AHFS Class:

• Prostacyclin and Prostacyclin Derivatives 48:48.28

Generic Name(s):

• Epoprostenol Sodium

Epoprostenol (PGI₂, PGX, prostacyclin), a naturally occurring prostaglandin, is a short-acting vasodilator and platelet-aggregation inhibitor.1,60

Pulmonary Arterial Hypertension

Epoprostenol sodium is used in the management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) to improve exercise capacity.1,5,6,14,48,60 Clinical studies establishing efficacy of the drug were conducted principally in patients with New York Heart Association (NYHA) functional class III or IV PAH (idiopathic, heritable, or associated with connective tissue diseases).1,5,6,7,60,96 Epoprostenol has been designated an orphan drug by FDA for use in the treatment of PAH.4

Pulmonary hypertension is defined by the National Institutes of Health Registry as a mean pulmonary artery pressure exceeding 25 mm Hg at rest with a pulmonary capillary or left atrial pressure less than 15 mm Hg.2,7,14,18,23,29,32,37

Clinical Experience in Patients with Idiopathic or Heritable PAH

Efficacy of epoprostenol in the treatment of idiopathic or heritable PAH has been established in 2 prospective, multicenter, randomized, open-label studies; these studies were of 8 or 12 weeks' duration and were conducted principally in adults with NYHA/WHO class III or IV PAH.1,5,7,60 In these studies, epoprostenol (infused IV at a mean dosage of 9.2 ng/kg per minute by the end of the studies) added to standard therapy (e.g., anticoagulants, oral vasodilators, diuretics, cardiac glycosides, supplemental oxygen) and titrated according to clinical response, was compared with standard therapy alone.1,5,7,60 Pooled data from these studies indicate that epoprostenol's effect on exercise capacity (i.e., a median increase of 47 m from baseline in the distance walked in 6 minutes) was statistically significant compared with a median decrease of 29 m in patients receiving standard therapy alone. 1,5,7,60 Improvement in walking distance was apparent after 1 week of therapy with epoprostenol.1,60 Epoprostenol therapy was associated with improvements of indices of dyspnea and fatigue.1,5,60 Patients receiving epoprostenol also experienced improvements in hemodynamic parameters (e.g., increases in cardiac index, stroke volume, and arterial oxygen saturation, associated with reductions in mean pulmonary arterial pressure, total pulmonary resistance, pulmonary vascular resistance, mean right atrial pressure, mean systemic arterial pressure, and systemic vascular resistance) compared with baseline;1,2,5,7,60 hemodynamic effects generally were similar following acute and long-term administration of epoprostenol.1,60 Although a 20% decrease in mortality was reported at the end of the 12-week clinical study in patients receiving epoprostenol compared with those receiving standard therapy alone,1,5,13,60 some clinicians suggest that mortality data interpretation was confounded by baseline differences in exercise capacity between surviving and dying patients.5,9

Clinical Experience in Patients with PAH Associated with Scleroderma Spectrum of Diseases

Efficacy of epoprostenol in the treatment of PAH associated with the scleroderma spectrum of diseases has been established in a 12-week multicenter, randomized, open-label study principally in 111 adults with NYHA/WHO class III or IV symptoms.1,6,60 In this study, epoprostenol (infused IV at a mean dosage of 11.2 ng/kg per minute by week 12) added to standard therapy (e.g., anticoagulants, oral vasodilators, diuretics, cardiac glycosides, supplemental oxygen) and titrated according to clinical response, was compared with standard therapy alone.1,6,60 Results from this study indicate that epoprostenol's improvement on exercise capacity (i.e., a median increase of 46 m from baseline in the distance walked in 6 minutes) was statistically significant compared with a median decrease of 48 m in patients receiving standard therapy alone.6 Improvement in 6-minute walking distance (the primary end point) was apparent in some patients after 1 week of therapy with epoprostenol.1,60

