Epoprostenol (DB01240): A Comprehensive Pharmacological and Clinical Monograph

1.0 Introduction and Drug Identification

1.1 Overview of Epoprostenol as a Therapeutic Agent

Epoprostenol is a synthetic preparation of prostacyclin (PGI2​), a naturally occurring prostaglandin that functions as a potent vasodilator and a powerful inhibitor of platelet aggregation.[1] Identified as a small molecule drug with the DrugBank accession number DB01240, it has become a cornerstone in the management of severe cardiovascular disease, particularly pulmonary arterial hypertension (PAH).[1]

The therapeutic importance of Epoprostenol is rooted in its landmark regulatory approval. In 1995, it became the first therapy sanctioned by the U.S. Food and Drug Administration (FDA) for the treatment of PAH, a rare and progressive disease.[5] Prior to its introduction, PAH was characterized by a grim prognosis, with a median survival of only 2.8 years from diagnosis.[8] The approval of Epoprostenol, supported by compelling clinical trial data and patient testimony, fundamentally transformed the natural history of the disease, converting it from a rapidly fatal condition into a chronic, manageable illness.[7] This milestone not only provided a life-saving treatment but also validated the prostacyclin pathway as a critical therapeutic target. The success of Epoprostenol spurred the development of an entire class of prostacyclin analogs and related therapies, profoundly altering the therapeutic landscape for patients with pulmonary hypertension.[8]

1.2 Chemical and Physical Properties

Epoprostenol is a complex eicosanoid with a well-defined chemical structure and distinct physical properties. It is supplied commercially as a sterile, white to off-white lyophilized powder that requires reconstitution prior to intravenous administration.[2] The key chemical and identifying properties of Epoprostenol are summarized in Table 1.

Table 1: Epoprostenol Drug Identification Summary

Attribute	Value	Source(s)
Common Name	Epoprostenol	4
IUPAC Name	(5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid	2
DrugBank ID	DB01240	1
CAS Number	35121-78-9	10
ATC Code	B01AC09	4
Molecular Formula	C20​H32​O5​	1
Molecular Formula (Sodium Salt)	C20​H31​NaO5​	2
Average Molecular Weight	352.47 g/mol	1
Molecular Weight (Sodium Salt)	374.45 g/mol	2
Synonyms	Prostacyclin, PGI₂, PGX, U-53,217, Flolan, Veletri, ACT-385781A	1

1.3 Regulatory History and Formulations (Flolan vs. Veletri)

Epoprostenol was first approved by the FDA in December 1995, following a rigorous review process that included public advisory committee hearings where patient experiences provided compelling evidence of its efficacy.[5] The originator brand, Flolan®, is manufactured by GlaxoSmithKline.[13] Subsequently, another formulation, Veletri®, and generic versions of epoprostenol sodium have become available.[3]

While these formulations contain the same active pharmaceutical ingredient (epoprostenol sodium), they differ significantly in their excipients and reconstitution requirements, which has major practical implications for patient care.

• Flolan®: This formulation contains glycine, sodium chloride, and mannitol as excipients. A critical aspect of its use is the requirement for reconstitution with a proprietary, highly alkaline (pH 12) STERILE DILUENT for FLOLAN. This specialized diluent is necessary to raise the pH of the final solution to between 10.2 and 10.8, which is essential for maintaining the chemical stability of the epoprostenol molecule.[2]
• Veletri®: This formulation was designed to improve stability and simplify preparation. It substitutes L-glycine with L-arginine as a key excipient, which acts as a buffering agent to increase the pH of the reconstituted solution intrinsically.[15] Consequently, Veletri® does not require a special diluent and can be reconstituted with standard Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.[6]

This distinction in formulation represents a significant advancement in drug delivery. The elimination of the proprietary diluent for Veletri® simplifies the complex daily mixing process that patients or their caregivers must perform. This can reduce the potential for preparation errors and lessen the logistical burden of therapy. Pharmacokinetic studies have confirmed that despite these formulation differences, Veletri® and Flolan® are bioequivalent, demonstrating comparable plasma concentration curves of their primary metabolites and similar hemodynamic and safety profiles.[15] This ensures that the simplification in preparation does not come at the cost of clinical efficacy, representing a meaningful improvement in the therapeutic application of epoprostenol.

2.0 Clinical Pharmacology

2.1 Mechanism of Action: The Prostacyclin Pathway

Epoprostenol is a synthetic analog of the endogenous prostaglandin PGI2​, a powerful signaling molecule derived from arachidonic acid that plays a crucial role in maintaining vascular homeostasis.[1] The entirety of its pharmacological effects stems from a single, specific molecular interaction: the binding and activation of the G protein-coupled prostacyclin receptor, also known as the IP receptor.[1] These receptors are prominently expressed on the surface of vascular smooth muscle cells and platelets.

Upon binding to the IP receptor, Epoprostenol triggers a conformational change that activates the associated enzyme, adenylate cyclase. This enzyme then catalyzes the intracellular conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP).[1] The resulting elevation in intracellular cAMP concentration is the pivotal event that initiates distinct downstream signaling cascades in different cell types, leading to Epoprostenol's dual therapeutic actions of vasodilation and platelet inhibition.

