描述

BRETYLIUM（甲苯磺酸苄酯注射液）TOSYLATE注射液

静脉或肌内使用

甲苯磺酸注射液是一种抗纤维和抗心律不齐药; 用于静脉内或肌内使用。 它有一个分子形式：C18H24BrNO3S。Bretylium（甲苯磺酸苄酯注射液）甲苯磺酸盐是一种白色结晶性粉末，味道极强。 它易溶于水和酒精。 每毫升无菌无热原溶液含有50mg注射用水（USP）中的甲苯磺酸溴化物（甲苯磺酸苄酯注射液）。 必要时用稀盐酸和/或氢氧化钠调节pH值。 Bretylium（甲苯磺酸苄酯注射液）甲苯磺酸盐注射液不含防腐剂。

适应症

在预防和治疗心室纤维性颤动时应注意甲苯磺酸盐（甲苯磺酸苄酯注射液）甲苯磺酸盐。

在危及生命的室性心律失常如室性心动过速的治疗中也显示了甲苯磺酸盐（甲苯磺酸苄酯注射液）甲苯磺酸盐对于一线抗心律失常药物（如利多卡因）无效的反应。

使用BRETYLIUM（甲苯磺酸苄酯注射液）甲苯磺酸注射液应限于重症监护病房，冠心病监护病房或其他可持续监测心律失常和血压的设备和人员。

在注射BRETYLIUM（甲苯磺酸苄酯注射液）注射剂后，在抗心律失常作用开始时，可能会延迟20分钟至2小时，尽管它似乎在几分钟内起作用于心室纤维性颤动。肌注后延迟效果似乎比静脉注射后延长。

剂量和给药

BRETYLIUM（甲苯磺酸苄酯注射液）甲苯磺酸注射液仅在临床上用于在持续心电图监测下治疗危及生命的室性心律失常。 BRETYLIUM（甲苯磺酸苄酯注射液）甲苯磺酸注射液的临床应用仅限于短期使用。患者应在bretylium（甲苯磺酸苄酯注射液）治疗过程中保持仰卧位或密切观察体位性低血压。尚未确定药物远期给药的最佳剂量方案。对于剂量大于40mg / kg /天的经验相对较少，尽管已经使用了这样的剂量而没有明显的不利影响。

建议使用以下时间表：

A.对于即刻危及生命的室性心律失常如心室颤动或血流动力学不稳定的室性心动过速：

通过快速静脉注射以5mg / kg体重的剂量施用未稀释的BRETYLIUM（甲苯磺酸苄酯注射液）甲苯磺酸注射液。根据良好的医疗实践，在注射之前和之后应采用其他常用的心肺复苏手术，包括电复律。如果心室纤维颤动持续存在，剂量可增至10mg / kg，并根据需要重复。

对于连续抑制，使用下表将美国药典或氯化钠注射液USP或氯化钠注射液USP或甲基磺酸稀释的注射剂甲苯磺酸盐注射液稀释并以1至2mg的溴化甲苯磺酸盐注射液甲苯磺酸盐注射液持续输注分钟，（见下表）。当通过持续静脉输注施用甲苯磺酸注射液（或甲苯磺酸注射液）甲苯磺酸盐注射液（或任何有效药物）时，建议使用精密体积控制装置。另一种维护方案是每6小时以5至10毫克剂量的甲苯磺酸盐（注射甲苯磺酸苄酯）每公斤体重的剂量注入稀释的溶液，持续时间大于8分钟。更快速的输液可能导致恶心和呕吐，并且在65岁以上的患者中，可能增加发生体位性低血压的风险。

B.其他室性心律失常：

1）静脉注射使用：在静脉注射前必须按照上述方法稀释甲苯磺酸注射液（甲苯磺酸苄酯注射液）。在大于8分钟的时间内通过静脉内输注以每kg体重5mg至10mg甲苯磺酸盐（甲苯磺酸苄酯注射液）剂量施用稀释的溶液。更快速的输液可能导致恶心和呕吐，并且在65岁以上的患者中，可能增加发生体位性低血压的风险。如果心律不齐者出现，则可以间隔1至2小时给予后续剂量。对于维持治疗，可每6小时给予相同的剂量，或每分钟给予1至2mg的甲苯磺酸盐（甲苯磺酸苄酯注射液）持续输注（参见下表）。建议的Bretylium（甲苯磺酸苄酯注射液）甲苯磺酸盐注射液外用剂连续输液维持疗法的稀释和给药率按浓度降序排列。

*lV fluid may be either Dextrose Injection, USP or Sodium Chloride Injection, USP. This table does not consider the overfill volume present in the IV fluids.

