Am J Cardiovasc Drugs (2014) 14:463–470 DOI 10.1007/s40256-014-0093-0

ADIS DRUG EVALUATION

Epoprostenol (VeletriÒ, CaripulÒ): A Review of Its Use in Patients with Pulmonary Arterial Hypertension Sarah L. Greig • Lesley J. Scott • Greg L. Plosker

Published online: 14 October 2014 Ó Springer International Publishing Switzerland 2014

Abstract A bioequivalent formulation of intravenous epoprostenol containing the excipients arginine and sucrose (epoprostenol AS) (VeletriÒ, CaripulÒ) is approved in the USA, UK, and other countries for the treatment of pulmonary arterial hypertension (PAH), and has improved thermal stability compared with epoprostenol containing glycine and mannitol (epoprostenol GM) (FlolanÒ). Epoprostenol, a synthetic prostacyclin, is a potent pulmonary vasodilator. Epoprostenol GM was originally approved for use as a longterm continuous infusion in patients with PAH nearly 20 years ago in the USA; however, this formulation has limited stability at room temperature, and requires the use of cooling or frequent medication changes during administration. The prolonged thermal stability of epoprostenol AS compared with epoprostenol GM allows for its extended administration at room temperature and/or refrigerated storage of prepared solutions. This article summarizes the pharmacology of epoprostenol AS and reviews its therapeutic use in adult patients with PAH. In clinical trials, epoprostenol AS provided sustained efficacy in terms of hemodynamic and symptomatic outcomes, and was generally well tolerated after transitioning from stable epoprostenol GM therapy and during an open-label extension study. Furthermore, there was a significant increase in the treatment convenience with epoprostenol AS compared with epoprostenol GM. Therefore, epoprostenol AS is a valuable therapeutic option that has

the potential to overcome some of the limitations of long-term intravenous epoprostenol therapy in patients with PAH.

The manuscript was reviewed by: H. W. Farber, The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA; K. Fukuda, Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; O. Sitbon, Faculte´ de Me´decine, Universite´ Paris XI Sud, Paris, France.

1 Introduction

S. L. Greig (&)
L. J. Scott
G. L. Plosker Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand e-mail: [email protected]

Epoprostenol in Pulmonary Arterial Hypertension: A Summary Epoprostenol (a synthetic prostacyclin) is a potent pulmonary vasodilator, and inhibits platelet aggregation and vascular smooth muscle proliferation Epoprostenol with arginine and sucrose (epoprostenol AS) has improved thermal stability compared with epoprostenol with glycine and mannitol (epoprostenol GM) Epoprostenol AS is bioequivalent to epoprostenol GM with a similar pharmacokinetic profile Epoprostenol AS provides sustained treatment efficacy in patients switching from epoprostenol GM Epoprostenol AS significantly increases treatment convenience compared with epoprostenol GM Epoprostenol AS is generally well tolerated

Pulmonary arterial hypertension (PAH) is a chronic, progressive disease of the small pulmonary arteries, characterized by vascular remodeling that results in increased pulmonary vascular resistance and pulmonary arterial pressure, and ultimately leads to right ventricular failure and death [1]. PAH is characterized by pre-capillary pulmonary

