（包括患者信息和药物治疗指南）

在开处方Serzone之前，医生应该完全熟悉此开处方信息的细节。

Serzone说明

奈法唑酮®（奈法唑酮盐酸盐）是用于口服给药的与无关的选择性血清素再摄取抑制剂，三环类，tetracyclics，或单胺氧化酶抑制剂（MAOI）的化学结构的抗抑郁药。

盐酸奈法唑酮是一种合成的苯基哌嗪抗抑郁药。盐酸奈法唑酮的化学名称为2- [3- [4-（3-氯苯基）-1-哌嗪基]丙基] -5-乙基-2,4-二氢-4-（2-苯氧基乙基）-3H-1， 2,4-三唑-3-一盐酸盐。分子式为C 25 H 32 ClN 5 O 2 •HCl，其分子量为506.5。结构式为：

盐酸奈法唑酮是一种不吸湿的白色结晶固体。它可自由溶于氯仿，可溶于丙二醇和微溶于聚乙二醇和水。

Serzone以六角片形式提供，其中包含50 mg，100 mg，150 mg，200 mg或250 mg盐酸奈法唑酮和以下非活性成分：微晶纤维素，聚维酮，羟乙酸淀粉钠，胶体二氧化硅，硬脂酸镁和氧化铁（红色和/或黄色）作为着色剂。

Serzone-临床药理学

药效学

与其他抗抑郁药一样，奈法唑酮的作用机理尚不清楚。

临床前研究表明，奈法唑酮可抑制5-羟色胺和去甲肾上腺素的神经元摄取。

奈法唑酮在纳摩尔浓度下占据中心5-HT 2受体，并作为该受体的拮抗剂。奈法唑酮显示出拮抗阿尔法1 -肾上腺素能受体，它可以与体位性低血压相关联的属性。体外结合研究表明，奈法唑酮具有以下受体没有亲和性显著：阿尔法2和β肾上腺素能，5-HT 1A，胆碱能，多巴胺能，或苯二氮卓。

药代动力学

盐酸奈法唑酮可快速，完全吸收，但会进行广泛的代谢，因此其绝对生物利用度较低，约为20％，并且可变。血浆峰值浓度约1小时，奈法唑酮的半衰期为2-4小时。

奈法唑酮及其药理上相似的代谢物羟基奈法唑酮在剂量和时间上均表现出非线性动力学，与单剂量相比，AUC和C max与剂量增加成比例地增加，并且随着时间的推移多次给药超过预期。例如，在一项涉及以50、100和200 mg BID剂量进行的多剂量研究中，奈法唑酮和羟基奈法唑酮的AUC增加了约4倍，剂量从每天200毫克增加到400毫克；在相同剂量下，C max增加约3倍。在一项涉及以25、50、100和150 mg的BID剂量进行的多剂量研究中，奈法唑酮和羟基奈法唑酮AUC的累积比率（相对于首剂）为5天，在较低剂量下约为3到4。剂量（50–100 mg /天）和较高剂量（200–300 mg /天）的5至7； BID给药5天后，C max相对于第一剂也增加了约2至4倍，这表明奈法唑酮及其羟基代谢产物在多次给药后的累积量大大超过了预期。在开始BID给药后4到5天内，或者在剂量增加或减少后，均达到稳态血浆奈法唑酮和代谢物浓度。

口服后，奈法唑酮会通过正脱烷基和脂肪族和芳香族羟基化而广泛代谢，不到1％的奈法唑酮会原样排泄在尿液中。试图表征血浆中鉴定出的三种代谢物，羟基nefazodone（HO-NEF），间氯苯基哌嗪（mCPP）和三唑二酮代谢物。这三种代谢物的AUC（以100 mg BID剂量的奈法唑酮的AUC的倍数表示）和消除半衰期如下：

HO-NEF具有定性和定量类似于奈法唑酮的药理学特征。 mCPP与奈法唑酮有一些相似之处，但在某些血清素能受体亚型上也具有激动剂活性。三唑-二酮代谢物的药理作用尚未得到很好的表征。除上述化合物外，血浆中还存在其他几种代谢物，但尚未对其药理活性进行测试。

