Epoprostenol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Flolan: 0.5 mg (1 ea); 1.5 mg (1 ea)

Veletri: 0.5 mg (1 ea); 1.5 mg (1 ea)

Generic: 0.5 mg (1 ea); 1.5 mg (1 ea)

Pharmacology

Mechanism of Action

Epoprostenol is also known as prostacyclin and PGI₂. It is a strong vasodilator of all vascular beds. In addition, it is a potent endogenous inhibitor of platelet aggregation. The reduction in platelet aggregation results from epoprostenol's activation of intracellular adenylate cyclase and the resultant increase in cyclic adenosine monophosphate concentrations within the platelets. Additionally, it is capable of decreasing thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.

Pharmacokinetics/Pharmacodynamics

Metabolism

Rapidly hydrolyzed; subject to some enzymatic degradation; forms two active metabolites (6-keto-prostaglandin F₁α and 6,15-diketo-13,14-dihydro-prostaglandin F₁α) with minimal activity and 14 inactive metabolites

Excretion

Urine (84%); feces (4%)

Half-Life Elimination

~6 minutes

Use: Labeled Indications

Pulmonary arterial hypertension: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in patients with NYHA Class III or IV symptoms to improve exercise capacity. Note: According to treatment guidelines from the Fifth World Symposium on Pulmonary Hypertension (WSPH) and the American College of Chest Physicians (ACCP), continuous IV epoprostenol is recommended as first-line therapy in PAH patients with WHO-FC IV symptoms (ACCP [Taichman 2014]; WSPH [Gailè 2013]).

Use: Off Label

Acute vasodilator testing in pulmonary arterial hypertensionyes

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Expert Consensus Document on Pulmonary Hypertension and the Fifth World Symposium on Pulmonary Hypertension (WSPH) updated treatment algorithm of pulmonary arterial hypertension (PAH), epoprostenol may be used as an alternative agent (inhaled nitric oxide is preferred) for acute vasodilator testing to identify those patients with PAH with a better prognosis and who will likely have a sustained response to oral calcium channel blockers (eg, high-dose extended-release nifedipine) which have been shown to increase survival. Response to acute vasodilator testing is currently defined as a reduction in mean pulmonary artery pressure (mPAP) of ≥10 mm Hg, to an absolute mPAP <40 mm Hg, with an unchanged or increased cardiac output. Of note, acute vasodilator testing is not recommended and may be harmful in patients with significantly elevated left heart filling pressures.

Guidelines from the European Society of Cardiology and the European Respiratory Society recommends testing only in patients with idiopathic, heritable, or drug-induced PAH ESC/ERS [Galiè 2016].

Hypoxia secondary to acute respiratory distress syndromec

Data from a limited number of patients studied suggest that inhaled epoprostenol (iEPO) may be beneficial for the treatment of hypoxia secondary to ARDS. In these two small retrospective studies, iEPO was found to be equal to iNO for this indication Ammar 2015, Torbic 2013. Additional data may be needed to define the role of iEPO in this condition.

Pulmonary arterial hypertension related to cardiopulmonary bypassb

Note: The formulation of the sterile diluent for Flolan has been modified to a pH of 12. The Flolan used in clinical trials for this indication was prepared using the original sterile diluent with a pH of 10. It is unknown whether or not the higher pH Flolan is safe to use via the inhalational route. However, in a retrospective single center study, the use of Veletri (formulated to a higher pH of 11 to 13) has been found to be no different when comparing change in the PaO2/FiO2 ratio, safety, and cost in critically-ill mechanically ventilated patients Torbic 2016.

Inhaled (off-label route) epoprostenol has been evaluated in 2 prospective, randomized, double-blind trials (one placebo-controlled) in cardiac surgery patients with pulmonary arterial hypertension to reduce pulmonary artery pressures (PAP) in both pulmonary hypertension patients undergoing cardiac surgery Fattouch 2006, Hache 2003 and in a prospective, open-label trial in postoperative cardiac surgery patients who have developed pulmonary hypertension, right heart dysfunction, or refractory hypoxemia De Wet 2004. Epoprostenol is effective in reducing PAP and improving oxygenation although one study did not demonstrate a significant reduction in mean PAP but did show a significant reduction in systolic PAP. Inhaled epoprostenol does not produce systemic manifestations such as hypotension at doses ≤50 ng/kg/minute and may be a cost effective strategy compared to inhaled nitric oxide in both of these patient populations McGinn 2016, Van Heerden 2000. Additional trials may be necessary to further define the role of inhaled epoprostenol in this setting.

