Romazicon

Romazicon说明

Romazicon®（氟马西尼）是一种苯并二氮杂受体拮抗剂。化学上，氟马西尼为8-氟-5,6-二氢-5-甲基-6-氧代-4H-咪唑并[1,5-a]（1,4）苯并二氮杂-3-羧酸乙酯。氟马西尼具有咪唑并二氮杂卓结构，计算分子量为303.3，并具有以下结构式：

氟马西尼是白色至类白色结晶化合物，在pH 7.4时，辛醇：缓冲液的分配系数为14：1。它不溶于水，但微溶于酸性水溶液。 Romazicon可作为无菌肠胃外剂型用于静脉内给药。每毫升包含0.1毫克氟马西尼，1.8毫克对羟基苯甲酸甲酯，0.2毫克对羟基苯甲酸丙酯，0.9％氯化钠，0.01％乙二胺四乙酸二钠和0.01％乙酸。用盐酸和/或氢氧化钠将pH调节至约4。

Romazicon-临床药理学

氟马西尼，一种咪唑并苯并二氮杂卓衍生物，拮抗苯并二氮杂卓对中枢神经系统的作用。氟马西尼竞争性地抑制GABA /苯并二氮杂receptor受体复合物上苯并二氮杂recognition识别位点的活性。氟马西尼在某些动物活动模型中是弱的部分激动剂，但在人类中几乎没有或没有激动剂活性。

氟马西尼不会通过苯二氮卓类受体（包括乙醇，巴比妥酸盐或全身麻醉药）以外的方法拮抗影响GABA能神经元的药物对中枢神经系统的作用，并且不会逆转阿片类药物的作用。

在数周内接受高剂量苯二氮卓预处理的动物中，Romazicon引起苯二氮卓戒断症状，​​包括癫痫发作。在成年人类受试者中观察到类似的效果。

药效学

在健康的人类志愿者中，静脉注射Romazicon已显示出拮抗苯二氮卓类药物产生的镇静，回忆障碍，精神运动障碍和通气抑制。

下列镇静苯二氮卓类药物镇静作用逆转的持续时间和程度与氟马西尼的剂量和血浆浓度有关，如以下来自正常志愿者的研究数据所示。

通常，约0.1 mg至0.2 mg的剂量（相当于3至6 ng / mL的峰值血浆水平）产生部分拮抗作用，而较高剂量的0.4至1 mg（峰值的血浆水平为12至28 ng / mL）通常产生部分拮抗作用。接受常规镇静剂量的苯二氮卓类药物的患者完全拮抗。通常在注射完成后1至2分钟内会出现逆转。在3分钟内将达到80％的响应，在6至10分钟时达到最佳效果。逆转的持续时间和程度与镇静的苯并二氮杂卓的血浆浓度以及所给予的Romazicon剂量有关。

在健康志愿者中，单独使用Romazicon不会改变眼压，并能逆转咪达唑仑给药后的眼压下降。

药代动力学

静脉注射后，氟马西尼的血浆浓度遵循两指数衰减模型。氟马西尼的药代动力学与剂量成比例，最高可达100 mg。

氟马西尼广泛分布在血管外空间，初始分布半衰期为4至11分钟，终末半衰期为40至80分钟。氟马西尼的峰值浓度与剂量成正比，表观初始分布体积为0.5 L / kg。稳态分布量为0.9至1.1 L / kg。氟马西尼是一种弱亲脂性基质。蛋白质结合率约为50％，药物未显示优先分配进入红细胞的现象。白蛋白占血浆蛋白结合的三分之二。

氟马西尼被完全（99％）代谢。尿液中几乎没有未改变的氟马西尼（<1％）。尿液中氟马西尼的主要代谢产物是脱乙基的游离酸及其葡糖醛酸苷结合物。在临床前研究中，没有证据表明脱乙基游离酸具有药理活性。

放射性标记药物的清除基本上在72小时内完成，其中90％至95％的放射性出现在尿液中，而5％至10％出现在粪便中。氟马西尼的清除主要通过肝代谢发生，并且取决于肝血流量。在正常志愿者的药代动力学研究中，总清除率范围为0.8至1.0 L / hr / kg。