口服放射性标记的奈法唑酮后，总标记物的平均半衰期为11至24小时。尿液中检出的放射性约为55％，粪便中检出的放射性约为20-30％。

分布-头孢唑酮广泛分布在包括中枢神经系统（CNS）在内的人体组织中。在人类中，奈法唑酮的分布体积为0.22至0.87 L / kg。

蛋白质结合-浓度为25–2500 ng / mL的奈法唑酮在体外与人血浆蛋白质广泛结合（> 99％）。在华法林治疗将凝血酶原时间延长至实验室对照的120-150％的受试者中，给予200 mg BID的奈法唑酮1周并未增加未结合的华法林的比例（请参见预防措施：药物相互作用）。虽然奈法唑酮不会改变氯丙嗪，地昔帕明，地西epa，二苯乙内酰脲，利多卡因，哌唑嗪，普萘洛尔或维拉帕米的体外蛋白质结合，但奈法唑酮或这些药物的取代是否在体内发生尚不清楚。氟哌啶醇的蛋白质结合降低了5％；这可能没有临床意义。

食物的影响-食物会延迟奈法唑酮的吸收并将奈法唑酮的生物利用度降低约20％。

肾脏疾病-在涉及29名肾功能不全患者的研究中，肾功能不全（肌酐清除率范围为7至60 mL / min / 1.73m 2 ）对稳态奈法唑酮血浆浓度没有影响。

肝病—在一项针对肝硬化患者的多剂量研究中，奈法唑酮和稳态HO-NEF的AUC值比正常志愿者高约25％。

年龄/性别影响-对年轻的（18-45岁）和年长的患者（> 65岁）单剂300 mg后，奈法唑酮和羟奈法唑酮的C max和AUC高达老年患者的两倍。但是，使用多次剂量后，差异要小得多，为10％至20％。性别也观察到相似的结果，单剂后女性的C max和AUC较高，但多剂后无差异。

Serzone的治疗应以老年患者（尤其是女性）的常规剂量的一半开始（参见剂量和用法），但年轻和老年患者的治疗剂量范围相似。

临床疗效试验结果

在其上市前的开发过程中，通过五项良好控制的短期（6-8周）临床研究，在治疗范围内的剂量下评估了Serzone的功效。这些试验招募了符合DSM-III或DSM-IIIR标准的重度抑郁症门诊患者。在这些试验中，有两项证明了Serzone的有效性，还有两项为该结论提供了额外的支持。

一项试验是为期6周的剂量滴定研究，按照BID时间表比较Serzone在两个剂量范围内（最高300 mg /天和最高600 mg /天[该组的平均模式剂量约为400 mg /天]） ）和安慰剂。第二项试验是为期8周的剂量滴定研究，比较了Serzone（最高600 mg /天；平均模式剂量为375 mg /天），丙咪嗪（最高300 mg /天）和安慰剂，所有治疗均按BID时间表进行。两项研究均表明，Serzone的日剂量介于300 mg至600 mg /天（治疗剂量范围）内，在以下四个指标中的至少三个指标上优于安慰剂：17项汉密尔顿抑郁量表或HDRS（总分） ，汉密尔顿抑郁情绪项，临床总体印象（CGI）严重度评分和CGI改善评分。对于HDRS的某些因素（例如焦虑因素，睡眠障碍因素和延迟因素）也发现了显着差异。在两项支持性研究中，Serzone的最高滴定剂量为500或600 mg /天（平均模式剂量为462 mg /天和363 mg /天）。在第五项研究中，Serzone和安慰剂之间的应答率差异无统计学意义。使用亚治疗剂量的Serzone进行了另外三项试验。

总体而言，这些试验中约三分之二的患者是女性，对性别对预后的影响分析表明，基于性别的反应不同。在这些试验中，老年患者太少，无法揭示可能的年龄相关反应差异。

自从最初作为抗抑郁药产品上市以来，已经对Serzone进行了其他临床研究。这些研究探讨了Serzone在最初获得市场批准时尚未得到充分评估的条件下的使用。

进行了两项研究，以评估Serzone在住院的重度抑郁症患者中的有效性。这些是为期6周的剂量滴定试验，按照BID时间表比较Serzone（最高600 mg /天）和安慰剂。在一项研究中，Serzone优于安慰剂。在这项研究中，Serzone的平均模式剂量为503 mg / day，其中85％的患者为忧郁病患者。在基线时，患者分布在7点CGI严重度量表的较高端，如下所示：4 =中病（17％）； 5 =重病（48％）； 6 =重病（32％）。在另一项研究中，Serzone和安慰剂之间的应答率差异无统计学意义。随机分配给安慰剂的患者中，自发改善的“高”率可以解释这一结果。

