Epoprostenol Sodium

Class: Vasodilating Agents
VA Class: HS875
CAS Number: 61849-14-7
Brands: Flolan, Veletri

Introduction

Vasodilator and platelet-aggregation inhibitor; a naturally occurring prostaglandin.1 2 5 10 21 41

Uses for Epoprostenol Sodium

Pulmonary Arterial Hypertension

Management of pulmonary arterial hypertension (PAH; WHO group 1) to improve exercise capacity; efficacy established principally in patients with NYHA/WHO functional class III or IV PAH (idiopathic, heritable, or associated with connective tissue diseases).1 5 6 14 48 60 61 Has been designated an orphan drug by FDA for treatment of PAH.4

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Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class III or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.52 56 Generally considered treatment of choice for patients with NYHA/WHO class IV PAH because of demonstrated benefit on survival.52

Individualize choice of PAH therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.8 48 52 56

In patients with inadequate response to initial monotherapy, may consider combination therapy with an endothelin-receptor antagonist, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially).52 Such combination therapy may provide additive and/or synergistic benefits by targeting different pathophysiologic pathways of disease.52 53 54 55

Safety and efficacy not systematically evaluated in patients with pulmonary hypertension associated with diseases other than scleroderma.1

Epoprostenol Sodium Dosage and Administration

Administration

Restricted Distribution

Epoprostenol and controlled-infusion device used for drug administration available only through specialty pharmacies.3 62 Contact manufacturers for specific information.3 70

IV Administration

For IV infusion only.1 8 10 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 (See Abrupt Withdrawal under Cautions.) Consider use of a multi-lumen catheter if patient receives other IV drugs routinely.1 60

The epoprostenol sodium formulation containing sucrose and arginine excipients (Veletri) has prolonged stability compared with formulations containing glycine and mannitol (e.g., Flolan); however, these formulations are similar in terms of pharmacokinetic and pharmacodynamic effects.1 60 61 62 65 68

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 61 See manufacturer’s labeling for details on reconstitution, preparation of solutions, and selection of drug concentration in solutions.1 60 61

Reconstitute epoprostenol sodium lyophilized powder for injection (Flolan or Teva generic preparation) only with sterile diluent provided by the respective manufacturer; do not reconstitute or mix with other parenteral solutions or medications.1 61 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

Following reconstitution (Flolan or generic preparation by Teva), administer immediately or store under refrigeration at 2–8°C for ≤40 hours (if room temperature administration is planned) or ≤24 hours (if administration with a cold pouch is planned); protect solution from light.1 61 (See Storage under Stability.) May administer reconstituted solution for ≤8 hours at room temperature or for ≤24 hours with a cold pouch.1 Change gel packs in cold pouch every 12 hours.1

Reconstitute Veletri lyophilized powder for injection 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 of Veletri, 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 62 65 66 (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 65

Table 1. Maximum Duration of Infusion of Veletri Solutions at Room Temperature (25°C)*60

Final Concentration (ng/mL)

Immediate Administration

Administration After Storage at 2–8°C for ≤8 Days

≥3000 to <15,000 (prepared using 0.5-mg vial)

48 hours

24 hours

≥15,000 to <60,000 (prepared using 1.5-mg vials)

48 hours

48 hours

≥60,000 (prepared using 1.5-mg vials)

72 hours

48 hours

Table 2. Maximum Duration of Infusion of Veletri Solutions at Temperatures ≤40°C60

Final Concentration (ng/mL)

Temperatures

Immediate Administration

Administration After Storage at 2–8°C for ≤8 Days

<60,000

>25°C to 30°C

24 hours

24 hours

≥60,000

>25°C to 30°C

48 hours

48 hours

≥60,000

>30°C and ≤40°C

24 hours

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 61

Avoid abrupt discontinuance or sudden large reductions in infusion rates.1 10 12 60 61 (See Abrupt Withdrawal under Cautions.) Consult manufacturer’s labeling for specific instructions on selection of infusion rate and drug concentration.1 60 61

Dosage

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

Considerable interindividual variability in patient response; individualize dosage.7 8 10 41 48

Titrate dosages carefully until desired therapeutic effect achieved or intolerable adverse effects occur.1 10 60 61

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 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 10 12 60 (See Abrupt Withdrawal under Cautions.)

Prolonged therapy may cause tachyphylaxis and require periodic dosage adjustments.7 10 35 41 47 (See Dosage Titration under Cautions.)