总共5 mg的Romazicon平均值输注5分钟后的药代动力学参数（变异系数，范围）：

在静脉内输注药物期间摄入食物会导致清除率增加50％，这很可能是由于用餐时肝血流量增加所致。

老人

老年人中氟马西尼的药代动力学没有明显改变。

性别

在男性和女性受试者中，氟马西尼的药代动力学没有差异。

肾衰竭（肌酐清除率<10 mL / min）和血液透析

氟马西尼的药代动力学没有受到明显影响。

肝功能不全患者

与年龄相匹配的健康受试者相比，中度肝功能异常的患者的平均总清除率降低至40％至60％，而重度肝功能异常的患者的平均总清除率降低至正常值的25％。这导致中度肝功能不全患者的半衰期延长至1.3小时，严重受损患者的半衰期延长至2.4小时。对肝病患者应谨慎使用初始和/或重复剂量。

药物相互作用：

在苯并二氮杂激动剂的存在下，氟马西尼的药代动力学特征没有改变，所研究的那些苯二氮卓类药物（即地西epa，氟尼西epa，洛美他西和咪达唑仑）的动力学特征没有改变。在4小时的稳态和乙醇输注期间，与静脉注射氟马西尼剂量（分别在2.5小时和6小时）相比，安慰剂与乙醇的平均血浆水平无药代动力学相互作用，在氟马西尼上也无乙醇相互作用消除发现的半衰期。

小儿患者的药代动力学

氟马西尼的药代动力学已在29位年龄在1至17岁之间的小儿患者中进行了小规模的外科手术。 1至5岁患者的平均剂量为0.53 mg（0.044 mg / kg），6至12岁患者的平均剂量为0.63 mg（0.020 mg / kg），而13岁患者的平均剂量为0.8 mg（0.014 mg / kg）到17年。与成人相比，小儿患者的消除半衰期变化更大，平均为40分钟（范围：20至75分钟）。以体重标准化的间隙和分布体积，与成人所见范围相同，尽管在儿科患者中观察到的变异性更大。

临床试验

已在成人中使用Romazicon来逆转苯二氮卓类药物在清醒镇静，全身麻醉和管理可疑苯二氮卓类药物过量中的作用。对于小儿患者的非对照研究，只有有限的信息可用于使用Romazicon逆转苯二氮卓类药物的镇静作用。

成人意识镇静

Romazicon在970例患者中进行了四项研究，这些患者平均接受30 mg地西epa或10 mg咪达唑仑镇静（有或没有麻醉药）以及住院和门诊诊断或手术程序。 Romazicon可有效逆转苯二氮卓的镇静和精神运动作用；然而，健忘症的病情不完全，逆转的可能性也较小。在这些研究中，Romazicon的初始剂量为0.4 mg IV（两次剂量为0.2 mg），并根据需要额外添加0.2 mg剂量以实现完全唤醒，最大总剂量为1 mg。

接受氟马西尼的患者中有78％的反应变得完全机敏。在这些患者中，大约一半对0.4 mg至0.6 mg的剂量有反应，而另一半对0.8 mg至1 mg的剂量有反应。尽管确实发生了注射部位疼痛，躁动和焦虑，但接受1mg或更少剂量的Romazicon的患者很少发生不良反应。在这些研究中，镇静逆转与镇痛作用不足的频率增加或麻醉剂需求的增加无关。尽管大多数患者在整个术后3小时观察期间保持警觉，但观察到3％至9％的患者会出现镇静作用，这在接受高剂量苯二氮卓类药物的患者中最为常见（请参阅注意事项）。

成人全身麻醉

Romazicon在644例患者中进行了四项研究，这些患者接受咪达唑仑作为平衡和吸入麻醉的诱导和/或维持剂。咪达唑仑通常单独和/或与肌肉松弛剂，一氧化二氮，局部或局部麻醉剂，麻醉剂和/或吸入麻醉剂一起以5mg至80mg的剂量给药。氟马西尼的初始剂量为0.2 mg静脉注射，需要额外的0.2 mg剂量才能达到完全缓解，最大总剂量为1 mg。这些剂量可有效逆转镇静作用和恢复精神运动功能，但不能完全恢复记忆，如通过图片回忆所测。对于除苯二氮卓类药物以外还接受了多种麻醉剂治疗的患者，Romazicon不能有效地逆转镇静作用。

用咪达唑仑镇静的患者中有81％对氟马西尼产生了完全戒备或略有困倦的反应。在这些患者中，有36％对0.4 mg至0.6 mg的剂量有反应，而64％对0.8 mg至1 mg的剂量有反应。

对Romazicon缓解的患者发生镇静的情况发生在所研究的患者的10％至15％中，并且在使用大剂量的咪达唑仑（> 20 mg），较长的操作时间（> 60分钟）和使用神经肌肉阻滞剂时更为常见（请参阅注意事项）。

