巴氯芬注射液的适应症和用法

巴氯芬注射液可用于治疗4岁及以上的成年和小儿严重痉挛。在考虑通过植入式泵进行长期输注之前，患者应首先对鞘内巴氯芬的筛查剂量作出反应。为了缓解脊髓起源的痉挛，应该对那些对口服巴氯芬治疗无反应的患者或在有效剂量下出现不可忍受的中枢神经系统副作用的患者，保留通过植入式泵对巴氯芬注射液的长期输注。因颅脑外伤而痉挛的患者应在受伤后至少等待一年，然后再考虑长期鞘内注射巴氯芬治疗。 Baclofen注射剂旨在通过鞘内途径以单次推注测试剂量（通过脊髓导管或腰椎穿刺）使用，并且对于长期使用，只能与MedtronicSynchroMed®II可编程泵或其他标有鞘内注射Baclofen注射剂的泵一起使用[请参阅临床研究（14）] 。

在植入用于慢性鞘内注射巴氯芬注射液的装置之前，患者必须在筛查试验中显示对巴氯芬注射液的反应[见剂量和给药方法（2.2）] 。

巴氯芬注射液剂量和给药

仅与MedtronicSynchroMed®II可编程泵（或其他标有鞘内注射巴氯芬注射液的泵）一起使用

巴氯芬注射液仅允许与MedtronicSynchroMed®II可编程泵或其他标有鞘内注射巴氯芬注射液的泵一起使用。有关对泵进行编程和/或加注储液罐的特定说明和预防措施，请参阅制造商手册。重要的是要为用于注射巴氯芬注射液的泵选择合适的补充工具包。巴氯芬注射液不得与其他药物混用。

筛选阶段

在泵植入和开始长期服用巴氯芬注射液之前，患者必须在筛选试验中证明对鞘内注射巴氯芬注射液推注剂量有积极的临床反应。筛选试验采用浓度为50 mcg / mL的巴氯芬注射液。 1 mL注射器（50 mcg / mL）可用于筛选试验。筛选步骤如下。在不少于一分钟的时间内，通过bar弹法将初始剂量为1毫升的50毫克微囊剂注入鞘内空间。在接下来的4到8个小时内观察患者。阳性反应包括肌肉张力和/或痉挛频率和/或严重程度明显降低。如果初始反应小于预期，则可在第一次推注后24小时进行第二次推注。第二次筛选推注剂量由1.5毫升中的75微克组成。同样，应观察患者4至8个小时的间隔。如果反应仍然不充分，则可以在24小时后给予100毫克/ 2毫升的最终推注筛选剂量。

小儿患者

小儿患者的起始筛查剂量与成人患者相同，即50 mcg。但是，对于非常小的患者，可以首先尝试25 mcg的筛查剂量。

对100 mcg鞘内推注无反应的患者不应被视为长期输注植入泵的候选人。

准备信息

筛选

仅将1 mL筛选注射器（50 mcg / mL）用于推注到蛛网膜下腔。对于50 mcg推注剂量，请使用1 mL的筛选注射器。使用1.5毫升50 mcg / mL巴氯芬注射液，剂量为75 mcg。对于100 mcg的最大筛选剂量，请使用2 mL的50 mcg / mL巴氯芬注射液（2个筛选注射器）。

保养

应使用的具体浓度取决于所需的总日剂量以及泵的输送速度。对于需要500 mcg / mL，1,000 mcg / mL或2,000 mcg / mL以外的浓度的患者，必须用无菌的不含防腐剂的注射用氯化钠USP稀释巴氯芬注射液。

行政资讯

只要溶液和容器允许，在给药前应检查肠胃外药品的颗粒物和变色情况。

Baclofen Injection预填充注射器的外表面（所有强度，包括50 mcg / mL强度）均未灭菌。不建议在患者植入之前在无菌环境（即手术室）中使用Baclofen注射液预填充注射器填充无菌鞘内泵。对于门诊患者，在填充泵的贮液器时，请修改无菌程序，以免无菌表面接触巴氯芬注射液预填充注射器的非无菌外部而受到污染[请参阅警告和注意事项（5.2）]。