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

Limited data suggest that patients who are stable on Flolan therapy may be transitioned directly to the Veletri preparation at the same dosage without any change in clinical efficacy or tolerability.66 67

Special Populations

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 Sodium

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.1 60

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

Warnings/Precautions

Warnings

Solution and Drug Compatibility

Reconstitute and dilute using only the appropriate diluent specified by the manufacturer.1 60 61 (See Reconstitution and Dilution under Dosage and Administration.) Do not admix or infuse in the same IV line with other solutions or drugs.1 60

Abrupt Withdrawal

Avoid abrupt discontinuance or sudden large reductions in dosage.1 10 12 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, and/or death.1 8 10 19 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 47 60

Sepsis

Aseptic technique must be used in routine catheter care and in the reconstitution and administration of drug solutions.1 64 Local infection and sepsis associated with drug delivery system (long-term indwelling central venous catheter) reported.1 2 5 10 11 12 19 28 41 60

General Precautions

Use Restrictions

Should be used only by qualified clinicians experienced in the diagnosis and management of PAH.1 23 60 Carefully establish the diagnosis of PAH before use.1 60

Consider referral of patients to specialized centers experienced in the management of pulmonary vascular diseases.10 11 16 18 23 31

Decision to initiate therapy must include careful consideration of the high likelihood that therapy will be needed for prolonged periods, possibly years, and of the patient’s ability to accept and care for a permanent IV catheter and infusion device.1 60

Initial dosage titration should be performed in a medically supervised setting adequately equipped for physiologic monitoring and emergency care.1 60

Increases in Pulmonary Arterial Pressure

Asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output reported rarely during initial dosage titration; such increases in pulmonary artery pressure do not necessarily preclude long-term therapy and may be controlled with dosage reduction.1 60

Initial dosage titration has been performed with and without right heart catheterization in clinical studies.1 41 60

Hematologic Effects

Inhibits platelet aggregation; potential risk of hemorrhage, particularly in patients with increased risk of bleeding (e.g., concomitant antiplatelet or anticoagulant therapy, congenital heart disease, scleroderma).1 45 46 48 60

Prophylaxis of Thromboembolism

Unless contraindicated, administer concomitant anticoagulant therapy to reduce the risk of pulmonary thromboembolism or systemic embolism associated with the permanent indwelling central venous catheter.1 16 18 23 31 36 47 48 60

Weigh benefits versus risks of anticoagulation, particularly in patients with increased risk of bleeding.1 48 (See Hematologic Effects under Cautions.)

Dosage Titration

Dosage adjustments during long-term use should be made immediately upon occurrence of dose-limiting adverse effects or worsening of symptoms associated with pulmonary hypertension.1 60 Following dosage adjustments, standing and supine BP and heart rate should be monitored closely for several hours.1 60 (See Dosage and Administration.)

Aggressive dosage titrations to overcome tachyphylaxis may result in elevated cardiac output and/or high output heart failure.47 48 Monitor PAH symptoms, exercise capacity, adverse effects, and hemodynamic function frequently when making dosage adjustments.1 47 48 60 Some experts recommend that periodic cardiac catheterizations be considered to prevent underdosing or overdosing of drug.47 48 Weigh risks versus benefits of cardiac catheterization.1 60

Specific Populations

Pregnancy

Category B.1 60

Safety and efficacy during labor, vaginal delivery, or cesarean section have not been established.1 60

Lactation

Not known whether epoprostenol is distributed into milk; use with caution in nursing women.1 60

Pediatric Use

Safety and efficacy not established in pediatric patients.1 43 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 with idiopathic or heritable PAH:1 60 61 dizziness,1 2 60 61 headache,1 2 5 7 8 9 10 11 12 18 20 60 61 nausea,1 2 6 8 9 10 11 20 60 61 vomiting,1 2 5 9 11 20 60 61 jaw pain,1 5 6 7 8 9 10 11 12 18 20 60 61 myalgia,1 60 61 flushing,1 2 5 7 8 9 10 18 20 60 61 diarrhea,1 5 6 7 8 9 10 11 12 60 61 tachycardia,1 2 60 nonspecific musculoskeletal pain,1 2 10 11 12 18 20 60 chills/fever/sepsis/flu-like symptoms,1 60 61 anxiety/nervousness/tremor,1 60 61 hypoesthesia/hyperesthesia/paresthesia.1 60 61

Patients with PAH associated with the scleroderma spectrum of diseases: pain/neck pain/arthralgia,1 60 61 jaw pain,1 60 61 anorexia,1 60 61 diarrhea,1 60 61 headache,1 60 61 nausea/vomiting,1 60 61 skin ulcer,1 60 61 eczema/rash/urticaria,1 60 61 flushing,1 60 61 hypotension.1 60 61