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hypertension (PH), which is defined as a mean pulmonary artery pressure C25 mmHg, a pulmonary artery wedge pressure B15 mmHg, and a pulmonary vascular resistance [3 Wood units [2]. According to the latest clinical classification, PAH is categorized as Group 1 PH, which encompasses idiopathic, heritable, drug- or toxin-induced PAH, or PAH associated with connective tissue disease, HIV infection, portal hypertension, congenital heart diseases, or schistosomiasis [3]. Based on registry data from the USA, France, and Spain, PAH has an estimated annual incidence of 2.0–3.2 cases/million population, and an estimated prevalence of 10.6–16.0 cases/million population [4]. The WHO functional classification system [modified from the New York Heart Association (NYHA) functional classification] is used to determine the severity of PAH in patients by assessing their symptoms and the degree of limitation in their daily activities [5]. PAH patients in WHO functional class (FC) IV are considered to have severe disease with a particularly poor prognosis [6]. The pathogenesis of PAH involves abnormal vascular smooth muscle and endothelial cell proliferation, inflammatory cell infiltration, and vascular fibrosis [1]. These changes in the pulmonary vasculature result in imbalances in the prostacyclin, nitric oxide (NO), and endothelin (ET)1 pathways, which lead to PAH patients having decreased levels of endogenous prostacyclin, a potent pulmonary vasodilator produced by vascular endothelial cells [1, 7]. Prostacyclin is also involved in inhibition of platelet aggregation, inflammation, and vascular smooth muscle proliferation [1]. Synthetic prostacyclin analogs, together with endothelin receptor antagonists (ERAs) (targeting the ET-1 pathway) and phosphodiesterase-5 inhibitors (PDE5is) (targeting the NO pathway), form the basis of current treatment options for PAH [1, 7]. Epoprostenol (Fig. 1) formulated with the excipients arginine and sucrose (epoprostenol AS) (VeletriÒ, CaripulÒ, epoprostenol ‘‘ACT’’) is a synthetic prostacyclin that is approved for the treatment of PAH (Group 1 PH) to improve exercise capacity [8–10] (Sect. 5). Epoprostenol formulated with glycine and mannitol (epoprostenol GM) (FlolanÒ) was originally approved in the USA in 1995 [11]. In randomized clinical trials in patients with severe primary pulmonary hypertension, continuous intravenous epoprostenol GM therapy resulted in symptomatic and hemodynamic improvements [12], as well as increased survival [13]. The current PAH treatment algorithm recommends continuous intravenous epoprostenol as first-line therapy for PAH patients in WHO FC IV [14, 15]. Epoprostenol may also be considered as first-line therapy for PAH patients in WHO FC III [5]. A recent analysis of REVEAL (the Registry to EValuate Early and Long-Term PAH disease management) found that despite current guideline recommendations, intravenous

S. L. Greig et al.

H

Na+ OOC O

H CH3 H OH

H

OH

Fig. 1 Chemical structure of epoprostenol (sodium salt)

epoprostenol was used inconsistently in patients at the time of their WHO FC IV diagnosis or before their death [16, 17]. A possible reason for this finding might be the complexities and inconveniences associated with intravenous epoprostenol therapy. One of the inconveniences of intravenous epoprostenol GM therapy is its limited thermal stability in solution [1]. Following reconstitution and dilution, epoprostenol GM must be administered within 8–12 h at room temperature or within 24 h at 2–8 °C (using frozen gel packs) [18]. To alleviate this inconvenience, a new epoprostenol formulation containing the excipients arginine and mannitol (epoprostenol AM) was developed with prolonged stability at room temperature [19]. Epoprostenol AM was approved for the treatment of PAH in the USA in 2008 [20]. In a randomized phase IV trial in PAH patients [EPITOME (Epoprostenol for Injection in Pulmonary Arterial Hypertension)-1], epoprostenol AM had a similar tolerability profile to epoprostenol GM, and improvements in exercise capacity and NYHA FC were observed in patients from both treatment groups during the 28-day study [21]. More recently, a second bioequivalent formulation, epoprostenol AS, was found to have superior stability in solution to epoprostenol AM [20]. Epoprostenol AS has since replaced epoprostenol AM, and is approved for the treatment of PAH in the USA, UK, and other countries [8, 9]. This article provides an overview of the pharmacologic properties of epoprostenol, and reviews the therapeutic efficacy, safety, and tolerability of epoprostenol AS in PAH treatment. An in-depth discussion of the use of epoprostenol GM or epoprostenol AM in PAH or the use of epoprostenol AS in other indications is beyond the scope of this review.

2 Pharmacologic Properties 2.1 Pharmaceutical Properties The active ingredient of epoprostenol AS is epoprostenol sodium (Fig. 1), which is formulated as a sterile lyophilized powder for intravenous administration [8, 9]. An in vitro study demonstrated that epoprostenol AS had improved thermal

Epoprostenol: A Review

stability compared with epoprostenol GM and epoprostenol AM [20]. In this study, epoprostenol AS remained stable (with [90 % initial potency) after reconstitution in sterile water or saline for injection for B7 days when stored at 5 °C or for B1 day when stored at 25 °C, while diluted epoprostenol AS solutions remained stable for B72 h depending on concentration and temperature (Sect. 5). Additionally, this study demonstrated no microbial growth after inoculation of epoprostenol AS solutions with a broad spectrum of potential contaminants, according to the US Pharmacopeia 51 antimicrobial effectiveness test. The improved stability and selfpreservation of epoprostenol AS relative to epoprostenol AM and epoprostenol GM may be because of the higher pH range of diluted epoprostenol AS (10.8–11.9) compared with epoprostenol AM (9.9–11.3) and epoprostenol GM (10.2–10.8). The arginine buffer (pKa = 13.2) in epoprostenol AS provides a higher pH in solution than glycine (pKa = 9.8). Epoprostenol AS also contains sucrose, which has a higher glass transition temperature (&40 °C) than mannitol (&30 °C), providing further stability and improving the appearance of the lyophilized powder [20]. 2.2 Pharmacodynamic Properties Epoprostenol is a potent vasodilator of systemic, pulmonary, and coronary vasculature, and inhibits platelet aggregation, inflammation, and vascular smooth muscle proliferation [1]. Epoprostenol binds to G-protein coupled prostanoid IP receptors on the surface of many cell types, including the smooth muscle cells of pulmonary arteries and veins [22]. Prostanoid IP receptor binding leads to increased levels of intracellular cyclic adenosine monophosphate, and ultimately results in the vasodilatory, platelet inhibitory, and antiproliferative effects of epoprostenol [22]. Studies in patients with either peripheral arterial disease [23] or primary pulmonary hypertension [24] showed that the vasodilatory properties of epoprostenol were associated with dose-dependent decreases in pulmonary vascular resistance. Similarly, a study in healthy volunteers demonstrated that epoprostenol GM and epoprostenol AM induced pronounced increases in heart rate, cardiac output, and cardiac index, with these hemodynamic effects appearing almost immediately after the start of the epoprostenol infusion [25]. The pharmacodynamic profiles of these two epoprostenol formulations both showed a linear and proportional relationship between cardiac index and plasma concentrations of an epoprostenol metabolite (i.e. 6-keto-prostacyclin F1a) (see Sect. 2.3 for metabolism details) [25]. In a subsequent study of healthy volunteers, epoprostenol AS was found to have a similar pharmacodynamic profile to epoprostenol GM and epoprostenol AM, with progressive increases in cardiac output, cardiac index, and heart rate over the 8-h infusion of epoprostenol [26].

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2.3 Pharmacokinetic Properties Epoprostenol has an in vitro half-life (t‘) of &6 min in human blood at physiological pH and temperature, and an estimated elimination t‘ of 3–5 min in humans in vivo [27]. In blood, epoprostenol undergoes rapid spontaneous hydrolysis and enzymatic degradation, resulting in its two primary metabolites, 6-keto-prostacyclin F1a and 6,15-diketo-13,14-dihydro-prostacyclin F1a, respectively [27]. The pharmacologic activity of these metabolites is orders of magnitude less than epoprostenol [9]. As the structure of epoprostenol in solution is prone to rapid degradation, it must be delivered by continuous intravenous infusion [27]. In a study of healthy volunteers receiving intravenous infusions of either epoprostenol GM or epoprostenol AM, 6-keto-prostacyclin F1a was detected in plasma almost immediately after the infusion start and reached plasma steady-state concentrations within 2 h, whereas 6,15-diketo-13,14-dihydro-prostacyclin F1a was not detected in plasma samples until [2 h after the start of epoprostenol administration [25]. The pharmacokinetics of 6-keto-prostacyclin F1a and 6,15-diketo-13,14-dihydro-prostacyclin F1a were characterized using a single compartment infusion model with first order elimination. Based on this model, the estimated epoprostenol metabolite clearance and volume of distribution were 85 L/h and 23.7 L, respectively, which corresponded to a clearance of 116 L/h and a volume of distribution of 26.8 L for a 75 kg adult. Food intake was estimated to increase clearance by 39 % at &30 min after eating, with the apparent effect of food on clearance almost disappearing by 2 h after eating [25]. In another study, in which radiolabeled epoprostenol was administered to healthy volunteers, 82 % of the radioactivity was recovered in the urine and 4 % was recovered in the feces, consistent with a predominantly urinary route of epoprostenol excretion [28]. At least 14 additional minor metabolites were detected in the urine, suggestive of an extensive epoprostenol metabolism [28]. The bioequivalence of epoprostenol AS compared with epoprostenol GM and epoprostenol AM was established in a study of healthy volunteers [26]. The plasma concentration-time curves of 6-keto-prostacyclin F1a and 6,15-diketo-13,14-dihydro-prostacyclin F1a for the three formulations were superimposable, indicating that the pharmacokinetic properties of epoprostenol were not affected by the altered excipients [26]. 2.4 Potential Drug Interactions Coadministration of epoprostenol with anticoagulants, NSAIDs, or other antiplatelet agents can potentially increase the risk of bleeding [8, 9]. The vasodilatory effects of epoprostenol may be potentiated by concomitant