交付方案

巴氯芬注射液通常在植入后立即以连续输注方式给药。对于那些植入了可编程泵的患者，他们在连续输注方面取得了相对令人满意的控制，使用更复杂的巴氯芬注射液给药方案可以进一步获得益处。例如，夜间痉挛加剧的患者可能需要每小时输注速率增加20％。应将流速变化编程为在达到预期临床效果之前两小时开始。

剂量滴定

植入后剂量滴定期

为了确定植入后巴氯芬注射液的初始日总剂量，应将能产生积极作用的筛查剂量加倍，并在24小时内给予，除非推注剂量的功效保持8小时以上，其中在这种情况下，起始日剂量应为24小时内提供的筛查剂量。在最初的24小时内（即，直到达到稳定状态），不应增加剂量。在大多数患者中，有必要随着时间的推移逐渐增加剂量以保持有效性。突然需要大量剂量升级通常表示导管并发症（即导管扭结或移位）。

成人脊髓源性痉挛患者

对于成年患者，最初的24小时后，每日剂量应以10％至30％的增量缓慢增加，并且每24小时仅增加一次，直到达到理想的临床效果为止。

成人脑源性痉挛患者

在最初的24小时后，每日剂量应每24小时仅缓慢增加5％至15％，直到达到所需的临床效果。

小儿患者

在最初的24小时后，每日剂量应每24小时仅缓慢增加5％至15％，直到达到所需的临床效果。如果对每日剂量的增加没有实质性的临床反应，请检查泵功能是否正常以及导管是否通畅。

在植入后即刻的筛选阶段和剂量滴定期间，必须在设备齐全且配备人员的环境中严密监视患者。如果有威胁生命或无法忍受的副作用，应立即使用复苏设备。

剂量调整的其他注意事项

当需要痉挛以维持直立姿势并保持运动平衡时，或者每当使用痉挛以获得最佳功能和护理时，都需要仔细滴定巴氯芬注射液的剂量。调整剂量以维持一定程度的肌肉张力并允许偶尔的痉挛可能很重要：1）帮助维持循环功能，2）可能防止深静脉血栓形成，3）优化日常生活活动并易于护理。

除与药物过量有关的紧急情况外，如果因任何原因停药，通常应缓慢降低巴氯芬注射液的剂量。

应尝试在筛查之前或在植入和开始长期服用巴氯芬注射液之后，中止同时使用口服抗痉挛药物，以避免可能的过量或不良药物相互作用。减少和终止口服解痉药的过程应缓慢进行，并应由医生进行仔细监测。应避免突然减少或停用伴随的抗痉挛药。

维持疗法

脊髓起源患者的痉挛

临床目标是保持肌张力尽可能接近正常，并在不引起无法忍受的副作用的情况下，将痉挛的频率和严重程度降至最低。通常，在治疗的最初几个月中需要调整维持剂量，而由于痉挛的缓解，患者需要适应生活方式的改变。在定期补充泵的过程中，每日剂量可增加10％至40％，但不超过40％，以保持足够的症状控制。如果患者出现副作用，则每日剂量可减少10％至20％。大多数患者需要随着时间的推移逐渐增加剂量，以在慢性治疗期间维持最佳反应。突然对剂量递增的大量需求表明导管并发症（即导管扭结或移位）。

鞘内长期服用巴氯芬的维持剂量范围为12 mcg /天至2,003 mcg /天，大多数患者每天可适当维持300毫克至800毫克的剂量。每日剂量大于

1,000 mcg /天。确定最佳的巴氯芬注射液剂量需要单独滴定。应使用具有最佳反应的最低剂量。

脑源性病人的痉挛

临床目标是保持肌张力尽可能接近正常，并在不引起无法忍受的副作用的情况下将痉挛的频率和严重程度降低到可能的程度，或者将剂量滴定至所需的肌张力程度以实现最佳功能。在治疗的最初几个月中，经常需要调整维持剂量，而由于痉挛的缓解，患者需要适应生活方式的改变。

在定期补充泵的过程中，每日剂量可增加5％至20％，但不超过20％，以保持足够的症状控制。如果患者出现副作用，则每日剂量可减少10％至20％。许多患者需要随着时间的推移逐渐增加剂量，以在慢性治疗期间维持最佳反应。突然的大量剂量增加需求提示导管并发症（即导管扭结或移位）。

长期连续鞘内注射巴氯芬的维持剂量范围为22 mcg /天至1,400 mcg /天，大多数患者每天可适当维持90毫克至703毫克的剂量。在临床试验中，每150名患者中只有3名每天需要的剂量大于1,000 mcg /天。

小儿患者

对于患有脑源性痉挛的患者，请使用相同的剂量建议。在临床试验中，12岁以下的小儿患者似乎需要降低每日剂量。 12岁以下患者的平均日剂量为274 mcg /天，范围为24 mcg /天至1,199 mcg /天。

12岁以上的小儿患者的剂量要求似乎与成年患者没有什么不同。确定最佳的巴氯芬注射液剂量需要单独滴定。应使用具有最佳反应的最低剂量。

长期使用中可能需要调整剂量

在长期治疗期间，约有5％（28/627）的患者无法耐受增加的剂量。没有足够的经验为耐受治疗提出坚定的建议；然而，这种“耐受性”有时在医院中通过“药物假期”来治疗，其中包括在2至4周的时间内逐渐减少鞘内巴氯芬的剂量，并改用其他痉挛治疗方法。在“药物休假”之后，鞘内注射巴氯芬可在初始连续输注剂量下重新开始。

禁忌症

对巴氯芬过敏的患者禁用巴氯芬注射液。请勿将巴氯芬注射液用于静脉内，肌肉内，皮下或硬膜外给药。

警告和注意事项

• 不要将巴氯芬注射液直接注入泵的导管入口，因为这可能会导致致命的过量服用（5.1）
• 预装注射器（5.2）的未灭菌外表面造成污染的可能性
• 潜在威胁生命的中枢神经系统抑郁，心血管衰竭和/或呼吸衰竭；在筛查，剂量滴定和补充过程中，必须有复苏设备和训练有素的工作人员（5.3）
• 过量可能导致嗜睡，头昏眼花，头晕，嗜睡，呼吸抑制，癫痫发作，眼前肌张力减退和意识丧失发展为昏迷（5.4）
• 精神病，精神分裂症或精神错乱的可能加重（5.6）

泵加注期间过量使用会危及生命的风险

给MedtronicSynchroMed®II可编程泵加注时要格外小心，该泵配备有可直接进入鞘内导管的注射端口。通过导管进入口直接注入导管可能导致危及生命的过量。

油箱加油必须由经过充分培训的合格人员按照泵制造商提供的说明进行。仔细计算补给间隔，以防止水库枯竭，因为这将导致严重的痉挛发作并可能出现戒断症状。

为了防止细菌污染和严重感染，需要严格的无菌灌装技术。每次补充或操作储药器后，均应进行一段适合临床情况的观察期。

预装注射器的外表面未灭菌导致污染的可能性

尽管巴氯芬注射液预装注射器中的药物溶液和途径是无菌的，但预装注射器的外表面（所有强度，包括50 mcg / mL强度）均未灭菌。这有可能导致污染和随之而来的不良反应。

不建议在患者植入之前在无菌环境（例如手术室）中使用Baclofen注射液预填充注射器填充无菌鞘内泵，除非对预填充注射器的外表面进行了处理以确保无菌。小瓶中提供的巴氯芬注射液可与常规无菌技术一起使用，以在植入前填充鞘内泵。在门诊环境中重新填充植入式鞘内泵时，也应制定规程，以免因接触到巴氯芬注射液预填充注射器的非无菌外部而污染无菌表面。

处方，护理人员和患者的培训和筛查程序/植入后环境

Baclofen注射剂可用于单次大剂量鞘内注射（通过放置在腰椎鞘内空间中的导管或通过腰椎穿刺注射）以及可植入的MedtronicSynchroMed®II可编程泵或其他标有鞘内注射Baclofen注射剂的泵。由于可能危及生命的中枢神经系统抑郁，心血管衰竭和/或呼吸衰竭，医生必须接受长期鞘内输注治疗的充分培训和教育。

在充分评估患者对推注巴氯芬注射液的反应之前，不得植入泵系统。评估（由筛查程序组成）要求将巴氯芬注射液通过导管或腰椎穿刺注射入鞘内空间[见剂量和用法（2.2）] 。由于存在与筛选程序和泵植入后调整剂量有关的风险，因此，这些阶段必须在“医学指导”和“剂量和给药”部分概述的说明下的充分装备的环境中进行[请参阅剂量和给药（2.2和2.5）。 ）] 。

应该有复苏设备。

在外科手术植入泵之后，尤其是在使用泵的初始阶段，应密切监视患者，直到确定患者对输液的反应是可接受的且相当稳定为止。

在每次调整泵的剂量率和/或储液中巴氯芬注射液的浓度时，都需要进行密切的医学监测，直到确定患者对输液的反应是可以接受的并且相当稳定为止。

必须让患者，所有患者护理人员以及负责患者的医生获得有关这种治疗方式风险的充分信息。应向所有医务人员和护理人员提供以下指导：1）剂量过大的体征和症状； 2）剂量过大时应遵循的程序； 3）泵和插入部位的适当家庭护理。

过量

服用过量的迹象可能突然或隐匿地出现。急性大量过量可能表现为昏迷。过量和/或减轻程度较轻的过量可能会出现嗜睡，头昏眼花，头晕，嗜睡，呼吸抑制，癫痫发作，眼前肌张力减退和意识丧失发展为昏迷的迹象。如果可能出现用药过量，应立即将患者送往医院进行评估并排空泵储液器。在迄今报道的病例中，过量通常与泵的故障或计量错误有关[见过量（10）] 。

填充可植入泵时，必须格外小心。

MedtronicSynchroMed®II可编程泵只能通过储液罐加注隔垫进行加注。 MedtronicSynchroMed®II可编程泵还配备了一个导管入口，可直接进入鞘内导管。直接注入该导管进入口可能会导致危及生命的药物过量。

退出

无论原因为何，鞘内巴氯芬的突然撤药都导致了后遗症，包括高烧，精神状态改变，夸张的痉挛性痉挛和肌肉僵硬，在极少数情况下会发展为横纹肌溶解，多器官系统衰竭甚至死亡。在上市后的前9年中，报告了27例暂时与停用巴氯芬有关的戒断病例； 6例患者死亡。在大多数情况下，巴氯芬治疗中断后数小时至数天内会出现戒断症状。

鞘内注射巴氯芬治疗突然中断的常见原因包括导管故障（尤其是断开连接），泵储液器容量不足以及泵电池寿命终止；在某些情况下，人为错误可能起到了因果作用。也已报道了在导管末端出现鞘内包块而导致戒断症状的病例，其中多数涉及药物复合镇痛剂[见警告和注意事项（5.10）] 。

预防鞘内注射巴氯芬的突然中断需要仔细注意输注系统的编程和监控，补充剂量的安排和程序以及泵的警报。应告知患者和护理人员定期进行补充治疗的重要性，并应接受巴氯芬停药的早期症状的教育。

所有接受鞘内巴氯芬治疗的患者都有撤药的危险。巴氯芬停药的早期症状可能包括基线痉挛，瘙痒，低血压和感觉异常恢复。晚期鞘内巴氯芬戒断综合征的某些临床特征可能类似于植物神经反射异常，感染（败血症），恶性高热，神经安定性恶性综合征或其他与代谢亢进状态或广泛横纹肌溶解有关的疾病。

在急诊室或重症监护室中进行快速，准确的诊断和治疗非常重要，以防止可能危及生命的中枢神经系统和鞘内撤回巴氯芬的全身作用。鞘内注射巴氯芬的建议治疗方法是鞘内注射巴氯芬的恢复剂量与中断治疗前相同或接近。但是，如果鞘内分娩的恢复被延迟，可以使用

GABA激动剂，例如口服或肠内巴氯芬，或口服，肠内或静脉内苯二氮卓类药物，可以预防潜在的致命后遗症。不应仅依靠口服或肠道巴氯芬来阻止鞘内巴氯芬撤药的进程。

据报道在用药过量期间以及从鞘内巴氯芬撤药以及维持鞘内巴氯芬治疗剂量的患者中发作。

精神病，精神分裂症或精神错乱的可能加重

患有精神病，精神分裂症或精神错乱状态的患者应谨慎接受巴氯芬注射液治疗，并保持仔细的监测，因为口服这些药物会加剧这些情况。

死亡人数

脊髓起源性痉挛

截至1992年12月，在上市前和上市后评估的576例接受鞘内注射巴氯芬治疗的美国患者中，有16例死亡。由于这些患者在不受控制的临床环境中接受治疗，因此无法确切确定其作用，如果有的话，鞘内注射巴氯芬致死。作为一个整体，死亡的患者相对年轻（平均年龄为47岁，范围从25到63），但是大多数患者遭受了多年持续的严重痉挛，无法行进，具有各种医疗并发症，例如肺炎，泌尿道疾病感染和褥疮，和/或已接受多种同时用药。对这16例死亡患者的临床病历进行逐例审查，未发现任何暗示鞘内注射巴氯芬治疗导致其死亡的独特体征，症状或实验室结果。但是，有2名患者在植入泵后2周内确实突然死亡，而一名患者在筛查后意外死亡。

一名患者，一名44岁的多发性硬化症男性，在泵植入后第二天在医院死亡。尸检显示冠状动脉传导系统严重纤维化。第二例患者是一名52岁的MS患者，有MS病史，有下壁心肌梗塞病史，在泵入植入后12天（已证明正常生命体征）2小时后发现死于床上。尸检显示肺充血和双侧胸腔积液。无法确定鞘内注射巴氯芬是否促成这些死亡。第三名患者接受了三项巴氯芬筛查试验。他的病史包括脊髓损伤，吸入性肺炎，败血症性休克，弥散性血管内凝血病，严重的代谢性酸中毒，肝毒性和癫痫持续状态。筛查后十二天（未植入），他再次出现癫痫持续状态，随后神经功能明显恶化。根据先前的指示，未采取特殊的复苏措施，患者死亡。

脑源性痉挛

截至1996年3月的上市前研究中，鞘内注射巴氯芬治疗的211例患者中有3例死亡。这些死亡不归因于该疗法。

有自主神经反射异常病史的患者慎用

有自主神经反射异常病史的患者应谨慎使用巴氯芬注射液。伤害性刺激的存在或巴氯芬注射液的突然停用可能会导致植物神经反射异常。

传染病

在使用巴氯芬注射液进行筛选试验之前，患者应无感染，因为全身感染的存在可能会影响对患者对单剂量巴氯芬注射液反应的评估。患者在植入泵之前应无感染。感染可能会增加手术并发症的风险。此外，全身感染可能使给药复杂化。

睡意

鞘内注射巴氯芬的患者有嗜睡的报道。应警告患者注意汽车或其他危险机械的操作，以及因警惕性降低而导致危险的活动。还应提醒患者，鞘内注射巴氯芬的中枢神经系统抑制作用可能会与酒精和其他中枢神经系统抑制药相加。

鞘内质量形成

已经报道了在植入导管的尖端鞘内包块的病例，其中大多数涉及药物复合镇痛剂。与鞘内包块相关的最常见症状是：1）治疗反应降低（痉挛加剧，先前得到良好控制时痉挛恢复，戒断症状，​​对剂量递增的反应不良或频繁或大剂量增加），2）疼痛，3）神经功能缺损/功能障碍。

临床医生应仔细监测接受脊柱内治疗的患者是否有任何新的神经系统症状或体征。对于具有鞘内包块的新神经系统症状或症状的患者，请考虑进行神经外科咨询，因为炎症性包块的许多症状与疾病引起的严重痉挛的患者所经历的症状完全不同。在某些情况下，执行成像程序可能适合确认或排除鞘内肿块的诊断。

卵巢囊肿

在长期口服巴氯芬治疗的雌性大鼠中观察到卵巢囊肿发生率的剂量相关性增加。通过口服巴氯芬治疗长达一年的多发性硬化症患者中，约有4％通过触诊发现了卵巢囊肿。在大多数情况下，这些囊肿会在患者继续接受药物治疗的同时自发消失。据估计，卵巢囊肿是自然发生的，大约占正常女性人口的1％至5％。

不良反应

脊髓起源性痉挛

脊柱痉挛患者最常见的不良反应

在上市前和上市后的临床试验中，与鞘内使用巴氯芬有关的最常见不良反应在安慰剂治疗的患者中没有以相同的发生率出现：嗜睡，头晕，恶心，低血压，头痛，抽搐和肌张力低下。

与中止治疗有关的不良反应

在美国上市前和上市后的临床研究中，有8/474名脊髓痉挛性患者接受鞘内注射巴氯芬的长期输注，由于不良反应而中止治疗。这些症状包括：泵囊感染（3），脑膜炎（2），伤口裂开（1），妇科肌瘤（1）和泵超压（1），后遗症不明（如有）。十一名因服药过量而昏迷的患者暂时中止治疗，但随后全部重新开始治疗，因此未视为真正停药。

死亡- [请参阅警告和注意事项（5.6）] 。

对照试验的发生率

在平行，安慰剂对照，随机研究中获得鞘内巴氯芬的经验，为评估不良反应的发生率提供了有限的基础，因为这些研究持续时间很短（最多输注三天），总共涉及63名患者。在两项随机，安慰剂对照试验中，在接受鞘内巴氯芬治疗的31例患者中发生了以下事件：低血压（2），头晕（2），头痛（2），呼吸困难（1）。在这些研究中，没有32名接受安慰剂的患者发生不良反应。

鞘内注射巴氯芬的上市前和上市后评估期间观察到的事件

与鞘内使用巴氯芬有关的不良事件反映了美国有576名患者的随访经验。他们接受鞘内巴氯芬治疗，为期一天（筛查）（N = 576）至八年以上（维持）（N = 10）。在这些研究中，在泵植入之前通常给予的筛查推注剂量通常为50 mcg。维持剂量为每天12 mcg至2,003 mcg。由于经验是开放的，不受控制的，因此在许多情况下无法可靠地评估观察到的事件与鞘内注射巴氯芬之间的因果关系，并且已知许多不良反应与所治疗的潜在疾病有关。但是，许多较普遍报道的反应性低渗，嗜睡，头晕，感觉异常，恶心/呕吐和头痛明显与药物有关。

表1列出了所有美国研究（对照和非对照）的不良经历。在474例通过植入泵进行慢性输注的患者中，有8例经历了不良经历，导致上市前和上市后不再接受长期治疗学习。

In addition to the more common (1% or more) adverse reactions reported in the prospectively followed 576 domestic patients in pre- and post-marketing studies, experience from an additional 194 patients exposed to intrathecal baclofen from foreign studies has been reported.的

following adverse reactions, not described in the table, and arranged in decreasing order of frequency, and classified by body system, were reported:

Nervous System: Abnormal gait, thinking abnormal, tremor, amnesia, twitching, vasodilatation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, hypertonia, ileus, drug dependence, incoordination, paranoid reaction and ptosis.

Digestive System: Flatulence, dysphagia, dyspepsia and gastroenteritis.

Cardiovascular: Postural hypotension, bradycardia, palpitations, syncope, arrhythmia ventricular, deep thrombophlebitis, pallor and tachycardia.

Respiratory: Respiratory disorder, aspiration pneumonia, hyperventilation, pulmonary embolus and rhinitis.

Urogenital: Hematuria and kidney failure. Skin and Appendages: Alopecia and sweating.

Metabolic and Nutritional Disorders: Weight loss, albuminuria, dehydration and hyperglycemia.

Special Senses: Abnormal vision, abnormality of accommodation, photophobia, taste loss and tinnitus.

Body as a Whole: Suicide, lack of drug effect, abdominal pain, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome and overdose.

Hemic and Lymphatic System: Anemia.

Spasticity of Cerebral Origin

最常见的不良反应

In pre-marketing clinical trials, the most common adverse reactions associated with use of intrathecal baclofen which were not seen at an equivalent incidence among placebo-treated patients included: agitation, constipation, somnolence, leukocytosis, chills, urinary retention and hypotonia.

Adverse Reactions Associated with Discontinuation of Treatment

Nine of 211 patients receiving intrathecal baclofen in pre-marketing clinical studies in the US discontinued long-term infusion due to adverse reactions associated with intrathecal therapy.

The nine adverse reactions leading to discontinuation were: infection (3), CSF leaks (2), meningitis (2), drainage (1), and unmanageable trunk control (1).

Fatalities

Three deaths, none of which were attributed to intrathecal baclofen, were reported in patients in clinical trials involving patients with spasticity of cerebral origin. See Warnings on other deaths reported in spinal spasticity patients.

Incidence in Controlled Trials

Experience with intrathecal baclofen obtained in parallel, placebo-controlled, randomized studies provides only a limited basis for estimating the incidence of adverse reactions because the studies involved a total of 62 patients exposed to a single 50 mcg intrathecal bolus. The following adverse reactions occurred among the 62 patients receiving intrathecal baclofen in two randomized, placebo-controlled trials involving cerebral palsy and head injury patients, respectively: agitation, constipation, somnolence, leukocytosis, nausea, vomiting, nystagmus, chills, urinary retention, and hypotonia.

Events Observed during the Pre-marketing Evaluation of Intrathecal Baclofen

Adverse events associated with the use of intrathecal baclofen reflect experience gained with a total of 211 US patients with spasticity of cerebral origin, of whom 112 were pediatric patients (under age 16 at enrollment). They received intrathecal baclofen for periods of one day (screening) (N=211) to 84 months (maintenance) (N=1). The usual screening bolus dose administered prior to pump implantation in these studies was 50 mcg to 75 mcg. The maintenance dose ranged from 22 mcg to 1,400 mcg per day. Doses used in this patient population for long-term infusion are generally lower than those required for patients with spasticity of spinal cord origin.

Because of the open, uncontrolled nature of the experience, a causal linkage between events observed and the administration of intrathecal baclofen cannot be reliably assessed in many cases. Nonetheless, many of the more commonly reported reactions somnolence, dizziness, headache, nausea, hypotension, hypotonia and coma appear clearly drug-related.

The most frequent (1%) adverse reactions reported during all clinical trials are shown in Table 2. Nine patients discontinued long term treatment due to adverse reactions.

The more common (1% or more) adverse reactions reported in the prospectively followed 211 patients exposed to intrathecal baclofen have been reported. In the total cohort, the following adverse reactions, not described in Table 2, and arranged in decreasing order of frequency, and classified by body system, were reported:

Nervous System: Akathisia, ataxia, confusion, depression, opisthotonos, amnesia, anxiety, hallucinations, hysteria, insomnia, nystagmus, personality disorder, reflexes decreased, and vasodilitation.

Digestive System: Dysphagia, fecal incontinence, gastrointestinal hemorrhage and tongue disorder.

Cardiovascular: Bradycardia.

Respiratory: Apnea, dyspnea and hyperventilation.

Urogenital: Abnormal ejaculation, kidney calculus, oliguria and vaginitis.

Skin and Appendages: Rash, sweating, alopecia, contact dermatitis and skin ulcer. Special Senses: Abnormality of accommodation.

Body as a Whole: Death, fever, abdominal pain, carcinoma, malaise and hypothermia. Hemic and Lymphatic System: Leukocytosis and petechial rash.

药物相互作用

There is inadequate systematic experience with the use of intrathecal baclofen in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of Baclofen Injection and epidural morphine include hypotension and dyspnea.

在特定人群中的使用

怀孕

怀孕类别C

没有针对孕妇的充分且对照良好的研究。 Baclofen Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 13 times on a mg/kg basis, or

3 times on a mg/m2 basis, the maximum oral dose recommended for human use; this dose also caused reductions in food intake and weight gain in the dams. This abnormality was not seen in mice or rabbits.

人工与分娩

The effect of baclofen on labor and delivery is unknown.

护理母亲

At therapeutic oral doses, baclofen is excreted in human milk. It is not known whether detectable levels of drug are present in milk of nursing mothers receiving Baclofen Injection. Because of the potential for serious adverse reactions in nursing infants from Baclofen Injection, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

儿科用

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manual for specific recommendations. Safety and effectiveness in pediatric patients below the age of 4 have not been established.

过量

Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titration phase of treatment, but also during re-introduction of Baclofen Injection after a period of interruption in therapy.

Symptoms of Intrathecal Baclofen Overdose

Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hours duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus.

Treatment Suggestions for Overdose

There is no specific antidote for treating overdoses of Baclofen Injection; however, the following steps should ordinarily be undertaken:

1) Residual intrathecal baclofen solution should be removed from the pump as soon as possible.

2) Patients with respiratory depression should be intubated if necessary, until the drug is eliminated.

Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia.

Physostigmine Doses for Adult Patients

Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur.

Physostigmine Doses for Pediatric Patients

Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than

0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained.

Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support.

If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration.

Baclofen Injection Description

Baclofen Injection is a muscle relaxant and antispastic. Baclofen's pharmacological class is a gamma-aminobutyric acid (GABA) ergic agonist. Baclofen's chemical name is 4-amino- 3-(4-chlorophenyl) butanoic acid, and its structural formula is:

Baclofen is a white to off-white, odorless or practically odorless crystalline powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.

Baclofen Injection - Clinical Pharmacology

作用机理

The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype.

Baclofen when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved with resultant plasma concentrations 100 times less than those occurring with oral administration. In people, as well as in animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.

药效学

Intrathecal Bolus

Adult Patients

The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms.

小儿患者

The onset, peak response and duration of action is similar to those seen in adult patients.

Continuous Infusion

Adult Patients

Intrathecal baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours.

小儿患者

No additional information on continuous infusions is available for pediatric patients.

药代动力学

The pharmacokinetics of cerebrospinal fluid (CSF) clearance of intrathecal baclofen calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF.

Intrathecal Bolus

After a bolus lumbar injection of 50 mcg or 100 mcg intrathecal baclofen in seven patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 mL/hour.

Continuous Infusion

The mean CSF clearance for intrathecal baclofen was approximately 30 mL/hour in a study involving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration are expected to be low (0 to 5 ng/mL). Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4:1 is established along the neuroaxis during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered by position. Six pediatric patients (age 8 to 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 to 400 mcg/day had plasma baclofen levels near or below 10 ng/mL.

非临床毒理学

致癌，诱变，生育力受损

No increase in tumors was seen in rats receiving baclofen orally for two years at approximately 30 to 60 times on a mg/kg basis, or 10 to 20 times on a mg/m2 basis, the maximum oral dose recommended for human use. Mutagenicity assays with baclofen have not been performed.

临床研究

Spasticity of Spinal Cord Origin

Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms.

Spasticity of Cerebral Origin

The efficacy of intrathecal baclofen was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal baclofen was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed.

供应/存储和处理方式

Baclofen Injection is a clear, colorless, sterile, pyrogen-free, isotonic solution consisting of the active ingredient, Baclofen USP, and the excipients Sodium Chloride USP and Water for Injection USP in single-dose clear glass vials.

Baclofen Injection is packaged in single-dose vials supplied as follows:

One vial containing 20,000 mcg/20 mL (1,000 mcg/mL) (NDC 70511-123-20).

Storage

Does not require refrigeration.

存放在20°至25°C（68°至77°F）; excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

不要冻结。

Do not heat sterilize.

病人咨询信息

Risks Related to Sudden Withdrawal of Baclofen Injection

Advise patients and caregivers that sudden withdrawal of Baclofen Injection, regardless of the cause, can result in serious complications that include high fever, confusion, muscle stiffness, multiple organ-system failure, and death. Inform patients that early symptoms of Baclofen Injection withdrawal may include increased spasticity, itching, and tingling of extremities. If Baclofen Injection withdrawal or a pump malfunction is suspected, patients should be brought immediately to a hospital for assessment and treatment.

Inform patients and caregivers that sudden withdrawal occurs most frequently due to a delivery problem with the catheter or the pump, or failure to refill the pump on schedule. Advise patients and their caregivers to pay careful attention to infusion system alarms. Instruct patients and caregivers that if they miss their scheduled pump refill, they should immediately contact their physician to reschedule the refill before the pump runs out of drug.

Baclofen Injection Overdose

Inform patients and their caregivers that Baclofen Injection overdose may occur suddenly or insidiously, and that symptoms may include confusion, drowsiness, lightheadedness, dizziness, slow or shallow breathing, seizures, loss of muscle tone, loss of consciousness, and coma. If an overdose appears likely, patients should be brought immediately to a hospital for assessment and possible emptying of the pump.

Operation of Automobiles and Other Dangerous Machinery

Advise patients that Baclofen Injection may cause drowsiness, and that they should exercise caution regarding the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness.

Increased Risk of Drowsiness with Alcohol and Other CNS Depressants

Inform patients and their caregivers that the drowsiness associated with Baclofen Injection use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their physician about all prescription and nonprescription drugs they may use.

Trademarks are the property of their respective owners.

制造用于：

MAIA Pharmaceuticals, Inc.

707 State Road

Suite 104, Princeton, NJ 08540

Made in India

主显示面板

​​Vial Label

NDC 70511-123-120

巴氯芬注射液

20,000 mcg/20 mL

(1,000 mcg/mL)

For Intrathecal Use Only

20 mL Single Dose Vial

​Carton Label

​NDC 70511-123-20

巴氯芬注射液

20,000 mcg/20 mL

(1,000 mcg/mL)

For Intrathecal Use Only

20 mL Single Dose Vial

Discard unused portion

仅接收