2）肌内注射：在肌内注射前不要稀释甲苯磺酸注射液（注射用甲苯磺酸盐）。每公斤体重注射5至10毫克溴化甲烷（甲苯磺酸苄酯注射液）甲苯磺酸盐。如果心律失常持续存在，则可以每隔1至2小时给予后续剂量。此后，每6至8小时保持相同的用量。肌内注射不应直接进入或接近主神经，并且重复注射时应改变注射部位。不应超过5mL肌内注射一个部位。 （见PRECAUTONS）尽可能快地指示患者应该改用口服抗心律失常药进行维持治疗。

注意：无论何时溶液和容器允许，应在注射之前视觉检查肠外药物产品中的颗粒物质和变色。

如何提供

•溴化乙锭（注射甲苯磺酸苄酯）甲苯磺酸盐注射液，50mg / mL

•0517-8810-01 10mL单剂量瓶单独包装

在室温控制在15°-30°C（59°-86°F）。

小心：联邦（美国）法律禁止在没有处方的情况下点胶。

副作用和药物相互作用

副作用

低血压和体位性低血压是最常报告的不良反应（见警告部分）。大约百分之三的患者发生恶心和呕吐，主要是当通过静脉内途径迅速给予百日咳（甲苯磺酸苄酯注射液）甲苯磺酸盐时（参见注意事项部分）。据报道，在1000名患者中约有7名患者出现眩晕，头晕，头晕和晕厥，有时伴有体位性低血压。也有少数患者报告有心动过缓，室性早搏的频率增加，暂时性高血压，心律失常的初始增加（见警告部分），心绞痛发作的沉淀以及胸骨下压的感觉，即约1-2名患者在1000。已报道了肾功能不全，腹泻，腹痛，打嗝，红斑黄斑疹，潮红，热疗，精神错乱，偏执性精神病，情绪不稳定，嗜睡，全身压痛，焦虑，气促，出汗，鼻塞和轻度结膜炎1000例患者中有1例患者。也报道了高热（参见警告）。尚未明确建立对这些反应的溴化甲苯磺酸盐注射剂（toltylium tosylate injection）甲苯磺酸盐给药的关系。

药物相互作用

洋地黄毒甙（甲苯磺酸苄酯注射液）甲苯磺酸盐注射液引起的去甲肾上腺素最初释放可加重洋地黄毒性。Bretylium（甲苯磺酸苄酯注射液）甲苯磺酸盐可增强多巴胺或去甲肾上腺素等儿茶酚胺的升压作用。当给予儿茶酚胺时，应使用稀释溶液并密切监测血压。 （见警告）

虽然关于利多卡因和溴化乙锭（甲苯磺酸苄酯注射液）同时给药的公开信息很少，但这些药物常常同时服用，没有任何相互作用的证据，导致副作用或效力降低。

警告和注意事项

警告

低血压：给予甲苯磺酸苄丙酯（注射甲苯磺酸苄酯）定期导致体位性低血压，主观认可为头晕，头晕，眩晕或晕眩。约50％的患者在仰卧时出现一定程度的低血压。在低于抑制心律失常所需剂量时可能发生低血压。

患者应保持在仰卧位，直至对溴硝灵（溴化甲苯磺酸注射液）的降压作用产生耐受。容差发生不可预测，但可能会在几天后出现。超过65岁的患者发生体位性低血压的风险可能会增加，特别是当超过静脉输液推荐速度时。见用法和管理除非有相关症状，否则需要治疗收缩压超过75毫米汞柱的低血压患者。如果仰卧收缩压降至75毫米汞柱以下，可以使用多巴胺或去甲肾上腺素输注来提高血压。当给予儿茶酚胺时，应使用稀释溶液并监测血压，因为儿茶酚胺的加压作用可通过溴化乙锭（甲苯磺酸苄酯注射液）增强。血液或血浆的体积扩张和脱水的纠正应在适当的时候进行。短暂性高血压和心律失常发生率增加：由于溴化乙锭（溴化甲苯磺酸注射液）能够从肾上腺素能神经节末神经末梢释放去甲肾上腺素，所以一些患者可能出现短暂性高血压或室性早搏的频率增加和其他心律失常。使用洋地黄糖苷时的注意事项：由溴化乙锭注射引起的去甲肾上腺素的初始释放可能会加重洋地黄的毒性。当数字化患者出现危及生命的心脏心律失常时，只有在心律失常的病因似乎不是洋地黄毒性和其他抗心律失常药物无效的情况下，才应使用溴苯丁酯（溴苯乙醇注射液）。应避免同时开始用洋地黄糖苷和溴化乙锭（甲苯磺酸苄酯注射液）治疗。心输出量固定的患者：在心输出量固定（即严重主动脉瓣狭窄或严重肺动脉高压）的患者中，应避免应用溴硝柳（注射用甲苯磺酸苄酯），因为严重低血压可能是由外周阻力下降引起的，而没有心输出量的代偿性增加。如果生存受到心律失常的威胁，可使用甲苯磺酸溴苄酯（甲苯磺酸苄酯注射液）甲苯磺酸盐，但如果出现严重低血压，则应立即给予血管收缩性儿茶酚胺。

热疗：在少数患者中，温度超过106°F的高热已报道与甲苯磺酸苄丙酯（溴化甲苯磺酸注射液）给予相关。温度升高可以在给药后1小时或更长时间内开始，并且在1至3天内达到峰值。如果怀疑或诊断出高温，应立即停止使用溴化甲烷（甲苯磺酸苄酯注射液）并采取适当的治疗措施。

注意事项

一般

静脉注射用稀释液：在静脉注射前，一瓶BRETYLIUM（甲苯磺酸苄酯注射液）甲苯磺酸注射液应至少用50 mL葡萄糖注射液5％，USP或氯化钠注射液USP稀释。快速静脉注射可能导致严重的恶心和呕吐。因此，稀释溶液应该在大于8分钟的时间内输注。在治疗现有的心室颤动时，应尽可能快地给予甲苯磺酸盐，并且可以在不稀释的情况下给予甲苯磺酸盐。

使用各种肌肉注射部位肌肉注射时，应在部位给予不超过5mL，注射部位应改变，因为反复肌肉注射到同一部位可能导致肌肉组织萎缩和坏死，纤维化，血管变性和炎症变化。

减少肾功能受损的剂量：由于溴化甲苯磺酸盐注射液主要通过肾脏排泄，肾功能受损患者的剂量间隔应该增加。有关肾功能减退对半衰期影响的信息，请参见临床药理学部分。

致癌，突变，生育力受损没有关于动物或人类致癌性，致突变性或生育力受损潜力的数据。使用聚丙烯注射器溶液的研究尚未进行评估致癌潜力，致突变潜能或对生育能力的影响。

怀孕

C类：动物生殖研究尚未用甲苯磺酸苄酯（甲苯磺酸苄酯注射液）进行。也不知道甲苯磺酸苄酯（甲苯磺酸苄酯注射液）甲苯磺酸盐是否会在给孕妇服用时造成伤害或可能影响生殖能力。只有在明确需要的情况下，才应该向孕妇分配甲苯磺酸盐（甲苯磺酸苄酯注射液）甲苯磺酸盐。

儿科用途

Bretylium（甲苯磺酸苄酯注射液）甲苯磺酸盐的安全性和有效性尚未建立。其在儿科患者中的有限用途不足以完全确定适当的剂量和使用限制。

老年人使用

临床研究中，临床研究不包括65岁以上的足够数量的受试者，以确定他们是否对年轻受试者的反应不同。一般来说，老年患者的剂量选择应谨慎，通常从剂量范围的低端开始，反映肝，肾或心脏功能降低以及伴随疾病或药物治疗的频率更高。

静脉输注，尤其是如果以超出“剂量和剂量”部分建议的剂量给药，可能会增加老年人体位性低血压的风险。见警告）已知这种药物基本上是由肾脏排泄的，肾功能受损患者的毒性反应风险可能更大。由于老年患者肾功能降低的可能性更大，因此应该在剂量选择时加以注意，并且可能有助于监测肾功能，见临床药理学。

过量和禁忌症

过量

在存在威胁生命的心律失常的情况下，低剂量溴苄（注射甲苯磺酸苄酯）可能会给患者带来更大的风险，而不是潜在的剂量过量。然而，一例意外过量已被报道，其中在室性心动过速发作期间给予30mg / kg的快速静脉内推注而不是预期的10mg / kg剂量。出现明显的高血压，随后出现持续性顽固性低血压。患者18小时后出现心脏停搏，并发肾功能衰竭和吸入性肺炎。 Bretylium（甲苯磺酸苄酯注射液）血清水平为8000ng / mL。夸张的血流动力学反应归因于快速注射非常大的剂量，同时仍然存在一些有效循环。在该患者中观察到的总剂量和血清水平都不与毒性相关。 30毫克/公斤的总剂量并不罕见，并且在心肺复苏术中逐渐给药时不会引起毒性。同样，维持在慢性甲状腺乳酸杆菌注射甲苯磺酸盐注射治疗的患者血清水平已达到12,000 ng / mL。这些水平是在连续剂量随时间增加而没有明显的不良影响后实现的。

如果甲苯磺酸酯注射剂甲苯磺酸酯注射剂量过量并出现毒性症状，应考虑给予硝普钠或其他短效静脉降压药物治疗高血压反应。不应使用长效药物，后者可能会加强丁苯乙酸注射液甲苯磺酸盐注射液随后的降血压作用。应该使用适当的液体疗法和多巴胺或去甲肾上腺素等压迫剂来治疗低血压。透析可能在治疗甲苯磺酸盐注射剂甲苯磺酸盐注射剂过量时无用。

禁忌症

用于治疗室颤或危及生命的难治性室性心律失常没有禁忌症。

临床药理学

Bretylium（甲苯磺酸苄酯注射液）甲苯磺酸盐是abromobenzyl季铵化合物，它选择性地积累在交感神经节及其节后肾上腺素能神经元，通过抑制肾上腺素能神经末梢兴奋性抑制去甲肾上腺素释放。

Bretylium（甲苯磺酸苄酯注射液）也抑制心室颤动和室性心律失常。没有建立溴化甲苯磺酸注射液抗纤颤和抗心律失常作用的机制。在确定这些机制的努力中，在动物实验中已经证实了以下的溴化甲基莲心碱（bretylium tosylate injection）的电生理作用：

1.增加心室颤动阈值。

2.增加动作电位持续时间和有效不应期，而不改变心率。

3.对正常心肌中心脏动作电位（0相）或静息膜电位（4相）的上升或振幅的影响不大。然而，当细胞损伤减慢上升速度，减小幅度并降低静息膜电位时，溴化甲烷（甲苯磺酸苄酯注射液）瞬时恢复这些参数向正常。

4.在具有梗塞区域的犬心脏中，溴化甲状腺注射（bretylium tosylate injection）降低了正常和梗塞区域之间动作电位持续时间的差异。

5.增加起搏器组织的脉冲形成和自发放电速率以及增加心室传导速度。

受损心肌细胞电生理学恢复正常，以及动作电位持续时间和有效不应期的增加而不改变它们之间的比率可能是抑制异常脉冲重新进入和减少局部诱发分散的重要因素令人兴奋的状态。

Bretylium（甲苯磺酸苄酯注射液）诱导化学交感神经切除状态，类似于手术交感神经切除术。儿茶酚胺贮存物未被溴化甲苯磺酸盐（注射甲苯磺酸苄酯注射液）甲苯磺酸盐耗尽，但儿茶酚胺对心肌和外周血管阻力的作用通常在给药后很短时间内发生，因为溴甲苯磺酸注射使肾上腺素能节后神经末梢早期释放去甲肾上腺素。随后，甲苯磺酸溴甲苄酯（注射甲苯磺酸苄酯）阻断去甲肾上腺素对神经元刺激反应的释放。外周肾上腺素能阻滞通常导致体位性低血压，但对仰卧位血压影响较小。肾上腺素能阻滞与溴化甲苯磺酸注射液抗纤颤和抗心律失常作用的关系尚不清楚。在一项研究中，在接受肌肉注射的小鼠肌肉注射后1小时内可观察到高压降压作用，这可能反映了肾上腺素能神经元阻滞。然而，在给药后6-9小时，当平均血浆浓度下降到低于峰值水平的一半时，抑制室性早搏并不是最大的。这表明除了神经元阻滞之外，较慢的机制参与抑制心律失常。另一方面，在静脉注射几分钟之后可以看到抗纤颤作用，表明对心肌的作用可能发生得相当快。

Bretylium（甲苯磺酸苄酯注射液）对心肌具有正性肌力作用，但尚未确定这种作用是直接还是由儿茶酚胺释放介导。

Bretylium（甲苯磺酸苄酯注射液）完全被肾脏消除。在人和实验室动物给予BRETYLIUM（甲苯磺酸苄酯注射液）甲苯磺酸注射剂后，未发现任何代谢物。在男性中，首次24小时内约有70％-80％的14C标记的肌内剂量在尿中排出，另外10％在接下来的三天内排出。

四名正常志愿者的终末半衰期平均为7.8±0.6小时（范围6.9-8.1）。 1例肌酐清除率为21.0 mL / min。 x 1.73m2半衰期为16小时。 1例肌酐清除率为1.0 mL / min。 x 1.73m2，半衰期为31.5小时。在血液透析过程中，该患者的动脉和静脉丙酸杆菌（甲苯磺酸注射液）浓度迅速下降，导致半衰期为13小时。在透析过程中，总溴值（甲苯磺酸苄酯注射液）清除率增加了两倍。

