Purpose The pharmacology and pharmacokinetics of a novel formulation of epoprostenol for the treatment of pulmonary arterial hypertension (PAH) are reviewed, with guidance on addressing a number of important safety considerations.
Summary Epoprostenol is a direct vasodilator of the pulmonary and systemic vasculature indicated for improving exercise capacity in patients with PAH. Veletri, a recently approved formulation of epoprostenol for continuous i.v. infusion, offers increased stability relative to other available epoprostenol products. Therefore, the use of Veletri can lessen the therapy burden associated with the other available formulation of the drug by allowing for the advance preparation of infusion pump cassettes (at certain concentrations) and administration at room temperature without the need for cooling with ice packs. Sterility, however, is of concern with outpatient preparation of epoprostenol-containing cassettes stored for the maximum duration according to stability guidelines. All epoprostenol infusions are classified as high-risk therapies due to complex dosing, the drug’s short half-life, and the potential for life-threatening rebound PAH with abrupt discontinuation. Adverse effects reported in ≥10% of participants in clinical trials of Veletri included flushing (58%), headache (49%), nausea or vomiting (32%), hypotension (16%), chest pain (11%), and anxiety, nervousness, or agitation (11%). As with other epoprostenol formulations, the use of Veletri requires an evaluation of health-system medication-use practices to ensure patient safety.
Conclusion Veletri provides an epoprostenol therapy option that reduces some of the inconveniences of the other formulation. Drug stability is dependent on cassette concentrations, which may be limited by sterility concerns with outpatient preparation. Use of this new agent within the health system requires an evaluation of practices to ensure patient safety.
Pulmonary arterial hypertension (PAH) is a chronic progressive disease of the pulmonary vasculature characterized by elevated pulmonary pressures.1,2 Affecting approximately 200,000 people worldwide, PAH once carried a significant mortality risk, with a median survival of about 2.8 years in untreated patients. In recent decades, advancements in the understanding of the disease and the development of directed therapies have improved 1-year survival estimates for treated patients with PAH to 88–91%.2 Various underlying conditions may contribute to the development of PAH and provide the structure for the PAH classification system established by the World Health Organization.1
Three major pathways have been implicated in the pathophysiology of PAH: (1) overexpression of endothelin, (2) reduced nitric oxide production, and (3) reduced prostacyclin production. The sustained pulmonary vasoconstriction and endothelial proliferation characteristic of PAH arise from these pathways. Multiple drug therapies targeting the three pathways are available for the treatment of PAH.3,4 Epoprostenol, treprostinil, and iloprost are synthetic prostacyclins that counter the imbalance of the arachidonic acid metabolites prostacyclin and thromboxane A2 (an imbalance favoring thromboxane A2 and its vasoconstrictive effects) that is seen in PAH. Prostacyclin, in contrast, exhibits antiproliferative, vasodilatory, and antithrombotic properties through the actions of cyclic adenosine monophosphate.3
Epoprostenol (marketed as Flolan, GlaxoSmithKline) received approval from the Food and Drug Administration (FDA) in 1995 as the first directed therapy for the management of PAH. It is indicated for the improvement of exercise capacity in patients with New York Heart Association (NYHA) functional class III or class IV symptoms5; a generic formulation was approved in 2008.6 The efficacy of this synthetic prostacyclin has been assessed in randomized clinical trials evaluating patients with idiopathic PAH, heritable PAH, and PAH associated with connective tissue diseases and congenital heart defects.7–10 In these trials, epoprostenol was found to be more effective in producing substantial and sustained hemodynamic and symptomatic responses, as well as increased exercise capacity, than conventional therapy consisting of anticoagulation, diuretics, calcium-channel blockers, and digoxin. The use of epoprostenol also improved survival among PAH patients, with reported 1-, 3-, and 5-year survival rates of approximately 85%, 63%, and 55%, respectively—markedly better than the corresponding survival rates of 68%, 48%, and 34% reported 30 years ago.11–13
Another formulation of epoprostenol (Veletri), marketed by Actelion Pharmaceuticals US, was approved by FDA in March 2011 for the same indication as Flolan.14 Veletri was approved as a new entity, as its formulation differed from that of Flolan. No issues of concern were identified during chemical and medical reviews of Veletri, and no additional clinical studies were required for U.S. marketing approval.15 This review outlines the properties of Veletri and discusses the differences among the available epoprostenol agents.
Veletri is available in 10-mL vials containing epoprostenol 1.5 mg, arginine 50 mg, and mannitol 50 mg; sodium hydroxide is included to maintain a pH of >11 when the formulation is reconstituted.14 In contrast, Flolan and its generic formulation contain glycine 3.76 mg instead of arginine, and the pH of reconstituted solutions is 10.2–10.8.5 Decreases in pH are primarily responsible for decreases in epoprostenol stability.
