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氯巴占治疗难治性癫痫专家共识(2022)

北京协和医院罕见病多学科协作组  中国罕见病联盟

北京协和医院罕见病多学科协作组  中国罕见病联盟. 氯巴占治疗难治性癫痫专家共识(2022)[J]. 协和医学杂志, 2022, 13(5): 768-782. doi: 10.12290/xhyxzz.2022-0421
引用本文: 北京协和医院罕见病多学科协作组  中国罕见病联盟. 氯巴占治疗难治性癫痫专家共识(2022)[J]. 协和医学杂志, 2022, 13(5): 768-782. doi: 10.12290/xhyxzz.2022-0421
Multi-disciplinary Team for Rare Diseases, Peking Union Medical College Hospital National Rare Diseases Committee. Expert Consensus on Clobazam in the Treatment of Refractory Epilepsy (2022)[J]. Medical Journal of Peking Union Medical College Hospital, 2022, 13(5): 768-782. doi: 10.12290/xhyxzz.2022-0421
Citation: Multi-disciplinary Team for Rare Diseases, Peking Union Medical College Hospital National Rare Diseases Committee. Expert Consensus on Clobazam in the Treatment of Refractory Epilepsy (2022)[J]. Medical Journal of Peking Union Medical College Hospital, 2022, 13(5): 768-782. doi: 10.12290/xhyxzz.2022-0421

氯巴占治疗难治性癫痫专家共识(2022)

doi: 10.12290/xhyxzz.2022-0421
基金项目: 

中国医学科学院医学与健康科技创新工程 2021-I2M-1-003

详细信息

    通信作者:张波1, 3, E-mail: zhangbopumch@163.com
    张抒扬2, 3, E-mail: zhangshuyang103@163.com
    1. 中国医学科学院北京协和医院药剂科,北京 100730
    2. 中国医学科学院北京协和医院心内科,北京 100730
    3. 中国医学科学院北京协和医院疑难重症及罕见病国家重点实验室,北京 100730

  • 中图分类号: R742.1

Expert Consensus on Clobazam in the Treatment of Refractory Epilepsy (2022)

Funds: 

CAMS Innovation Fund for Medical Sciences 2021-I2M-1-003

More Information

    Corresponding authors: ZHANG Bo1, 3, E-mail: zhangbopumch@163.com
    ZHANG Shuyang2, 3, E-mail: zhangshuyang103@163.com
    1. Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
    2. Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
    3. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