Contraindications

Hypersensitivity to epoprostenol, to structurally related compounds, or any component of the formulation; chronic use in patients with heart failure due to severe left ventricular systolic dysfunction; chronic use in patients who develop pulmonary edema during dose initiation (Caripul [Canadian product], Flolan [Canadian product], and Veletri only).

Dosage and Administration

Dosing: Adult

Pulmonary arterial hypertension (PAH): IV: Initial: 2 ng/kg/minute; a lower initial dose may be used if patient is intolerant of starting dose. Increase dose in increments of 1 to 2 ng/kg/minute at intervals of ≥15 minutes until dose-limiting side effects (eg, flushing, jaw pain, headache, hypotension, nausea) are noted or response to epoprostenol plateaus. The dose may also be lowered by 1 to 2 ng/kg/minute every 15 minutes to a dose that is tolerated (Bishop 2012). Usual optimal dose (monotherapy): 25 to 40 ng/kg/minute (McLaughlin 2009); significant patient variability in optimal dose exists. Maximum dose with chronic therapy has not been defined; however, doses as high as 195 ng/kg/minute have been described in children (Rosenzweig 1999).

Dose adjustment during chronic phase of treatment:

If PAH symptoms persist or recur following improvement, increase dose in 1 to 2 ng/kg/minute increments at intervals of ≥15 minutes. May also increase dose at intervals of 24 to 48 hours or longer (eg, every 1 to 2 weeks). Note: The need for increased doses should be expected with chronic use; incremental increases occur more frequently during the first few months after the drug is initiated.

In case of dose-limiting pharmacologic events (eg, hypotension, severe nausea, vomiting), decrease dose in 2 ng/kg/minute decrements at intervals of ≥15 minutes until dose-limiting effects resolve. Avoid abrupt withdrawal or sudden large dose reductions. Note: Adverse event may resolve without dosage adjustment.

Lung transplant: In patients receiving lung transplants, epoprostenol may be tapered after sequential lung transplantation once the allografts have been reperfused. If cardiopulmonary bypass utilized, epoprostenol may be tapered after pump perfusion has been initiated.

Acute vasodilator testing in patients with PAH (off-label use): Note: Acute vasodilator testing should only be done in patients who might be considered candidates for calcium channel blocker therapy.

IV: Initial: 2 ng/kg/minute; increase dose in increments of 2 ng/kg/minute every 10 to 15 minutes; dosing range during testing: 2 to 12 ng/kg/minute (ACC/AHA [McLaughlin 2009]; ESC/ERS [Galiè 2016])

Hypoxia secondary to acute respiratory distress syndrome (off-label use): Inhalation (off-label): Initial: 0.01 to 0.05 mcg/kg/minute; increase dose in stepwise fashion based on efficacy and tolerability. Wean by reducing dose by 0.01 mcg/kg/minute every 1 to 2 hours as tolerated (Ammar 2015; Torbic 2013).

Intraoperative pulmonary hypertension during cardiac surgery with cardiopulmonary bypass (CPB) (off-label use): Inhalation (off-label route): Note: Institution-specific protocols vary. Studies included utilized Flolan brand; however, formulary status of epoprostenol formulations may vary with some institutions utilizing Veletri, the more thermostable formulation.

