Two Formulations of Epoprostenol Sodium in the Treatment of Pulmonary Arterial Hypertension*

EPITOME-1 (Epoprostenol for Injection in Pulmonary Arterial Hypertension), a Phase IV, Open-Label, Randomized Study

Kelly M. Chin, MD; David B. Badesch, MD; Ivan M. Robbins, MD; Victor F. Tapson, MD; Harold I. Palevsky, MD; Nick H. Kim, MD; Steven M. Kawut, MD; Adaani Frost, MD; Wade W. Benton, PharmD; Jean-Christophe Lemarie, MSc; Frederic Bodin, MD; Lewis J. Rubin, MD; Vallerie McLaughlin, MD

Disclosures

Am Heart J. 2014;167(2):218-225.e1. 

In This Article

Abstract and Introduction

Abstract

Background Epoprostenol sodium with arginine-mannitol excipients (epoprostenol AM; Veletri [Actelion Pharmaceuticals Ltd, Allschwil, Switzerland]) and epoprostenol sodium with glycine-mannitol excipients (epoprostenol GM; Flolan [GlaxoSmithKline, Triangle Park, NC]) are intravenous treatments for pulmonary arterial hypertension (PAH). Epoprostenol AM contains different inactive excipients, resulting in greater stability at room temperature compared with epoprostenol GM.

Methods In this prospective, multicenter, open-label, randomized, phase IV exploratory study, epoprostenol-naïve patients in need of injectable prostanoid therapy were randomized 2:1 to open-label epoprostenol AM or epoprostenol GM. The study period was 28 days, followed by a 30-day safety follow-up. Study aims were to descriptively compare the safety, tolerability, drug metabolite levels, and treatment effects of epoprostenol AM and epoprostenol GM in PAH. Statistical analysis was descriptive only because of the exploratory nature of the study.

Results Thirty patients with PAH (18–70 years, 24 women, 20 idiopathic PAH) were randomized to epoprostenol AM (n = 20) or epoprostenol GM (n = 10). Most frequently reported adverse events included jaw pain, headache, nausea, and flushing. Two deaths occurred during the study period, and 1 death occurred during the 30-day safety follow-up period, all in patients receiving epoprostenol AM. All deaths were classified by the treating physician as unrelated to epoprostenol AM. The median (range) change from baseline to day 28 in 6-minute walk distance was 36 m (−127 to 210 m) and 49 m (−44 to 110 m) for the epoprostenol AM and epoprostenol GM groups, respectively.

Conclusions In this randomized clinical study of epoprostenol AM in PAH, use of this novel preparation with greater room temperature stability was well tolerated.

Introduction

Epoprostenol is a continuous intravenous prostacyclin analog used in the treatment of pulmonary arterial hypertension (PAH). The efficacy of epoprostenol was initially demonstrated in 3 randomized controlled trials.[1,2,3] Epoprostenol resulted in improvements in symptoms, exercise capacity, hemodynamics, and, in 1 trial,[1] survival compared with controls. Epoprostenol is recommended by international guidelines for first-line therapy in patients with New York Heart Association (NYHA) functional class III or IV PAH.[4,5]

In the United States, epoprostenol is currently available in 2 formulations: epoprostenol sodium with glycine-mannitol excipients (epoprostenol GM; Flolan [GlaxoSmithKline, Triangle Park, NC]) and epoprostenol sodium with arginine-mannitol excipients (epoprostenol AM; Veletri [Actelion Pharmaceuticals Ltd, Allschwil, Switzerland]). Epoprostenol AM contains the same active ingredient as epoprostenol GM, epoprostenol sodium, but with different excipients and a higher pH, resulting in greater room temperature stability.[6] As a result, ice packs are not required during administration of epoprostenol AM once a sufficient concentration is achieved, and at even higher concentrations, patients may prepare cassettes up to 7 days in advance.[7] Epoprostenol AM was approved by the US Food and Drug Administration in 2008 under section 505(b) (2) of the Federal Food, Drug and Cosmetic Act, which does not require bioequivalence or clinical studies for parenteral solutions containing the same active ingredient. However, biocomparability of both forms with regard to pharmacokinetic, pharmacodynamic, safety, and tolerability profiles has been demonstrated in a phase I study in healthy male volunteers.[8]

The aim of this study was to descriptively compare the safety, tolerability, drug metabolite levels, and treatment effects on clinical parameters of exercise capacity, functional ability, and mixed venous oxygen saturation (SvO2) of epoprostenol AM with epoprostenol GM in patients with PAH.

*This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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