Pediatric Acceptable Formulation of Amiodarone

描述（由申请方提供）：IV胺碘酮是危及生命的室性和室上性心律失常的一线治疗。然而，吐温80和苯甲醇稀释剂由于低血压和心肌收缩抑制而严重限制了给药速率。这些不良毒性导致心脏骤停患者的高死亡率，这些患者由于长期缺氧而具有显著的心肌抑制。已经开发了一种醋酸盐缓冲液（pH 3.8）中的新制剂，允许胺碘酮推注给药。然而，当通过外周静脉给药时，新制剂会导致明显更多的静脉炎。目前正在研究不在pH 6.8醋酸盐缓冲液中的胺碘酮新制剂。该制剂将不具有苯甲醇引起的儿科毒性，在临床研究中导致儿科患者死亡，停止进一步的临床试验以获得胺碘酮的儿科适应症。此外，新的中性pH制剂应减少所有当前胺碘酮制剂引起的低血压和静脉炎。本基金中提出的研究旨在确定具有更中性pH值的胺碘酮新制剂的抗心律失常疗效、降低低血压和减少静脉炎。公共卫生相关性：静脉注射胺碘酮是最有效的心脏紧急抗心律失常药物。它是ACLS指南推荐的心脏骤停患者的一线急救治疗。目前的制剂含有吐温80和苯甲醇，可引起低血压、负性肌力和儿科毒性（静脉炎和死亡）。API已开发了胺碘酮在醋酸盐缓冲液（pH 3.8）中的制剂，但当经外周静脉给药时，这会导致静脉炎的发生率更高。静脉炎限制了该制剂在儿科的应用。此外，苯甲醇对新生儿、婴儿和幼儿可能是致命的。IV胺碘酮制剂的重新配制在pH 6.8下获得了稳定的产品，不含任何潜在毒性稀释剂。本资助中提出的研究旨在评估新制剂在动物中治疗静脉炎、低血压和抗血栓的有效性;为儿科人群开发可行产品的必要步骤。成功完成临床前研究后，根据FDA批准的特殊方案评估，需要进行成人生物等效性研究以获得FDA批准。

DESCRIPTION (provided by applicant): IV amiodarone is the first line therapy for life threatening ventricular as well as supraventricular arrhythmias. However, the Tween 80 and benzyl alcohol diluents limits the rate of administration severely, due to hypotension and myocardial contractile depression. These adverse toxicities contribute to the high mortality of cardiac arrest patients who have marked myocardial depression due to prolonged hypoxia. A new formulation in an acetate buffer solution, pH 3.8 has been developed permitting bolus administration of amiodarone. However, the new preparation causes significantly more phlebitis when administered by peripheral vein. A reformulated preparation of amiodarone not in an acetate buffer, at pH 6.8 is currently under study. The formulation will not possess the pediatric toxicity that the benzyl alcohol causes, that in clinical studies resulted in deaths in pediatric patients, halting further clinical trials to obtain a pediatric indication for amiodarone. Additionally the new, neutral pH formulation should reduce the hypotension and phlebitis caused by all current amiodarone formulations. Studies proposed in this grant aim to establish the anti-arrhythmic efficacy, the reduced hypotension and reduced phlebitis that the newer preparation of amiodarone with the more neutral pH offers. PUBLIC HEALTH RELEVANCE: IV amiodarone is the most effective cardiac emergency anti-arrhythmic available. It is first line emergency therapy for cardiac arrest patients as recommended by ACLS guidelines. The current formulation has Tween 80 and benzyl alcohol that causes hypotension, negative inotrophy and pediatric toxicity (phlebitis and mortality). API has developed a formulation of amiodarone in an acetate buffer, pH 3.8 but this causes a higher incidence of phlebitis when administered into peripheral veins. The phlebitis limits the pediatric utility of the preparation. Additionally, benzyl alcohol may be fatal in the newborn, infant and small child. A reformulation of the IV amiodarone preparation has yielded a stable product at pH 6.8 that does not contain any potentially toxic diluent. The studies proposed in this grant aim to evaluate the new formulation for phlebitis, hypotension and anti-arrhythmic effectiveness in animals; requisite steps in the development of a viable product for the pediatric population. At the successful completion of the pre-clinical studies, a bioequivalence study in adults would be requisite for FDA approval based on a Special Protocol Assessment granted by FDA.