2.1.1 Vasodilatory Effects on Pulmonary and Systemic Vasculature

In vascular smooth muscle cells, the increase in intracellular cAMP leads to the activation of protein kinase A (PKA).[1] Activated PKA then phosphorylates and inhibits myosin light-chain kinase (MLCK). MLCK is essential for the phosphorylation of myosin, a key step in smooth muscle contraction. By inhibiting MLCK, Epoprostenol effectively uncouples the contractile apparatus, leading to a reduction in intracellular calcium levels and profound smooth muscle relaxation.[1] This mechanism results in potent, direct vasodilation of both the pulmonary and systemic arterial vascular beds, which is the basis for its use in lowering blood pressure in the lungs and heart.[1] In addition to this direct effect, Epoprostenol may also exert indirect vasodilatory actions by inhibiting the production of endothelin-1, a potent endogenous vasoconstrictor.[8]

2.1.2 Inhibition of Platelet Aggregation

Within platelets, the cAMP-mediated signaling cascade serves to powerfully inhibit their activation and aggregation. The elevated cAMP levels prevent the rise in intracellular calcium that is typically induced by pro-thrombotic agents like thromboxane A2​ (TXA2​).[1] This inhibition of calcium signaling prevents the release of pro-aggregatory granules from the platelet and blocks the conformational change and expression of the glycoprotein IIb/IIIa receptor on the platelet surface.[17] Since the GPIIb/IIIa receptor is the final common pathway for platelet aggregation (by binding fibrinogen), its inhibition effectively prevents the formation of a platelet plug.[17]

This mechanism places Epoprostenol (PGI2​) and TXA2​ in direct physiological antagonism. While PGI2​ promotes vasodilation and inhibits platelet function, TXA2​ promotes vasoconstriction and platelet aggregation.[5] The pathophysiology of PAH is characterized by a critical disruption of this homeostatic balance, with studies showing depressed production of endogenous

PGI2​ and increased levels of TXA2​.[8] This imbalance creates a pro-constrictive and pro-thrombotic state within the pulmonary vasculature. Therefore, Epoprostenol therapy functions not merely as a generic vasodilator but as a targeted replacement therapy designed to restore this crucial balance and counteract the specific pathological drivers of the disease.

2.1.3 Antiproliferative and Anti-inflammatory Properties

Beyond its well-established vasodilatory and antiplatelet effects, Epoprostenol exhibits additional biological activities that may contribute to its long-term efficacy in PAH. These include antiproliferative, anti-inflammatory, and anti-mitogenic properties.[8] The vascular remodeling seen in PAH involves the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). In vitro studies have demonstrated that high-dose Epoprostenol can induce apoptosis (programmed cell death) in these cells, an effect mediated through the IP receptor and the upregulation of Fas ligand.[21] These cytoprotective and anti-remodeling actions suggest that Epoprostenol's therapeutic benefits may extend beyond immediate hemodynamic improvements. By potentially reversing the underlying structural changes in the pulmonary vasculature, these properties could help explain the unique mortality benefit observed with Epoprostenol compared to other therapies that provide only vasodilation.

2.2 Pharmacodynamics: Hemodynamic and Systemic Effects

The pharmacological mechanisms of Epoprostenol translate into significant and measurable pharmacodynamic effects. In patients with PAH, continuous intravenous infusion produces marked improvements in cardiopulmonary hemodynamics. It causes dose-related decreases in pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR), which are the primary indicators of afterload on the right ventricle.[2] This reduction in right ventricular afterload, along with a reduction in left ventricular afterload from systemic vasodilation, leads to clinically significant increases in cardiac output (CO) and stroke volume (SV).[1] The effect on mean pulmonary artery pressure (PAPm) is often more variable and less pronounced.[2]

The systemic vasodilatory effects also influence heart rate in a dose-dependent manner. At very low, sub-therapeutic doses, a vagally mediated bradycardia may be observed.[1] However, at the higher doses used for chronic treatment, the more common effect is a reflex tachycardia, which occurs as a compensatory response to systemic vasodilation and a decrease in systemic blood pressure.[1] No major effects on cardiac conduction have been observed.[1]

3.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

3.1 Administration and Bioavailability

Epoprostenol is formulated exclusively for intravenous administration and is delivered via a continuous infusion.[2] Because the drug is introduced directly into the systemic circulation, its bioavailability is, by definition, 100%, and the pharmacokinetic phase of absorption is not applicable.[24] Steady-state plasma concentrations are typically reached within 15 minutes of initiating or changing an infusion rate.[2]

3.2 Distribution, Metabolism, and Elimination

Following administration, Epoprostenol is rapidly processed by the body.

• Distribution: Animal studies have indicated a small volume of distribution of approximately 357 mL/kg, suggesting that the drug is primarily confined to the vascular compartment.[2]
• Metabolism: Epoprostenol is characterized by its extreme chemical instability at physiological pH, leading to extensive and rapid metabolism through two main pathways.[2]

1. Spontaneous Hydrolysis: In the blood, it undergoes rapid, non-enzymatic degradation through hydration to form its primary metabolite, 6-keto-prostaglandin F1α​ (6-keto-PGF1α​).[1]
2. Enzymatic Degradation: Epoprostenol is also a substrate for enzymatic degradation, which forms a second primary metabolite, 6,15-diketo-13,14-dihydro-prostaglandin F1α​.[1]

Both of these primary metabolites possess pharmacological activity that is several orders of magnitude less than that of the parent Epoprostenol compound.[1] Further metabolism is extensive, with at least 14 additional minor metabolites having been isolated from urine, underscoring the comprehensive degradation of the drug in humans.[1]

• Excretion: The metabolites of Epoprostenol are primarily eliminated from the body via the kidneys. In studies using radiolabeled Epoprostenol in humans, 82% of the radioactivity was recovered in the urine and 4% in the feces over a one-week period.[25]

3.3 Pharmacokinetic Profile and Half-Life Implications

The single most defining pharmacokinetic characteristic of Epoprostenol is its extremely short biological half-life. The in vitro half-life in human blood at 37°C and a pH of 7.4 is approximately 6 minutes; consequently, the in vivo half-life in humans is expected to be no greater than this duration.[1] This rapid elimination is a direct result of its high clearance rate and inherent chemical instability.[2]

This ultra-short half-life is the central property that dictates the entire therapeutic paradigm of Epoprostenol, creating a unique and challenging balance of risk and benefit.

• First, the rapid elimination makes continuous intravenous infusion the only viable method of administration to maintain stable, therapeutic plasma concentrations.[6]
• Second, this property provides a significant clinical advantage in a controlled setting. It allows for precise and rapid dose titration; clinicians can quickly increase the infusion rate to achieve a desired hemodynamic effect or, conversely, decrease the rate to manage dose-limiting side effects like hypotension or headache, with the physiological response occurring within minutes.[5]
• Third, and most critically, this same property creates the drug's most severe risk. Any interruption in drug delivery—whether from a pump malfunction, a dislodged catheter, or an empty drug cassette—causes plasma concentrations to plummet to sub-therapeutic levels almost immediately. This abrupt withdrawal of vasodilatory and antiplatelet effects leads to acute and potentially fatal rebound pulmonary hypertension, characterized by severe dyspnea, hypoxia, and hemodynamic collapse.[20]

This high-stakes therapeutic profile has necessitated the development of a complex support ecosystem for Epoprostenol therapy. It requires the use of specialized, highly reliable ambulatory infusion pumps with multiple safety alarms, the surgical placement of a permanent central venous catheter, and rigorous, comprehensive education for patients and their caregivers on sterile technique, medication preparation, and emergency procedures. The absolute requirement for patients to have immediate access to a backup pump and medication at all times is a direct and unavoidable consequence of this fundamental pharmacokinetic property.[6]

4.0 Approved Clinical Indications: Pulmonary Arterial Hypertension (PAH)

4.1 Pathophysiological Rationale for Use in PAH

Pulmonary arterial hypertension is a disease driven by a complex interplay of vasoconstriction, in-situ thrombosis, and proliferative remodeling of the small pulmonary arteries.[21] A key element in its pathogenesis is a profound imbalance in endogenous vasoactive mediators. Lung tissue from patients with PAH exhibits decreased expression of prostacyclin synthase, the enzyme responsible for producing the vasodilator

PGI2​, and a corresponding increase in the production of the vasoconstrictor and pro-aggregatory agent thromboxane A2​.[8] This pathological state creates a local environment within the pulmonary vasculature that favors constriction, clotting, and abnormal cell growth. Epoprostenol therapy is rationally designed to counteract this deficiency. By acting as a

PGI2​ replacement, it directly targets multiple pathogenic pathways of the disease, aiming to restore a more balanced, vasodilated, and anti-thrombotic state.[21]

4.2 Efficacy in WHO Group 1 PAH (NYHA Class III-IV)

The FDA-approved indication for Epoprostenol (marketed as Flolan®, Veletri®, and generic epoprostenol sodium) is the long-term intravenous treatment of pulmonary arterial hypertension (WHO Group 1) to improve exercise capacity.[3] The pivotal clinical trials that established its efficacy predominantly enrolled patients with severe disease, specifically those with New York Heart Association (NYHA) Functional Class III or Class IV symptoms, who had not responded adequately to conventional therapy.[1]

The approved indication covers several etiologies within WHO Group 1, including:

• Idiopathic PAH (IPAH) [8]
• Heritable PAH (HPAH) [8]
• PAH associated with connective tissue diseases (PAH-CTD), particularly the scleroderma spectrum of disease [1]

4.3 Impact on Exercise Capacity, Hemodynamics, and Survival

Clinical trials have robustly demonstrated the benefits of Epoprostenol therapy across multiple key endpoints.

• Exercise Capacity: A landmark 12-week, randomized controlled trial showed that patients receiving continuous intravenous Epoprostenol in addition to conventional therapy had a statistically significant improvement in exercise capacity, as measured by the 6-minute walk test, compared to patients receiving conventional therapy alone.[2]
• Hemodynamics: Treatment consistently leads to substantial improvements in cardiopulmonary hemodynamics. As summarized in Table 2, studies have documented marked reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), along with increases in cardiac output.[8] High-dose therapy has been associated with particularly profound hemodynamic improvements.[21]
• Survival: Most importantly, Epoprostenol remains the only therapy in its class to have demonstrated a statistically significant reduction in mortality in patients with IPAH in a randomized controlled trial.[8] This unique survival benefit solidifies its position as the gold-standard treatment and first-line choice for patients with the most severe forms of PAH.

Table 2: Summary of Hemodynamic Effects in PAH from Select Studies

Study	Patients (n)	Mean Epoprostenol Dose (ng/kg/min)	Duration (months)	Parameter	Baseline	Post-Treatment	Reduction (%)
McLaughlin et al.	27	40±15	16.7±5.2	mPAP (mmHg)	67	52	-22%
				PVR (Wood units)	16.7	7.9	-53%
Sitbon et al.	107	21±7	12	mPAP (mmHg)	68	60	-12%
				PVR (Wood units)	37.3	25.4	-32%
Akagi et al. (High-Dose)	14	107±40	45±20	mPAP (mmHg)	66	47	-30%
				PVR (Wood units)	21.6	6.9	-68%
Data adapted from sources 23 and.21

5.0 Off-Label and Investigational Uses

While its primary approval is for chronic PAH, the potent and rapid pharmacological effects of Epoprostenol have led to its adoption in critical care settings for off-label indications, primarily via the inhaled route of administration.

5.1 Inhaled Epoprostenol for Acute Respiratory Distress Syndrome (ARDS)

Inhaled (nebulized) Epoprostenol is used as an off-label adjunctive therapy for patients with ARDS, especially those who exhibit refractory hypoxemia complicated by acute pulmonary hypertension and right ventricular dysfunction.[23] The therapeutic rationale for inhaled administration is fundamentally different from that of intravenous use. When delivered directly to the lungs, Epoprostenol acts as a selective pulmonary vasodilator. It is preferentially distributed to well-ventilated alveoli, where it causes localized vasodilation.[32] This effect improves ventilation-perfusion (V/Q) matching by shunting pulmonary blood flow away from poorly ventilated, edematous, or consolidated areas of the lung and towards regions that are actively participating in gas exchange.[23]

A key advantage of this approach is the minimization of systemic absorption, which largely avoids the systemic hypotension that is a major dose-limiting side effect of intravenous Epoprostenol.[23] While inhaled Epoprostenol has been shown to improve oxygenation and reduce mean pulmonary artery pressure in this patient population, robust data from large clinical trials demonstrating a definitive benefit in clinical outcomes, such as a reduction in mortality or duration of mechanical ventilation, are still lacking.[23]

5.2 Perioperative Right Ventricular (RV) Support in Major Cardiac Surgery

A significant off-label application for inhaled Epoprostenol (iEPO) is in the prevention and management of acute postoperative right ventricular failure (RVF). RVF is a devastating complication and a leading driver of morbidity and mortality following major cardiac surgeries for advanced heart failure, such as orthotopic heart transplantation (OHT) and left ventricular assist device (LVAD) implantation.[34]

5.2.1 Rationale and Hemodynamic Impact

Following these procedures, the right ventricle is abruptly subjected to significant changes in loading conditions. Inhaled Epoprostenol is administered perioperatively to reduce RV afterload by selectively dilating the pulmonary vasculature. This unloading of the right ventricle helps it adapt to the new circulatory physiology, augmenting RV stroke volume and improving overall systemic cardiac output without the deleterious effect of systemic hypotension that would be caused by an intravenous vasodilator.[34]

5.2.2 Comparative Efficacy with Inhaled Nitric Oxide (iNO)

For many years, inhaled nitric oxide (iNO) was considered the prototypical agent for this indication.[32] Both agents are selective pulmonary vasodilators, but they achieve this effect through distinct biochemical pathways: iNO activates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP), whereas iEPO activates adenylate cyclase to increase cAMP.[32]

The clinical equivalence of these two agents was tested in the INSPIRE-FLO trial, a large, double-blind, randomized controlled trial. The study compared iEPO to iNO for RV support in patients undergoing OHT or LVAD implantation. The results demonstrated that treatment with iEPO was associated with similar risks for the development of acute postoperative RVF and other key secondary outcomes (e.g., duration of mechanical ventilation, ICU length of stay, mortality) when compared to treatment with iNO.[34]

The finding of clinical equivalence between iEPO and iNO has profound clinical and economic implications. Given that iEPO offers several logistical and financial advantages—including significantly lower cost, easier administration via a standard ventilator nebulizer (as opposed to specialized delivery systems for iNO), and the absence of risk for methemoglobinemia (a potential side effect of iNO)—it stands as a highly attractive, evidence-based alternative.[23] This evidence supports a potential shift in the standard of care, allowing medical centers to achieve substantial cost savings and simplify clinical protocols in the operating room and ICU without compromising patient safety or outcomes.

6.0 Dosage, Administration, and Patient Management

The administration of Epoprostenol is a complex process that demands meticulous attention to detail from both healthcare providers and patients.

6.1 Formulations and Reconstitution Procedures

Epoprostenol is supplied as a lyophilized powder in single-use vials containing either 0.5 mg or 1.5 mg of the active drug.[2] Strict aseptic technique is imperative during preparation.

