Epoprostenol (Monograph)

Brand names: Flolan, Veletri
Drug class: Prostacyclin and Prostacyclin Derivatives
CAS number: 61849-14-7

Medically reviewed by Drugs.com on Mar 27, 2023. Written by ASHP.

Introduction

Vasodilator and platelet-aggregation inhibitor; a naturally occurring prostaglandin.^{1 60}

Uses for Epoprostenol

Pulmonary Arterial Hypertension

Management of pulmonary arterial hypertension (PAH; WHO group 1) to improve exercise capacity; efficacy established principally in patients with NYHA functional class III or IV PAH (idiopathic, heritable, or associated with connective tissue diseases).^{1 5 6 7 60 96} Designated an orphan drug by FDA for treatment of PAH.⁴

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with established PAH-specific medications.⁷⁰⁰ IV epoprostenol is recommended among several options for treatment of WHO/NYHA class III or IV PAH, generally in those with disease progression and/or severe disease.⁷⁰⁰ Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.⁷⁰⁰

Acute Respiratory Distress Syndrome

Has been used by oral inhalation (via nebulization) in patients with acute respiratory distress syndrome (ARDS)^{† [off-label]}, generally in those with refractory hypoxemia accompanied by pulmonary hypertension and right ventricular dysfunction.^{78 81 83 86 87 88 89 90 91 92}

Treatment of ARDS is largely supportive; mechanical ventilation is the only intervention proven to reduce mortality.^{78 85} Selective pulmonary vasodilators such as inhaled epoprostenol may be used adjunctively to improve oxygenation; localized effects in lung parenchyma may improve ventilation-perfusion mismatch.^{77 78 79 80 81 82 83 84 91 92}

Inhaled epoprostenol has been suggested as an alternative to nitric oxide due to its similar efficacy, lower potential for systemic adverse effects, lower cost, and ease of delivery (can be nebulized through the ventilator circuit).^{78 81 91 92}

Substantially reduces mean pulmonary artery pressure and improves oxygenation; however, data demonstrating clinical benefit are lacking.^{78 83 88 89 90 91 92} Additional studies needed to evaluate potential role.^{88 89 90 91 92}

Epoprostenol Dosage and Administration

General

Pretreatment Screening

• Monitor BP and symptoms regularly during initiation of epoprostenol.^{1 60}

Patient Monitoring

• Initiate epoprostenol therapy in a setting with adequate personnel and equipment to allow for proper physiologic monitoring and emergency care, if needed.^{1 60}

• Monitor BP, heart rate, and symptoms regularly for several hours after dosage changes.^{1 60}

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), IV epoprostenol is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.⁹³

Administration

Administer by IV infusion.¹ Also has been administered by oral inhalation via nebulization^{† [off-label]} through the ventilator circuit in patients with ARDS^{† [off-label]} receiving mechanical ventilation.^{78 81 91 92}

IV Administration

For IV infusion only.^{1 60}

Administer by continuous IV infusion via a central venous catheter with a portable controlled-infusion device; peripheral IV catheter may be used temporarily until central venous access is established.^{1 2 39 60} Consult manufacturer’s labeling for infusion-device specifications.^{1 60}

Do not mix or administer in same IV line with other parenteral solutions or medications.^{1 60}

Delivery system malfunctions (e.g., infusion-device failure, occluded catheter) may result in inadvertent overdosage or underdosage.^{1 60} To avoid potential interruptions in drug delivery, patient must have access to a backup IV infusion device and infusion sets.^{1 47 60} Consider use of a multi-lumen catheter if patient receives other IV drugs routinely.^{1 60}

Reconstitution and Dilution

Reconstitute only with appropriate diluent specified by manufacturer; the drug is stable only when reconstituted as directed using the recommended diluent(s).^{1 60} See manufacturer’s labeling for details on reconstitution, preparation of solutions, and selection of drug concentration in solutions.^{1 60}

Flolan lyophilized powder for injection (or generic equivalent): Reconstitute only with the pH 12 sterile diluent provided by manufacturer; do not reconstitute or mix with other parenteral solutions or medications.¹ Further dilute solution with a sufficient volume of the same diluent to provide a final concentration compatible with the infusion pump (with respect to minimum and maximum flow rates and other infusion pump criteria) and capacity of the drug delivery reservoir.¹ Typical drug reservoirs for long-term epoprostenol therapy contain a total reservoir volume of 100 mL.¹ Use reconstituted solutions immediately or store under refrigeration at 2–8°C and protect from light; do not freeze.¹ Freshly reconstituted solutions or reconstituted solutions that have been stored under refrigeration for a maximum of 8 days can be administered up to 72 hours at temperatures up to 25°C, 48 hours at temperatures up to 30°C, 24 hours at temperatures up to 35°C, or 12 hours at temperatures up to 40°C.¹