Epoprostenol has a small volume of distribution (357 mL/kg) after i.v. administration and a short elimination half-life (approximately 6 minutes), with steady-state concentrations achieved within 15 minutes.5,14 The agent is rapidly hydrolyzed and enzymatically degraded into 2 weakly active metabolites—6-keto-prostaglandin F1α (PGF1α and 6,15-diketo-13, 14-dihydro-PGF1α—and 14 minor metabolites. Eighty-two percent of the drug is renally excreted, with 4% eliminated through the fecal route. Once an epoprostenol infusion is discontinued, its therapeutic effects dissipate within 2–3 minutes.
The dosage of epoprostenol is guided by patient response and tolerability. The labeling of the Flolan and Veletri formulations recommends initiating therapy at 2 ng/kg/min, with upward adjustments of 2 ng/kg/min after 15 minutes or longer until dose-limiting adverse effects are observed.5,14 No specific dosage limit has been identified, but optimal dosage when epoprostenol is used as a monotherapy ranges from 25 to 40 ng/kg/min.11 Further dosage increases are to be calculated according to the patient’s initial dosing weight regardless of subsequent weight fluctuations, as patients require continual dosage increases due to the development of tachyphylaxis. The calculation of dosage adjustments based on the initial dosing weight prevents overdosing or underdosing due to weight fluctuations.5,7,14 Flolan and Veletri are of equal potency, but experience with the interchange of the two agents has not been reported.15
The adverse effects of epoprostenol are mainly observed during upward dosage adjustments and serve as a measure of drug tolerability. In clinical trials, common adverse effects during initial therapy and dose escalation included the following (rates of occurrence are given in parentheses): flushing (58%); headache (49%); nausea or vomiting (32%); hypotension (16%); anxiety, nervousness, or agitation (11%); chest pain (11%); dizziness (8%); and bradycardia (5%). Long-term epoprostenol administration has been linked to increased rates of jaw pain (54%), myalgias (44%), muscle pain (35%), tachycardia (35%), and chills or flulike symptoms (25%).5,14
Due to the long-term venous access required for the delivery of epoprostenol, there is a risk of infusion-line infections (an infection rate of 21% has been reported5,14). Fatal rebound PAH can occur if epoprostenol is abruptly discontinued. Patients experiencing rebound PAH may have asthenia, dizziness, and dyspnea as presenting symptoms. Abrupt therapy cessation and significant decreases in the infusion rate should be avoided, with a backup infusion kept readily available in case of equipment malfunction. When reintroducing epoprostenol is not feasible, acute management should focus on reversing the loss of pulmonary vasodilation by providing optimized ventilation and supplemental pulmonary vasodilators.16,17
Administration and stability
All epoprostenol formulations are delivered through a dedicated central line using an ambulatory infusion pump with medication delivery cassettes.5,14 The pump must be lightweight, capable of measuring doses in 2-ng/kg/min increments, accurate to within ±6% of the programmed rate, and positive pressure driven; it must also provide alarm signals when occlusions occur, at the end of the infusion, and when the batteries are low. If an ambulatory infusion pump is not available, administration through conventional infusion pumps may be performed provided that the above requirements are met. Epoprostenol can be prepared in 100-mL i.v. infusion bags, with administration reported in terms of milliliters per hour.
Flolan and generic epoprostenol must be reconstituted with the provided sterile diluent.5 Veletri allows for reconstitution with either sterile water for injection or 0.9% sodium chloride injection, but it cannot be reconstituted using the diluent provided with Flolan.14 Vials of reconstituted Flolan and generic epoprostenol can be kept in refrigerated storage or administered with ice packs (or a combination of the two methods used) for a total of 48 hours.5 Vials of Veletri are viable for five days after reconstitution if refrigerated and for up to 48 hours if maintained at room temperature.14 Prepared Flolan and generic epoprostenol cassettes require refrigerated storage and the use of cooling packs that should be changed every 12 hours during administration.5 Veletri stability, however, is concentration and temperature dependent. The maximum duration of infusion increases as the concentration of the solution increases. Stability, however, decreases as the time of refrigerated storage increases (Table 1).14 For example, if the final concentration is ≥12,000 but <30,000 ng/mL and the cassette is refrigerated at 2–8 °C for 24 hours as a backup, the solution can be infused at room temperature over 24 hours. If the cassette contains a concentration of ≥30,000 ng/mL and is refrigerated for seven days, it can also be infused over 24 hours at room temperature. As an exception, cassettes prepared from stored vials of reconstituted Veletri at concentrations of <15,000 ng/mL should be changed at least every 12 hours, and cassettes containing concentrations of >15,000 ng/mL should be changed every 24 hours.
Concerns over sterility arise with the long-term storage of prepared Veletri cassettes. Chapter 797 of The United States Pharmacopeia (USP) defines beyond-use dating for sterile product preparations based on environmental risks for pathogen growth.18 When prepared within a cleanroom environment satisfying USP chapter 797 requirements, epoprostenol cassettes are classified as low-risk preparations, with beyond-use dating limited by medication stability; however, cassettes prepared in ambulatory care settings (i.e., outside a controlled environment) are classified as high-risk preparations, which limits beyond-use dating to three days (with refrigeration) despite the demonstrated seven-day stability of properly refrigerated Veletri cassettes at concentrations of ≥9000 ng/mL. Patient education on these limitations, as well as proper aseptic technique, can reduce the risk of contamination and line infections.
Considerations in drug selection
Epoprostenol was the first drug demonstrated to produce long-term improvements in hemodynamics, exercise capacity, and survival in patients with PAH. Treprostinil, a newer prostacyclin, produces the same pharmacologic effects as epoprostenol; its half-life, however, is considerably longer (two to four hours), and the medication is stable at a neutral pH at room temperature, allowing for continuous subcutaneous administration through a self-inserted subcutaneous catheter.19 Treprostinil was approved for the treatment of patients with PAH who have NYHA class II–IV symptoms on the basis of two concurrent controlled clinical trials involving patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts.19–21 In those trials, treprostinil therapy improved hemodynamics and reduced PAH symptoms and did not pose safety concerns. However, no reductions in mortality or the need for lung transplantation and no change in the time to clinical worsening of PAH were observed with the use of treprostinil in comparison to conventional treatment. Trials of epoprostenol versus treprostinil therapy for PAH demonstrated no comparative advantage for either agent with regard to hemodynamic parameters, change in functional classification, or the results of a six-minute walking test.22,23 Treprostinil is a viable treatment option for patients with class II–IV symptoms, but there is stronger evidence to support the use of epoprostenol in patients with class IV symptoms, given the lack of a demonstrated mortality benefit with treprostinil use.11–13,19
Considerations in the selection of an epoprostenol formulation should focus on patient cost and convenience. The average wholesale prices (AWPs) of equivalent vials of Flolan and Veletri are comparable ($54.17 and $45.50, respectively, for vials containing 1.5 mg of epoprostenol).24 A generic formulation of Flolan is available at an AWP of $33.53.
The ice packs required during the administration of Flolan and generic epoprostenol may be bothersome to patients. Veletri offers the convenience of administration at room temperature and allows for advance preparation and storage of cassettes. Additional data on the use of Veletri will be available through the PROSPECT registry.25 Actelion Pharmaceuticals launched this multicenter, observational, U.S.-based registry to prospectively collect information on the demographics and disease characteristics of patients with PAH receiving Veletri therapy. Information on dosing regimens and dosage adjustments in approximately 300 patients in up to 60 U.S. centers will be gathered. PROSPECT data collection began in the second quarter of 2010 and closed in the second quarter of 2011.
The Institute for Safe Medication Practices has identified epoprostenol as a “high-alert medication” (i.e., one that can pose a heightened risk of significant patient harm if used in error).26 Hospitals and health systems must evaluate epoprostenol use to safeguard patients from potential errors during all steps in the medication-use process. Orders for epoprostenol cassettes should be verified for appropriateness, and dose calculations should be reviewed for accuracy. If complete medication records are lacking when patients receiving epoprostenol therapy as outpatients are admitted to the hospital, outpatient medication provider companies are available for dose verification. Technical staff will require training on the calculation of epoprostenol concentrations and proper cassette preparation and storage. Nurses should be educated on dose-limiting adverse effects and ambulatory pump programming (for dosage-adjustment purposes) when epoprostenol therapy is initiated.
Other medication safety considerations include ensuring the availability of a backup cassette at the time of hospital admission and at every patient transfer, changing cassettes at a standard time to reduce the potential for errors, and avoiding tests or procedures that require the patient to be away from trained staff during a cassette change. All staff should be educated on the importance of continuing epoprostenol therapy despite emergency situations, imaging tests, or procedures, as well as whom to contact for an emergency cassette change. These measures can reduce the likelihood of adverse effects due to abrupt discontinuation and help ensure effective inpatient care for patients requiring treatment with epoprostenol.
On a patient’s discharge from the hospital, patient education is necessary to help ensure safety at home. Instruction should focus on sterile technique and dose calculation for cassette preparation and administration requirements to maintain drug stability. The need for regular follow-up care should be discussed with the patient, and contact information for outpatient medication provider companies should be provided.
Veletri provides an epoprostenol therapy option that reduces some of the inconveniences of the other formulation. Drug stability is dependent on cassette concentrations, which may be limited by sterility concerns with outpatient preparation. Use of this new agent within the health system requires an evaluation of practices to ensure patient safety.
The authors have declared no potential conflicts of interest.
The Clinical Consultation section features articles that provide brief advice on how to handle specific drug therapy problems. All articles are based on a systematic review of the literature. The assistance of ASHP’s Section of Clinical Specialists and Scientists in soliciting Clinical Consultation submissions is acknowledged. Unsolicited submissions are also welcome.
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