成人疑似苯二氮卓过量的管理

在两项试验中对Romazicon进行了研究，涉及497位被认为单独或与多种其他药物合用的过量苯二氮卓的患者。在这些试验中，有299名患者被证明服用过量的苯二氮卓类药物，在接受Romazicon的148名患者中，有80％的患者意识水平得到了改善。在对氟马西尼有反应的患者中，有75％对1 mg至3 mg的总剂量有反应。

镇静作用的逆转与中枢神经系统兴奋症状的频率增加有关。在接受氟马西尼治疗的患者中，有1％至3％的患者因躁动或焦虑而接受治疗。在这些研究中，严重的副作用并不常见，但在446名接受氟马西尼治疗的患者中观察到了6次癫痫发作。这6例患者中有4例摄入了大剂量的环状抗抑郁药，这增加了癫痫发作的风险（请参阅警告）。

剂量个性化

一般原则

Romazicon的严重不良反应与苯二氮卓类作用的逆转有关。大多数患者可以耐受使用Romazicon的最低有效剂量以上的剂量，但可能会使身体上依赖苯二氮卓类药物的患者或依赖苯二氮卓类药物的患者（例如抑制循环性抗抑郁药过量的癫痫发作）的治疗复杂化。

在高危患者中，重要的是要施用有效的最小量的Romazicon。对于一般临床人群，建议的剂量滴定中各个剂量之间的1分钟等待时间对于高危患者可能太短了。这是因为任何单剂量的氟马西尼都需要6到10分钟才能达到完全的效果。从业者应按照以下建议放慢对高危患者使用Romazicon的给药速度。

成年患者的麻醉和清醒镇静

对于对苯二氮卓类药物没有耐受性（或依赖于苯二氮卓类药物的个体），在推荐剂量下Romazicon具有良好的耐受性。在大多数临床情况下，接受单次苯二氮卓类药物暴露逆转的患者，在麻醉和清醒镇静中的推荐剂量和滴定速率（0.2 mg / min，0.2 mg / min给予1 mg）耐受良好（请参阅“不良反应” ）。主要风险将是镇静作用，因为长效（或大剂量短效）苯二氮卓类药物的作用持续时间可能超过Romazicon。镇静作用可以通过以不少于20分钟的间隔重复给药来治疗。对于重复治疗，任何一次都不应超过1 mg（以0.2 mg / min的剂量），任何一小时内不应超过3 mg。

成年患者苯二氮卓过量

在苯二氮卓过量患者（以0.5 mg / min的剂量服用3 mg至5 mg）中推荐的剂量下出现混淆，躁动，情绪不稳和知觉扭曲的风险可能比较低剂量和缓慢给药时的预期更大。推荐剂量代表了理想的缓慢苏醒与快速反应的需要之间的折衷，并且在剂量过量的情况下会持续产生影响。如果情况允许，医生可以选择使用0.2 mg / min的滴定速率在5至10分钟内缓慢唤醒患者，这可能有助于减少出现的体征和症状。

如果苯二氮卓类药物不引起镇静作用，则Romazicon无效。一旦达到3 mg至5 mg的剂量而无临床反应，则另外的Romazicon可能无效。

耐苯二氮卓类药物的患者

在服用苯二氮卓类药物足够长时间以达到一定程度的耐受性的个体中，Romazicon可能会引起苯二氮卓类戒断症状。在进入Romazicon试验之前服用苯二氮卓类药物的患者，接受氟马西尼的剂量超过1 mg，其经历戒断样事件的频率是少于1 mg的患者的2至5倍。

如临床病史或需要比平常更大剂量的苯二氮卓类药物耐受，对苯二氮卓类药物具有耐受性的患者中，较慢的0.1 mg / min滴定速率和较低的总剂量可有助于减少出现精神错乱和躁动的频率。在这种情况下，由于使用的Romazicon剂量较低，因此必须特别注意监测患者的镇静作用。

身体依赖苯二氮卓类药物的患者

众所周知，Romazicon会在物理上依赖苯二氮卓类药物的患者中引起抽搐发作，即使这种依赖在重症监护病房（ICU）环境中的高剂量镇静相对几天后就已经建立。在这种情况下，发生癫痫发作或再镇静的风险很高，并且患者在恢复意识之前经历了癫痫发作。由于尚未研究在这种情况下使用氟马西尼，并且尚无有关剂量和滴定速率的信息，因此在此类情况下应谨慎使用Romazicon。仅当使用这种药物的潜在益处超过沉淀性癫痫发作的风险时，才应在此类患者中使用Romazicon。医生可以直接向科学文献咨询该领域的最新信息。