  • 摘要: 多数癫痫患者经规范化抗癫痫治疗后,症状可得到良好控制或缓解,但30%~40%患者经长期药物干预后,仍反复出现癫痫发作,进展为难治性癫痫。Lennox-Gastaut综合征、Dravet综合征和肌阵挛-失张力癫痫均为儿童期起病的难治性癫痫,严重威胁患者的身心健康。2011年美国食品药品监督管理局批准氯巴占用于年龄≥ 2岁Lennox-Gastaut综合征患者癫痫发作的辅助治疗,且该药品在Dravet综合征和肌阵挛-失张力癫痫的治疗中也有一定应用。目前,氯巴占的药理作用机制尚未完全明确,可能通过与γ-氨基丁酸A受体上的苯二氮艹卓类位点相结合发挥药理作用。在体内,氯巴占和N-去甲氯巴占主要经CYP3A4、CYP2C19代谢,临床应用时需警惕与其他药物的相互作用。对于CYP2C19慢代谢患者,还应关注N-去甲氯巴占的血药浓度,并监测药物相关不良反应。为促进氯巴占在我国临床应用的进一步规范化,保障临床用药的有效性和安全性,北京协和医院罕见病多学科协作组联合中国罕见病联盟,组织相关领域专家,经多次讨论、修改,最终制定了本共识,以供临床参考。
    声明:随着用药经验的积累及相关临床研究的开展,本共识必然会表现出其在氯巴占临床应用中的局限性。为此,专家组将与时俱进,继续跟进相关研究证据,并及时更新。本共识仅供临床医生和医疗服务机构参考,不作为法律依据及临床诊治准则,实际应用时应结合具体临床情况和患者自身状况。专家组不承担应用共识产生不良后果的任何法律责任。
    作者贡献:本专家共识由北京协和医院罕见病多学科协作组和中国罕见病联盟共同发起,张抒扬组织建立了共识组和秘书组,并任命张波全权负责共识的制订工作;许婷婷、刘鑫、孙卓、田欣、安鹏姣共同起草了共识初稿,在张抒扬、张波的组织协调下联合其他专家对共识进行讨论、凝练推荐意见;常青、陈孟莉、陈耀龙、封卫毅、何艳玲、胡欣、季涛云、姜玉武、李大魁、李林康、李娜、李智平、廖建湘、刘韶、刘鑫、卢强、马明圣、梅丹、潘慧、秦炯、邱峰、史录文、宋红梅、宋燕青、孙咸泽、王晓玲、王艺、吴晶、夏泉、许婷婷、尹飞、泽碧、张波、张丁丁、张抒扬、张文宝、张玉琴、张占杰、郑佳音、周颖、朱以诚、邹丽萍共同参与了推荐意见的商讨与修订工作;张抒扬、张波对共识全文进行了最终审校,所有参与者均对共识终稿表示认同。
    利益冲突:所有参与本共识制订的人员均声明不存在利益冲突
    专家组 (按姓氏首字母排序):
    常青(中国医学科学院北京协和医院医务处),陈孟莉(中国人民解放军总医院药品供应保障中心),陈耀龙(兰州大学健康数据科学研究院),封卫毅(西安交通大学第一附属医院药学部),何艳玲(广州市妇女儿童医疗中心药剂科),胡欣(北京医院药学部),季涛云(北京大学第一医院儿科),姜玉武(北京大学第一医院儿科),李大魁(中国医学科学院北京协和医院药剂科),李林康(中国罕见病联盟),李娜(《协和医学杂志》编辑部),李智平(复旦大学附属儿科医院药剂科),廖建湘(深圳市儿童医院小儿神经科和癫痫诊疗中心),刘韶(中南大学湘雅医院药学部),刘鑫(中国医学科学院北京协和医院药剂科),卢强(中国医学科学院北京协和医院神经科),马明圣(中国医学科学院北京协和医院儿科),梅丹(中国医学科学院北京协和医院药剂科),潘慧(中国医学科学院北京协和医院内分泌科),秦炯(北京大学人民医院儿科),邱峰(重庆医科大学附属第一医院药学部),史录文(北京大学医药管理国际研究中心),宋红梅(中国医学科学院北京协和医院儿科),宋燕青(吉林大学第一医院药学部),孙咸泽(中国药学会),王晓玲(首都医科大学附属北京儿童医院药学部),王艺(复旦大学附属儿科医院),吴晶(天津大学卫生事业与药事管理专业),夏泉(安徽医科大学第一附属医院药剂科),许婷婷(中国医学科学院北京协和医院药剂科),尹飞(中南大学湘雅医院儿科),泽碧(西藏自治区人民医院药学部),张波(中国医学科学院北京协和医院药剂科),张丁丁(中国医学科学院北京协和医院医学科学研究中心),张抒扬(中国医学科学院北京协和医院疑难重症及罕见病国家重点实验室),张文宝(国家卫生健康委医政医管局医疗管理处),张玉琴(天津市儿童医院神经内科),张占杰(中国医学科学院北京协和医院医务处),郑佳音(中国罕见病联盟),周颖(北京大学第一医院药学部),朱以诚(中国医学科学院北京协和医院神经科),邹丽萍(中国人民解放军总医院儿童医学中心)
    秘书组:
    许婷婷(中国医学科学院北京协和医院药剂科),刘鑫(中国医学科学院北京协和医院药剂科),孙卓(中国医学科学院北京协和医院药剂科/中国医学科学院北京协和医学院药物研究所),田欣(中国医学科学院北京协和医院药剂科),安鹏姣(中国医学科学院北京协和医院药剂科),屈静晗(中国医学科学院北京协和医院药剂科),尚俊美(中国医学科学院北京协和医院药剂科),于佳鑫(中国医学科学院北京协和医院药剂科)
    执笔人:许婷婷,刘鑫,孙卓,田欣,安鹏姣
  • 图  1  GABAA受体结构及BZD药物作用位点[19]

    GABA:γ-氨基丁酸;BZD:苯二氮类

    表  1  氯巴占治疗难治性癫痫拟解决的临床问题及推荐意见

    序号 临床问题 推荐意见
    1 氯巴占在难治性癫痫中的临床应用 推荐意见1:年龄≥2岁LGS患者应用丙戊酸、拉莫三嗪治疗无效时,可添加氯巴占作为辅助治疗,尤其适用于跌倒发作的治疗[证据等级:2b;推荐强度:B]。(共识度:100%)
    推荐意见2:若丙戊酸治疗无效,可辅助添加氯巴占用于年龄≥ 3岁DS患儿的治疗[证据等级:4;推荐强度:C]。(共识度:100%)
    推荐意见3:对于年龄≥ 2岁EMAS患儿,若丙戊酸和拉莫三嗪治疗无效,可尝试添加氯巴占辅助治疗[证据等级:5;推荐强度:D]。(共识度:100%)
    2 起始治疗方案和剂量调整方案 推荐意见4:对于氯巴占的给药方案,建议根据患者体质量不同给予不同的剂量,并均从小剂量开始给药[证据等级:5;推荐强度:D];建议根据患者临床表现及耐受性调整氯巴占剂量,调整时间间隔不应小于1周[证据等级:5;推荐强度:D];与其他常用的ASMs合用时,氯巴占给药剂量无需常规调整[证据等级:2b;推荐强度:B]。(共识度:100%)
    3 血药浓度监测 推荐意见5:应用氯巴占治疗难治性癫痫时,无需常规进行TDM[证据等级:5;推荐强度:D];一旦出现明显不良反应,需对疑似CYP2C19慢代谢患者进行基因检测,若确定为CYP2C19慢代谢者,则需进行TDM,并需考虑是否存在其他加重不良反应的危险因素;若非CYP2C19慢代谢者,则需重点考虑是否存在合用依曲韦林或其他加重不良反应的危险因素,并进行TDM,上述两种情况均需根据监测结果调整氯巴占用药剂量[证据等级:5;推荐强度:D]。(共识度:100%)
    4 药物相互作用 推荐意见6:与影响CYP3A4和CYP2C19活性或CYP2D6和CYP3A4底物的药物合用时,应关注氯巴占相关药物相互作用,监测患者对合用药物的反应;发生疑似不良反应时,应结合临床症状和TDM结果,及时调整给药方案[证据等级:5;推荐强度:D]。(共识度:100%)
    5 特殊人群用药 推荐意见7:CYP2C19慢代谢者、老年人及轻中度肝功能不全患者应从小剂量开始服用氯巴占,缓慢增加剂量并降低维持剂量。轻中度肾功能不全患者无需调整用药剂量。目前尚缺少该药在年龄 < 2岁患儿及重度肝、肾功能不全患者中的安全性数据,建议在个体化基础上经多学科讨论后确定给药方案。不建议妊娠期和哺乳期女性使用氯巴占[证据等级:5;推荐强度:D]。(共识度:100%)
    6 不良反应、超剂量用药及中毒处置 推荐意见8:氯巴占使用前及使用过程中,应评估患者成瘾和中枢镇静的风险,尤其在合用中枢抑制类药物的情况下,必要时从小剂量开始或减量观察,不建议超剂量用药。氯巴占立即停药可诱发癫痫持续发作、神经精神异常等戒断症状。如果使用过程中发生皮肤过敏反应,可能存在出现SJS/TEN的风险,应尽快就近至医疗机构诊治,在医疗机构指导/监护下立即停药,并积极对症治疗,同时避免再次使用。若出现过量或中毒症状,建议采取常规支持治疗,不建议使用氟马西尼进行解救[证据等级:5;推荐强度:D]。(共识度:100%)
    LGS:Lennox-Gastaut综合征;DS:Dravet综合征;EMAS:肌阵挛-失张力癫痫;ASMs:抗癫痫发作药物;TDM:治疗药物监测;SJS/TEN:史蒂文约翰逊综合征/中毒性表皮坏死松解症
    下载: 导出CSV

    表  2  2009年牛津循证医学中心制定的证据等级和推荐强度分级标准[18]