进行了两项研究，以评估Serzone在接受Serzone公开治疗16周（滴定剂量高达600毫克/天）后，已被确定已充分缓解（HDRS总评分≤10）的急性抑郁症患者维持临床缓解的能力。 ）。在一项研究中，Serzone优于安慰剂。在这项研究中，患者（n = 131）被随机分配接受Serzone或安慰剂治疗，持续另外36周（共1年）。这项研究表明，与安慰剂组相比，服用Serzone的患者复发率显着降低（HDRS总分≥18）。第二项研究具有适当的设计和功效，但接受评估的患者样本并未以足够高的发病率遭受复发，从而无法为Serzone的这种功效提供有意义的测试。

在所有抗抑郁药的临床开发中已经看到了高度可变的结果。此外，在没有在同一对照临床试验中研究药物的情况下，评估不同抗抑郁药产品有效性的研究结果之间的比较本质上是不可靠的。由于试验的条件（例如，患者样品，研究者，所用和比较的治疗剂量，结局指标等）在各个试验中有所不同，因此实际上不可能将药物效果的差异与一种或多种药物引起的差异区分开来。刚才列举的混杂因素。

Serzone的适应症和用法

Serzone（盐酸奈法唑酮）适用于治疗重度抑郁症。在决定可用于这种情况的替代治疗方法时，处方者应考虑与Serzone治疗相关的肝衰竭风险（请参阅警告）。在许多情况下，这将得出结论，应首先尝试使用其他药物。

Serzone在重度抑郁症治疗中的功效在门诊患者的6-8周对照试验和在抑郁症患者的6周对照试验中得到证实，这些患者的诊断与主要抑郁症的DSM-III或DSM-IIIR类型最接近抑郁症（请参阅临床药理学）。

严重的抑郁发作意味着显着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）。它必须包括情绪低落或失去兴趣或愉悦，以及以下九种症状中的至少五种：情绪低落，对日常活动失去兴趣，体重和/或食欲明显改变，失眠或失眠，精神运动性躁动或智力低下，疲劳加剧，内或一文不值的感觉，思维减慢或注意力不集中，自杀未遂或自杀念头。

在一项随机安慰剂对照试验中已证实，Serzone降低了被认为对16周开放标签Serzone治疗急性抑郁发作具有令人满意的临床反应的重度抑郁症患者复发的功效（请参阅临床药理学）。尽管在引用的研究中对缓解的患者进行了长达36周的随访（即总共52周），但是选择长期使用Serzone的医生应定期重新评估该药物对单个患者的长期实用性。

禁忌症

禁忌特非那定，阿司咪唑，西沙必利，匹莫齐或卡马西平与Serzone（盐酸奈法唑酮）同时使用（请参阅“警告和注意事项” ）。

由于肝损伤的证据而退出Serzone的患者禁忌使用Serzone片剂（请参阅盒装警告）。对于已证明对盐酸奈法唑酮，其无效成分或其他苯基哌嗪类抗抑郁药过敏的患者，禁用Serzone片剂。

三唑仑和奈法唑酮的共同给药会导致三唑仑的血浆水平显着升高（请参阅警告和注意事项），如果将两种药物一起使用，建议将三唑仑的初始剂量降低75％。由于并非所有的三唑仑市售剂型都可以充分降低剂量，因此对于大多数患者，包括老年人，应避免三唑仑与Serzone并用。

警告事项

肝毒性（见盒装警告。）

据报道，用Serzone治疗的患者有危及生命的肝衰竭病例。

在美国，据报道，每250,000-300,000患者年的Serzone治疗，约有1例肝衰竭导致死亡或移植。这代表估计的肝衰竭背景发生率的约3-4倍。由于报告不足，因此该比率被低估了，真正的风险可能远大于此。一项针对抗抑郁药使用者的大型队列研究发现，在约30,000患者-年的暴露量下，未出现导致Serzone使用者死亡或移植的肝衰竭病例。自发的报告数据和队列研究结果提供了使用奈法唑酮治疗的患者的肝衰竭风险上限和下限的估算值，但无法提供准确的风险估算值。