Interactions for Epoprostenol Sodium

In clinical studies, epoprostenol was used concomitantly with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.1 5 6 7 19 20 60 61

Specific Drugs

Drug

Interaction

Comments

Anticoagulants

Potential for increased risk of bleeding1 60 61

Antiplatelet agents

Potential for increased risk of bleeding1 60 61

Digoxin

Potential decreased clearance of digoxin; possible digoxin toxicity1 60 61

Clinically important elevations in digoxin concentration may occur upon initiation of epoprostenol therapy in patients prone to digoxin toxicity1 60 61

Diuretics

Potential decreased clearance of furosemide1 60 61

Possible additive hypotensive effect1 60 61

Changes in furosemide clearance not considered clinically important1 60 61

Hypotensive agents

Possible additive hypotensive effect1 60 61

Vasodilators

Possible additive hypotensive effect1 60 61

Epoprostenol Sodium Pharmacokinetics

Chemical assays with sufficient sensitivity and specificity to assess the in vivo pharmacokinetics of epoprostenol in humans not currently available.1 60 61

Distribution

Extent

Animal studies indicate a small volume of distribution (357 mL/kg).1 60 61

Elimination

Metabolism

Rapidly hydrolyzed at neutral pH in blood and also subject to enzymatic degradation.1 2 60 61 Metabolized to 2 primary metabolites, 6-keto-PGF (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF (enzymatically formed); data in animals indicate that both metabolites have pharmacologic activity orders of magnitude less than parent drug.1 2 60 61 Extensively metabolized; 14 additional minor metabolites isolated from urine.1 60 61

Elimination Route

82% in urine and 4% in feces.1 2 60 61

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 10 60 61

2.7 minutes (animals).1 60 61

Special Populations

No gender difference observed in in vitro (human plasma) half-life based on inhibition of platelet aggregation.1 60 61

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

Epoprostenol sodium injection (generic by Teva): 15–30°C in original carton; protect from light.61 Store diluent for epoprostenol sodium for injection at 20–25°C; do not freeze.61

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

Reconstituted solutions of Flolan and epoprostenol sodium (generic by Teva): Store at 2–8°C for ≤48 hours; protect from light and do not freeze.1 61 Discard solutions if frozen or stored at 2–8°C for >48 hours.1 (See Reconstitution and Dilution under Dosage and Administration.)

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 64 65 (See Reconstitution and Dilution under Dosage and Administration.)

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug and Solution Compatibility

Do not dilute or administer with other parenteral solutions or drugs.1 60 61

Actions

  • Direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.1 2 10 60 61

  • May have antiproliferative effects on the intimal layer of precapillary arteries.2 5 8 9 11 12 18 19 20 22 25 26 27 31 32 35 41

  • Produces dose-related increases in cardiac index and stroke volume.1 2 41 60 61

  • Produces dose-related decreases in pulmonary vascular resistance, total pulmonary resistance, and mean systemic arterial pressure.1 2 41 60 61

  • Associated with improvement in survival, exercise capacity, and quality of life assessments.1 2 5 6 47 48 60 61

  • 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 61

  • No major effects on cardiac conduction in animals.1 60 61

  • Additional pharmacologic effects observed in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.1 60 61

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 61

  • Importance of advising patient that therapy probably will be needed for prolonged periods, possibly years.1 60 61

  • Importance of careful consideration of patient’s ability to accept and care for a permanent central venous catheter and infusion device.1 60 61

  • 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 10 60 61

  • Importance of advising patient that sterile technique must be adhered to in drug preparation and catheter care to prevent sepsis.1 60 61 64

  • Importance of reconstitution only with the appropriate diluent specified by the manufacturer.1 60 61

  • Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 60 61

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 60 61

  • Importance of informing patients of other important precautionary information.1 60 61 (See Cautions.)

Preparations

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

Epoprostenol sodium for injection is available only through specialty pharmacies. (See Restricted Distribution under Dosage and Administration.)

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

Epoprostenol Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

0.5 mg (of epoprostenol)*

Epoprostenol Sodium for Injection (available with diluent)

Flolan (available with diluent)

GlaxoSmithKline

Veletri

Actelion

1.5 mg (of epoprostenol)*

Epoprostenol Sodium for Injection (available with diluent)

Flolan (available with diluent)

GlaxoSmithKline

Veletri

Actelion

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 4, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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