Patients receiving epoprostenol experienced a reduction in symptoms, as determined by substantial improvement in Borg dyspnea score and dyspnea fatigue index.1,6 While no change in NYHA/WHO functional class at 12 weeks of therapy was observed in 55 or 73% of patients receiving epoprostenol therapy or standard therapy alone, respectively, NYHA/WHO functional class improved in 41 or 0% of patients receiving epoprostenol therapy or standard therapy alone, respectively; worsening of functional status was reported in the remaining patients of both groups.1,60 In addition, epoprostenol therapy resulted in substantial hemodynamic changes (e.g., increases in cardiac index associated with reductions in mean pulmonary arterial pressure, mean right arterial pressure, pulmonary vascular resistance, and mean systemic arterial pressure) compared with baseline.1,6,60 Epoprostenol therapy was not associated with a survival benefit when compared with standard therapy alone.1,6,60 An uncontrolled open-label extension study of this trial found that patients with PAH associated with the scleroderma spectrum of diseases who received IV epoprostenol had improved survival over a period of 3 years compared to historical controls.96 Safety and efficacy of epoprostenol have not been systematically evaluated in patients with pulmonary hypertension associated with other diseases.1,60

Clinical Perspective

Current expert consensus guidelines from the American College of Chest Physicians (ACCP) recommend that all adult patients with symptomatic (World Health Organization [WHO] or New York Heart Association [NYHA] functional classification [FC] II-IV) pulmonary arterial hypertension (PAH) be treated with established PAH-specific medications (e.g., prostacyclin derivative [e.g., epoprostenol, treprostinil], PDE type 5 inhibitor [i.e. sildenafil, tadalafil], endothelin receptor antagonist [e.g., ambrisentan, bosentan, macitentan], or a soluble guanylate cyclase stimulator [e.g., riociguat]) to reduce symptoms, improve functional capacity, and to delay progression of PAH, hospitalization, and death.700 Selection of drug therapy should be based on disease severity (WHO/NYHA class), risk of further short-term deterioration, comorbid illnesses, concomitant medications, expected tolerance of known side effects, route of administration (i.e., oral, parenteral, inhaled), costs of therapy, and patient preferences.700 In addition, patients with PAH should receive supportive care (e.g., oxygen, diuretics, anticoagulants).700

For treatment-naive adults with WHO/NYHA FC II or III PAH who are not candidates for, or who have failed calcium-channel blocking agent therapy, ACCP recommends initial combination therapy with ambrisentan and tadalafil, but gives this a weak recommendation based on moderate quality evidence.700 Monotherapy with an endothelin-receptor antagonist (e.g., ambrisentan, bosentan, macitentan), phosphodiesterase type 5 inhibitor (e.g., sildenafil, tadalafil), or soluble guanylate cyclase stimulator (e.g., riociguat) can be initiated for patients who are intolerant to or unwilling to take combination treatment.700 Initial treatment with continuous IV epoprostenol, IV treprostinil, or subcutaneous treprostinil is recommended in patients with WHO/NYHA FC III who have evidence of rapid disease progression or poor prognosis; inhaled or oral prostanoids are recommended in patients who are unwilling and not able to manage parenteral prostanoids.700 In patients with WHO FC III PAH who have evidence of disease progression and/or poor clinical prognosis despite treatment with one or two classes of oral agents, consideration should be given to the addition of a parenteral or inhaled prostanoid (e.g., IV epoprostenol, IV treprostinil, inhaled treprostinil, inhaled iloprost).700 In treatment-naive PAH patients in WHO FC IV, initiation of a parenteral prostanoid agent (e.g., IV epoprostenol, IV treprostinil, subcutaneous treprostinil) is advised.700 Addition of a second or third class of PAH therapy may be considered in patients with WHO FC III or IV PAH who experience unacceptable or deteriorating clinical status despite their current PAH-specific regimen.700

Acute Respiratory Distress Syndrome

Epoprostenol has been used by oral inhalation (via nebulization) in the treatment of acute respiratory distress syndrome (ARDS)†, generally in patients 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 with mechanical ventilation being the only proven intervention that reduces mortality.78,85 Selective pulmonary vasodilators such as inhaled nitric oxide and epoprostenol have been used adjunctively to improve oxygenation in patients with ARDS.77,78,79,80,81,82,83,84,91,92 The localized effect of these drugs in lung parenchyma may improve the ventilation-perfusion mismatch seen in these patients.91 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 (i.e., can be nebulized through the ventilator circuit).78,81,91,92 Although inhaled epoprostenol can substantially reduce mean pulmonary artery pressure and improve oxygenation in patients with ARDS, data demonstrating clinical benefit are lacking and only one retrospective study has evaluated mortality as an end point; this study found that treatment of ARDS patients with either inhaled nitric oxide or inhaled epoprostenol led to similar mortality rates.83,88,89,90,91,92 Additional studies are needed to evaluate the potential role of inhaled prostacyclins in the treatment of ARDS.88,89,90,91,92

General

Pretreatment Screening

• Monitor blood pressure 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 blood pressure, 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

Epoprostenol sodium is administered by continuous IV infusion via a central venous catheter with a portable controlled-infusion device.1,2,60 A peripheral IV catheter may be used temporarily to administer the infusion until central venous access is established. 1,2,39,60 Consult the manufacturer's labeling for ambulatory infusion-device specifications.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 secondary to equipment malfunction, patients should have access to a back-up IV infusion device and infusion sets.1,47,60 A multi-lumen catheter should be considered for patients who routinely receive other IV drugs.1,60

Epoprostenol also has been administered by oral inhalation (via nebulization† through the ventilator circuit) in patients with acute respiratory distress syndrome (ARDS)† receiving mechanical ventilation.78,81,91,92

Store unopened vials of Flolan^® powder for injection at room temperature (15-25°C), in the carton, and protect from light.1 Store unopened vials of the sterile diluent for Flolan^® at room temperature (15-25°C).1 Do not freeze the diluent.1

Store vials of Veletri^® at controlled room temperature (20-25°C); store in the carton and do not expose to direct sunlight.60

Reconstitution and Dilution

Commercially available epoprostenol sodium for injection must be reconstituted with the appropriate diluent specified by the manufacturer; the drug is stable only when reconstituted as directed using the recommended diluent(s).1,60 Consult the manufacturers' labeling for details on reconstitution, preparation of solutions of epoprostenol, and selection of drug concentration in solutions.1,60

Reconstituted solutions of epoprostenol sodium should not be admixed or administered with other parenteral solutions or medications.1,60

Flolan®

Epoprostenol sodium lyophilized powder for injection (Flolan^® or generic equivalent) must be reconstituted only with the pH 12 sterile diluent provided by the respective manufacturer.1 Further dilute the reconstituted solution with a sufficient volume of the same diluent to provide a final concentration of epoprostenol sodium that is 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 used for long-term epoprostenol therapy contain a total reservoir volume of at least 100 mL.1 Reconstituted solutions can be used immediately or stored under refrigeration at 2-8°C and protected from light; do not freeze reconstituted solutions.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®

Epoprostenol sodium lyophilized powder for injection (Veletri^® or generic equivalents) should be reconstituted only with sterile water for injection or 0.9% sodium chloride injection.60 Further dilute the reconstituted solution immediately with a sufficient volume of the same diluent to provide a final concentration of epoprostenol sodium that is compatible with the infusion pump being used (with respect to minimum and maximum flow rates and other specified infusion pump criteria) and the 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 Do not expose reconstituted solutions of Veletri^® to direct sunlight.60

Following reconstitution and dilution, administer Veletri^® solutions immediately or store for up to 8 days under refrigeration (2-8°C).60 The stability of the solution is temperature and concentration dependent.60 When reconstituted and diluted as directed, Veletri^® solutions are stable at room temperature for 24, 48, or 72 hours depending on the final concentration of the solution and timing of administration (immediately or after storage for up to 8 days at 2-8°C).60 Veletri^® solutions with a final concentration of at least 3000 ng/mL but less than 15,000 ng/mL (prepared with the vial labeled as containing 0.5 mg of drug) may be infused at room temperature for a maximum of 48 hours if administered immediately or 24 hours if stored for up to 8 days at 2-8°C; short excursions to 40°C for up to 2 hours are permitted.60 Solutions with a final concentration of at least 15,000 ng/mL but less than 60,000 ng/mL (prepared with 1.5-mg vials of drug) may be infused at room temperature (either immediately or after refrigerator storage) for a maximum of 48 hours; short excursions to 40°C for up to 4 hours are permitted.60 For solutions with a concentration of 60,000 ng/mL or greater (prepared with 1.5-mg vials of drug), the maximum duration of infusion at room temperature is 72 hours if administered immediately or 48 hours if stored for up to 8 days at 2-8°C; short excursions to 40°C for up to 8 hours are permitted.60

Veletri^® solutions also may be administered at higher temperatures (up to 40°C) according to the following guidelines.60 At temperatures of greater than 25°C and up to 30°C, Veletri^® solutions with a concentration of at least 60,000 ng/mL may be infused (either immediately or after storage for up to 8 days at 2-8°C) for up to 48 hours; solutions with a concentration less than 60,000 ng/mL are less stable at these temperatures and should therefore be infused for no longer than 24 hours.60 At temperatures exceeding 30°C and up to 40°C, Veletri^® solutions with a concentration of at least 60,000 ng/mL may be infused only if administered immediately after preparation and for a period of up to 24 hours.60

Rate of Administration

Avoid abrupt discontinuance or sudden large reductions in dosage of epoprostenol as this may result in worsening of disease symptoms.1,60 Adjust the infusion rate only under the direction of a physician, except in life-threatening situations (e.g., unconsciousness, collapse).1,60 Observe the patient following changes in infusion rates; monitor standing and supine blood pressure and heart rate for several hours.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)

Dosage

Dosage of epoprostenol sodium is expressed in terms of epoprostenol.1,2,60 There is considerable interindividual variability in patient response to epoprostenol and dosage must be individualized.7 Dosage should be carefully titrated until therapeutic effect is achieved or adverse effects become intolerable.1,60

Pulmonary Arterial Hypertension

Initiation and Titration of Therapy

For the treatment of idiopathic/heritable pulmonary arterial hypertension (PAH) or PAH associated with the scleroderma spectrum of disease in adults, the recommended initial dosage of epoprostenol is 2 ng/kg per minute.1,60 If the initial dosage is not tolerated, use a lower dosage.1,60

Increase the initial tolerated epoprostenol dosage in increments of 1-2 ng/kg per minute at intervals of at least 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 the epoprostenol dosage at a level where pharmacologic effects are tolerated.1,5,60

In clinical studies in adults with PAH associated with the scleroderma spectrum of disease, 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

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 In addition, tolerance (tachyphylaxis) to therapeutic effects may occur in patients receiving long-term epoprostenol therapy and periodic dosage adjustment generally is required.7,35,47

Adjust the epoprostenol dosage in increments of 1-2 ng/kg per minute at intervals of at least 15 minutes.1,60 In clinical studies, incremental dosage adjustments were made in intervals of at least 24-48 hours.1,60 If dose-limiting adverse effects (nausea, vomiting, hypotension, sepsis, headache, abdominal pain, and/or respiratory disorder) occur, gradually decrease the dosage in decrements of 2 ng/kg per minute at intervals of at least 15 minutes until dose-limiting effects resolve; avoid abrupt withdrawal of epoprostenol or sudden large reductions in infusion rates.1,60 Adverse effects occasionally may resolve without dosage adjustment.1,60

In clinical studies, epoprostenol therapy was tapered in patients receiving lung transplantation after initiation of cardiopulmonary bypass.1,60

Acute Respiratory Distress Syndrome

In the treatment of acute respiratory distress syndrome (ARDS)†, various dosages of inhaled epoprostenol have been used in clinical studies.81,91,92 Although the initial dosage has varied, most protocols titrated the dosage to response (usually with a 15- to 30-minute interval between doses).81,91 Data from clinical studies suggest that 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 is 20-30 ng/kg per minute in adults and 30 ng/kg per minute in pediatric patients; higher dosages have not been shown to provide any additional therapeutic 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

The manufacturers make no specific dosage recommendations for patients with hepatic impairment.1,60

Renal Impairment

The manufacturers make no specific dosage recommendations for patients with renal impairment.1,60

Geriatric Patients

Select an initial dosage in geriatric patients with caution (usually at the low end of the 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

Contraindications

• Long-term use in patients with 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 withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol because symptoms associated with rebound pulmonary hypertension (e.g., dyspnea, dizziness, asthenia) may occur.1,60 To avoid potential interruptions in drug delivery secondary to equipment malfunction, patients should have access to a back-up IV infusion device and infusion sets.1,60

Pulmonary Edema

Because some patients have developed pulmonary edema during dose initiation, chronic use of Veletri^® in patients who develop pulmonary edema during dose initiation is contraindicated.60 If a patient develops pulmonary edema during initiation of therapy with Flolan^®, discontinue therapy and do not readminister the drug.1 Consider the possibility of associated pulmonary veno-occlusive disease in such patients.1

Vasodilation

Epoprostenol is a potent pulmonary and systemic vasodilator.1,60 The drug can cause hypotension and other reactions including flushing, nausea, vomiting, dizziness, and headache.1 Monitor blood pressure and symptoms regularly while initiating therapy and after dosage adjustments.1

Adequate Patient Evaluation and Monitoring

Initiate epoprostenol therapy in a setting equipped for adequate monitoring and emergency care.1,60 Dosage initiation has been performed during right heart catheterization and without cardiac catheterization.60 Rarely, asymptomatic increases in pulmonary artery pressure have occurred in association with increases in cardiac output during dose initiation.1,60 If pulmonary artery pressure increases occur, the manufacturer of Veletri^® states to consider dosage reduction.60

During chronic use, administer epoprostenol continuously on an ambulatory basis through a permanent indwelling central venous catheter.1,60 Unless contraindicated, the manufacturer of Veletri^® states to administer anticoagulant therapy to reduce the risk of pulmonary or systemic embolism through a patent foramen ovale.60 Use aseptic technique when preparing epoprostenol for administration, and in routine catheter care.1,60 Because epoprostenol is metabolized rapidly, even brief interruptions in drug delivery may result in symptoms associated with rebound pulmonary hypertension (i.e., dyspnea, dizziness, and asthenia).1,60 Continuous IV therapy will likely be needed for prolonged periods, possibly years; therefore, consider the patient's capacity to accept and care for a permanent IV catheter and infusion pump.1,60

Based on clinical trials, the acute hemodynamic response (reduction in pulmonary artery resistance) to epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of epoprostenol.1,60 Adjust the dosage of epoprostenol during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or when other drug-associated adverse events occur.1,60 Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.60

Increased Risk for Bleeding

Epoprostenol is a potent inhibitor of platelet aggregation.1 Therefore, expect an increased risk for hemorrhagic complications, particularly in patients with other risk factors that place them at a higher risk for bleeding events.1

Specific Populations

Pregnancy

A drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes has not been demonstrated in limited data from case reports and case series describing epoprostenol use during pregnancy.1,60 Untreated pulmonary arterial hypertension (PAH) in pregnancy increases the risk for maternal heart failure, stroke, preterm delivery, and maternal and fetal death.1,60

Lactation

It is not known whether epoprostenol is distributed into milk.1,60 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for epoprostenol and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1,60

Pediatric Use

Safety and efficacy of epoprostenol have not been established in pediatric patients.1,60

Geriatric Use

Clinical studies of epoprostenol sodium did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.1,60 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.1,60 In general, titrate dosage carefully in geriatric patients.1,60 Consider the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.1,60

Common Adverse Effects

The most common adverse reactions reported among patients treated with Flolan^® include dizziness, jaw pain, headache, musculoskeletal pain, and nausea/vomiting.1

The most common adverse reactions reported among patients initiating treatment with Veletri^® include nausea/vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia.60 The most common adverse reactions reported among patients receiving chronic dosing of Veletri^® include headache, jaw pain, flushing, diarrhea, nausea/vomiting, flu-like symptoms, and anxiety/nervousness.60

During clinical trials, epoprostenol sodium was used concomitantly with anticoagulants, cardiac glycosides, diuretics, oral vasodilators, and supplemental oxygen.1,60

Anticoagulants

Concomitant use of epoprostenol and anticoagulants may increase the risk of bleeding; however, patients in clinical trials of epoprostenol were maintained on anticoagulants without evidence of increased bleeding.1,60

Antihypertensive Agents

Concomitant use of epoprostenol and antihypertensive agents can result in additive hypotensive effects.1,60

Antiplatelet Agents

Concomitant use of epoprostenol and antiplatelet agents may increase the risk of bleeding.1,60

Digoxin

In patients with congestive heart failure receiving digoxin, oral clearance of digoxin was reduced by 15% during concurrent epoprostenol therapy, but returned to baseline values.1,60 The clinical significance of this interaction is not known; however, elevations in serum digoxin concentration that occur upon initiation of epoprostenol therapy may be clinically important in patients who are prone to digoxin toxicity.1,60