Administration after induction of anesthesia before incision: 60 mcg (4 mL of 15,000 ng/mL concentration) via jet nebulizer; effect persists for ~25 minutes (Hache 2003)

or

Intraoperative administration: Nebulization via ventilator circuit: Using a 15,000 ng/mL concentration and an oxygen flow of 8 L/minute, begin administration via jet nebulizer 5 minutes prior to weaning from CPB; discontinue at least 60 minutes after CPB weaned (Fattouch 2006)

Post-cardiothoracic surgery pulmonary hypertension, right ventricular dysfunction, or refractory hypoxemia (off-label use) (DeWet 2004): Inhalation (off-label route): Study utilized Flolan brand; however, formulary status of epoprostenol formulations may vary with some institutions utilizing Veletri, the more thermostable formulation. If using Flolan, may need to change ventilator filter every 2 hours due to glycine buffer diluent ; may cause ventilator valve malfunction. Tidal volume delivered by ventilator may require adjustment.

Nebulization via ventilator circuit: Using a 20,000 ng/mL concentration, prime nebulizer chamber with 15 mL; administer remainder at a constant rate of 8 mL/hour; delivers ~38 ng/kg/minute (based on a 70 kg patient); set oxygen flow at 2 to 3 L/minute; wean as tolerated. Note: Although not achieved with this regimen, in general, doses >50 ng/kg/minute do not provide additional benefit, may increase the risk of hypotension, and should be avoided.

or

Nebulization via facemask with Venturi attachment: Using a 20,000 ng/mL concentration, prime nebulizer chamber with 15 mL; set oxygen flow at 2 to 3 L/minute; 8 mL/hour will be nebulized; wean as tolerated.

Weaning procedure: Reduce dose by 50% every 2 to 4 hours (ie, 20,000 ng/mL to 10,000 ng/mL to 5,000 ng/mL) until a concentration of 2,500 ng/mL is reached; carefully discontinue once patient remains stable on this concentration for at least 4 hours.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Doses are expressed in units of nanograms (ng)/kg/minute.

Pulmonary hypertension: Limited data available: Infants, Children, and Adolescents:

Continuous IV infusion: Initial: 1 to 2 nanograms/kg/minute; titrate to clinical effect (eg, improvement in pulmonary pressures or right ventricular mechanics) or dose-limiting side effects (eg, nausea, diarrhea, jaw pain, bone pain, headache); average effective dose: 80 nanograms/kg/minute; dose range: 40 to >150 nanograms/kg/minute in some patients. Note: Excessive epoprostenol can lead to a high-output state (hyperdynamic right ventricle with impact on cardiac output) and require a decrease in dose (AHA/ATS [Abman 2015]).

Inhalation: Very limited data available; efficacy results vary with patient age and etiology of pulmonary hypertension. Other factors that may impact efficacy include product formulation (eg, pH, dilution, stability) and the drug delivery system (eg, type of nebulizer, placement in ventilator circuit, ventilator settings) (Davis 2017).

Continuous nebulization: 20 to 50 nanograms/kg/minute; dosing based on a small prospective trial of 14 children (median age: 54 months) with acute lung injury who received either aerosolized saline or inhaled epoprostenol administered in incremental doses (10, 20, 30, 40, and 50 nanograms/kg/minute); significant improvement of the oxygenation index was observed at the 30 nanograms/kg/minute dose level and values close to significant at the 20, 40, and 50 nanograms/kg/minute dose were observed; eight of the 14 children were considered responders to therapy with an improvement in oxygenation, and the calculated number needed to treat was 1.8 (95% CI, 1.2 to 3.2); during the trial, no significant changes in respiratory or systemic cardiovascular variables (eg, HR, MAP, arterial pH) or ventilator settings were reported (Dahlem 2004). A very small retrospective descriptive analysis (n=20, infants: n=7) using a dose of 50 nanograms/kg/minute reported minimal decrease in oxygenation index (baseline: 29.6 ± 15; with inhaled epoprostenol: 25.6 ± 17.8); however, the subset of term neonates (n=13) experienced significant improvement in oxygenation index and echocardiogram findings (Brown 2012).

Reconstitution

Table has been converted to the following text.

Preparation of Epoprostenol Infusion

Note: Flolan may only be prepared with sterile diluent provided. If using pH 12 sterile diluent for Flolan, then avoid materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG) for preparation. Veletri or Caripul may only be prepared with sterile water for injection (SWFI) or NS.

To make solution with the following concentrations:

3000 ng/mL:

Flolan: Dissolve one 0.5 mg vial with 5 mL supplied diluent, withdraw 3 mL, and add to a sufficient volume of supplied diluent to make a total of 100 mL.

Veletri, Caripul: Dissolve one 0.5 mg vial with 5 mL of SWFI or NS, withdraw 3 mL, and add to a sufficient volume of the identical diluent to make a total of 100 mL.

5000 ng/mL:

Flolan: Dissolve one 0.5 mg vial with 5 mL supplied diluent, withdraw entire vial contents, and add to a sufficient volume of supplied diluent to make a total of 100 mL.

Veletri, Caripul: Dissolve one 0.5 mg vial with 5 mL of SWFI or NS, withdraw entire vial contents, and add to a sufficient volume of the identical diluent to make a total of 100 mL.

10,000 ng/mL:

Flolan: Dissolve two 0.5 mg vials each with 5 mL supplied diluent, withdraw entire vial contents, and add to a sufficient volume of supplied diluent to make a total of 100 mL.

Veletri, Caripul: Dissolve two 0.5 mg vials each with 5 mL of SWFI or NS, withdraw entire vial contents, and add to a sufficient volume of the identical diluent to make a total of 100 mL.

15,000 ng/mL:

Flolan: Dissolve one 1.5 mg vial with 5 mL supplied diluent, withdraw entire vial contents, and add to a sufficient volume of supplied diluent to make a total of 100 mL.

Veletri, Caripul: Dissolve one 1.5 mg vial with 5 mL of SWFI or NS, withdraw entire vial contents, and add to a sufficient volume of the identical diluent to make a total of 100 mL.

20,000 ng/mL: Flolan: Dissolve two 0.5 mg vials each with 5 mL supplied diluent, withdraw entire vial contents, and add to a sufficient volume of supplied diluent to make a total of 50 mL (DeWet, 2004).

30,000 ng/mL: Veletri, Caripul: Dissolve two 1.5 mg vials each with 5 mL of SWFI or NS, withdraw entire vial contents, and add to a sufficient volume of the identical diluent to make a total of 100 mL.

Administration

IV: For IV use via an infusion pump. Use infusion sets with an in-line 0.22 micron filter. When administered on an ongoing basis, must be infused through a central venous catheter. Peripheral infusion may be used temporarily until central line is established. Do not administer as a bolus injection. Avoid abrupt withdrawal (including interruptions in delivery) or sudden large reductions in dosing. The ambulatory infusion pump should be small and lightweight, be able to adjust infusion rates in 2 ng/kg/minute increments, have occlusion, end of infusion, and low battery alarms, have ± 6% accuracy of the programmed rate, and have positive continuous or pulsatile pressure with intervals ≤3 minutes between pulses. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Immediate access to back up pump, infusion sets and medication is essential to prevent treatment interruptions. Consult manufacturer’s labeling for infusion rate example calculations.

Flolan-specific administration considerations: If Flolan reconstituted using pH 12 sterile diluent for Flolan, then avoid administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG); consult administration set manufacturer to confirm compatibility with highly alkaline solutions (eg, pH 12 sterile diluent for Flolan).

Inhalation (off-label route):

Intraoperative administration: Administer via jet nebulizer connected to the inspiratory limb of the ventilator near the endotracheal tube with a bypass oxygen flow of 8 L/minute to achieve administration of a high proportion of small particles (Fattouch 2006; Hache 2003).

Post-cardiothoracic surgery: May also be administered via jet nebulizer connected to the inspiratory limb of the ventilator near the endotracheal tube or via face mask with a Venturi attachment for aerosolization with a bypass oxygen flow of 2 to 3 L/minute (De Wet 2004). Note: Glycine buffer diluent may cause ventilator valve malfunction; it has been recommended that filters be changed on the ventilator every 2 hours; may also use a ventilator heating coil (De Wet 2004).