对心率的影响：当给予溴化甲烷磺酸（注射用甲苯磺酸苄酯）甲苯磺酸盐时，心率有时会出现初始小幅增加，但这是一种不一致和短暂的事件。

血液动力学效应：对急性心肌梗死患者静脉注射5mg / kg BRETYLIUM（甲苯磺酸注射液）注射液后，动脉压力轻度升高，随后适度下降，始终保持在正常范围内。肺动脉压力，肺毛细血管楔压，右心房压力，心脏指数，每搏输出量指数和卒中功指数没有显着变化。这些血液动力学效应与抗心律失常活性无关。

行动开始：抑制心室颤动的速度很快，通常在静脉给药后数分钟内发生。抑制室性心动过速和其他室性心律失常的发生更慢，通常在胃肠外给药后20分钟至2小时。

DESCRIPTION

BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION

For Intravenous or Intramuscular Use

Bretylium (bretylium tosylate injection ) tosylate injection is an antifibrillatory and antiarrhythmic agent; intended for intravenous or intramuscular use. It has a molecular formular: C18H24BrNO3S.

Bretylium (bretylium tosylate injection ) tosylate is a white, crystalline powder with an extremely bitter taste. It is freely soluble in water and alcohol. Each mL of sterile, nonpyrogenic solution contains 50mg bretylium (bretylium tosylate injection ) tosylate in Water for Injection, USP. The pH is adjusted, when necessary, with dilute hydrochloric acid and/or sodium hydroxide. Bretylium (bretylium tosylate injection ) tosylate injection contains no preservative.

Indications & Dosage

INDICATIONS

Bretylium (bretylium tosylate injection ) Tosylate is indicated in the prophylaxis and therapy of ventricular fibrillation.

Bretylium (bretylium tosylate injection ) tosylate is also indicated in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine.

Use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION should be limited to intensive care units, coronary care units or other facilities where equipment and personnel for constant monitoring of cardiac arrhythmias and blood pressure are available.

Following injection of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION there may be a delay of 20 minutes to 2 hours in the onset of antiarrhythmic action, although it appears to act within minutes in ventricular fibrillation. The delay in effect appears to be longer after intramuscular than after intravenous injection.

DOSAGE AND ADMINISTRATION

BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION is to be used clinically only for treatment of life-threatening ventricular arrhythmias under constant electrocardiographic monitoring. The clinical use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION is for short-term use only. Patients should either be kept supine during the course of bretylium (bretylium tosylate injection ) therapy or be closely observed for postural hypotension. The optimal dose schedule for parenteraladministration of the drug has not been determined. There is comparatively little experience with dosages greater than 40mg/kg/day, although such doses have been used without apparent adverse effects. The following schedules are suggested:

A. For immediately Life-threatening Ventricular Arrhythmias such as Ventricular Fibrillation or Hemodynamically Unstable Ventricular Tachycardia:

Administer undiluted BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION at a dosage of 5mg/kg of body weight by rapid intravenous injection. Other usual cardiopulmonary resuscitative procedures, including electrical cardioversion, should be employed prior to and following the injection in accordance with good medical practice. If ventricular fibrillation persists, the dosage may be increased to 10mg/kg and repeated as necessary.

For continuous suppression, dilute Bretylium (bretylium tosylate injection ) Tosylate Injection with Dextrose Injection, USP or Sodium Chloride Injection, USP using the table below and administer the diluted solution as a constant infusion of 1 to 2mg Bretylium (bretylium tosylate injection ) Tosylate Injection per minute, (see Table below). When administering Bretylium (bretylium tosylate injection ) Tosylate Injection (or any potent medication) by continuous intravenous infusion, it is advisable to use a precision volume control device. An alternative maintenance schedule is to infuse the diluted solution at a dosage of 5 to 10mg Bretylium (bretylium tosylate injection ) Tosylate per kg body weight, over a period greater than 8 minutes, every 6 hours. More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension.

B. Other ventricular arrhythmias:

1) Intravenous Use: Bretylium (bretylium tosylate injection ) tosylate injection must be diluted as described above before intravenous use.

Administer the diluted solution at a dosage of 5 to 10mg bretylium (bretylium tosylate injection ) tosylate per kg of body weight by intravenous infusion over a period greater than 8 minutes. More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension. Subsequent doses may be given at 1 to 2 hour intervals if the arrhythmiapersists.