Romazicon的适应症和用法

成年病人

如果使用苯二氮卓诱导和/或维持全身麻醉，用苯二氮卓产生镇静作用以用于诊断和治疗程序以及管理苯二氮卓过量，则使用Romazicon可以完全或部分逆转苯二氮卓的镇静作用。 。

小儿患者（1至17岁）

Romazicon可以逆转苯二氮卓类药物引起的镇静作用（请参阅预防措施：儿科使用）。

禁忌症

Romazicon被禁用：

• 对氟马西尼或苯二氮卓类药物过敏的患者。
• 接受苯二氮卓治疗可能危及生命的疾病（例如，控制颅内压或癫痫持续状态）的患者。
• 在出现严重的循环抗抑郁药过量迹象的患者中（请参阅警告）。

警告事项

癫痫发作的风险

某些高危人群中苯二氮卓类药物作用的逆转可能与癫痫发作有关。癫痫发作的可能危险因素包括：同时服用大量镇静催眠药，近期重复用药剂量的肠胃外反复苯二氮卓类药物治疗，过量服用氟马西尼之前肌阵挛性抽搐或癫痫发作，或同时发生周期性抗抑郁药中毒。

不建议将Romazicon用于严重的周期性抗抑郁药中毒，如运动异常（抽搐，僵硬，局灶性癫痫发作），心律不齐（广泛QRS，室性心律不齐，心脏传导阻滞），抗胆碱能征象（散瞳，黏膜干燥，下丘脑炎）和出现心血管衰竭。在这种情况下，应停用Romazicon，并应让患者保持镇静作用（根据需要给予通风和循环支持），直到抗抑郁药毒性的迹象消失为止。除反向镇静外，用Romazicon进行的治疗对重症混合过量患者没有已知的益处，并且在可能因任何原因发作的情况下，不应使用Romazicon。

与氟马西尼给药相关的大多数惊厥需要治疗，并已成功用苯二氮卓类，苯妥英钠或巴比妥类药物治疗。由于存在氟马西尼，可能需要比通常剂量更高的苯二氮卓类药物。

换气不足

接受Romazicon逆转苯二氮卓类药物作用（清醒镇静或全身麻醉后）的患者，应根据剂量和持续时间在适当的时间段（最长120分钟）内监测镇静，呼吸抑制或其他残留的苯二氮卓类药物作用。苯二氮卓类药物的效果。

这是因为由于给予苯二氮卓类药物，尚未在患者中建立Romazicon作为通气不足的有效治疗方法。在健康的男性志愿者中，Romazicon能够逆转苯二氮卓类药物引起的对高碳酸血症和低氧的通气反应的抑制，而仅使用苯二氮卓类药物即可。但是，这种抑郁症可能会复发，因为典型剂量的Romazicon（1mg或更少）的通气作用可能会在许多苯二氮卓类药物作用之前消失。 Romazicon联合苯二氮卓类药物与阿片类药物镇静后对通气反应的影响尚不一致，因此尚未进行充分研究。氟马西尼的可用性不会减少对通气不足的迅速检测的需求，也不会减少通过建立气道和辅助通气进行有效干预的能力。

过量用药的病例应始终监测镇静作用，直到患者稳定并且不太可能发生镇静作用为止。

预防措施

镇静剂的归还

Romazicon有望改善从使用苯二氮卓类药物进行镇静或麻醉的过程中康复的患者的警觉性，但不应代替术后进行适当的监测。 Romazicon的可用性不会降低与使用大剂量苯二氮卓镇静相关的风险。

服用Romazicon后，应在足够长的时间内对患者进行镇静，呼吸抑制（见警告）或其他持续性或复发性激动剂作用的监测。

如果使用Romazicon来逆转小剂量的短效苯并二氮杂（<10 mg咪达唑仑），则镇静作用最不可能。在长期的过程中，与神经肌肉阻滞剂和多种麻醉剂一起服用大剂量的单剂或累积剂量的苯二氮卓类药物的可能性最大。

在临床研究中，在1％至3％的成年患者中观察到严重的镇静作用。在必须防止成年患者产生镇静作用的临床情况下，医生可能希望在30分钟（可能在60分钟）再次重复初始剂量（以0.2 mg / min的剂量最多服用1 mg Romazicon）。尽管在临床试验中未研究此剂量方案，但在药理学研究中可有效预防正常志愿者中的镇静作用。