Diuretics

Concomitant use of epoprostenol and diuretics can result in additive hypotensive effects.1,60

In patients with congestive heart failure receiving furosemide, oral clearance of furosemide was reduced by 13% during concurrent epoprostenol therapy, but returned to baseline values; this change is not considered clinically important.1,60

Vasodilating Agents

Concomitant use of epoprostenol and other vasodilating agents can result in additive hypotensive effects.1,60

Description

Epoprostenol sodium (PGI₂, PGX, prostacyclin), the synthetic salt of a naturally occurring prostaglandin, possesses the pharmacologic actions (e.g., vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation) of endogenous prostacyclin, a naturally occurring prostaglandin and arachidonic acid metabolite.1,2,5,21,23,32,60 Epoprostenol, a short-acting vasodilating agent and a platelet-aggregation inhibitor,1,2,5,21,30,60 produces dose-related increases in cardiac index and stroke volume and dose-related decreases in pulmonary vascular resistance, total pulmonary resistance, and mean systemic arterial pressure.1,2,60

In animals, epoprostenol reduces right and left ventricular afterload and increases cardiac output and stroke volume as a result of the drug's vasodilatory effects.1,60 Studies have shown that cardiac effects of the drug are dose dependent; low doses of epoprostenol may cause a vagally mediated bradycardia while high doses of the drug cause a reflex tachycardia secondary to direct vasodilation and hypotension.1,60 Epoprostenol and synthetic prostacyclin analogs may have antiproliferative effects, including inhibition of fibromuscular proliferation of the intima of precapillary arteries which may be involved in the pathogenesis of pulmonary hypertension.2,5,9,18,19,20,22,25,26,27,32,35 Major effects on cardiac conduction have not been reported.1,60 Additional pharmacologic effects of epoprostenol observed in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.1,60

Since epoprostenol is unstable at pH values below 10.2-10.8 (for Flolan^®) and 11-13 (for the Veletri^® preparation), oral administration is not possible and continuous IV administration is necessary, because of the drug's short half-life (about 6 minutes).1,2,5,9,15,18,22,30,60 Administration of the drug is complex, because of the requirements for continuous IV infusion (using permanent indwelling catheters), drug reconstitution by patients, operation of infusion pump, and protection from light.2,5,7,15,18,22,28 The benefits of epoprostenol therapy in patients with pulmonary arterial hypertension (e.g., improvement in survival, exercise capacity, and quality of life assessments) and the logistical issues associated with drug's administration have led to the development of more stable synthetic prostacyclin analogs with similar pharmacologic actions and less complicated routes of administration (e.g., iloprost by oral inhalation, treprostinil by continuous subcutaneous infusion).5,13,15,18,30

Epoprostenol is rapidly hydrolyzed at neutral pH in plasma and also undergoes enzymatic degradation.1,60 Chemical assays with sufficient sensitivity and specificity to assess the in vivo pharmacokinetics of epoprostenol in humans are not currently available.1,60 Epoprostenol is metabolized to 2 major metabolites, 6-keto-PGF_1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF_1α (formed by enzymatic degradation), which appear to have minimal pharmacological activity based on laboratory animal data.1,60 In addition, 14 minor metabolites have been isolated from urine.1,60 Following IV administration of radiolabeled epoprostenol in adults, 82 and 4% of the total radioactivity was recovered in urine and feces, respectively, over 7 days.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 Flolan^® 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.

1. GlaxoSmithKline. Flolan^® (epoprostenol sodium for injection) prescribing information. Research Triangle Park, NC; 2021 Augr.

2. Herner SJ, Mauro LS. Epoprostenol in primary pulmonary hypertension. Ann Pharmacotherapy . 1999; 33:340-7.

4. Food and Drug Administration. Search orphan drug designations and approvals. From FDA web site. Accessed 2006 Jul 12. [Web]

5. Barst RJ, Rubin LJ, Long WA et al for the Primary Pulmonary Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.. N Engl J Med . 1996; 334:296-301. [PubMed 8532025]

6. Badesch DB, Tapson VF, McGoon MD et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med . 2000; 132:425-34. [PubMed 10733441]

7. Rubin LJ, Mendoza J, Hood M et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med . 1990; 112:485-91. [PubMed 2107780]

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