Storage

Flolan: Prior to use, store intact vials and diluent at 15°C to 25°C (59°F to 77°F); do not freeze. Protect from light. Following reconstitution, solution must be stored at 2°C to 8°C (36°F to 46°F) if not used immediately; do not freeze. Protect from light. Storage and administration limits for reconstituted solution are dependent on type of diluent use during reconstitution:

Sterile diluent for Flolan: When used at 15°C to 25°C (59°F to 77°F), reconstituted solutions are stable for up to 8 hours following reconstitution or removal from refrigerator. May also be stored for up to 40 hours at 2°C to 8°C (36°F to 46°F) before use. When used with a cold pack, reconstituted solutions are stable for up to 24 hours; may also be stored at 2°C to 8°C (36°F to 46°F) before use as long as the total time of refrigerated storage and infusion does not exceed 48 hours. Change cold packs every 12 hours.

pH 12 sterile diluent for Flolan: Freshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2°C to 8°C (36°F to 46°F) for no longer than 8 days can be administered up to 72 hours at up to 25°C (77°F); 48 hours at up to 30°C (86°F); 24 hours at up to 35°C (95°F); 12 hours at up to 40°C (104°F).

Veletri: Prior to use, store intact vials at 20°C to 25°C (68°F to 77°F); do not freeze. Protect from light. Reconstituted vials must be further diluted prior to use.

Caripul [Canadian product]: Prior to use, store intact vials at 15°C to 30°C (59°F to 86°F); do not freeze. Reconstituted vials must be further diluted prior to use.

Reconstituted solutions of Veletri or Caripul immediately diluted with NS to a final concentration within a drug delivery reservoir may be administered immediately or stored at 2°C to 8°C (36°F to 46°F) for up to 8 days; do not freeze. Protect from light.

If administered immediately, the following maximum durations of administration at room temperature (25°C [77°F]) according to solution concentration are recommended:

US labeling (Veletri):

3,000 to <15,000 ng/mL: 48 hours

15,000 to <60,000 ng/mL: 48 hours

≥60,000 ng/mL: 72 hours

Canadian labeling (Caripul):

3,000 to <15,000 ng/mL: 48 hours

≥15,000: 48 hours

If stored at 2°C to 8°C (36°F to 46°F) for up to 8 days, the following maximum durations of administration at room temperature (25°C [77°F]) according to solution concentration are recommended:

3,000 to <15,000 ng/mL: 24 hours

15,000 to <60,000 ng/mL: 48 hours

≥60,000 ng/mL: 48 hours

Short excursions at 40°C (104°F) are permitted as follows:

Solution concentration <15,000 ng/mL: Up to 2 hours

Solution concentration 15,000 to <60,000 ng/mL: Up to 4 hours

Solution concentration ≥60,000 ng/mL: Up to 8 hours

The following maximum durations of administration at temperatures >25°C to 40°C (>77°F up to 104°F) administered either immediately or after up to 8 days storage at 2°C to 8°C (36°F to 46°F) according to solution concentration are recommended:

Use at temperature >25°C to 30°C (>77°F up to 86°F):

US labeling (Veletri):

<60,000 ng/mL: 24 hours

≥60,000 ng/mL: 48 hours

Canadian labeling (Caripul): All concentrations: 24 hours

Use at temperature up to 40°C (104°F):

US labeling (Veletri): ≥60,000 ng/mL: 24 hours (immediately administered after preparation)

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Prostacyclin Analogues may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anticoagulants: Prostacyclin Analogues may enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: Prostacyclin Analogues may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Digoxin: Epoprostenol may increase the serum concentration of Digoxin. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Thrombolytic Agents: May enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Flushing (23% to 58%), tachycardia (1% to 43%), hypotension (13% to 27%), chest pain (11%)

Central nervous system: Headache (46% to 83%), dizziness (8% to 83%), chills (≤25%), anxiety (≤21%), nervousness (≤21%), hyperesthesia (≤12%), hypoesthesia (≤12%), paresthesia (≤12%), agitation (11%)

Dermatologic: Dermal ulcer (39%), eczema (≤10% to ≤25%), skin rash (≤10% to ≤25%), urticaria (≤10% to ≤25%)

Gastrointestinal: Nausea and vomiting (32% to 67%), anorexia (25% to 66%), diarrhea (37% to 50%)

Infection: Sepsis (≤25%)