• Flolan® Reconstitution: Must be reconstituted only with the specific pH 12 STERILE DILUENT for FLOLAN provided by the manufacturer.[2]
• Veletri® Reconstitution: May be reconstituted with 5 mL of either standard Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP.[6]

The stability of the reconstituted solution is highly dependent on the formulation and storage conditions. Veletri®'s formulation, which uses L-arginine as a stabilizing excipient, provides a significant advantage in this regard.[15] While reconstituted Flolan® must typically be kept cold with ice packs and used within 48 hours, certain concentrations of reconstituted Veletri® are stable under refrigeration for up to 8 days.[14] This extended stability is a direct result of the formulation chemistry and has a direct, positive impact on patient quality of life by reducing the frequency of the burdensome daily mixing ritual, allowing for the preparation of several days' worth of medication at one time.

6.2 Intravenous Administration Protocol

Epoprostenol is administered as a continuous intravenous infusion through a surgically placed central venous catheter, connected to a portable ambulatory infusion pump.[6] Bolus injections are strictly contraindicated due to the risk of severe hemodynamic effects.[28] The dosing protocol is highly individualized and divided into distinct phases, as summarized in Table 3.

6.2.1 Dose Initiation and Titration

Initiation of Epoprostenol therapy must be performed in a hospital setting with the capacity for intensive hemodynamic monitoring and emergency care.[20] The initial infusion rate is typically started at 2 ng/kg/min.[29] The dose is then carefully titrated upwards in increments of 1 to 2 ng/kg/min at intervals of at least 15 minutes. This gradual escalation continues until either the patient achieves the desired clinical response or experiences dose-limiting pharmacological effects, such as headache, nausea, or hypotension.[27]

6.2.2 Chronic Dosing and Adjustments

Once a stable and tolerated dose is established, the patient is discharged on a chronic infusion. The dose of Epoprostenol is not static; as the disease progresses, most patients require gradual dose increases over time to maintain efficacy.[27] It is not uncommon for patients to be on chronic doses of 40-70 ng/kg/min, and some high-dose protocols have used doses exceeding 100 ng/kg/min.[21] Adjustments are made based on clinical symptoms. Dose increases are typically made in 1-2 ng/kg/min increments.[27] If adverse effects occur, the dose should be decreased gradually in 2 ng/kg/min decrements until the side effects resolve.[27]

Table 3: Dosing and Titration Guide for Intravenous Epoprostenol

Phase of Therapy	Parameter	Guideline	Source(s)
Dose Initiation	Setting	Hospital with intensive monitoring capabilities	20
	Starting Dose	2 ng/kg/min (or lower if not tolerated)	27
	Titration Increment	1-2 ng/kg/min	27
	Titration Interval	Every 15 minutes or longer	27
	Endpoint	Desired clinical response or onset of dose-limiting adverse effects	38
Chronic Dose Adjustment (Increase)	Rationale	Persistence or recurrence of PAH symptoms	27
	Increment	1-2 ng/kg/min at intervals of ≥15 minutes	27
Management of Adverse Effects (Decrease)	Rationale	Onset of dose-limiting pharmacologic events	27
	Decrement	2 ng/kg/min every 15 minutes or longer until effects resolve	27
All Phases	Monitoring	Frequent monitoring of standing and supine blood pressure and heart rate	27
	Critical Precaution	Avoid abrupt withdrawal or sudden large dose reductions	27

6.3 Patient and Equipment Management Considerations

Successful long-term therapy with Epoprostenol requires a substantial commitment from the patient and their support system.[31] Management involves:

• Infusion Pump: The ambulatory pump must be small, lightweight, highly accurate (to ±6% of the programmed rate), and equipped with multiple safety alarms (e.g., occlusion, low battery, end-of-infusion). It must be capable of adjusting infusion rates in small, 2 ng/kg/min increments.[27]
• Patient Education: Patients and caregivers must be extensively trained in sterile medication preparation, operation of the infusion pump, and meticulous care of the central venous catheter to prevent life-threatening infections.[19]
• Emergency Preparedness: Due to the fatal risk of infusion interruption, patients must have immediate access to a backup infusion pump, spare infusion sets, and extra medication at all times.[20]

7.0 Safety Profile: Adverse Reactions and Contraindications

The safety profile of Epoprostenol is largely defined by the predictable consequences of its potent pharmacology and the complexities of its delivery system.

7.1 Common and Serious Adverse Reactions

Many of the most common adverse reactions are direct extensions of Epoprostenol's powerful vasodilatory properties.[5]

• Adverse Reactions During Dose Initiation and Escalation: These are frequent and often dose-limiting. They include nausea, vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia or tachycardia, dyspnea, and abdominal pain.[16]
• Adverse Reactions During Chronic Dosing: While some initial side effects may lessen over time, others persist. The most common chronic adverse events include jaw pain (a characteristic side effect, often occurring with the first bite of a meal), headache, flushing, diarrhea, nausea, and musculoskeletal pain.[6]

In addition to these mechanism-based effects, several serious adverse reactions can occur:

• Pulmonary Edema: The development of pulmonary edema during dose initiation is a critical safety signal. It may indicate the presence of underlying pulmonary veno-occlusive disease or severe left ventricular systolic dysfunction. If this occurs, Epoprostenol therapy must be discontinued immediately and not readministered.[20]
• Hemorrhagic Complications: Epoprostenol's potent antiplatelet activity increases the risk of bleeding. This risk is elevated in patients with other risk factors for bleeding or those receiving concomitant anticoagulant or antiplatelet therapies.[14]
• Catheter-Related Bloodstream Infections (CRBSI): The requirement for a long-term indwelling central venous catheter places patients at significant risk for local site infections and life-threatening sepsis.[6]

A summary of common adverse reactions is provided in Table 4.