在一项涉及107位年龄在1至17岁之间的儿科患者的开放临床试验中，已经评估了使用Romazicon逆转用于有意识镇静作用的苯二氮卓类药物的作用。这项研究表明，用氟马西尼治疗后完全清醒的儿科患者可能会出现镇静复发，尤其是年轻患者（1至5岁）。 Romazicon给药开始后10分钟，完全戒备的60名患者中有7名出现了镇静作用。没有患者恢复到镇静的基线水平。平均镇静时间为25分钟（范围：19至50分钟）（请参见预防措施：小儿使用）。尚未确定在患有镇静作用的小儿患者中反复给予氟马西尼的安全性和有效性。

在ICU中使用

在ICU中应谨慎使用Romazicon，因为在这种情况下无法识别的苯二氮卓依赖性药物的风险增加。 Romazicon可能会在物理上依赖苯二氮卓类药物的患者中引起惊厥（请参阅剂量和警告的个性化）。

不建议使用Romazicon来诊断ICU中苯二氮卓类药物引起的镇静作用，因为存在上述不良事件的风险。此外，在代谢紊乱，创伤性损伤，苯二氮卓类药物以外的药物或与苯二氮卓类受体占用无关的任何其他原因所造成的混淆的情况下，患者对氟马西尼没有反应的预后意义尚不清楚。

在苯二氮卓过量中使用

Romazicon旨在作为对气道的适当管理，辅助呼吸，循环通路和支持，灌洗和木炭的内部净化以及充分的临床评估的辅助，而不是替代。

给予氟马西尼前应采取必要措施以确保气道，通气和静脉通路。唤醒后，由于觉醒后出现混乱和激动，患者可能会尝试拔出气管插管和/或静脉输液管。

头部受伤

Romazicon在头部受伤的患者中应谨慎使用，因为它可能会在接受苯二氮卓类药物的患者中引起抽搐或改变脑血流量。只有准备好处理此类并发症的医生才可以使用它。

与神经肌肉阻滞剂一起使用

在完全消除神经肌肉阻滞作用之前，不应使用Romazicon。

用于精神病患者

据报道，Romazicon对患有恐慌症的患者引起恐慌发作。

注射时疼痛

为了最大程度地减少注射部位疼痛或发炎的可能性，应通过向大静脉内自由流动的静脉输液来施用Romazicon。渗入血管周围组织后可能会发生局部刺激。

用于呼吸系统疾病

对于严重的肺部疾病患者，由于苯二氮卓类药物导致严重的呼吸抑制，其主要治疗方法应该是适当的呼吸支持（请参阅预防措施），而不是使用Romazicon。氟马西尼能够部分逆转健康志愿者中苯二氮卓类药物引起的通气驱动改变，但尚未显示出临床疗效。

用于心血管疾病

在临床文献报道的研究中，当以0.1 mg / min的速率以小于0.5 mg的总剂量给予Romazicon逆转心脏患者的苯并二氮杂dia时，Romazicon不会增加心脏的功。当对稳定的缺血性心脏病患者给药时，单独使用氟马西尼对心血管参数无明显影响。

用于肝病

对于轻度至中度肝病的患者，Romazicon的清除率降低至正常水平的40％至60％，而对于严重肝功能不全的患者，清除率降至正常水平的25％（请参阅临床药理学：药代动力学）。虽然不影响用于最初逆转苯二氮卓类作用的氟马西尼的剂量，但应减少肝脏疾病中该药物的重复剂量的大小或频率。

在药物和酒精依赖患者中使用

对于酒精中毒和其他药物依赖性患者，应谨慎使用Romazicon，因为苯二氮卓类药物耐受性的频率增加，并且在这些患者人群中观察到依赖性。

不建议将Romazicon用于治疗苯二氮卓依赖性药物或治疗旷日持久的苯二氮卓戒断综合征，因为尚未研究此类用途。

氟马西尼的给药可促使动物和人体内苯二氮卓类药物戒断。在接受治疗剂量口服劳拉西m长达2周的健康志愿者中已经看到了这一点，当他们接受了累计剂量不超过3 mg的氟马西尼治疗时，它们表现出诸如潮热，躁动和震颤等效果。

在临床试验中，一些成年患者发生了类似的不良反应，表明氟马西尼会导致苯二氮卓类药物戒断。这些患者患有短暂的综合症，其特征为头昏眼花，轻度混乱，情绪不稳，躁动（伴有焦虑症状和体征）以及轻度的感觉扭曲。这种反应与剂量有关，最常见的是高于1 mg的剂量，除了放心之外很少需要治疗，而且通常寿命短。必要时，这些患者（5至10例）已成功用常规剂量的巴比妥酸盐，苯二氮卓或其他镇静药物治疗。