Neuromuscular & skeletal: Musculoskeletal pain (3% to 84%), arthralgia (≤84%), neck pain (≤84%), jaw pain (54% to 75%), myalgia (44%), hyperkinesia (≤21%), tremor (≤21%)

Respiratory: Flu-like symptoms (≤25%)

Miscellaneous: Fever (≤25%)

1% to 10%:

Cardiovascular: Bradycardia (5%)

Dermatologic: Diaphoresis (1%)

Gastrointestinal: Abdominal pain (5%), dyspepsia (1%)

Neuromuscular & skeletal: Back pain (2%)

Respiratory: Dyspnea (2%)

<1%, postmarketing, and/or case reports: Anemia, cardiac failure, fatigue, hemorrhage, hepatic failure, hypersplenism, hyperthyroidism, increased pulmonary artery pressure, pallor, pancytopenia, pulmonary edema, pulmonary embolism, splenomegaly, thrombocytopenia

Warnings/Precautions

Concerns related to adverse effects:

• Pulmonary edema: Some patients with PAH have developed pulmonary edema during dosing adjustment and acute vasodilator testing (an off-label use), which may be associated with concomitant heart failure (LV systolic dysfunction with significantly elevated left heart filling pressures) or pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. If pulmonary edema develops during therapy initiation, discontinue and do not readminister.
• Rebound pulmonary hypertension: Avoid abrupt interruptions or large sudden reductions in dosage; may result in rebound pulmonary hypertension (eg, dyspnea, dizziness, asthenia). A fatal case occurred following interruption. Immediate access to medication or pump and infusion sets is essential to prevent treatment interruptions.
• Vasodilation: Epoprostenol is a potent pulmonary and systemic vasodilator and can cause hypotension and other reactions such as flushing, nausea, vomiting, dizziness, and headache. Monitor blood pressure and symptoms regularly during initiation and after dose change.

Disease-related concerns:

• Conditions that increase bleeding risk: Epoprostenol is a potent inhibitor of platelet aggregation. Use with caution in patients with other risk factors for bleeding.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate Use: Initiation or transition to epoprostenol requires specialized cardiopulmonary monitoring in a critical care setting where clinicians are experienced in advanced management of pulmonary arterial hypertension. To reduce the risk of thromboembolism during chronic use, anticoagulants should be coadministered unless contraindicated.
• Infection: Chronic continuous IV infusion of epoprostenol via a chronic indwelling central venous catheter (CVC) has been associated with local infections and serious blood stream infections.

Monitoring Parameters

Monitor for improvements in pulmonary function, decreased exertional dyspnea, fatigue, syncope and chest pain, blood pressure, pulmonary vascular resistance, pulmonary arterial pressure and quality of life. Following establishment of a new chronic infusion rate, measure standing and supine blood pressure for several hours. In addition, the pump device and catheters should be monitored frequently to avoid “system” related failure. Monitor arterial pressure; assess all vital functions. Hypoxia, flushing, and tachycardia may indicate overdose.

Pregnancy

Pregnancy Considerations

Information related to the use of epoprostenol in pregnancy is limited (Geohas 2003; Kawabe 2018; Martinez 2013; Smith 2012; Timofeev 2013); however, the manufacturer notes adverse maternal or fetal outcomes have not been associated with its use based on the available data.

Untreated pulmonary arterial hypertension (PAH) is associated with adverse pregnancy outcomes, including heart failure, stroke, preterm delivery, and maternal and fetal death.

Patient Education

What is this drug used for?

• It is used to treat high blood pressure in the lungs.

Frequently reported side effects of this drug

• Anxiety
• Back pain
• Diarrhea
• Flushing
• Lack of appetite
• Jaw pain
• Bone pain
• Muscle pain
• Joint pain
• Nausea
• Vomiting
• Flu-like symptoms

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Shortness of breath
• Severe dizziness
• Passing out
• Severe headache
• Dark urine
• Chest pain
• Fast heartbeat
• Slow heartbeat
• Abnormal heartbeat
• Pale skin
• Tremors
• Abnormal movements
• Severe loss of strength and energy
• Burning or numbness feeling
• Abdominal edema
• Skin sores
• Injection site redness
• Edema
• Severe irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.