochloride extended-release tablets (SR) does not exceed 400 mg,
• the daily dose is administered twice daily, and
• the rate of incrementation of dose is gradual.
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion and/or its metabolites.

Bupropion hydrochloride extended-release tablets (SR) should be administered with extreme caution to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with other agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.

Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 100 mg every day or 150 mg every other day in these patients (see CLINICAL PHARMACOLOGY , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ).

In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.

预防措施

一般

Patients in placebo-controlled trials with bupropion hydrochloride extended-release tablets (SR) experienced agitation, anxiety, and insomnia as shown in Table 2.

In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.

Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion hydrochloride extended-release tablets (SR) and 0.8% of patients treated with placebo.

Depressed patients treated with an immediate-release formulation of bupropion or with bupropion hydrochloride extended-release tablets (SR) have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Bupropion hydrochloride extended-release tablets (SR) are expected to pose similar risks.

In placebo-controlled studies, patients experienced weight gain or weight loss as shown in Table 3.

In studies conducted with the immediate-release formulation of bupropion, 35% of patients receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride extended-release tablets (SR) should be considered.

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 extended-release tablets (SR) 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.

The 100 mg strength of this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.

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 1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with ZYBAN ® or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

There is no clinical experience establishing the safety of bupropion hydrochloride extended-release tablets (SR) 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.

重型肝硬化患者应谨慎使用盐酸安非他酮缓释片（SR）。 In these patients, a reduced frequency and/or dose is required. Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and 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 ).

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 C max 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 extended-release tablets (SR) 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 extended-release tablets (SR) 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 Extended-Release Tablets (SR)?" is available for bupropion hydrochloride extended-release tablets (SR). The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets (SR).

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. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Although bupropion hydrochloride extended-release tablets (SR) 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.

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in ZYBAN ® , used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN ® or any other medications that contain bupropion hydrochloride (such as WELLBUTRIN ® , the immediate-release formulation and WELLBUTRIN XL ® , the extended-release formulation).

As dose is increased during initial titration to doses above 150 mg/day, patients should be instructed to take bupropion hydrochloride extended-release tablets (SR) in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.

Patients should be told that bupropion hydrochloride extended-release tablets (SR) 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 extended-release tablets (SR) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion hydrochloride extended-release tablets (SR) 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 extended-release tablets (SR). 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 extended-release tablets (SR) 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.

Patients should be advised to swallow bupropion hydrochloride extended-release tablets (SR) whole so that the release rate is not altered. Do not chew, divide, or crush tablets, as this may lead to an increased risk of adverse effects, including seizures.

实验室测试

There are no specific laboratory tests recommended.

药物相互作用

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 extended-release tablets (SR) and drugs that are substrates of 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 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 bupropion hydrochloride extended-release tablets (SR) 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 C max , 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%. Similarly, efavirenz 600 mg once daily for 2 weeks reduced the exposure of bupropion by approximately 55%. This effect of ritonavir, KALETRA ® , and efavirenz is thought to be due to the induction of bupropion metabolism. Patients receiving any of these drugs with bupropion 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.

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 CYP2D6 isoenzyme in vitro . In a study of 15 male subjects (aged 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 C max , AUC, and t 1/2 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, coadministration 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