从业人员应假定氟马西尼的给药可能对已建立身体依赖性的苯二氮卓类药物的患者引发剂量依赖性戒断综合症，并使酒精，巴比妥类药物和交叉耐受性镇静药的戒断综合症的治疗复杂化。

药物相互作用

与苯二氮卓类药物以外的中枢神经系统抑制剂的相互作用尚未得到专门研究。但是，在麻醉，吸入麻醉剂，肌肉松弛剂和肌肉松弛剂拮抗剂联合镇静或麻醉后使用Romazicon时，未见有害的相互作用。

当混合使用过量药物时，使用Romazicon时需要特别注意，因为过量服用的其他药物（特别是循环性抗抑郁药）所产生的其他毒性作用（例如惊厥和心律失常）可能会因氟马西尼逆转苯二氮卓类药物而出现（请参阅警告） ）。

不建议在长期接受苯二氮卓治疗的癫痫患者中使用Romazicon。尽管Romazicon发挥了轻微的内在抗惊厥作用，但突然抑制苯并二氮杂ist激动剂的保护作用仍会引起癫痫患者惊厥。

Romazicon通过在受体水平上的竞争性相互作用来阻断苯并二氮杂卓的中心作用。 Romazicon也可阻止非苯二氮杂激动剂对苯二氮杂receptor受体（如佐匹克隆，三唑并哒嗪等）的作用。

在氟马西尼的存在下，苯并二氮杂卓的药代动力学没有改变，反之亦然。

乙醇和氟马西尼之间没有药代动力学相互作用。

在门诊病人中使用

在长效苯并二氮杂卓从体内完全清除之前，Romazicon的作用可能消失。通常，如果患者在服用1 mg氟马西尼后2小时内未出现镇静迹象，则不太可能在以后出现严重镇静作用。对于使用长效苯二氮卓类药物（例如地西epa）或大剂量短效苯并二氮杂类药物（例如> 10 mg咪达唑仑）的患者，必须提供足够的观察时间（请参见剂量的个体化）。

由于定期服用苯二氮卓类药物的患者发生不良反应的风险增加，因此在进行任何手术之前，医生应仔细询问患者或其监护人苯二氮卓类药物，酒精和镇静剂的使用史，这一点尤其重要。已计划使用Romazicon（请注意：在药物和酒精依赖患者中使用）。

给患者的信息

Romazicon不能持续逆转失忆症。不能期望患者记住手术后告诉他们的信息，应该以书面形式或给予负责任的家庭成员加强对患者的指示。建议医师在手术前和出院时与患者或其监护人讨论，尽管患者在出院时可能会感到警觉，但苯二氮卓类药物（例如镇静剂）的作用可能会再次出现。因此，应以书面形式（最好是书面形式）指导患者记忆和判断力受损，并特别建议：

1. 在出院后的头24小时内不要从事任何需要完全戒备的活动，也不要操作危险的机械或机动车辆，并且可以确定苯二氮卓没有残留的镇静作用。
2. 在氟马西尼给药后的最初24小时内或如果苯二氮卓类药物的作用持续存在，则不要服用任何酒精或非处方药。

实验室测试

建议不要进行特定的实验室测试来跟踪患者的反应或确定可能的不良反应。

药物/实验室测试的相互作用

尚未评估氟马西尼与常用实验室测试的可能相互作用。

致癌，诱变，生育力受损

尚未在动物中进行评估氟马西尼致癌潜力的研究。

在使用五种不同测试菌株的Ames测试中，没有发现致突变性的证据。酿酒酵母D7和中国仓鼠细胞中的致突变潜力测定被认为是阴性的，体外人外周血淋巴细胞的成骨作用测定和小鼠微核试验中的体内成生测定也被认为是阴性的。 Flumazenil caused a slight increase in unscheduled DNA synthesis in rat hepatocyte culture at concentrations which were also cytotoxic; no increase in DNA repair was observed in male mouse germ cells in an in vivo DNA repair assay.

A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120× the human exposure from a maximum recommended intravenous dose of 5 mg.

怀孕

There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120× to 600× the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200× the human exposure from a maximum recommended intravenous dose of 5 mg. The no-effect dose of 15 mg/kg in rabbits represents 60× the human exposure.

An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with a delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120× the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24× the human exposure from an intravenous dose of 5 mg.

人工与分娩

The use of Romazicon to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown.

护理母亲

Caution should be exercised when deciding to administer Romazicon to a nursing woman because it is not known whether flumazenil is excreted in human milk.