Veletri lyophilized powder for injection (or generic equivalent): Reconstitute with sterile water for injection or 0.9% sodium chloride injection; do not reconstitute or mix with other parenteral solutions or medications.⁶⁰ Further dilute solution immediately with a sufficient volume of the same diluent to provide a final concentration compatible with the infusion pump (with respect to minimum and maximum flow rates and other infusion pump criteria) and capacity of the drug delivery reservoir.⁶⁰ Typical drug reservoirs used for long-term epoprostenol therapy contain a total reservoir volume of 100 mL.⁶⁰ Following reconstitution and dilution, administer immediately or store at 2–8°C for ≤8 days.⁶⁰ May infuse at room temperature for periods of 24, 48, or 72 hours depending on final concentration of solution and timing of administration (immediately or after storage for ≤8 days at 2–8°C).⁶⁰ (See Table 1.) Also may administer at higher temperatures (≤40°C) according to manufacturer's guidelines.⁶⁰ (See Table 2.)

Short excursions to higher temperatures (i.e., ≤40°C) are permitted for up to 2, 4, or 8 hours for solution concentrations of <15,000 ng/mL, 15,000–60,000 ng/mL, or >60,000 ng/mL, respectively.⁶⁰

Rate of Administration

Adjust infusion rates only under the direction of a physician, except in life-threatening situations (e.g., unconsciousness, collapse).^{1 60} Observe patient and monitor standing and supine BP and heart rate for several hours following changes in infusion rates.^{1 60}

Avoid abrupt discontinuance or sudden large reductions in infusion rates.^{1 60} Consult manufacturer’s labeling for specific instructions on selection of infusion rate and drug concentration.^{1 60}

Dosage

Available as epoprostenol sodium; dosage expressed in terms of epoprostenol.^{1 2 60}

Considerable interindividual variability in patient response; individualize dosage.^{7 48}

Titrate dosages carefully until desired therapeutic effect achieved or intolerable adverse effects occur.^{1 60}

Pediatric Patients

Acute Respiratory Distress Syndrome† [off-label]

Oral nebulization

Various dosages of inhaled epoprostenol have been used in clinical studies.^{81 91} Although initial dosage has varied, most protocols titrated dosage to response (usually with a 15- and 30-minute interval between doses).^{81 91} The most effective and safest dosage of inhaled epoprostenol that provides a clinically important increase in the partial pressure of oxygen in arterial blood (PaO₂) and reduction in pulmonary artery pressure appears to be 30 ng/kg per minute in pediatric patients; higher dosages not shown to provide any additional benefit.⁹¹

Adults

Pulmonary Arterial Hypertension

Initiation and Titration of Therapy

Continuous IV Infusion

Initially, 2 ng/kg per minute (or a lower dose if not tolerated); increase in increments of 1–2 ng/kg per minute at intervals of ≥15 minutes until dose-limiting pharmacologic effects are elicited or a tolerance limit to the drug is established and further increases in the infusion rate are not clinically warranted.^{1 60} Maintain dosage at a level where pharmacologic effects are tolerated.^{1 60}

Infusion rates may be calculated using the following formula:^{1 60}

Infusion rate (mL/hr) = [dose (ng/kg per min) × wt (in kg) × 60 min/hr] / final concentration of epoprostenol solution (ng/mL)

In clinical studies in patients with PAH associated with the scleroderma spectrum of diseases, the average initial dosage of 2.2 ng/kg per minute was increased during the first week of therapy to 4.1 ng/kg per minute on day 7, and the mean dosage was 11.2 ng/kg per minute by the end of week 12; incremental increases in dosage averaged 2–3 ng/kg per minute every 3 weeks.^{1 60}

Long-term Therapy

Continuous IV Infusion

During long-term infusion, dosage increases generally are required based on persistence, recurrence, or worsening of disease symptoms; dosage reductions may be needed because of adverse effects.^{1 60}

Adjust dosage in increments of 1–2 ng/kg per minute at intervals of ≥15 minutes.^{1 60} If dose-limiting adverse effects occur, decrease dosage gradually in decrements of 2 ng/kg per minute at intervals of ≥15 minutes until dose-limiting effects resolve; avoid abrupt withdrawal or sudden large reductions in infusion rates.^{1 60}

Prolonged therapy may cause tachyphylaxis and require periodic dosage adjustments.^{7 35 47}

In clinical studies, therapy was tapered in patients receiving lung transplants after initiation of cardiopulmonary bypass.¹

Acute Respiratory Distress Syndrome† [off-label]

Oral Nebulization

Various dosages of inhaled epoprostenol have been used in clinical studies.^{81 91 92} Although initial dosage has varied, most protocols titrated dosage to response (usually with a 15- to 30-minute interval between doses).^{81 91} The most effective and safest dosage of inhaled epoprostenol that provides a clinically important increase in PaO₂ and reduction in pulmonary artery pressure appears to be 20–30 ng/kg per minute in adults; higher dosages not shown to provide any additional benefit.⁹¹ One study utilized a fixed dosage of epoprostenol in adults; in this study, a 20,000 ng/mL epoprostenol solution was nebulized at a rate of 8 mL/hour.⁹² The dosage could be weaned by reducing to a 10,000 ng/mL epoprostenol solution nebulized at the same rate.⁹²

Special Populations

Hepatic Impairment

Manufacturers make no specific dosage recommendations.^{1 60}

Renal Impairment

Manufacturers make no specific dosage recommendations.^{1 60}

Geriatric Patients

Select initial dosage in geriatric patients with caution (at low end of dosage range) and titrate carefully because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^{1 60}

Cautions for Epoprostenol

Contraindications

• Long-term use in CHF due to severe left ventricular systolic dysfunction.^{1 60}

• Long-term use in patients who develop pulmonary edema during initial dosage titration (Veletri only).⁶⁰

• Known hypersensitivity to epoprostenol or structurally related drugs.^{1 60}

Warnings/Precautions

Warnings

Rebound Pulmonary Hypertension Following Abrupt Withdrawal of Therapy

Avoid abrupt discontinuance or sudden large reductions in dosage.^{1 60}

Because of the drug’s rapid metabolism, abrupt withdrawal (including interruptions in drug delivery), sudden large reductions in dosage, or even brief interruptions in drug delivery may result in symptoms associated with rebound pulmonary hypertension (e.g., dyspnea, dizziness, asthenia).^{1 60}

Patient should have access to a backup IV infusion device and infusion sets to avoid interruptions in drug delivery due to equipment malfunction.^{1 60}

Pulmonary Edema

Because some patients have developed pulmonary edema during dose initiation, do not use Veletri chronically in patients who develop pulmonary edema during dose initiation.⁶⁰ (See Contraindications under Cautions.)

If a patient develops pulmonary edema during initiation of Flolan, discontinue therapy and do not readminister.¹ Consider possibility of associated pulmonary veno-occlusive disease in such patients.¹

Vasodilation

Epoprostenol is a potent pulmonary and systemic vasodilator.^{1 60}

Possible hypotension and other reactions including flushing, nausea, vomiting, dizziness, and headache may occur.¹

Monitor BP and symptoms regularly while initiating therapy and after changing dosage.¹

Adequate Patient Evaluation and Monitoring

Initiate therapy in a setting equipped for adequate monitoring and emergency care.^{1 60} Asymptomatic increases in pulmonary artery pressure have occurred with increases in cardiac output during dose initiation.^{1 60} If pulmonary artery pressure increases occur, manufacturer of Veletri states to consider dosage reduction.⁶⁰

During chronic use, administer continuously on an ambulatory basis through a permanent indwelling central venous catheter.^{1 60} Unless contraindicated, administer anticoagulant therapy to reduce risk of pulmonary or systemic embolism.⁶⁰ Use aseptic technique at all times.^{1 60} Consider patient's capacity to accept and care for a permanent IV catheter and infusion pump, as prolonged IV therapy will likely be needed.⁶⁰

Adjust dosage during chronic use at first sign of recurrence or worsening of PAH symptoms or when other drug-associated adverse events occur.⁶⁰ Following dosage adjustments, monitor standing and supine BP and heart rate closely for several hours.⁶⁰

Bleeding

Epoprostenol is a potent inhibitor of platelet aggregation.¹ Possible risk of hemorrhagic complications, particularly in patients with other risk factors for bleeding.¹

Specific Populations

Pregnancy

No evidence of drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes in case reports or case series.^{1 60}

Lactation

Not known whether epoprostenol is distributed into milk.^{1 60} Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for epoprostenol and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.^{1 60}

Pediatric Use

Safety and efficacy not established.^{1 60}

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.^{1 60}

Common Adverse Effects

Patients treated with Flolan: dizziness, jaw pain, headache, musculoskeletal pain, nausea/vomiting.¹

Patients initiating treatment with Veletri: nausea/vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, tachycardia.⁶⁰

