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Pacerone

Amiodarone belongs to a class of drugs called Vaughan-Williams Class III antiarrhythmic agent. It is used in the treatment of a wide range of cardiac tachyarhthmias, including both ventricular and supraventricular (atrial) arrhythmias. The chemical name for amiodarone is 2-butyl-3-benzofuranyl 4--3,5-diiodophenyl ketone hydrochloride. more...

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History

Amiodarone was initially developed in 1961 in Belgium as a treatment for angina. It was widely used throughout Europe as an anti-anginal medication, and was soon found to suppress arrhythmias.

Dr. Bramah Singh determined that amiodarone and sotalol belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents) that would prolong repolarization of the cardiac action potential. Based on this, the Argentinian physician Dr. Mauricio Rosenbaum began using amiodarone to treat his patients who suffered from supraventricular and ventricular arrhythmias, with impressive results. Based on papers written by Dr. Rosenbaum, physicians in the United States began prescribing amiodarone to their patients with potentially life-threatening arrhythmias in the late 1970s. By that time, amiodarone was commonly prescribed throughout Europe for the treatment of arrhythmias. Because amiodarone was not approved by the FDA for use in the United States at the time, physicians were forced to directly obtain amiodarone from pharmaceutical companies in Canada and Europe.

The FDA was reluctant to officially approve the use of amiodarone, since initial reports had shown increased incidence of serious pulmonary side-effects of the drug. In the mid 1980s, the European pharmaceutical companies began putting pressure on the FDA to approve amiodarone by threatening to cut the supply to the American physicians if it was not approved. In December of 1985, amiodarone was approved by the United States FDA for the treatment of arrhythmias. This makes amiodarone one of the few drugs approved by the FDA without rigorous randomized clinical trials.

Dosing

Amiodarone is available in oral and intravenous formulations. Orally, it is available under the trade names Pacerone^® (produced by Upsher-Smith Laboratories, Inc.) and Cordarone^® (produced by Wyeth-Ayerst Laboratories) in 200 mg and 400 mg tablets. It is also available in intravenous ampules and vials, typically in 150mg increments.

The dose of amiodarone administered is tailored to the individual and the dysrhythmia that is being treated. When administered orally, the bioavailability of amiodarone is quite variable. Absorption ranges from 22 to 95%, with better absorption when it is given with food.

Amiodarone is fat-soluble, and tends to concentrate in tissues including fat, muscle, liver, lungs, and skin. This confers a high volume of distribution (5000 liters in a 70kg adult) and a long half-life. Due to the long half-life of amiodarone, oral loading typically takes days to weeks.

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Formulation and accelerated stability studies for an extemporaneous suspension of amiodarone hydrochloride
From International Journal of Pharmaceutical Compounding, 9/1/03 by Alexander, Kenneth S

Abstract

Amiodarone is commercially available as both a tablet and an injectable formulation. It is widely dispensed as an extemporaneously compounded suspension for pediatric and geriatric patients. Extensive stability data at numerous temperatures and a calculated shelf life based on kinetics for such a formulation have not been reported. Refrigeration and room temperature data for finite times have been reported in the literature.

In this study, a stable extemporaneous formulation of amiodarone hydrochloride was formulated using Pacerone tablets. The formulation consisted of 0.75% carboxymethylcellulose and 0.75% Veegum as suspending agents; 25% sucrose, provided as simple syrup; and aqueous strawberry concentrate as flavor. A total of 2.5 L of the formulation was compounded and stored in quantities of 150 mL in 8-oz glass containers. The initial drug content was determined by reverse-phase high-performance liquid chromatography, with a method that was developed in our laboratory. The stability study was carried out by storing three containers at five different temperatures, namely 4, 30, 40, 50 and 60 deg C. The suspension was analyzed at the end of 2, 6, 12, 24 and 48 hours at 7 days, and, thereafter, at the end of every week for 13 weeks. The percentage of drug remaining was plotted against time for each temperature. The slope of the regression line was obtained for each temperature and the zero-order degradation rate constant obtained. The logarithm of the zero-order degradation rate constants was plotted against the inverse of the temperature in degrees Kelvin to obtain the Arrhenius plot. From the regression line for the Arrhenius plot, the zero-order degradation constant at 25 deg C was calculated to be 0.0517 day^sup -1^. The shelf life for the formulation at 25 deg C was calculated to be 193.4 days; the shelf life under refrigeration (4 deg C) was found to be 677.3 days. The degradation products were characterized using high-performance liquid chromatographic-mass spectrometry. Data obtained from the analysis suggested that amiodarone cleaved at its ketone and ether linkages to yield corresponding degradation products.

Introduction

Amiodarone is one of the most powerful anti-arrhythmic drugs used in the treatment of ventricular and supraventricular tachycardias, including those associated with Wolff-Parkinson-White (WPW) syndrome.1,2 Amiodarone is a class III anti-arrhythmic agent that acts by delaying repolarization and prolonging the action-potential duration of atrial and ventricular muscles without altering the resting membrane potential. Amiodarone thus lengthens the refractory period of the atrial and ventricular myocardia, atrioventricular node and accessory pathways that mediate WPW syndrome.3

The drug is commercially available as tablet and injectable formulations. Since it is widely used in pediatric and geriatric patients, it has been widely dispensed as extemporaneously compounded suspensions. Stability data to calculate the shelf life for such a formulation at any temperature have not been reported. However, stability data for extemporaneously compounded formulations at room temperature and under refrigeration have been previously reported.4,5 The purpose of this study was to improve upon previous extemporaneous formulations of amiodarone hydrochloride and to study its stability at various temperature conditions as per International Conference of Harmonization guidelines. Characterization of the degradation products was also undertaken using high-performance liquid chromatographic-mass spectrometry (HPLC-MS).

Methods

Preparation of Amiodarone Hydrochloride Suspension

Conclusions

This study achieved three goals. The extemporaneously compounded formulation provided a reasonably palatable amiodarone hydrochloride formulation that can be used for both pediatric and geriatric patients. The formulation extended the shelf life that was previously reported by Nahata et al.7 The shelf life was calculated to be 193.42 36 days at 25 deg C. At 4 deg C, the shelf life was found to be 677.26 days. A mechanism has been proposed that can explain the presence of degradation products. The proof for this proposed mechanism is left to the medicinal chemists to ponder.

Acknowledgment

The authors wish to acknowledge the generous contribution of Pacerone tablets by Upsher Smith, Minneapolis, Minnesota, which facilitated the timely progression of this project.

References

1. Florey K. Analytical Profiles of Drug Substances. New York:Academic Press, Inc.; 1991;20:1-88.

2. Nuwer MR, Browne TR, Dodson WE et al. Generic substitutions for antiepilectic drugs. Neurology 1990;40:1647-1651.

3. Kuga K, Yamaguchi I, Sugishita Y. Effect of intravenous amiodarone on electrophysiologic variables and on the modes of termination of atrioventricular reciprocating tachycardia in Wolff-Parkinson-White syndrome. Jpn Circ J 1999;63:189-195.

4. Nahata MC. Stability of amiodarone in an oral suspension stored under refrigeration and at room temperature. Ann Pharmacother 1997;31:851-852.

5. Nahata MC, Morosco RS, Hipple TF. Stability of amiodarone in extemporaneous oral suspensions prepared from commercially available vehicles. J Ped Pharm Pract 1999;4:186-189.

6. Lachman L, Deluca P, Akers M. Kinetic principles and stability testing. In: Lachman L, Lieberman HA, Kanig JL, eds. The Theory and Practice of Industrial Pharmacy. Philadelphia:Lea & Febiger; 1972:671-673.

7. Nahata MC, Hipple TF Pediatric Drug Formulations. 2nd ed. Cincinnati:Harvey Whitney Books; 1992:25.

Address correspondence to: Kenneth S. Alexander, PhD, RPh, The College of Pharmacy, The University of Toledo, Toledo, OH 43606. E-mail: kalexan@utnet.utoledo.edu

Kenneth S. Alexander, PhD, RPh

N. Thyagarajapuram

College of Pharmacy

The University of Toledo

Toledo, Ohio

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