儿科用

The safety and effectiveness of Romazicon have been established in pediatric patients 1 year of age and older. Use of Romazicon in this age group is supported by evidence from adequate and well-controlled studies of Romazicon in adults with additional data from uncontrolled pediatric studies including one open-label trial.

The use of Romazicon to reverse the effects of benzodiazepines used for conscious sedation was evaluated in one uncontrolled clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. At the doses used, Romazicon's safety was established in this population. Patients received up to 5 injections of 0.01 mg/kg flumazenil up to a maximum total dose of 1.0 mg at a rate not exceeding 0.2 mg/min.

Of 60 patients who were fully alert at 10 minutes, 7 experienced resedation. Resedation occurred between 19 and 50 minutes after the start of Romazicon administration. None of the patients experienced a return to the baseline level of sedation. All 7 patients were between the ages of 1 and 5 years. The types and frequency of adverse events noted in these pediatric patients were similar to those previously documented in clinical trials with Romazicon to reverse conscious sedation in adults. No patient experienced a serious adverse event attributable to flumazenil.

The safety and efficacy of Romazicon in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Pediatric Patients ).

The safety and efficacy of Romazicon have not been established in pediatric patients for reversal of the sedative effects of benzodiazepines used for induction of general anesthesia, for the management of overdose, or for the resuscitation of the newborn, as no well-controlled clinical studies have been performed to determine the risks, benefits and dosages to be used. However, published anecdotal reports discussing the use of Romazicon in pediatric patients for these indications have reported similar safety profiles and dosing guidelines to those described for the reversal of conscious sedation.

The risks identified in the adult population with Romazicon use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS , and ADVERSE REACTIONS sections when using Romazicon in pediatric patients.

老人用

Of the total number of subjects in clinical studies of flumazenil, 248 were 65 and over.在这些受试者和较年轻的受试者之间未观察到安全性或有效性的总体差异。其他报告的临床经验尚未发现老年患者和年轻患者之间反应的差异，但是不能排除某些老年患者的敏感性更高。

The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of Romazicon in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of Romazicon may be used for reversal.

不良反应

Serious Adverse Reactions

Deaths have occurred in patients who received Romazicon in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose.

Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. Romazicon administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose) (see WARNINGS ).

Two of the 446 patients who received Romazicon in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia).

Adverse Events in Clinical Studies

The following adverse reactions were considered to be related to Romazicon administration (both alone and for the reversal of benzodiazepine effects) and were reported in studies involving 1875 individuals who received flumazenil in controlled trials. Adverse events most frequently associated with flumazenil alone were limited to dizziness, injection site pain, increased sweating, headache, and abnormal or blurred vision (3% to 9%).

Body as a Whole: fatigue (asthenia, malaise), headache, injection site pain1, injection site reaction (thrombophlebitis, skin abnormality, rash)

Cardiovascular System: cutaneous vasodilation (sweating, flushing, hot flushes)

Digestive System: nausea, vomiting (11%)

Nervous System: agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation)1, dizziness (vertigo, ataxia) (10%), emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia)

Special Senses: abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia)

All adverse reactions occurred in 1% to 3% of cases unless otherwise marked.

Observed percentage reported if greater than 9%.

The following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to Romazicon administration and/or reversal of benzodiazepine effects:

Nervous System: confusion (difficulty concentrating, delirium), convulsions (see WARNINGS ), somnolence (stupor)

Special Senses: abnormal hearing (transient hearing impairment, hyperacusis, tinnitus)

The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to Romazicon administration is unknown, but they are included as alerting information for the physician.

Body as a Whole: rigors, shivering

Cardiovascular System: arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension, chest pain

Digestive System: hiccup

Nervous System: speech disorder (dysphonia, thick tongue)

Not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure.

1个

indicates reaction in 3% to 9% of cases.

Additional Adverse Reactions Reported During Postmarketing Experience

The following events have been reported during postapproval use of Romazicon.

Nervous System: Fear, panic attacks in patients with a history of panic disorders.

Withdrawal symptoms may occur following rapid injection of Romazicon in patients with long-term exposure to benzodiazepines.

药物滥用和依赖性

Romazicon acts as a benzodiazepine antagonist, blocks the effects of benzodiazepines in animals and man, antagonizes benzodiazepine reinforcement in animal models, produces dysphoria in normal subjects, and has had no reported abuse in foreign marketing.

Although Romazicon has a benzodiazepine-like structure it does not act as a benzodiazepine agonist in man and is not a controlled substance.

过量

There is limited experience of acute overdose with Romazicon.

There is no specific antidote for overdose with Romazicon. Treatment of an overdose with Romazicon should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Intravenous bolus administration of doses ranging from 2.5 to 100 mg (exceeding those recommended) of Romazicon, when administered to healthy normal volunteers in the absence of a benzodiazepine agonist, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory test abnormalities. In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.

Reversal with an excessively high dose of Romazicon may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures (see WARNINGS ).

Romazicon Dosage and Administration

Romazicon is recommended for intravenous use only. It is compatible with 5% dextrose in water, lactated Ringer's and normal saline solutions. If Romazicon is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours. For optimum sterility, Romazicon should remain in the vial until just before use. As with all parenteral drug products, Romazicon should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

To minimize the likelihood of pain at the injection site, Romazicon should be administered through a freely running intravenous infusion into a large vein.

Reversal of Conscious Sedation

For the reversal of the sedative effects of benzodiazepines administered for conscious sedation, the recommended initial dose of Romazicon is 0.2 mg (2 mL) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a second dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL). The dosage should be individualized based on the patient's response, with most patients responding to doses of 0.6 mg to 1 mg (see INDIVIDUALIZATION OF DOSAGE ).

In the event of resedation, repeated doses may be administered at 20-minute intervals as needed. For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour.

It is recommended that Romazicon be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see INDIVIDUALIZATION OF DOSAGE ).

For the reversal of the sedative effects of benzodiazepines administered for conscious sedation in pediatric patients greater than 1 year of age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. The dose should be individualized based on the patient's response. The mean total dose administered in the pediatric clinical trial of flumazenil was 0.65 mg (range: 0.08 mg to 1.00 mg). Approximately one-half of patients required the maximum of five injections.

Resedation occurred in 7 of 60 pediatric patients who were fully alert 10 minutes after the start of Romazicon administration (see PRECAUTIONS: Pediatric Use ). The safety and efficacy of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.

It is recommended that Romazicon be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see INDIVIDUALIZATION OF DOSAGE ).

The safety and efficacy of Romazicon in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established.

Reversal of General Anesthesia in Adult Patients

For the reversal of the sedative effects of benzodiazepines administered for general anesthesia, the recommended initial dose of Romazicon is 0.2 mg (2 mL) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL). The dosage should be individualized based on the patient's response, with most patients responding to doses of 0.6 mg to 1 mg (see INDIVIDUALIZATION OF DOSAGE ).

In the event of resedation, repeated doses may be administered at 20-minute intervals as needed. For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour.

It is recommended that Romazicon be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see INDIVIDUALIZATION OF DOSAGE ).

Management of Suspected Benzodiazepine Overdose in Adult Patients

For initial management of a known or suspected benzodiazepine overdose, the recommended initial dose of Romazicon is 0.2 mg (2 mL) administered intravenously over 30 seconds. If the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 mL) can be administered over another 30 seconds. Further doses of 0.5 mg (5 mL) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg.

Do not rush the administration of Romazicon. Patients should have a secure airway and intravenous access before administration of the drug and be awakened gradually (see PRECAUTIONS ).

Most patients with a benzodiazepine overdose will respond to a cumulative dose of 1 mg to 3 mg of Romazicon, and doses beyond 3 mg do not reliably produce additional effects. On rare occasions, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg (administered slowly in the same manner).

If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg of Romazicon, the major cause of sedation is likely not to be due to benzodiazepines, and additional Romazicon is likely to have no effect.

In the event of resedation, repeated doses may be given at 20-minute intervals if needed. For repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour.

Safety and Handling

Romazicon is supplied in sealed dosage forms and poses no known risk to the healthcare provider. Routine care should be taken to avoid aerosol generation when preparing syringes for injection, and spilled medication should be rinsed from the skin with cool water.

How is Romazicon Supplied

5 mL multiple-use vials containing 0.1 mg/mL flumazenil — boxes of 10 (NDC 0004-6911-06); 10 mL multiple-use vials containing 0.1 mg/mL flumazenil — boxes of 10 (NDC 0004-6912-06).

存储

储存在25°C（77°F）; excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

分配者：
Genentech USA, Inc.
罗氏集团成员
1 DNA方式
南旧金山，加利福尼亚州94080-4990

Revised: April 2010

RNI_151788_PI_AR2010_K
10118961

© 2010 Genentech, Inc. All rights reserved.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 5 mL Vial Carton

NDC 0004-6911-06

Romazicon ®
(flumazenil) Injection

0.5 mg/5 mL

5 mL Multiple-Use Vials (0.1 mg/mL)

For IV Use
Sterile

仅Rx

10 Vials
(5 mL Size)

Genentech