Patients receiving chronic Veletri: headache, jaw pain, flushing, diarrhea, nausea/vomiting, flu-like symptoms, anxiety/nervousness.⁶⁰

Drug Interactions

In clinical studies, epoprostenol was used concomitantly with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.^{1 60}

Specific Drugs

Epoprostenol Pharmacokinetics

Chemical assays with sufficient sensitivity and specificity to assess the in vivo pharmacokinetics of epoprostenol in humans not currently available.^{1 60}

Distribution

Extent

Animal studies indicate a small volume of distribution (357 mL/kg).^{1 60}

Elimination

Metabolism

Rapidly hydrolyzed at neutral pH in blood and also subject to enzymatic degradation.^{1 2 60} Metabolized to 2 primary metabolites, 6-keto-PGF_1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF_1α (enzymatically formed); data in animals indicate that both metabolites have pharmacologic activity orders of magnitude less than parent drug.^{1 2 60} Extensively metabolized; 14 additional minor metabolites isolated from urine.^{1 60}

Elimination Route

82% in urine and 4% in feces.^{1 2 60}

Half-life

In vitro, approximately 6 minutes in human blood at 37°C and pH 7.4; in vivo, expected to be ≤6 minutes.^{1 2 60}

2.7 minutes (animals).^{1 60}

Stability

Storage

Parenteral

Powder for Injection

Flolan: 15–25°C in original carton; protect from light.¹ Store Sterile Diluent for Flolan at 15–25°C; do not freeze.¹

Veletri: 20–25°C in original carton; protect from direct sunlight.⁶⁰ Single-use vials; discard unused portions.⁶⁰

Reconstituted solutions of Flolan: Store at 2–8°C for up to 8 days if not used immediately.¹ Protect reconstituted solutions from light; do not freeze.¹

Reconstituted solutions of Veletri: Store at 2–8°C for ≤8 days if not used immediately.⁶⁰ Protect from direct sunlight.⁶⁰ Stability of reconstituted solutions of Veletri is temperature and concentration dependent.⁶⁰

Compatibility

Parenteral

Drug and Solution Compatibility

Do not dilute or administer with other parenteral solutions or drugs.^{1 60}

Actions

• Direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.^{1 2 60}

• May have antiproliferative effects on the intimal layer of precapillary arteries.^{2 5 9 18 19 20 22 25 26 27 32 35}

• Produces dose-related increases in cardiac index and stroke volume.^{1 2 60}

• Produces dose-related decreases in pulmonary vascular resistance, total pulmonary resistance, and mean systemic arterial pressure.^{1 2 60}

• Associated with improvement in survival, exercise capacity, and quality of life assessments.^{1 2 5 6 47 48 60}

• Effect on heart rate varies with dose in animals; vagally mediated bradycardia at lower doses and reflex tachycardia in response to direct vasodilation and hypotension at higher doses.^{1 2 60}

• No major effects on cardiac conduction in animals.^{1 60}

• Additional pharmacologic effects observed in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.^{1 60}

Advice to Patients

• Importance of advising patient that therapy is infused continuously through a permanent indwelling central venous catheter via a portable infusion device and requires sustained commitment to drug reconstitution, drug administration, and care of the permanent central venous catheter.^{1 60}

• Importance of advising patient that therapy probably will be needed for prolonged periods, possibly years.^{1 60}

• Importance of careful consideration of patient’s ability to accept and care for a permanent central venous catheter and infusion device.^{1 60}

• Importance of advising patients that abrupt withdrawal or sudden interruptions in drug delivery may result in symptoms associated with rebound pulmonary hypertension (e.g., dyspnea, dizziness, asthenia) and/or death.^{1 60} Even brief interruptions in the delivery of epoprostenol may result in rapid symptomatic deterioration.¹

• Importance of advising patient that sterile technique must be adhered to in drug preparation and catheter care to prevent sepsis.^{1 60 64}

• Importance of reconstitution only with the appropriate diluent specified by the manufacturer.^{1 60} Reconstituted solutions of Flolan prepared with the appropriate diluent do not require use with a cold pouch.¹

• Importance of avoiding preparation of Flolan with any preparation or administration materials containing PET or PETG.¹

• Importance of informing patients that infusion rates should only be adjusted under the direction of a physician.¹ Patients should have access to a backup infusion pump and IV infusion sets to avoid interruptions in drug delivery.¹

• Importance of patient informing their healthcare provider if any unusual bruising or bleeding occurs.¹

• Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{1 60}

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 60}

• Importance of informing patients of other important precautionary information.^{1 60} (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Epoprostenol sodium can only be obtained through designated specialty pharmacies.^{94 95}

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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