Table 4: Adverse Reactions by Frequency and System Organ Class

System Organ Class	Very Common (≥10%)	Common (1% to <10%)
Cardiovascular	Flushing, Tachycardia, Hypotension, Palpitations, Chest Pain	Bradycardia, Myocardial Infarction, Shock
Gastrointestinal	Nausea, Vomiting, Diarrhea, Esophageal Reflux	Abdominal Pain, Dyspepsia, Ascites
Musculoskeletal	Jaw Pain, Arthralgia, Myalgia, Back Pain, Musculoskeletal Pain	Leg Cramps
Nervous System	Headache, Dizziness, Anxiety/Nervousness, Agitation	Tremor, Paresthesia, Insomnia
General/Systemic	Flu-like Symptoms, Chills, Fever, Pain, Asthenia	Sepsis, Procedural Complications
Dermatologic	Skin Rash/Eczema, Sweating, Skin Ulcer	Cellulitis
Hematologic	N/A	Bleeding, Thrombocytopenia
Data compiled from sources.16

7.2 Key Warnings and Precautions

• Rebound Pulmonary Hypertension following Abrupt Withdrawal: As detailed previously, abrupt cessation or large, sudden reductions in the Epoprostenol infusion rate can be fatal. This is the most critical warning associated with the drug's use.[6]
• Vasodilation: The potent vasodilatory effects require regular monitoring of systemic blood pressure, especially during therapy initiation and after any dose change.[20]
• Increased Risk for Bleeding: Caution is required in patients with underlying bleeding risks.[28]

7.3 Contraindications and Management of Overdose

Epoprostenol is specifically contraindicated in the following situations:

1. Congestive heart failure due to severe left ventricular systolic dysfunction (HFrEF): In this condition, the potent systemic vasodilation caused by Epoprostenol can lead to a critical reduction in cardiac filling and output, and has been associated with increased mortality.[14]
2. Development of pulmonary edema during dose initiation: As this may unmask underlying conditions where the drug is harmful.[14]
3. Known hypersensitivity to Epoprostenol or any of its structural components.[20]

Notably, there are no black box warnings reported in the FDA labeling for Epoprostenol.[46]

Overdose: Symptoms of overdose are predictable extensions of the drug's primary pharmacological effects and include severe flushing, headache, hypotension, nausea, vomiting, and diarrhea. Management consists of reducing the infusion rate or temporarily withholding the drug until symptoms resolve. Most overdose events are self-limiting due to the drug's extremely short half-life.[1]

8.0 Drug and Food Interactions

8.1 Pharmacodynamic Interactions with Cardiovascular and Hemostatic Agents

The most clinically significant drug-drug interactions with Epoprostenol are pharmacodynamic in nature and are predictable based on its mechanisms of action. These interactions arise from additive or synergistic effects when Epoprostenol is co-administered with other agents that affect blood pressure or hemostasis.

• Antihypertensive Agents and Vasodilators: Concomitant use of Epoprostenol with other drugs that lower blood pressure—including diuretics, ACE inhibitors, beta-blockers, calcium channel blockers, and other PAH-specific therapies (e.g., endothelin receptor antagonists, PDE-5 inhibitors)—will potentiate the hypotensive effect, increasing the risk of dizziness, syncope, and symptomatic hypotension. Close blood pressure monitoring is essential.[1]
• Antiplatelet Agents and Anticoagulants: Epoprostenol's inhibition of platelet aggregation is additive with that of other antiplatelet drugs (e.g., aspirin, clopidogrel, NSAIDs) and anticoagulants (e.g., warfarin, heparin, direct oral anticoagulants). Co-administration significantly increases the risk of bleeding complications.[1]
• Digoxin: Epoprostenol may increase the serum concentration of digoxin. In patients prone to digoxin toxicity, monitoring of digoxin levels is recommended when initiating or adjusting Epoprostenol therapy.[20]

A summary of these critical interactions is provided in Table 5.