    推荐强度 证据等级 描述
    A 1a 同质随机对照试验的系统评价
    1b 单个随机对照试验(可信区间窄)
    1c “全或无”证据(有治疗之前,所有患者死亡;有治疗之后,有患者能存活。或者有治疗之前,一些患者死亡;有治疗之后,无患者死亡)
    B 2a 同质队列研究的系统评价
    2b 单个队列研究(包括低质量的随机对照试验,如 < 80%随访)
    2c 结果研究或生态学研究
    3a 同质病例-对照研究的系统评价
    3b 单个病例-对照研究
    C 4 病例系列报道(包括低质量队列或病例-对照研究)
    D 5 基于未经验证的专家意见或评论或基础实验
    下载: 导出CSV

    表  3  氯巴占给药方案

    适应证 给药方案 用法用量
    LGS 体质量≤ 30 kg 体质量 > 30 kg
    起始剂量 5 mg/d 10 mg/d
    第7天 10 mg/d 20 mg/d
    第14天 20 mg/d 40 mg/d
    DS 起始剂量 0.2~0.3 mg/(kg·d)
    第14~21天后 0.5~1.0 mg/(kg·d)
    1.5~2.0 mg/(kg·d)*
    EMAS 尚不明确 尚不明确
    LGS、DS、EMAS:同表 1*最高剂量
    下载: 导出CSV

    表  4  中毒症状患者的氯巴占及其代谢产物监测

    研究者 氯巴占剂量(mg/d) 合并用药/疾病情况 氯巴占血药浓度(μg/L) N-去甲氯巴占血药浓度(μg/L) 毒性表现
    Guberman等[62] 10~60 NA NA > 3141 共济失调、眩晕、嗜睡、疲劳
    Aylett等[63] 15 CYP2C19慢代谢 最高达100 最高达14 400 共济失调、不自主运动
    Montenegro等[64] NA NA 3900 NA 呼吸抑制
    Naccarato等[65] 20 同服CYP3A4诱导剂和CYP2C19抑制剂依曲韦林 最高达423 最高达3302 共济失调、构音障碍、严重嗜睡
    Parmeggiani等[66] 20 CYP2C19慢代谢 190 14 700 严重嗜睡、遗尿、体质量增加
    Pok等[67] NA 老年患者,同服抗焦虑药* 720 36 000 死亡
    Proença等[68] NA 同服抗精神病药* 3900 NA 死亡
    *毒理学报告排除了其他药物的影响;NA:不适用
    下载: 导出CSV

    表  5  易与氯巴占发生相互作用的药物及临床管理方案

    药物 相互作用强度 影响原因 临床管理方案
    氯巴占对其他药物的影响
        硫利达嗪 禁忌 硫利达嗪为CYP2D6的底物,氯巴占对其代谢具有抑制作用,增加该药物的不良反应发生风险(QTc间期延长)[74] 尽量避免二者同时使用,若确需合用应密切监测QTc间期
        右美沙芬 重度 右美沙芬为CYP2D6的底物,多次给予氯巴占可增加右美沙芬的血浆暴露量(药-时曲线下面积和峰浓度分别增加92%和59%)[58] 降低右美沙芬剂量
        激素类避孕药 重度 一些激素类避孕药为CYP3A4的底物,氯巴占可降低此类药物的疗效[8] 选择非激素类避孕药
    其他药物对氯巴占的影响
        奥美拉唑、氟康唑、氟西汀、氟伏沙明、噻氯匹定 重度 奥美拉唑为CYP2C19中度抑制剂,氟康唑、氟西汀、氟伏沙明和噻氯匹定为CYP2C19强抑制剂,与氯巴占合用时,可增加N-去甲氯巴占血药浓度;此外,氟康唑、氟西汀和氟伏沙明对CYP3A4具有中度抑制作用,亦可增加氯巴占血药浓度[8, 73, 75] 降低氯巴占剂量或对氯巴占及N-去甲氯巴占进行TDM
    TDM:同表 1
    下载: 导出CSV

    表  6  CYP2C19慢代谢者氯巴占给药方案

    给药方案 体质量≤ 30 kg 体质量 > 30 kg
    起始剂量 5 mg/d 5 mg/d
    第7天 5 mg/d 10 mg/d
    第14天 10 mg/d 20 mg/d
    第21天 20 mg/d 40 mg/d
    下载: 导出CSV
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