For maintenance therapy, the same dosage may be administered every 6 hours, or a constant infusion of 1 to 2mg bretylium (bretylium tosylate injection ) tosylate per minute may be given, (See following table).

Suggested Bretylium (bretylium tosylate injection ) Tosylate Injection Admixture Dilution and Administration rates for Continuous Infusion Maintenance Therapy Arranged in Descending Order of Concentration.

*lV fluid may be either Dextrose Injection, USP or Sodium Chloride Injection, USP. This table does not consider the overfill volume present in the IV fluids.

2) For Intramuscular Injection: DO NOT DILUTE BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION PRIOR TO INTRAMUSCULAR INJECTION.

Inject 5 to 10mg bretylium (bretylium tosylate injection ) tosylate per kg of body weight. Subsequent doses may be given at 1 to 2 hour intervals if the arrhythmia persists. Thereafter, maintain the same dosage every 6 to 8 hours. Intramuscular injection should not be made directly into or near a major nerve, and the site of injection should be varied on repeated injection.

Not more than 5mL should be injected intramuscularly in one site. (See PRECAUTONS) As soon as possible, and when indicated, patients should be changed to an oral antiarrhythmic agent for maintenance therapy.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

HOW SUPPLIED

· Bretylium (bretylium tosylate injection ) Tosylate Injection, 50mg/mL

· 0517-8810-01 10mL Single Dose Vial Packaged individually

Store at controlled room temperature 15°-30°C(59°-86°F).

CAUTION: Federal (USA) law prohibits dispensing without prescription.

Side Effects & Drug Interactions

SIDE EFFECTS

Hypotension and postural hypotension have been the most frequently reported adverse reactions (See WARNINGS section). Nausea and vomiting occurred in about three percent of patients, primarily when bretylium (bretylium tosylate injection ) tosylate was administered rapidly by the intravenous route (See PRECAUTIONS section). Vertigo, dizziness, light-headedness and syncope, which sometimes accompanied postural hypotension, were reported in about 7 patients in 1000.

Bradycardia, increased frequency of premature ventricular contractions, transitory hypertension, initial increase in arrhythmias (See WARNINGS section), precipitation of anginal attacks, and sensation of substernal pressure have also been reported in a small number of patients, i.e., approximately 1-2 patients in 1000.

Renal dysfunction, diarrhea, abdominal pain, hiccups, erythematous macular rash, flushing, hyperthermia, confusion, paranoid psychosis, emotional lability, lethargy, generalized tenderness, anxiety, shortness of breath, diaphoresis, nasal stuffiness and mild conjunctivitis, have been reported in about 1 patient in 1000. Hyperthermia has also been reported (see WARNINGS). The relationship of bretylium (bretylium tosylate injection ) tosylate administration to these reactions has not been clearly established.

DRUG INTERACTIONS

Digitalis toxicity may be aggravated by the initial release of norepinephrine caused by Bretylium (bretylium tosylate injection ) Tosylate Injection.

The pressor effects of catecholamines such as dopamine or norepinephrine are enhanced by Bretylium (bretylium tosylate injection ) Tosylate. When catecholamines are administered, dilute solutions should be used and blood pressure should be monitored closely. (See WARNINGS)

Although there is little published information on concomitant administration of lidocaine and Bretylium (bretylium tosylate injection ) Tosylate, these drugs are often administered concurrently without any evidence of interactions resulting in adverse effects or diminished efficacy.

Warnings & Precautions

WARNINGS

Hypotension: Administration of bretylium (bretylium tosylate injection ) tosylate regularly results in postural hypotension, subjectively recognized by dizziness, light-headedness, vertigo or faintness. Some degree of hypotension is present in about 50% of patients while they are supine. Hypotension may occur at doses lower than those needed to suppress arrhythmias.

Patients should be kept in the supine position until tolerance to the hypotensive effect of bretylium (bretylium tosylate injection ) develops. Tolerance occurs unpredictably but may be present after several days.

Patients over 65 years may be at increased risk of developing orthostatic hypotension, especially when the recommended rate of intravenous infusion is exceeded. See DOSAGE AND ADMINISTRATION

Hypotension with supine systolic pressure greater than 75 mm Hg need not be treated unless there are associated symptoms. If supine systolic pressure falls below 75 mm Hg, an infusion of dopamine or norepinephrine may be used to raise blood pressure. When catecholamines are administered, a dilute solution should be employed and blood pressure monitored dosely because the pressor effects of the catecholamines are enhanced by bretylium (bretylium tosylate injection ) . Volume expansion with blood or plasma and correction of dehydration should be carried out where appropriate.