Table 5: Clinically Significant Drug Interactions

Interacting Drug Class	Example Agents	Mechanism of Interaction	Clinical Consequence	Recommended Management/Monitoring
Antihypertensives / Vasodilators	ACE inhibitors (e.g., Captopril), Beta-blockers, Diuretics, Other PAH agents	Pharmacodynamic Synergism	Increased risk of systemic hypotension	Monitor blood pressure closely, especially during dose titration. Consider dose adjustments of concomitant medications.
Antiplatelet Agents	Aspirin, NSAIDs (e.g., Ibuprofen), Clopidogrel	Additive antiplatelet effect	Increased risk of bleeding	Use with caution. Monitor for signs of bleeding (e.g., bruising, epistaxis, GI bleeding).
Anticoagulants	Warfarin, Heparin, DOACs	Additive antithrombotic effect	Increased risk of serious hemorrhage	Use with caution. Monitor coagulation parameters (e.g., INR for warfarin) and for clinical signs of bleeding.
Cardiac Glycosides	Digoxin	Unspecified (potential for altered clearance or distribution)	Increased serum digoxin concentration	Monitor serum digoxin levels, especially in patients at risk for toxicity.
Data compiled from sources.1

8.2 Other Clinically Significant Drug and Herbal Supplement Interactions

• Food and Alcohol: There are no known clinically significant interactions between Epoprostenol and specific foods.[19] The consumption of alcohol may exacerbate the drug's side effects of dizziness and lightheadedness due to additive vasodilatory effects.[45]
• Herbal Supplements: Patients should be counseled to use caution with herbal supplements, as many possess intrinsic antiplatelet or anticoagulant properties. Supplements such as garlic, ginger, ginkgo biloba, alfalfa, and American ginseng can increase the risk of bleeding when taken concomitantly with Epoprostenol.[38]

9.0 Concluding Analysis and Future Perspectives

9.1 Summary of Epoprostenol's Therapeutic Role

Epoprostenol occupies a unique and vital position in modern medicine. For patients with severe, advanced pulmonary arterial hypertension (NYHA Class IV), it remains the undisputed gold-standard therapy, distinguished by its proven ability to improve hemodynamics, exercise capacity, and, most importantly, survival.[8] Its introduction fundamentally altered the course of this devastating disease.

Simultaneously, the therapeutic application of Epoprostenol is profoundly constrained by its challenging pharmacokinetic profile. The ultra-short half-life necessitates a complex, continuous intravenous delivery system that is burdensome for patients and carries significant inherent risks, including life-threatening rebound pulmonary hypertension upon interruption and catheter-related infections.[21] In recent years, its utility has expanded beyond PAH into the critical care arena, where inhaled Epoprostenol has emerged as an effective, evidence-based, and more economical alternative to inhaled nitric oxide for the management of acute right ventricular failure in the perioperative setting.[34]

9.2 Challenges in Therapy and Future Research Directions

The primary challenges in Epoprostenol therapy continue to be the cumbersome and high-risk delivery method and the significant impact it has on patient quality of life.[21] These limitations have been the principal driver of innovation in the field of PAH therapeutics.

Future research and development are intensely focused on overcoming these challenges. The goal is to replicate the profound biological efficacy of intravenous Epoprostenol while providing a more favorable safety and usability profile. This has led to the development of more chemically stable prostacyclin analogs (e.g., treprostinil, iloprost, selexipag) and the exploration of alternative, less invasive routes of administration, including oral, inhaled, and subcutaneous delivery systems.[8] The ultimate objective is to develop therapies that harness the power of the prostacyclin pathway with the convenience and safety of an oral medication, thereby liberating patients from the constraints of continuous infusion therapy.

Works cited

1. Epoprostenol: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 22, 2025, https://go.drugbank.com/drugs/DB01240
2. FLOLAN (epoprostenol sodium) for Injection - Amazon S3, accessed August 22, 2025, https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB01240.pdf?1265922811
3. Clinical Policy: Epoprostenol Sodium (Flolan, Veletri) - NH Healthy Families, accessed August 22, 2025, https://www.nhhealthyfamilies.com/content/dam/centene/NH%20Healthy%20Families/Medicaid/pdfs/CP.PHAR.192%20Epoprostenol.pdf
4. Epoprostenol - brand name list from Drugs.com, accessed August 22, 2025, https://www.drugs.com/ingredient/epoprostenol.html
5. EPOPROSTENOL (PD014373, KAQKFAOMNZTLHT-OZUDYXHBSA-N) - Probes & Drugs, accessed August 22, 2025, https://www.probes-drugs.org/compound/PD014373/
6. Epoprostenol - Pulmonary Hypertension Association, accessed August 22, 2025, https://phassociation.org/patients/treatments/epoprostenol/
7. FDA Approval of Epoprostenol to Treat Primary Pulmonary Hypertension - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12351391/
8. Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience, accessed August 22, 2025, https://publications.ersnet.org/content/errev/26/143/160055
9. FLOLAN® - accessdata.fda.gov, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020444s016lbl.pdf
10. Epoprostenol | CAS#35121-78-9 | prostaglandin - MedKoo Biosciences, accessed August 22, 2025, https://www.medkoo.com/products/26856
11. Epoprostenol - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed August 22, 2025, https://www.ncbi.nlm.nih.gov/books/n/lactmed/epoprostenol/
12. CAS No : 35121-78-9 | Product Name : Epoprostenol - API | Pharmaffiliates, accessed August 22, 2025, https://www.pharmaffiliates.com/en/35121-78-9-epoprostenol-pa3227000.html
13. Epoprostenol | 35121-78-9 - ChemicalBook, accessed August 22, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2969864.htm
14. Flolan (Epoprostenol): Uses, Side Effects, Interactions & More - GoodRx, accessed August 22, 2025, https://www.goodrx.com/epoprostenol/what-is
15. Pharmacokinetics of VELETRI for Injection Compared to Epoprostenol for Injection (eg, Flolan®) - J&J Medical Connect, accessed August 22, 2025, https://www.jnjmedicalconnect.com/media/attestation/products/veletri/veletri-pharmacokinetics-of-veletri-compared-to-flolan.pdf
16. VELETRI (epoprostenol for injection) - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022260s002lbl.pdf
17. What is the mechanism of Epoprostenol Sodium? - Patsnap Synapse, accessed August 22, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-epoprostenol-sodium
18. go.drugbank.com, accessed August 22, 2025, https://go.drugbank.com/drugs/DB01240#:~:text=Epoprostenol%20has%20two%20major%20pharmacological,cardiac%20output%20and%20stroke%20volume.
19. Epoprostenol (intravenous route) - Side effects & dosage - Mayo Clinic, accessed August 22, 2025, https://www.mayoclinic.org/drugs-supplements/epoprostenol-intravenous-route/description/drg-20063700
20. Epoprostenol | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 22, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5035
21. Epoprostenol sodium for treatment of pulmonary arterial hypertension - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4437604/
22. Prostacyclin or Epoprostenol • LITFL • CCC Pharmacology, accessed August 22, 2025, https://litfl.com/prostacyclin-or-epoprostenol/
23. Epoprostenol Monograph for Professionals - Drugs.com, accessed August 22, 2025, https://www.drugs.com/monograph/epoprostenol.html
24. Pharmacokinetics: Definition & Use in Drug Development - Allucent, accessed August 22, 2025, https://www.allucent.com/resources/blog/what-pharmacokinetics-and-adme
25. 2 FLOLAN - accessdata.fda.gov, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020444s018lbl.pdf
26. Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3522811/
27. Epoprostenol Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 22, 2025, https://www.drugs.com/dosage/epoprostenol.html
28. FLOLAN (epoprostenol sodium) for injection - accessdata.fda.gov, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020444s025lbl.pdf
29. 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE FLOLAN is indicated for the treatment of pulmonary arterial hypertension, accessed August 22, 2025, https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Flolan/pdf/FLOLAN-PI-PIL.PDF
30. Epoprostenol Sodium - Johns Hopkins Medicine, accessed August 22, 2025, https://www.hopkinsmedicine.org/-/media/johns-hopkins-health-plans/documents/ppmco/pp_epoprostenol_flolan_veletri_criteria.pdf
31. FDA-approved Treatments for Pulmonary Hypertension - Stanford Medicine, accessed August 22, 2025, https://med.stanford.edu/wallcenter/patient-resources/fda.html
32. Inhaled pulmonary vasodilators: a narrative review - PMC, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8105872/
33. Inhaled Epoprostenol, accessed August 22, 2025, https://www.utmb.edu/policies_and_procedures/18935604
34. Inhaled Epoprostenol Compared With Nitric Oxide for Right ..., accessed August 22, 2025, https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.062464
35. Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery. - DukeSpace, accessed August 22, 2025, https://dukespace.lib.duke.edu/items/a2eb54fe-3763-4d74-94c3-f68d82e4de07
36. Inhaled Pulmonary Vasodilators for the Treatment of Right Ventricular Failure in Cardio-Thoracic Surgery: Is One Better than the Others? - MDPI, accessed August 22, 2025, https://www.mdpi.com/2077-0383/13/2/564
37. Inhaled Epoprostenol Compared With Nitric Oxide for Right ..., accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/37401479/
38. Flolan (epoprostenol) dosing, indications, interactions, adverse effects, and more, accessed August 22, 2025, https://reference.medscape.com/drug/flolan-epoprostenol-342398
39. VELETRI (epoprostenol) for Injection - accessdata.fda.gov, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022260s005lbl.pdf
40. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE FLOLAN is indicated for the treatment of pulmonary arterial hypertension (P - accessdata.fda.gov, accessed August 22, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020444s022lbl.pdf
41. Epoprostenol (Flolan®) - Pulmonary Hypertension Association, accessed August 22, 2025, https://phassociation.org/wp-content/uploads/2017/01/Patients-Treatment-Epoprostenol.pdf
42. Epoprostenol | Memorial Sloan Kettering Cancer Center, accessed August 22, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/epoprostenol
43. Epoprostenol Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 22, 2025, https://www.drugs.com/sfx/epoprostenol-side-effects.html
44. Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension - PMC - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5841898/
45. Epoprostenol (Veletri, Flolan): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing, accessed August 22, 2025, https://www.webmd.com/drugs/2/drug-154854/veletri-intravenous/details
46. Veletri (Epoprostenol): Uses, Side Effects, Dosage & More - GoodRx, accessed August 22, 2025, https://www.goodrx.com/veletri/what-is
47. Clinical Policy: Epoprostenol (Flolan, Veletri) - Health Net, accessed August 22, 2025, https://www.healthnet.com/static/general/unprotected/html/national/pa_guidelines/1232.pdf
48. Epoprostenol injection - Cleveland Clinic, accessed August 22, 2025, https://my.clevelandclinic.org/health/drugs/19539-epoprostenol-injection
49. Pharmacokinetic evaluation of continuous intravenous epoprostenol - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/21077785/