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administration with antihypertensives, diuretics, or other vasodilators [27]. In a study in patients with end-stage congestive heart failure, the estimated oral clearance of digoxin decreased by &15 % after initiation of epoprostenol therapy [29]. While this effect was not thought to be clinically relevant in most patients, it may have clinical significance in patients who are susceptible to digoxin toxicity [29]. Another study in patients with end-stage congestive heart failure demonstrated that short-term concomitant administration of epoprostenol decreased the oral clearance of furosemide by 13 %; however, this interaction was not statistically or clinically significant and was no longer apparent by the end of the 12-week study [30]. Epoprostenol may increase hepatic clearance of tissue plasminogen activator, thereby reducing its thrombolytic efficacy [8].

40.1 ng/kg/min for the EPITOME-4 trial [31]. At month 3, the mean dosage of intravenous epoprostenol AS was 30.2 ng/kg/min in the EPITOME-2 trial; four patients required dosage increases and two patients had dosage reductions during the study [18]. There were no dosage adjustments for any of the patients in the EPITOME-4 trial [31]. The mean durations of exposure to epoprostenol AS were 87.7 and 86.9 days in the EPITOME-2 and EPITOME-4 trials, respectively [18, 31]. The efficacy endpoints included hemodynamic and symptomatic outcomes, and patient-assessed health-related quality of life (HR-QOL) [18, 31]. Both trials used exploratory statistical analysis, with no formal set hypothesis. The all-treated populations, which included all enrolled patients who received the study drug, were used for all analyses, although data were missing for a small number of patients for some parameters [18, 31].

3 Therapeutic Efficacy

3.1 Effects on Efficacy Endpoints

The therapeutic efficacy of intravenous epoprostenol AS after transitioning from stable therapy with epoprostenol GM was evaluated in two small, single-arm, 3-month, open-label, phase IIIb studies of adult patients (aged C18 [18] or C20 [31] years) with PAH. The EPITOME-2 trial (n = 41) was a multicenter study conducted in Europe and Canada [18], while the EPITOME-4 trial (n = 8) was a two-site Japanese study [31]. Both studies enrolled patients with stable idiopathic or heritable PAH, PAH associated with connective tissue disease, or PAH induced by drugs or toxins, who had been receiving intravenous epoprostenol GM therapy for C12 months with a stable dose for C3 months (EPITOME2) [18], or C3 months with a stable dose for C30 days (EPITOME-4) [31]. In the EPITOME-2 trial, concomitant PAH-specific therapies were permitted if patients had been receiving them for 90 days with a stable dose for 30 days before study enrollment; calcium channel antagonists, oral anticoagulants, diuretics, and oxygen were also permitted [18]. At study entry, 80.5 % of patients (n = 33) were receiving oral PAH-specific concomitant treatment, including ERAs (17.1 %), PDE-5is (22.0 %), or a combination of the two therapies (41.5 %) [18]. Exclusion criteria were similar for both trials and included confirmed or suspected pulmonary veno-occlusive disease, a history of myocardial infarction, a resting heart rate of C120 beats/min, and diagnosis of a respiratory or cardiovascular disorder requiring immediate surgery [18, 31]. In both trials, all patients received intravenous epoprostenol AS by continuous infusion, with the cassette containing epoprostenol GM directly replaced with a cassette containing epoprostenol AS at the same dosage. The mean dosages of intravenous epoprostenol AS at baseline were 29.9 ng/kg/min for the EPITOME-2 trial [18] and

Patients in the EPITOME-2 and EPITOME-4 trials were effectively transitioned to intravenous epoprostenol AS from stable epoprostenol GM therapy [18, 31]. Patients remained clinically stable, with no significant changes from baseline in hemodynamic parameters, including pulmonary vascular resistance, right atrial pressure, and mean pulmonary artery pressure, at 3 months after transitioning to epoprostenol AS [18, 31] (Table 1). In the EPITOME-2 trial, individual patient data showed no significant changes from baseline in pulmonary vascular resistance, consistent with the hemodynamic parameters remaining stable overall [18]. In the EPITOME-4 trial, there were no significant differences in the hemodynamic parameters between baseline and 60 min after the first dose of epoprostenol AS or 3 months after the transition [31]. There were also no significant changes in systolic and diastolic pulmonary artery pressure and mixed venous oxygen saturation at 60 min and 3 months after transitioning to epoprostenol AS [31]. There were no relevant changes from baseline in other efficacy endpoints at 3 months after transitioning to intravenous epoprostenol AS in the EPITOME-2 [18] and EPITOME-4 trials [31] (Table 1). The baseline mean 6-min walk distance (6MWD) was &500 m in the EPITOME-2 trial, indicating that these patients were receiving optimal PAH therapy and were clinically stable. Exercise capacity remained stable for most patients at 3 months after transitioning to epoprostenol AS [18] (Table 1). N-terminal pro-brain natriuretic peptide levels showed no significant change after the transition, and remained within the proposed threshold for indicating a good prognosis for PAH patients [18]. Three months after transitioning to epoprostenol AS, there was no change in WHO FC for 87.5 % of patients in the EPITOME-2 trial, with one

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patient showing improvement in WHO FC from III to II and four patients developing WHO FC worsening [18]. The WHO FC remained unchanged for all patients at study end in the EPITOME-4 trial [31]. 3.2 Effects on Health-Related Quality of Life HR-QOL was assessed in both trials using the nine-item abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9), in which the patient’s perception of treatment effectiveness, convenience, and global satisfaction was recorded at baseline and at 3 months after transitioning to intravenous epoprostenol AS [18, 31]. In both the EPITOME2 and EPITOME-4 trials, there was a significant increase in the perception of treatment convenience score at 3 months after transitioning to epoprostenol AS therapy compared with baseline [18, 31] (Table 2). There were no significant changes in the other HR-QOL domains of the TSQM-9.

4 Safety and Tolerability Intravenous epoprostenol AS was generally well tolerated in the 3-month EPITOME-2 [18] and EPITOME-4 [31] trials. All adverse events from throughout the study period were recorded for both trials [18, 31]; the EPITOME-2 trial safety analysis also included adverse events at 24 h (all events) and 30 days (serious events only) after the study end [18]. In both trials, most treatment-emergent adverse events (i.e. adverse

events that occurred during the study treatment) were of mild or moderate severity, with no adverse events leading to treatment discontinuation. In the EPITOME-2 trial, 78 % of patients experienced C1 treatment-emergent adverse event [18]. The most common of these adverse events (occurring in [10 % patients) included headache (29.3 %), nasopharyngitis (17.1 %), flushing (14.6 %), jaw pain (14.6 %), and dyspnea (12.2 %), which are typical of intravenous prostacyclin treatment given its potent vasodilatory properties. Catheter-related local infections occurred in three patients (7.3 %) in the EPITOME-2 trial [18]. In the EPITOME-4 trial, two patients experienced moderate nausea, while each of the other treatment-emergent adverse events occurred in one patient only [31]. Serious treatment-emergent adverse events occurred in six patients in the EPITOME-2 trial [18] and two patients in the EPITOME-4 trial [31]; none of these serious adverse events were considered to be related to epoprostenol AS by the investigators. There were no clinically significant changes from baseline in vital signs (including heart rate and blood pressure), bodyweight, and clinical laboratory tests (including thyroid function and hematology tests) at 3 months after transitioning to epoprostenol AS [18, 31]. The long-term safety and tolerability of epoprostenol AS was assessed in an open-label extension study, in which all patients enrolled in the EPITOME-2 trial (n = 41) continued to receive epoprostenol AS (reported in an abstract) [33]. In this study, the safety and tolerability of epoprostenol AS were consistent with intravenous prostacyclin therapy after up to 22 months of treatment. Epoprostenol

Table 1 Efficacy outcomes at 3 months after transitioning patients with pulmonary arterial hypertension from epoprostenol with glycine and mannitol to epoprostenol with arginine and sucrose. Results from open-label, single-arm, phase IIIb trials Parameter

EPITOME-2 [18] (n = 41) Mean BL

Mean change from BL

EPITOME-4 [31] (n = 8) Geometric mean percentage ratio (95 % CI)a

Mean BL

Mean change from BL

p valueb

Hemodynamics RAP (mmHg) mPAP (mmHg) mPCWP (mmHg)

7.9

-0.8

86.0 (70.3–105.1)

4.8

0.0

1.0000

51.9

-0.2

98.6 (94.2–103.3)

31.1

0.3

0.8906

c

10.2

-0.2

100.3 (84.9–118.6)

8.4

Cardiac index (L/min/m2)

3.3

0.0

100.4 (95.9–105.0)

2.98

0.14

0.6563

PVR (Wood units)d

7.5c

-0.1

98.0 (91.3–105.2)

5.60

0.07

0.5469

498.1e

-5.3

99.1 (97.0–101.3)

e

-0.7

80.1 (67.9–94.3)

598.1c

13.6

97.8 (83.1–115.1)

Other clinical parameters 6MWD (m) Borg dyspnea score NT-proBNP (ng/L)

4.0

139

-1.1

-43.3

0.2344

0.5781

6MWD 6-min walk distance, BL baseline, mPAP mean pulmonary artery pressure, mPCWP mean pulmonary capillary wedge pressure, NT-proBNP N-terminal pro-brain natriuretic peptide, PVR pulmonary vascular resistance, RAP right atrial pressure a

Exploratory statistical analyses, with 95 % CI of the geometric mean percentage ratio (month 3/baseline) used to estimate level of change

b

Exploratory statistical analyses, with p values based on Wilcoxon signed rank sum test

c

n = 36 Values provided in dyne
s/cm5 were converted to Wood units by dividing by a conversion factor of 80 [32]

d e

n = 40

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Table 2 Treatment satisfaction outcomes at 3 months after transitioning patients with pulmonary arterial hypertension from epoprostenol with glycine and mannitol to epoprostenol with arginine and sucrose. Results from open-label, single-arm, phase IIIb trials TSQM-9 parametera

EPITOME-2 [18] (n = 38)b

EPITOME-4 [31] (n = 8) Mean BL

Mean change from BL (p valued)

-3.5 (-8.7 to 1.7)

56.3

2.06 (0.9063)

12.7 (6.1–19.3)

51.4

5.6 (0.0313)

54.0

1.4 (0.7188)

Mean BL

Mean change from BL (95 % CI)

Effectiveness

78.2

Convenience

53.6

Global satisfaction

71.8

c

3.4 (-1.3 to 8.1)

BL baseline, TSQM-9 abbreviated 9-item Treatment Satisfaction Questionnaire for Medication a

TSQM-9 scores range from 0 to 100, with higher scores reflecting improved patient perception of these parameters

b

Treatment satisfaction data were not available for three patients

c

Exploratory statistical analyses, with 95 % CI of the mean difference (month 3 minus baseline) used to estimate level of change

d

Exploratory statistical analyses, with p values based on Wilcoxon signed rank sum test

AS was discontinued in five patients; four patients underwent lung transplantation and sudden death occurred in one patient. Almost all patients (98 %) experienced C1 treatment-emergent adverse event, with the most common ([10 %) being delivery system complications, headache, nasopharyngitis, dyspnea, extremity or jaw pain, flushing, bronchitis, fatigue, and diarrhea. Serious treatment-emergent adverse events included catheter-related infections (n = 6), other delivery system associated complications (n = 12), right ventricular failure (n = 3), and syncope (n = 2) [33].

5 Dosage and Administration In the USA [9], UK [8], and other countries, epoprostenol AS is indicated for the treatment of PAH (WHO Group 1) to improve exercise capacity in patients with WHO/NYHA FC III–IV symptoms. Long-term continuous infusion of epoprostenol AS is administered through a central venous catheter using an ambulatory infusion pump. The US prescribing information recommends starting the long-term infusion of epoprostenol AS at 2 ng/kg/min, with incremental increases of 2 ng/kg/min every C15 min until the maximum hemodynamic benefits or dose-limiting pharmacologic effects occur [9]. In the UK, a short-term doseranging procedure using the same dosage schedule is recommended, after which the long-term infusion rate should be started at 4 ng/kg/min less than the maximum tolerated infusion rate [8]. If the maximum tolerated infusion rate is \5 ng/kg/min, the long-term infusion should be initiated at half the maximum tolerated infusion rate [8]. In general, increases in epoprostenol AS dosage from the initial infusion rate should be expected over time, and may be considered in patients with persistence, recurrence, or deterioration of PAH symptoms [8, 9]. Epoprostenol AS infusion rate reduction may be required because of treatment-related adverse events. These adjustments should be gradual decreases of 2 ng/kg/min every C15 min until the

adverse effects resolve. Abrupt discontinuation or large decreases in the epoprostenol AS infusion rate should be avoided because of the risk of a rebound effect, which could be potentially fatal [8, 9]. After reconstitution and dilution, intravenous epoprostenol AS solution can be immediately used at room temperature (25 °C) for 48 h at concentrations\60,000 ng/mL or for 72 h at concentrations C60,000 ng/mL [8, 9] (Sect. 2). Epoprostenol AS solutions can also be stored for B8 days at 2–8 °C, after which the solutions can be used at room temperature for 24 h (at concentrations C3,000 to \15,000 ng/mL) or 48 h (at concentrations C15,000 ng/ mL). Epoprostenol AS solutions are also stable at higher temperatures (25–40 °C) for 24–48 h depending on concentration. Long-term epoprostenol AS therapy is contraindicated in patients with congestive heart failure associated with left ventricular dysfunction, and in patients who develop pulmonary edema during dosage initiation [8, 9]. Local prescribing information should be consulted for more detailed information, including dosage regimens, administration for special patient populations, warnings and precautions, contraindications, and potential drug interactions.

6 Current Status of Epoprostenol (VeletriÒ, CaripulÒ) in Pulmonary Arterial Hypertension Treatment with epoprostenol GM is complicated by its limited thermal stability in solution [18]. During epoprostenol GM therapy, patients must either use frozen gel packs to maintain the solution at 2–8 °C during administration over 24 h or frequently replace the intravenous solution (B8–12 h) during room temperature administration [18, 20]. In addition to the considerable inconvenience to the patient, the risk of blood stream infections may be increased by the frequent changes of medication cassettes [20]. While all formulations of epoprostenol have comparable pharmacologic profiles [26], epoprostenol AS has improved

Epoprostenol: A Review

thermal stability over epoprostenol GM and epoprostenol AM [20], and has been approved for the long-term treatment of PAH in the USA, UK, and other countries [8, 9]. The extended thermal stability of epoprostenol AS may be attributed to its increased pH in solution, which may also prevent microbial growth (Sect. 2). Reconstituted epoprostenol AS can be immediately administered at room temperature for B72 h, or stored refrigerated for B8 days and administered at room temperature for B48 h (Sect. 5). This provides patients with the option of storage, eliminates the need for frozen gel packs during therapy, and enables continuous epoprostenol AS administration at room temperature, with longer intervals between medication preparation and/or changes [18]. Therefore, these improvements in the epoprostenol AS formulation are expected to result in an increased convenience of long-term intravenous epoprostenol therapy for PAH patients [18]. The prolonged stability of epoprostenol AS at room temperature may also be beneficial for maintaining continuous therapy during emergency circumstances when essential services could be lost and cooling may not be available [31]. Furthermore, epoprostenol AS remains stable after reconstitution and dilution with commercially available sterile water or saline for injection [8, 9], whereas epoprostenol GM preparation requires a proprietary diluent [34]. Two 3-month, phase IIIb studies in adult PAH patients demonstrated continuous effective therapy with intravenous epoprostenol AS after transitioning from stable epoprostenol GM therapy (Sect. 3). In these trials, there were generally no significant changes in the efficacy endpoints at study end (Sect. 3.1). HR-QOL assessment showed a significant increase in the patients’ perception of treatment convenience with epoprostenol AS compared with epoprostenol GM (Sect. 3.2). Epoprostenol AS was also generally well tolerated, with most treatment-emergent adverse events being of mild to moderate intensity and typical of those occurring with intravenous prostacyclin treatment (Sect. 4). These studies were limited by their small patient populations, short duration, and single-arm design [18, 31]. However, preliminary data from an EPITOME-2 open-label extension study demonstrated that epoprostenol AS continued to be generally well tolerated after up to 22 months of treatment [33]. PROSPECT (the Registry to PROSPECTively Describe the Use of Epoprostenol for Injection in Patients with Pulmonary Arterial Hypertension) is a multicenter, observational, US registry to assess the use of all prolonged room temperature-stable epoprostenol (including epoprostenol AS) in [300 PAH patients (reported in an abstract) [35]. Data from the PROSPECT registry will enable comparison of prostacyclin-naı¨ve PAH patients with those patients who transitioned to prolonged room temperature-stable intravenous epoprostenol from epoprostenol GM or prostacyclin analog therapy. This study

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should also facilitate the development of treatment guidelines for patients with PAH who are starting intravenous epoprostenol therapy or transitioning from other prostacyclin therapy [35]. As the PROSPECT registry continues to evaluate real-world data from PAH patients receiving intravenous epoprostenol AS in clinical practice, future results from this ongoing study are anticipated with interest. The current evidence-based treatment algorithm for PAH recommends that patients with WHO FC IV receive initial therapy with continuous intravenous epoprostenol [14, 15]. In patients with an inadequate clinical response to initial monotherapy, sequential combination therapy with the addition of an ERA and/or a PDE-5i is then recommended. In a recent study, the addition of oral sildenafil (a PDE-5i) to background intravenous epoprostenol therapy resulted in improved or maintained 6MWD and WHO FC after 3 years in 33 and 46 % of patients, respectively [36]. Furthermore, initial combination therapy may be considered for patients in WHO FC IV [14]. A retrospective study of PAH patients receiving first-line triple therapy with epoprostenol, bosentan (an ERA), and sildenafil demonstrated significant improvements in exercise capacity, WHO FC, and hemodynamics after 4 months (p \ 0.01 for all parameters), with better than expected 3-year survival estimates compared with baseline [37]. In conclusion, the prolonged thermal stability of epoprostenol AS increases the convenience of long-term intravenous epoprostenol therapy in patients with PAH, which may result in significant improvements in their HRQOL. Therefore, epoprostenol AS is a valuable therapeutic option for adult patients with PAH. Data selection sources: Relevant medical literature (including published and unpublished data) on intravenous epoprostenol was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 29 September 2014], bibliographies from published literature, clinical trial registries/databases, and websites. Additional information was also requested from the company developing the drug. Search terms: Intravenous epoprostenol, IV epoprostenol, Actelion, Veletri, pulmonary arterial hypertension, pulmonary artery hypertension, PAH, pulmonary. Study selection: Studies in patients with pulmonary arterial hypertension who received intravenous epoprostenol. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit. Sarah Greig, Lesley Scott, and Greg Plosker are salaried employees of Adis/Springer.

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