在Serzone治疗中，报告的肝衰竭病例导致死亡或移植的肝损伤时间通常为2周至6个月。尽管一些报告描述了尿液呈黑色和非特异性的前驱症状（例如厌食，不适和胃肠道症状），但其他报告并未描述黄疸发作之前先驱症状明显的发作。

医生可能会考虑肝功能检查的价值。尚未进行定期的血清转氨酶测试可以预防严重伤害，但通常认为，尽早发现药物引起的肝损伤以及立即停用可疑药物会增加康复的可能性。

建议患者警惕肝功能不全的体征和症状（黄疸，厌食，胃肠道不适，全身不适等），并在发生时立即向医生报告。正在进行的患者临床评估应控制医师的干预措施，包括诊断评估和治疗。

如果临床体征或症状提示肝功能衰竭，应停用Serzone（请参阅预防措施：患者信息）。有肝细胞损伤迹象的患者，例如血清AST升高或血清ALT水平≥正常上限的3倍，而服用Serzone的患者应退出药物治疗。如果重新引入Serzone，应假定这些患者的肝损伤风险增加。因此，此类患者不应考虑再次治疗。

与单胺氧化酶抑制剂相互作用的潜力

在接受与奈法唑酮具有相似药理特性的抗抑郁药联合单胺氧化酶抑制剂（MAOI）的患者中，有严重反应的报道，有时甚至是致命的。对于选择性5-羟色胺再摄取抑制剂（SSRI），这些反应包括体温过高，僵化，肌阵挛，自主神经系统不稳定，生命体征可能快速波动，以及精神状态变化，包括剧烈躁动发展为ir妄和昏迷。在最近停止使用该药物并开始使用MAOI的患者中，也已报道了这些反应。一些病例表现出类似精神安定性恶性综合征的特征。与三环类抗抑郁药和MAOI的联合使用已报道了严重的体温过高和癫痫发作，有时甚至致命。在最近停止使用这些药物并已开始使用MAOI的患者中，也已经报道了这些反应。

尽管尚未在人或动物中评估奈法唑酮和MAOI的联合使用的效果，但由于奈法唑酮是5-羟色胺和去甲肾上腺素再摄取的抑制剂，因此建议不要将奈法唑酮与MAOI组合使用停止使用MAOI治疗。停用奈法唑酮后应至少保留1周，然后再开始进行MAOI。

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。长期以来，人们一直担心抗抑郁药可能在某些患者中引起抑郁症的恶化和自杀倾向的发生。在患有重性抑郁症（MDD）和其他精神疾病的儿童和青少年的短期研究中，抗抑郁药增加了自杀思维和行为（自杀）的风险。

对患有MDD，OCD或其他精神疾病的儿童和青少年对9种抗抑郁药（SSRIs和其他药物）进行的短期，安慰剂对照试验的汇总分析（共涉及24项试验，涉及4400多例患者）显示出更大的风险在接受抗抑郁药治疗的最初几个月中，代表自杀行为或思维（自杀）的不良事件。接受抗抑郁药的患者发生此类事件的平均风险为4％，是安慰剂风险（2％）的两倍。药物之间的风险差异很大，但几乎所有研究的药物都有增加的趋势。在MDD试验中最常观察到自杀风险，但在其他精神病适应症（强迫症和社交焦虑症）中，也有一些试验引发自杀风险。在这些试验中，没有自杀发生。尚不知道小儿患者的自杀倾向是否会扩展到长期使用，即超过几个月。自杀风险是否扩展到成人也未知。

应密切观察所有接受抗抑郁药治疗的小儿患者的任何适应症，以观察其临床恶化，自杀倾向和异常行为改变，尤其是在药物治疗过程的最初几个月中，或者在剂量变化时，无论增加还是减少。这种观察通常包括在治疗的前4周内至少每周与患者或其家人或看护者进行面对面接触，然后在接下来的4周内每隔一周进行一次就诊，然后在12周内，并根据临床表现超过12周。面对面访问之间可能需要通过电话进行更多联系。

在接受其他抗精神病药物治疗的其他精神疾病患者中，患有MDD或合并症的成年人的临床恶化和自杀倾向也应得到类似观察，尤其是在药物治疗过程的最初几个月中，或者在剂量变化时，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。

对于因严重抑郁症或其他精神病和非精神病用抗抑郁药接受抗抑郁药治疗的小儿科患者的家属和照顾者，应提醒他们有必要监测患者的躁动，烦躁，行为异常变化以及其他所描述症状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。 Serzone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。应同样建议接受抑郁症治疗的成年人的家庭和照顾者。

筛查双相情感障碍患者：主要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，Serzone未获批准用于治疗双相抑郁症。

与三唑并二氮杂卓的相互作用

奈法唑酮与两种三唑并苯并二氮杂s，即三唑仑和阿普唑仑，被细胞色素P450 3A4代谢，相互作用研究表明，与奈法唑酮同时给药时，这些化合物的血浆浓度显着增加，并且在临床上具有重要意义。

在稳态下，单次口服0.25 mg剂量的三唑仑与奈法唑酮（200 mg BID）并用时，三唑仑的半衰期和AUC增加4倍，峰浓度增加1.7倍。奈法唑酮的血浆浓度不受三唑仑的影响。奈法唑酮的共同给药增强了三唑仑对精神运动能力测试的影响。如果将三唑仑与Serzone并用，建议将三唑仑的初始剂量减少75％。由于并非所有的三唑仑市售剂型都能充分降低剂量，因此对于大多数患者，包括老年人，应避免将三唑仑与Serzone并用。在认为三唑仑与Serzone并用的特殊情况下，应仅使用最低剂量的三唑仑（请参阅禁忌症和预防措施）。

当阿普唑仑（1 mg BID）和奈法唑酮（200 mg BID）并用时，阿普唑仑的稳态峰值浓度，AUC和半衰期值增加约2倍。奈法唑酮的血浆浓度不受阿普唑仑的影响。如果阿普唑仑与Serzone并用，建议将阿普唑仑的初始剂量减少50％。 Serzone无需调整剂量。

潜在的特非那定，阿司咪唑，西沙必利和匹莫西德相互作用

特非那定，阿司咪唑，西沙必利和匹莫齐都被细胞色素P450 3A4（CYP3A4）同工酶代谢，并且已证明酮康唑，红霉素和其他CYP3A4抑制剂可阻断这些药物的代谢，从而导致血浆增加母体药物的浓度。特非那定，阿司咪唑，西沙必利和匹莫齐德的血浆浓度升高与QT延长有关，并与罕见的严重心血管不良事件（包括死亡）有关，这主要归因于尖尖扭转型室性心动过速。奈法唑酮在体外已显示是CYP3A4的抑制剂。因此，建议不要将奈法唑酮与特非那定，阿司咪唑，西沙必利或匹莫齐德组合使用（请参阅禁忌症和注意事项）。

两种药物在稳态下卡马西平200 mg BID和奈法唑酮200 mg BID的共同给药导致奈法唑酮和羟基奈法唑酮的AUC降低近95％，可能导致血浆奈法唑酮和羟基奈法唑酮浓度不足以实现Serzone的抗抑郁作用。因此，建议不要将Serzone与卡马西平组合使用（请参阅禁忌症和注意事项）。

预防措施

一般

体位性低血压

安慰剂对照的上市前研究中监测到的生命体征的汇总分析显示，奈法唑酮患者的5.1％与安慰剂患者的2.5％（p≤0.01）相比，符合治疗期间某些时间血压潜在重要降低的标准（收缩压血压≤90mmHg，并且与基线相比变化≥20 mmHg）。奈法唑酮和安慰剂患者发生不良反应的特征为“晕厥”（奈法唑酮，0.2％；安慰剂，0.3％）的比例没有差异，但以“姿势性低血压”为特征的不良事件发生率如下：奈法唑酮（ 2.8％），三环类抗抑郁药（10.9％），SSRI（1.1％）和安慰剂（0.8％）。因此，开处方者应意识到与奈法唑酮联用时存在体位性低血压的风险。在已知的心血管或脑血管疾病患者中应谨慎使用Serzone，这些患者可能因低血压（心肌梗塞，心绞痛或局部缺血性中风的病史）和易患低血压的病症（脱水，血容量不足以及使用降压药治疗）而恶化）。

躁狂症/低躁狂症的激活

在上市前测试中，奈法唑酮治疗的单相患者中发生躁狂或躁狂的比例为0.3％，三环治疗组为0.3％，安慰剂治疗组为0.4％。在被分类为双相情感障碍的患者中，奈法唑酮的躁狂发作率为1.6％，三环联合治疗组为5.1％，安慰剂治疗组为0％。躁狂/低躁狂的激活是一小部分使用其他市售抗抑郁药治疗的严重情感障碍患者的已知风险。与所有抗抑郁药一样，对于有躁狂病史的患者，应谨慎使用Serzone（盐酸奈法唑酮）。

癫痫发作

在上市前的测试中，观察到接受奈法唑酮治疗的患者中有小癫痫发作的复发，这种患者有这种癫痫病的病史。此外，据报道，一名非研究参与者在服用多种药物后出现惊厥（未记录类型）（参见OVERDOSAGE ）。自投放市场以来，已报告了服用奈法唑酮后很少发生惊厥（包括癫痫大发作）。与奈法唑酮的因果关系尚未建立（请参阅“不良反应” ）。

独裁者

尽管在使用奈法唑酮的上市前经验中并没有发生阴茎异常勃起，但自市场引入以来，阴茎异常勃起的报道很少。与奈法唑酮的因果关系尚未建立（请参阅“不良反应” ）。如果患者出现长期或不适当的勃起，应立即停止治疗并咨询医生。如果病情持续超过24小时，应咨询泌尿科医师以确定适当的治疗方法。

用于伴发疾病的患者

对于最近有心肌梗塞或不稳定心脏病史的患者，未评估Serzon或未在任何程度上使用Serzone。在产品的上市前测试期间，有这些诊断的患者被系统地排除在临床研究之外。 Evaluation of electrocardiograms of 1153 patients who received nefazodone in 6- to 8-week, double-blind, placebo-controlled trials did not indicate that nefazodone is associated with the development of clinically important ECG abnormalities. However, sinus bradycardia, defined as heart rate ≤50 bpm and a decrease of at least 15 bpm from baseline, was observed in 1.5% of nefazodone-treated patients compared to 0.4% of placebo-treated patients (p≤0.05). Because patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical trials, such patients should be treated with caution.

In patients with cirrhosis of the liver, the AUC values of nefazodone and HO-NEF were increased by approximately 25%.

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 Serzone and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Serzone.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。应该使患者有机会讨论《药物指南》的内容，并获得他们可能遇到的任何问题的答案。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 Serzone.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, agressiveness, 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 observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.此类症状应报告给患者的开处方者或卫生专业人员，特别是如果症状严重，起病突然或不属于患者出现的症状。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。

Patients should be informed that Serzone therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with Serzone. Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc) and to report them to their doctor immediately if they occur.

Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's physician, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

As with all antidepressants, several weeks on treatment may be required to obtain the full antidepressant effect. Once improvement is noted, it is important for patients to continue drug treatment as directed by their physician.

Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Serzone therapy does not adversely affect their ability to engage in such activities.

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

Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS: Nursing Mothers ).

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Significant caution is indicated if Serzone is to be used in combination with XANAX ® , concomitant use with HALCION ® should be avoided for most patients including the elderly, and concomitant use with SELDANE ® , HISMANAL ® , PROPULSID ® , ORAP ® , or TEGRETOL ® is contraindicated (see CONTRAINDICATIONS and WARNINGS ).

Patients should be advised to avoid alcohol while taking Serzone.

Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.

There have been reports of visual disturbances associated with the use of nefazodone, including blurred vision, scotoma, and visual trails. Patients should be advised to notify their physician if they develop visual disturbances. (See ADVERSE REACTIONS .)

实验室测试

没有推荐的具体实验室测试。

药物相互作用

Because nefazodone is highly bound to plasma protein (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), administration of Serzone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodone by other highly bound drugs.

Warfarin—There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease the subjects' exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices.

Monoamine Oxidase Inhibitors—See WARNINGS .

Haloperidol—When a single oral 5-mg dose of haloperidol was coadministered with nefazodone (200 mg BID) at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance. Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary when coadministered with nefazodone.

Lorazepam—When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either drug compared to each drug administered alone. Therefore, dosage adjustment is not necessary for either drug when coadministered.

Triazolam/Alprazolam—See CONTRAINDICATIONS and WARNINGS .

Alcohol—Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of Serzone and alcohol in depressed patients is not advised.

Buspirone—In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in C max and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With 5-mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%). Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.

Pimozide—See CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS: Pharmacokinetics of Nefazodone in 'Poor Metabolizers' and Potential Interaction with Drugs that Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes .

Fluoxetine—When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3- to 6-fold and 1.3-fold, respectively. When a 200-mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables.

Phenytoin—Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300-mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically. However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices.

Desipramine—When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and C max of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly. Subsequent dose adjustments should be made on the basis of clinical response.

Lithium—In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazole-dione, which are considered not to be of clinical significance. Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered.

Carbamazepine—The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration. With coadministration of the two drugs there were significant increases in the steady-state C max and AUC of carbamazepine (23% and 23%, respectively), while the steady-state C max and the AUC of the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state C max and AUC of nefazodone by 86% and 93%, respectively. Similar reductions in the C max and AUC of HO-NEF were also observed (85% and 94%), while the reductions in C max and AUC of mCPP and triazole-dione were more modest (13% and 44% for the former and 28% and 57% for the latter). Due to the potential for coadministration of carbamazepine to result in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for Serzone, it is recommended that Serzone not be used in combination with carbamazepine (see CONTRAINDICATIONS and WARNINGS ).

General Anesthetics—Little is known about the potential for interaction between nefazodone and general anesthetics; therefore, prior to elective surgery, Serzone should be discontinued for as long as clinically feasible.

Other CNS-Active Drugs—The use of nefazodone in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if concomitant administration of Serzone (nefazodone hydrochloride) and such drugs is required.

When nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered for one week, no change in the steady-state pharmacokinetics of either nefazodone or cimetidine was observed compared to each dosed alone. Therefore, dosage adjustment is not necessary for either drug when coadministered.

When nefazodone (200 mg BID) was given to patients being treated with theophylline (600-1200 mg/day) for chronic obstructive pulmonary disease, there was no change in the steady-state pharmacokinetics of either nefazodone or theophylline. FEV 1 measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (ie, when theophylline was administered alone). Therefore, dosage adjustment is not necessary for either drug when coadministered.

Digoxin—When nefazodone (200 mg BID) and digoxin (0.2 mg QD) were coadministered for 9 days to healthy male volunteers (n=18) who were phenotyped as CYP2D6 extensive metabolizers, C max , C min , and AUC of digoxin were increased by 29%, 27%, and 15%, respectively. Digoxin had no effects on the pharmacokinetics of nefazodone and its active metabolites. Because of the narrow therapeutic index of digoxin, caution should be exercised when nefazodone and digoxin are coadministered; plasma level monitoring for digoxin is recommended.

Propranolol—The coadministration of nefazodone (200 mg BID) and propranolol (40 mg BID) for 5.5 days to healthy male volunteers (n=18), including 3 poor and 15 extensive CYP2D6 metabolizers, resulted in 30% and 14% reductions in C max and AUC of propranolol, respectively, and a 14% reduction in C max for the metabolite, 4-hydroxypropranolol. The kinetics of nefazodone, hydroxynefazodone, and triazole-dione were not affected by coadministration of propranolol. However, C max , C min , and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively. No change in initial dose of either drug is necessary and dose adjustments should be made on the basis of clinical response.

HMG-CoA Reductase Inhibitors—When single 40-mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received Serzone 200 mg BID for 6 days, approximately 20-fold increases in plasma concentrations of simvastatin and simvastatin acid and 3- to 4-fold increases in plasma concentrations of atorvastatin and atorvastatin lactone were seen. These effects appear to be due to the inhibition of CYP3A4 by Serzone because, in the same study, Serzone had no significant effect on the plasma concentrations of pravastatin, which is not metabolized by CYP3A4 to a clinically significant extent.

There have been rare reports of rhabdomyolysis involving patients receiving the combination of Serzone and either simvastatin or lovastatin, also a substrate of CYP3A4 (see ADVERSE REACTIONS: Postintroduction Clinical Experience ). Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors administered alone (at recommended dosages) and in particular, for certain drugs in this class, when given in combination with inhibitors of the CYP3A4 isozyme.

Caution should be used if Serzone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. Since metabolic interactions are unlikely between Serzone and HMG-CoA reductase inhibitors that undergo little or no metabolism by the CYP3A4 isozyme, such as pravastatin or fluvastatin, dosage adjustments should not be necessary.

There have been reports of increased blood concentrations of cyclosporine and tacrolimus into toxic ranges when patients received these drugs concomitantly with Serzone. Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodone is known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered with Serzone, blood concentrations of the immunosuppressive agent should be monitored and dosage adjusted accordingly.

CYP3A4 Isozyme—Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. This is consistent with the interactions observed between nefazodone and triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugs metabolized by this isozyme. Consequently, caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by CYP3A4. In particular, the combined use of nefazodone with triazolam should be avoided for most patients, including the elderly. The combined use of nefazodone with terfenadine, astemizole, cisapride, or pimozide is contraindicated (see CONTRAINDICATIONS and WARNINGS ).

CYP2D6 Isozyme—A subset (3% to 10%) of the population has reduced activity of the drug-metabolizing enzyme CYP2D6. Such individuals are referred to commonly as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not altered in these “poor metabolizers.” Plasma concentrations of one minor metabolite (mCPP) are increased in this population; the adjustment of Serzone dosage is not required when administered to “poor metabolizers.” Nefazodone and its metabolites have been shown in vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodone will decrease the metabolic clearance of drugs metabolized by this isozyme.

CYP1A2 Isozyme—Nefazodone and its metabolites have been shown in vitro not to inhibit CYP1A2. Thus, metabolic interactions between nefazodone and drugs metabolized by this isozyme are unlikely.

There are no clinical studies of the combined use of ECT and nefazodone.

致癌，诱变，生育力受损

There is no evidence of carcinogenicity with nefazodone. The dietary administration of nefazodone to rats and mice for 2 years at daily doses of up to 200 mg/kg and 800 mg/kg, respectively, which are approximately 3 and 6 times, respectively, the maximum human daily dose on a mg/m 2 basis, produced no increase in tumors.

Nefazodone has been shown to have no genotoxic effects based on the following assays: bacterial mutation assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, an in vivo cytogenetics assay in rat bone marrow cells, and a rat dominant lethal study.

A fertility study in rats showed a slight decrease in fertility at 200 mg/kg/day (approximately three times the maximum human daily dose on a mg/m 2 basis) but not at 100 mg/kg/day (approximately 1.5 times the maximum human daily dose on a mg/m 2 basis).

怀孕

Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m 2 basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning.这些死亡的原因尚不清楚。 The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m 2 basis.没有针对孕妇的充分且对照良好的研究。 Nefazodone 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 Serzone on labor and delivery in humans is unknown.

护理母亲

It is not known whether Serzone or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Serzone is administered to a nursing woman.

儿科用

Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS: Clinical Worsening and Suicide Risk ). Two placebo-controlled trials in 286 pediatric patients with MDD have been conducted with Serzone, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Serzone in a child or adolescent must balance the potential risks with the clinical need.

老人用

Of the approximately 7000 patients in clinical studies who received Serzone for the treatment of major depressive disorder, 18% were 65 years and older, while 5% were 75 years and older. Based on monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety between elderly and younger patients were observed in clinical studies. Efficacy in the elderly has not been demonstrated in placebo-controlled trials. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Due to the increased systemic exposure to nefazodone seen in single-dose studies in elderly patients (see CLINICAL PHARMACOLOGY: Pharmacokinetics ), treatment should be initiated at half the usual dose, but titration upward should take place over the same range as in younger patients (see DOSAGE AND ADMINISTRATION ). The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant drugs.

不良反应

与停止治疗有关

Approximately 16% of the 3496 patients who received Serzone (nefazodone hydrochloride) in worldwide premarketing clinical trials discontinued treatment due to an adverse experience. The more common (≥1%) events in clinical trials associated with discontinuation and considered to be drug related (ie, those events associated with dropout at a rate approximately twice or greater for Serzone compared to placebo) included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), an