Pediatric Acceptable Formulation of Amiodarone

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.