Transient hypertension and increased frequency of arrhythmias: Due to the initial release of norepinephrine from adrenergic postganglionic nerve terminals by bretylium (bretylium tosylate injection ) , transient hypertension or increased frequency of premature ventricular contractions and other arrhythmias may occur in some patients.

Caution during use with digitalis glycosides: The initial release of norepinephrine caused by bretylium (bretylium tosylate injection ) may aggravate digitalis toxicity. When a life-threatening cardiacarrhythmia occurs in a digitalized patient, bretylium (bretylium tosylate injection ) should be used only if the etiology of the arrhythmia does not appear to be digitalis toxicity and other antiarrhythmic drugs are not effective. Simultaneous initiation of therapy with digitalis glycosides and bretylium (bretylium tosylate injection ) should be avoided.

Patients with fixed cardiac output: In patients with fixed cardiac output (i.e., severe aortic stenosis or severe pulmonary hypertension) bretylium (bretylium tosylate injection ) should be avoided since severe hypotension may result from a fall in peripheral resistance without a compensatory increase in cardiac output. If survival is threatened by the arrhythmia, bretylium (bretylium tosylate injection ) tosylate may be used but vasoconstrictive catecholamines should be given promptly if severe hypotension occurs.

Hyperthermia: In a small number of patients, hyperthermia, characterized by temperature in excess of 106°F, has been reported in association with bretylium (bretylium tosylate injection ) tosylate administration. Temperature rise can begin within one hour or later after administration of drug, and reach a peak within 1 to 3 days. If hyperthermia is suspected or diagnosed, bretylium (bretylium tosylate injection ) should be discontinued and appropriate treatment instituted immediately.

PRECAUTIONS

General

Dilution for Intravenous use: One vial of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION should be diluted with a minimum of 50 mL of Dextrose Injection 5%, USP, or Sodium Chloride Injection, USP, prior to intravenous use. Rapid intravenous administration may cause severe nausea and vomiting. Therefore, the diluted solution should be infused over a period greater than 8 minutes. In treating existing ventricular fibrillation bretylium (bretylium tosylate injection ) tosylate should be given as rapidly as possible and may be given without dilution.

Use various sites for intramuscular injection: When injected intramuscularly, not more than 5mL should be given in a site, and injection sites should be varied since repeated intramuscular injection into the same site may cause atrophy and necrosis of muscle tissue, fibrosis, vascular degeneration and inflammatory changes.

Reduce dosage in impaired renal function: Since bretylium (bretylium tosylate injection ) is excreted principally via the kidney, the dosage interval should be increased in patients with impaired renal function. See CLINICAL PHARMACOLOGY section for information of the effect of reduced renal function on half-life.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No data are available on potential for carcinogenicity, mutagenicity or impairment of fertility in animals or humans. Studies with solutions in polypropylene syringes have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.

Pregnancy

Category C: Animal reproduction studies have not been conducted with bretylium (bretylium tosylate injection ) tosylate. It is also not known whether bretylium (bretylium tosylate injection ) tosylate can cause harm when administered to a pregnant woman or can affect reproduction capacity. Bretylium (bretylium tosylate injection ) tosylate should be given to pregnant women only if clearly needed.

Pediatric Use

The safety and effectiveness of Bretylium (bretylium tosylate injection ) Tosylate have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

Geriatric Use

Clinical studies of bretylium (bretylium tosylate injection ) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or drug therapy.

Intravenous infusion, especially if administered at a rate beyond that recommended in the DOSAGE AND ADMNISTRATION section, may produce an increased risk of orthostatic hypotension in the elderly. See WARNINGS)

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function, See CLINICAL PHARMACOLOGY.

Overdosage & Contraindications

OVERDOSE

In the presence of life-threatening arrhythmias, underdosing with bretylium (bretylium tosylate injection ) probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium (bretylium tosylate injection ) serum levels were 8000 ng/mL.

The exaggerated hemodynamic response was attributed to the rapid injection of a very large dose while some effective circulation was still present. Neither the total dose nor the serum levels observed in this patient are in themselves associated with toxicity. Total doses of 30 mg/kg are not unusual and do not cause toxicity when given incrementally during cardiopulmonary resuscitation procedures. Similarly, patients maintained on chronic Bretylium (bretylium tosylate injection ) Tosylate Injection therapy have had documented serum levels of 12,000 ng/mL. These levels were achieved after sequential dosage increases over time with no apparent ill effects.

If Bretylium (bretylium tosylate injection ) Tosylate Injection is overdosed and symptoms of toxicity develop, administration of nitroprusside or another short acting intravenous antihypertensive agent should be considered for the treatment of the hypertensive response. Long acting drugs that might potentiate the subsequent hypotensive effects of Bretylium (bretylium tosylate injection ) Tosylate Injection should not be used. Hypotension should be treated with appropriate fluid therapy and pressoragents such as dopamine or norepinephrine. Dialysis is probably not useful in the treatment of Bretylium (bretylium tosylate injection ) Tosylate Injection overdose.

CONTRAINDICATIONS

There are no contraindications to use in treatment of ventricular fibrillation or life-threatening refractory ventricular arrhythmias.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Bretylium (bretylium tosylate injection ) tosylate is abromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability.

Bretylium (bretylium tosylate injection ) also suppresses ventricular fibrillation and ventricular arrhythmias. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium (bretylium tosylate injection ) are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium (bretylium tosylate injection ) have been demonstrated in animal experiments:

1. Increase in ventricular fibrillation threshold.

2. Increase in action potential duration and effective refractory period without changes in heart rate.

3. Little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium. However, when cell injury slows the rate of rise, decreases amplitude, and lowers resting membrane potential, bretylium (bretylium tosylate injection ) transiently restores these parameters toward normal.

4. In canine hearts with infarcted areas bretylium (bretylium tosylate injection ) decreases the disparity in action potential duration between normal and infarcted regions.

5. Increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity.

The restoration of injured myocardial cell electrophysiology toward normal, as well as the increase of the action potential duration and effective refractory period without changing their ratio to each other, may be important factors in suppressing re-entry of aberrant impulses and decreasing induced dispersion of local excitable states.

Bretylium (bretylium tosylate injection ) induces a chemical sympathectomy-like state which resembles a surgical sympathectomy. Catecholamine stores are not depleted by bretylium (bretylium tosylate injection ) tosylate, but catecholamine effects on the myocardium and on peripheral vascular resistanceare often seen shortly after administration because bretylium (bretylium tosylate injection ) causes an early release of norepinephrine from the adrenergic postganglionic nerve terminals. Subsequently, bretylium (bretylium tosylate injection ) tosylate blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade regularly causes orthostatic hypotension but has less effect on supine blood pressure. The relationship of adrenergic blockade to the antifibrillatory and antiarrhythmic actions of bretylium (bretylium tosylate injection ) is not clear. In a study in patients with bretylium (bretylium tosylate injection ) , peak hypotensive effects were seen within one hour of intramuscular administration, presumably reflecting adrenergic neuronal blockade. However, suppression of premature ventricular beats was not maximal until 6-9 hours after dosing, when mean plasma concentration had declined to less than one-half of peak level. This suggests a slower mechanism, other than neuronal blockade, was involved in suppression of the arrhythmia. On the other hand, antifibrillatory effects can be seen wfthin minutes of an intravenous injection, suggesting that the effect on the myocardium may occur quite rapidly.

Bretylium (bretylium tosylate injection ) has a positive inotropic effect on the myocardium, but it is not yet certain whether this effect is direct or is mediated by catecholamine release.

Bretylium (bretylium tosylate injection ) is eliminated intact by the kidneys. No metabolites have been identified following administration of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION in man and laboratory animals. In man, approximately 70%-80% of a 14C-labelled intramuscular dose is excreted in the urine during the first 24 hours, with an additional 10% excreted over the next three days.

The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). In one patient with a creatinine clearance of 21.0 mL/min. x 1.73m2 the half-life was 16 hours. In one patient with a creatinine clearance of 1.0 mL/min. x 1.73m2 the half-life was 31.5 hours. During hemodialysis, this patient†s arterial and venous bretylium (bretylium tosylate injection ) concentrations declined rapidly, resulting in a half-life of 13 hours. During dialysis there was two-fold increase in total bretylium (bretylium tosylate injection ) clearance.

Effect on heart rate: There is sometimes an initial small increase in heart rate when bretylium (bretylium tosylate injection ) tosylate is administered, but this is an inconsistent and transient occurrence.

Hemodynamic effects: Following intravenous administration of 5mg/kg of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION to patients with acute myocardial infarction, there was a mild increase in arterial pressure, followed by a modest decrease, remaining within normal limits throughout. Pulmonary artery pressures, pulmonary capillary wedge pressure, right atrial pressure, cardiac index, stroke volume index, and stroke work index were not significantly changed. These hemodynamic effects were not correlated with antiarrhythmic activity.

Onset of action: Suppression of ventricular fibrillation is rapid, usually occurring within minutes following intravenous administration. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration.