在开Tegretol之前，医生应完全熟悉此开处方信息的细节，尤其是与其他药物一起使用时，尤其是那些具有潜在毒性的药物。

替格列醇描述

Tegretol（卡马西平USP）是三叉神经痛的抗惊厥药和特效镇痛药，可以口服100毫克咀嚼片，200毫克片剂，100毫克，200毫克和400毫克XR片剂以及100毫克/ 5 mL（茶匙）。它的化学名称是5 H -dibenz [ b，f ] azepine-5-carboxamide，其结构式为：

卡马西平USP是白色至类白色粉末，几乎不溶于水，可溶于乙醇和丙酮。其分子量为236.27。

非活性成分片剂：胶体二氧化硅，D＆C红色30号铝色淀（仅可咀嚼片），FD＆C红色40号（仅200 mg片），调味剂（仅可咀嚼片），明胶，甘油，硬脂酸镁，淀粉羟乙酸钠（仅限咀嚼片），淀粉，硬脂酸和蔗糖（仅限咀嚼片）。悬浮液：柠檬酸，FD＆C黄色6号，调味剂，聚合物，山梨酸钾，丙二醇，纯净水，山梨糖醇，蔗糖和黄原胶。 Tegretol-XR片剂：纤维素化合物，糊精，氧化铁，硬脂酸镁，甘露醇，聚乙二醇，十二烷基硫酸钠，二氧化钛（仅200毫克片剂）。

Tegretol-临床药理学

在对照临床试验中，Tegretol已被证明可有效治疗精神运动性癫痫和大发作，以及三叉神经痛。

作用机理

Tegretol在具有电和化学诱发性癫痫发作的大鼠和小鼠中显示出抗惊厥特性。它似乎通过减少多突触反应和阻断强直后增强而起作用。 Tegretol极大地减轻或消除了猫和大鼠的眶下神经刺激引起的疼痛。它会降低丘脑电位以及猫的延髓和多突触反射，包括舌下颌反射。 Tegretol在化学上与其他抗惊厥药或其他用于控制三叉神经痛的药物无关。作用机理仍然未知。

Tegretol的主要代谢产物卡马西平10,11-环氧化物具有抗惊厥活性，在几种癫痫发作的体内动物模型中均得到证实。尽管已经假定了环氧化物的临床活性，但尚未确定其活性对替格列醇的安全性和有效性的重要性。

药代动力学

在临床研究中，Tegretol悬浮液，常规片剂和XR片剂将等量的药物递送至全身循环。但是，悬浮液的吸收速度比常规片剂要快一些，而XR片剂则要稍慢一些。与悬浮液相比，XR片剂的生物利用度为89％。一天两次的给药方案后，与从相同剂量方案的常规片剂获得的峰相比，该悬浮液提供了更高的峰水平和更低的谷水平。另一方面，按照每天三次的剂量方案，Tegretol悬浮液的稳态血浆水平可与以相同的每日总mg剂量每天两次给药的Tegretol片剂相媲美。每天两次的剂量方案后，当以相同的每日总剂量mg给药时，Tegretol-XR片剂可提供与常规Tegretol片剂相当的稳态血浆水平，每天给药四次。血液中的Tegretol与血浆蛋白结合率为76％。 Tegretol的血浆水平是可变的，可能在0.5到25 mcg / mL之间，与药物的每日摄入量没有明显的关系。通常成人的治疗水平在4到12 mcg / mL之间。在多药疗法中，在治疗过程中，可能会增加或降低Tegretol及其伴随药物的浓度，并且可能会改变药物作用（请参阅预防措施，药物相互作用）。长期口服混悬液后，血浆水平在约1.5小时达到峰值，而常规Tegretol片剂给药后为4至5小时，而Tegretol-XR片剂给药后为3至12小时。 CSF /血清比率为0.22，类似于血清中24％未结合的Tegretol。由于Tegretol会诱导自身的新陈代谢，因此半衰期也是可变的。固定剂量给药方案3到5周后，自动诱导完成。初始半衰期值范围为25至65小时，重复剂量则降至12至17小时。 Tegretol在肝脏中代谢。细胞色素P450 3A4被确定为负责由Tegretol形成卡马西平10,11-环氧化合物的主要同工型。人微粒体环氧水解酶已被鉴定为负责由卡马西平-10,11环氧化合物形成10,11-反式二醇衍生物的酶。口服14 C-卡马西平后，尿中发现放射性72％，粪便中发现28％。这种尿放射性主要由羟基化的和共轭的代谢物组成，只有3％的不变白藜芦醇。

Tegretol处置的药代动力学参数在儿童和成人中相似。但是，儿童的卡马西平血浆浓度和替格列醇剂量之间的相关性较差。与成年人相比，卡马西平在年轻人组中更迅速地代谢为卡马西平-10,11-环氧化物（一种在动物筛查中与卡马西平等效的代谢产物，作为抗惊厥药）。在15岁以下的儿童中，CBZ-E / CBZ比率与年龄的增长呈反比关系（一份报告显示，年龄从1岁以下的儿童为0.44到10至15岁的儿童为0.18）。

种族和性别对卡马西平药代动力学的影响尚未得到系统评估。

替格列醇的适应症和用法

癫痫

Tegretol被指定用作抗惊厥药。支持Tegretol作为抗惊厥药功效的证据来自积极的药物控制研究，该研究招募了以下癫痫发作类型的患者：

1. 症状复杂的部分发作（精神运动，颞叶）。与其他类型的癫痫发作相比，这些癫痫发作的患者似乎表现出更大的改善。
   
2. 全身性强直阵挛性癫痫发作（严重）。
   
3. 包括以上或其他部分或广义癫痫发作的混合性癫痫发作模式。缺席发作（小发作）似乎不受Tegretol的控制（请参见“注意事项”，一般）。

三叉神经痛

Tegretol可用于治疗真正的三叉神经痛。

舌咽神经痛也有报道。

这种药物不是简单的止痛药，不应用于减轻琐碎的疼痛或疼痛。

禁忌症

Tegretol不适用于既往有骨髓抑制史，对该药物过敏或已知对任何三环化合物敏感的患者，例如阿米替林，地昔帕明，丙咪嗪，普罗替林，去甲替林等。同样，基于理论基础不建议将其与单胺氧化酶（MAO）抑制剂一起使用。在施用Tegretol之前，应停用MAO抑制剂至少14天，或在临床情况允许的情况下更长的时间。

卡马西平和奈法唑酮的共同给药可能导致奈法唑酮及其活性代谢物的血浆浓度不足以达到治疗效果。禁止将卡马西平与奈法唑酮合用。

警告事项

严重的皮肤病反应

用Tegretol治疗已报道了严重的，有时甚至是致命的皮肤反应，包括毒性表皮坏死溶解（TEN）和史蒂文斯-约翰逊综合症（SJS）。在以白种人为主的国家中，这些事件的风险估计为每10,000个新用户大约1到6。但是，据估计，在某些亚洲国家中，这一风险要高出约10倍。除非出现明显的皮疹与药物无关，否则在出现皮疹的最初迹象时应停止使用Tegretol。如果体征或症状提示为SJS / TEN，则不应恢复使用该药，应考虑替代疗法。

SJS / TEN和HLA-B * 1502等位基因

回顾性病例对照研究发现，在中国血统的患者中，卡马西平治疗导致SJS / TEN发生的风险与HLA-B基因的遗传变异HLA-B * 1502的存在密切相关。在这些等位基因频率较高的国家中，这些反应的发生率较高，表明该风险可能在任何种族的等位基因阳性个体中均增加。

在亚洲人群中，HLA-B * 1502的患病率存在​​显着差异。据报道，香港，泰国，马来西亚和菲律宾部分地区有超过15％的人口为阳性，而台湾地区约为10％，华北地区约为4％。包括印度人在内的南亚人似乎具有中等水平的HLA-B * 1502患病率，平均为2％至4％，但在某些人群中更高。在日本和韩国，HLA-B * 1502仅占不到1％的人口。

非亚洲血统的人（例如，高加索人，非裔美国人，西班牙裔和美洲原住民）基本上没有HLA-B * 1502。

在开始Tegretol治疗之前，应在可能存在HLA-B * 1502的人群中对有血统的患者进行HLA-B * 1502检测。在确定要筛查的患者时，上面提供的HLA-B * 1502患病率可能会提供一个粗略的指导，要记住这些数字的局限性，即使在种族群体中，由于比率的巨大差异，也难以确定种族血统，以及混合血统的可能性。如果HLA-B * 1502阳性的患者不应使用Tegretol，除非其益处明显大于风险。被发现等位基因阴性的接受测试的患者被认为患SJS / TEN的风险较低（请参见盒装警告和预防措施，实验室测试）。

在接受Tegretol治疗的患者中，有90％以上会经历SJS / TEN的患者在治疗的最初几个月内会出现这种反应。在确定是否需要筛查目前使用Tegretol的有遗传风险的患者时，可以考虑使用此信息。

还没有发现HLA-B * 1502等位基因可预测Tegretol引起的较轻不良皮肤反应的风险，例如斑丘疹（MPE）或预测与嗜酸性粒细胞增多和全身症状的药物反应（DRESS）。

有限的证据表明，在中国血统患者中，服用其他与SJS / TEN相关的抗癫痫药物包括苯妥英钠，HLA-B * 1502可能是SJS / TEN发生的危险因素。当替代疗法同样可以接受时，应考虑避免在HLA-B * 1502阳性患者中使用与SJS / TEN相关的其他药物。

过敏反应和HLA-A * 3101等位基因

在欧洲，韩国和日本血统的患者中进行的回顾性病例对照研究发现，患者中发生超敏反应的风险与HLA-A * 3101（HLA-A基因的遗传等位基因变体）的存在之间存在中等关联使用卡马西平。这些超敏反应包括SJS / TEN，斑丘疹喷发以及与嗜酸性粒细胞增多和全身症状的药物反应（请参阅下面的DRESS /多器官超敏反应）。

预计HLA-A * 3101将由15％以上的日本人，美洲原住民，南印度人（例如，泰米尔纳德邦）和某些阿拉伯血统的患者携带；汉人，韩国人，欧洲人，拉丁美洲人和其他印度血统的患者中高达约10％；在非裔美国人以及泰国，台湾和中国（香港）血统的患者中高达5％。

在已知对HLA-A * 3101呈阳性的患者中考虑使用Tegretol之前，应权衡使用Tegretol治疗的风险和益处。

HLA基因分型作为筛查工具的应用具有重要的局限性，绝不能替代适当的临床警惕性和患者管理。接受Tegretol治疗的许多HLA-B * 1502阳性和HLA-A * 3101阳性患者不会出现SJS / TEN或其他超敏反应，这些反应在HLA-B * 1502-阴性和HLA-A中仍然很少发生*任何种族的3101阴性患者。尚未研究过其他可能因素在SJS / TEN和其他超敏反应发生和发病中的作用，例如抗癫痫药（AED）剂量，依从性，伴随用药，合并症和皮肤病学监测水平。

再生障碍性贫血和粒细胞缺乏症

再生障碍性贫血和粒细胞缺乏症的报道与替格列醇的使用有关（见盒装警告）。对任何药物都有血液学不良反应史的患者可能特别有骨髓抑制的风险。

嗜酸性粒细胞增多和全身症状（DRESS）/多器官超敏反应的药物反应

Tegretol引起了与嗜酸性粒细胞增多和全身症状（DRESS）的药物反应，也称为多器官超敏反应。其中一些事件是致命的或威胁生命的。 DRESS通常（尽管不是唯一）表现为发烧，皮疹，淋巴结病和/或面部肿胀，并伴有其他器官系统受累，例如肝炎，肾炎，血液学异常，心肌炎或有时类似于急性病毒感染的肌炎。嗜酸性粒细胞增多症经常存在。该疾病的表达是可变的，可能涉及此处未提及的其他器官系统。重要的是要注意，即使皮疹不明显，也可能出现超敏反应的早期表现（例如发烧，淋巴结肿大）。如果出现此类征兆或症状，应立即对患者进行评估。如果无法确定其他迹象或症状的病因，则应停用Tegretol。

过敏症

在以前曾对包括苯妥英钠，奎尼酮和苯巴比妥在内的抗惊厥药发生过这种反应的患者中，已报告了对卡马西平过敏的反应。如果存在此类病史，则应仔细考虑益处和风险，如果开始使用卡马西平，则应仔细监测超敏反应的体征和症状。

患者应被告知有关谁曾过敏反应也卡马西平与奥卡西平（Trileptal®）经验过敏反应的患者的三分之一。

过敏反应和血管性水肿

在服用首批或后续剂量的Tegretol后，患者中出现罕见的过敏反应和血管水肿，涉及喉，声门，嘴唇和眼睑。与喉头水肿相关的血管性水肿可能是致命的。如果患者在使用Tegretol治疗后出现上述任何反应，则应停用该药物并开始其他治疗。这些患者不应再次服用该药物。

自杀行为和观念

包括Tegretol在内的抗癫痫药（AED）会增加服用这些药物用于任何适应症的患者发生自杀念头或行为的风险。应监测接受任何AED治疗的任何适应症患者的抑郁症，自杀念头或行为和/或情绪或行为的任何异常变化的出现或恶化。

对199种安慰剂对照的11种不同AED的临床试验（单一疗法和辅助疗法）的汇总分析显示，随机分配到其中一种AED的患者发生自杀的风险约为两倍（调整后相对风险1.8，95％CI：1.2，2.7）。与随机接受安慰剂的患者相比。在这些中位治疗时间为12周的试验中，在27,863例接受AED治疗的患者中，自杀行为或意念的估计发生率为0.43％，相比之下，在1,029例接受安慰剂治疗的患者中，自杀行为或意念的发生率为0.24％，增加了约一倍。每530名接受治疗的患者有自杀念头或行为。在试验中，接受药物治疗的患者中有四种自杀，而在接受安慰剂治疗的患者中没有自杀，但是数量太少，无法得出有关药物对自杀影响的任何结论。

最早在开始使用AED进行药物治疗后一周，就观察到AED产生自杀念头或行为的风险增加，并且在评估的治疗期间一直存在。由于分析中包括的大多数试验都没有超过24周，因此无法评估24周后有自杀念头或行为的风险。

在所分析的数据中，自杀想法或行为的风险在药物之间通常是一致的。发现具有不同作用机制且适应症范围广泛的AED会增加患病风险，这表明该风险适用于用于任何适应症的所有AED。在所分析的临床试验中，该风险在年龄（5至100岁）之间没有显着变化。表1通过指示显示了所有评估的AED的绝对和相对风险。

在癫痫症的临床试验中，自杀想法或行为的相对风险高于在精神病或其他疾病的临床试验中，但对于癫痫症和精神病指征，绝对风险差异相似。

任何考虑开Tegretol或任何其他AED处方的人都必须在自杀念头或行为的风险与未治疗疾病的风险之间取得平衡。开具AED的癫痫病和许多其他疾病本身与发病率和死亡率以及自杀念头和行为的风险增加有关。如果在治疗过程中出现自杀念头和行为，则处方者需要考虑在任何给定患者中这些症状的出现是否与所治疗的疾病有关。

一般

Tegretol已显示出轻度的抗胆碱能活性，可能与眼内压升高有关。因此，在治疗期间应密切观察眼内压升高的患者。

由于药物与其他三环化合物的关系，应牢记潜在的精神病激活的可能性，以及在老年患者中引起混乱或激动的可能性。

有肝卟啉病史的患者（例如急性间歇性卟啉症，杂色卟啉症，角质卟啉菌）应避免使用Tegretol。据报道，接受特格列醇治疗的此类患者发生急性发作。还证明了卡马西平的给药可增加啮齿动物中卟啉的前体，这是诱导卟啉症急性发作的一种推测机制。

与所有抗癫痫药一样，应逐渐停用Tegretol，以最大程度地降低癫痫发作频率。

低聚血症可能是由于替格列醇治疗的结果。在许多情况下，低钠血症似乎是由于抗利尿激素分泌不足综合征（SIADH）引起的。用Tegretol治疗发展为SIADH的风险似乎与剂量有关。老年患者和接受利尿剂治疗的患者发生低钠血症的风险更大。低钠血症的体征和症状包括头痛，新发或发作频率增加，注意力不集中，记忆力减退，精神错乱，虚弱和不稳定，这可能导致跌倒。有症状的低钠血症患者应考虑停用Tegretol。

怀孕使用

给孕妇服用卡马西平会造成胎儿伤害。

流行病学数据表明，怀孕期间使用卡马西平与先天性畸形（包括脊柱裂）之间可能存在关联。也有报道称卡马西平与发育障碍和先天性异常（例如颅面缺陷，心血管畸形和涉及各种身体系统的异常）有关。据报道，基于神经行为评估的发育迟缓。在对有生育能力的妇女进行治疗或咨询时，开处方的医生希望权衡治疗的益处和风险。如果在怀孕期间使用该药物，或者如果患者在服用该药物时怀孕，则应告知患者对胎儿的潜在危害。

回顾性病例回顾表明，与单一疗法相比，与抗惊厥药联合治疗相关的致畸作用的患病率可能更高。因此，如果要继续治疗，则对孕妇最好采用单一疗法。

在人类中，卡马西平的经胎盘传递很快（30至60分钟），药物在胎儿组织中积累，肝脏和肾脏中的含量高于脑和肺中的含量。

卡马西平在大鼠生殖研究中已显示出不利影响，口服剂量为每毫克1200毫克最大人类每日剂量（MHDD）的10到25倍（毫克/千克）或MHDD的1.5到4倍（毫克/千克） m 2为基础。在大鼠畸变学研究中，135个后代中有2个显示出250 mg / kg的扭结肋骨，而650 mg / kg时则有119个后代中的4个显示其他异常（c裂，1； ipe骨，1； anophthalmos，2）。在大鼠的生殖研究中，哺乳后代在母体200 mg / kg的剂量水平下表现出体重增加不足和蓬乱的外表。

服用抗癫痫药以预防重大癫痫发作的患者不应突然停用抗癫痫药，因为这很可能导致癫痫持续状态并伴有缺氧和生命危险。在个别情况下，癫痫发作的严重程度和频率足以使药物去除不会对患者构成严重威胁，尽管在怀孕前和怀孕期间都可以考虑停药，但不能肯定地说即使轻微的癫痫发作也不会对发育中的胚胎或胎儿造成危害。

对于接受卡马西平的育龄妇女，应采用目前接受的程序进行检测以发现缺陷，这应视为常规产前检查的一部分。

曾有几例新生儿癫痫发作和/或呼吸抑制与母体Tegretol和其他同时使用的抗惊厥药物有关。还报告了几例新生儿呕吐，腹泻和/或进食减少与母体使用Tegretol有关的情况。这些症状可能代表新生儿戒断综合征。

为了提供有关子宫内暴露于Tegretol的影响的信息，建议医师建议服用Tegretol的怀孕患者参加北美抗癫痫药物（NAAED）怀孕登记。可以通过拨打免费电话1-888-233-2334来完成，并且必须由患者自己完成。有关注册表的信息也可以在网站http://www.aedpregnancyregistry.org/上找到。

预防措施

一般

在开始治疗之前，应进行详细的病史和身体检查。

对于包括非典型性癫痫发作在内的混合性癫痫病患者，应谨慎使用Tegretol，因为在这些患者中，Tegretol与全身性惊厥的发生频率增加相关（请参见适应症和用法）。

仅在有心脏传导障碍史（包括二级和三级房室传导阻滞）的患者进行关键的获益至风险评估后，才应进行治疗；心脏，肝脏或肾脏损害；对其他药物的不良血液学或超敏反应，包括对其他抗惊厥药的反应；或中断使用Tegretol的疗程。

接受Tegretol治疗后，已经报道了包括二，三级传导阻滞在内的AV心脏传导阻滞。这种情况通常（但不是唯一）发生在具有潜在的心电图异常或传导障碍危险因素的患者中。

已经报道了肝脏的影响，从肝酶的轻微升高到罕见的肝功能衰竭（参见不良反应和预防措施，实验室测试）。在某些情况下，尽管停用了药物，肝功能仍可能会进展。另外，已经报道了罕见的胆管综合征消失的情况。该综合征包括一个胆汁淤积过程，其临床过程从暴发到惰性，变化无常，涉及肝内胆管的破坏和消失。一些（但不是全部）病例具有与其他免疫过敏性综合征（如多器官超敏反应（DRESS综合征）和严重的皮肤病学反应）重叠的特征。例如，已有报告说史蒂文斯-约翰逊综合症消失的胆管综合症消失，在另一种情况下则与发烧和嗜酸性粒细胞增多有关。

由于给定剂量的Tegretol悬浮液会产生比片剂相同剂量更高的峰值水平，因此建议给予该悬浮液的患者以较低剂量开始服用，并缓慢增加剂量以免产生不良副作用（请参阅剂量和用法）。

Tegretol悬浮液含有山梨糖醇，因此，不应将其用于果糖耐受不良的罕见遗传问题患者。

给患者的信息

应该告知患者药物指南的可用性，并应指导他们在服用Tegretol之前阅读药物指南。

应该使患者意识到潜在血液学问题的早期中毒症状和体征，以及皮肤病学，超敏反应或肝反应。这些症状可能包括但不限于发烧，喉咙痛，皮疹，口腔溃疡，容易瘀伤，淋巴结病和瘀斑或紫癜性出血，如果发生肝反应，厌食，恶心/呕吐或黄疸。应当告知患者，因为这些体征和症状可能表示严重的反应，因此必须立即将任何情况报告给医生。另外，应告知患者即使轻度或长期使用后也应报告这些体征和症状。

应告知患者，已报告与替格列醇有关的严重皮肤反应。如果服用Tegretol会引起皮肤反应，患者应立即咨询医生（请参阅警告）。

应建议患者在使用Tegretol治疗期间可能发生过敏反应和血管性水肿（请参阅警告）。劝告患者立即报告有迹象表明血管性水肿（面部，眼睛，嘴唇或舌头肿胀，或吞咽或呼吸困难）的症状和体征，并停止服用该药物，直到他们咨询医疗人员为止。

应告知患者，其护理人员和家人，包括Tegretol在内的AED可能会增加自杀念头和行为的风险，并应告知需要警惕抑郁症状的出现或恶化，任何异常的情绪变化或行为，或自杀念头，行为或关于自我伤害的念头的出现。关注的行为应立即报告给医疗保健提供者。

Tegretol可能与某些药物相互作用。因此，应建议患者向医生报告使用任何其他处方药或非处方药或草药产品。

如果将酒精与Tegretol疗法联合使用，应谨慎行事，因为这可能会加重镇静作用。

由于可能会出现头昏眼花和嗜睡，应警告患者操作机械或汽车或从事其他潜在危险任务的危险。

如果患者怀孕，应鼓励患者参加NAAED妊娠登记。该注册表收集有关妊娠期抗癫痫药物安全性的信息。要注册，患者可以拨打免费电话1-888-233-2334（请参阅“警告”，“怀孕中的使用”小节）。

实验室测试

对于有遗传风险的患者（请参阅警告），建议使用高分辨率的“ HLA -B * 1502类型”。如果检测到一个或两个HLA-B * 1502等位基因，则测试为阳性；如果未检测到HLA-B * 1502等位基因，则测试为阴性。

应获取包括血小板在内的完整预处理血细胞计数，可能还包括网状细胞和血清铁，作为基线。如果患者在治疗过程中白细胞或血小板计数低或减少，则应严密监视患者。如果出现任何明显的骨髓抑制迹象，应考虑停药。

由于可能会发生肝损害，因此在使用该药治疗期间必须对肝功能进行基线和定期评估，尤其是在有肝病史的患者中（请注意预防，一般和不良反应）。如果出现新的或正在恶化的肝功能异常或肝损害的临床或实验室证据，或者活动性肝病，则应根据临床判断停用卡马西平。

建议进行基线和定期的眼睛检查，包括裂隙灯，眼底镜检查和眼压计检查，因为已证明许多吩噻嗪和相关药物会引起眼睛改变。

由于观察到的肾功能不全，建议对使用该药物治疗的患者进行基线和定期的全面尿检和BUN测定。

监测血液水平（参见临床药理学）提高了抗惊厥药的疗效和安全性。在癫痫发作频率急剧增加并验证依从性的情况下，这种监视可能特别有用。 In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with Tegretol administered alone.

Interference with some pregnancy tests has been reported.

药物相互作用

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine ® * solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril ® , resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).

Clinically meaningful drug interactions have occurred with concomitant medications and include (but are not limited to) the following:

Agents That May Affect Tegretol Plasma Levels

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

Agents That Increase Carbamazepine Levels

CYP3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (eg, ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, and protease inhibitors.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations. Accordingly, the dosage of Tegretol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid.

Agents That Decrease Carbamazepine Levels

CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.

Effect of Tegretol on Plasma Levels of Concomitant Agents

Decreased Levels of Concomitant Medications

Tegretol is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6, 2C9/19, and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP 1A2, 2B6, 2C9/19, and 3A4, through induction of their metabolism. When used concomitantly with Tegretol, monitoring of concentrations or dosage adjustment of these agents may be necessary:

• When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole dose should be reduced.
• When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.
• The use of concomitant strong CYP3A4 inducers, such as carbamazepine should be avoided with temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of temsirolimus dosage should be considered.
• The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib dose should be reduced.
• Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).
• Monitor concentrations of valproate when Tegretol is introduced or withdrawn in patients using valproic acid.

In addition, Tegretol causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (eg, prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (eg, felodipine), doxycycline, eslicarbazepine, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (eg, imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

Other Drug Interactions

• Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide are reportedly increased by chronic coadministration of CYP3A4 inducers. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
• Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
• Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.
• Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.
• Concomitant use of Tegretol with hormonal contraceptive products (eg, oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.
• Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine. Whether or not carbamazepine has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
• Concomitant use of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban (direct acting oral anticoagulants) is expected to result in decreased plasma concentrations of these anticoagulants that may be insufficient to achieve the intended therapeutic effect. In general, coadministration of carbamazepine with rivaroxaban, apixaban, dabigatran, and edoxaban should be avoided.

致癌，诱变，生育力受损

Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

怀孕使用

(see WARNINGS).

人工与分娩

The effect of Tegretol on human labor and delivery is unknown.

护理母亲

Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breastfeeding are in the range of 2 to 5 mg daily for Tegretol and 1 to 2 mg daily for the epoxide.

Because of the potential for serious adverse reactions in nursing infants from carbamazepine, 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

Substantial evidence of Tegretol's effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.

Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (ie, 4 to 12 mcg/mL) is the same in children and adults.

The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.

老人用

No systematic studies in geriatric patients have been conducted.

不良反应

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended.

The following additional adverse reactions have been reported:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism. In certain cases, discontinuation of therapy may be necessary.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (eg, pulmonary embolism), and adenopathy or lymphadenopathy.

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been rare reports of impaired male fertility and/or abnormal spermatogenesis.

Testicular atrophy occurred in rats receiving Tegretol orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure (see WARNINGS, General) as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills. Hyponatremia (see WARNINGS, General). Decreased levels of plasma calcium have been reported. Osteoporosis has been reported.

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

Drug Abuse and Dependence

No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans.

过量

Acute Toxicity

Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).

Oral LD 50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.

治疗

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded.没有特定的解毒剂。

Elimination of the Drug: Induction of vomiting.

Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.

Measures to Reduce Absorption: Activated charcoal, laxatives.

Measures to Accelerate Elimination: Forced diuresis.

Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children.

Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Hypotension, Shock: Keep the patient's legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.

Convulsions: Diazepam or barbiturates.

Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).

Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.

Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59 Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A 2 and F hemoglobin, and (7) serum folic acid and B 12 levels.

A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which specialized consultation should be sought.

DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)

Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medications or diluents.

Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very gradually to the minimum effective level. Medication should be taken with meals.

Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended to start with low doses (children 6 to 12 years: ½ teaspoon four times a day and to increase slowly to avoid unwanted side effects.

Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by administering the same number of mg per day in smaller, more frequent doses (ie, twice a day tablets to three times a day suspension).

Tegretol-XR is an extended-release formulation for twice a day administration. When converting patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be administered. Tegretol -XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be noticeable in the stool.

Epilepsy (SEE INDICATIONS AND USAGE)

Adults and children over 12 years of age-Initial: Either 200 mg twice a day for tablets and XR tablets, or 1 teaspoon four times a day for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a twice a day regimen of Tegretol-XR or a three times a day or four times a day regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 15 years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level, usually 800 to 1200 mg daily.

Children 6 to 12 years of age-Initial: Either 100 mg twice a day for tablets or XR tablets, or ½ teaspoon four times a day for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a twice a day regimen of Tegretol-XR or a three times a day or four times a day regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level, usually 400 to 800 mg daily.

Children under 6 years of age-Initial: 10 to 20 mg/kg/day twice a day or three times a day as tablets, or four times a day as suspension. Increase weekly to achieve optimal clinical response administered three times a day or four times a day. Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made.

Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug Interactions, and Pregnancy).

Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)

Initial: On the first day, either 100 mg twice a day for tablets or XR tablets, or ½ teaspoon four times a day for suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (½ teaspoon) four times a day for suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in most patients with 400 to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug.