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Pronunciation:

(e poe PROST en ole)

U.S. Brand Names:

Flolan®

Synonyms:

Epoprostenol Sodium; PGI2; PGX; Prostacyclin

Generic Available:

Canadian Brand Names:

Flolan®

Use:

Orphan drug: Treatment of primary pulmonary hypertension; treatment of secondary pulmonary hypertension due to intrinsic precapillary pulmonary vascular disease

Use - Unlabeled/Investigational:

Other potential uses include pulmonary hypertension associated with ARDS, SLE, or CHF; neonatal pulmonary hypertension; cardiopulmonary bypass surgery; hemodialysis; atherosclerosis; peripheral vascular disorders; and neonatal purpura fulminans

Restrictions:

Orders for epoprostenol are distributed by two sources in the United States. Information on orders or reimbursement assistance may be obtained from either Accredo Health, Inc (1-800-935-6526) or TheraCom, Inc (1-877-356-5264).

Pregnancy Risk Factor:

Lactation:

Excretion in breast milk unknown

Contraindications:

Hypersensitivity to epoprostenol or to structurally-related compounds; chronic use in patients with CHF due to severe left ventricular systolic dysfunction

Warnings/Precautions:

Abrupt interruptions or large sudden reductions in dosage may result in rebound pulmonary hypertension; some patients with primary pulmonary hypertension have developed pulmonary edema during dose ranging, which may be associated with pulmonary veno-occlusive disease; during chronic use, unless contraindicated, anticoagulants should be coadministered to reduce the risk of thromboembolism

Adverse Reactions:

<1%, postmarketing, and/or case reports: Anemia, hypersplenism, hyperthyroidism, pancytopenia, splenomegaly

Overdosage/Toxicology:

Symptoms of overdose include headache, hypotension, tachycardia, nausea, vomiting, diarrhea, and flushing. If any of these symptoms occur, reduce the infusion rate until symptoms subside. If symptoms do not subside, consider drug discontinuation. No fatal events have been reported following overdose with epoprostenol.

Drug Interactions:

Antihypertensive agents: The hypotensive effects of epoprostenol may be exacerbated by other vasodilators, diuretics, or by using acetate in dialysis fluids.

Antiplatelet agents (aspirin, IIb/IIIa antagonists, clopidogrel, ticlopidine): Risk of bleeding may be increased

Digoxin: Serum levels may be increased; clearance decreased by 15%; monitor

Furosemide: Serum levels may be increased; clinical significance low; clearance decreased by 13%

Heparin (including low molecular weight heparins): Risk of bleeding may be increased

Warfarin: Risk of bleeding may be increased

Stability:

Refrigerate ampuls; protect from freezing; prepare fresh solutions every 24 hours; stable only when reconstituted with the diluent solution packaged with the medication. See table.

Compatibility:

Preparation of Epoprostenol Infusion

To make 100 mL of solution with concentration:	Directions
3000 ng/mL	Dissolve one 0.5 mg vial with 5 mL supplied diluent, withdraw 3 mL, and add to sufficient diluent to make a total of 100 mL.
5000 ng/mL	Dissolve one 0.5 mg vial with 5 mL supplied diluent, withdraw entire vial contents, and add a sufficient volume of diluent to make a total of 100 mL.
10,000 ng/mL	Dissolve two 0.5 mg vials each with 5 mL supplied diluent, withdraw entire vial contents, and add a sufficient volume of diluent to make a total of 100 mL.
15,000 ng/mL	Dissolve one 1.5 mg vial with 5 mL supplied diluent, withdraw entire vial contents, and add a sufficient volume of diluent to make a total of 100 mL.

Compatibility:

Compatible in D5W, D10W, and NS solutions. Do not mix or administer with any other drugs prior to or during administration. Stable for 8 hours at room temperature.

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.

Pharmacodynamics/Kinetics:

Metabolism: Rapidly hydrolyzed at neutral pH in blood and subject to some enzymatic degradation to one active metabolite and 13 inactive metabolites

Half-life elimination: 2.7-6 minutes; Continuous infusion: ~15 minutes

Excretion: Urine (12% as unchanged drug)

Dosage:

I.V.: The drug is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump; during dose ranging it may be administered peripherally

Acute dose ranging: The initial infusion rate should be 2 ng/kg/minute by continuous I.V. and increased in increments of 2 ng/kg/minute every 15 minutes or longer until dose-limiting effects are elicited (such as chest pain, anxiety, dizziness, changes in heart rate, dyspnea, nausea, vomiting, headache, hypotension and/or flushing)

Continuous chronic infusion: Initial: 4 ng/kg/minute less than the maximum-tolerated infusion rate determined during acute dose ranging

If maximum-tolerated infusion rate is <5 ng/kg/minute, the chronic infusion rate should be ¹/2 the maximum-tolerated acute infusion rate

Dosage adjustments: Dose adjustments in the chronic infusion rate should be based on persistence, recurrence, or worsening of patient symptoms of pulmonary hypertension

If symptoms persist or recur after improving, the infusion rate should be increased by 1-2 ng/kg/minute increments, every 15 minutes or greater; following establishment of a new chronic infusion rate, the patient should be observed and vital signs monitored.

Administration:

Using an ambulatory infusion pump, administer a chronic continuous infusion of epoprostenol through a central venous catheter. A peripheral intravenous catheter may be used during acute dose-ranging until central access is established. Consider a multilumen catheter if other intravenous therapies are routinely administered. During extended use at ambient temperatures exceeding 25°C (77°F), cold pouches with frozen gel packs were used during clinical trials.

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. The infusion pumps used in clinical trials were CADD-1 HFX 5100 (Pharmacia Deltec), Walk-Med 410 C (Medfusion, Inc) and the Auto Syringe AS2F (Baxter HealthCare).

Monitoring Parameters:

Monitor for improvements in pulmonary function, decreased exertional dyspnea, fatigue, syncope and chest pain, pulmonary vascular resistance, pulmonary arterial pressure and quality of life. 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.

Patient Education:

Therapy on this drug will probably be prolonged, possibly for years. You may experience mild headache, nausea or vomiting, and some muscular pains (use of a mild analgesia may be recommended by your prescriber). Report immediately any signs or symptoms of acute or severe headache, back pain, increased difficult breathing, flushing, fever or chills, any unusual bleeding or bruising, or any onset of unresolved diarrhea. Breast-feeding precaution: Consult prescriber if breast-feeding.

Cardiovascular Considerations:

The primary role of epoprostenol is in the treatment of primary pulmonary hypertension in patients unresponsive to other therapy. Response to initial therapy is evaluated in a controlled setting before chronic therapy is administered. The role of epoprostenol in the treatment of heart failure confers a negative impact on cardiovascular morbidity and mortality. Clinical trials showed improvement of heart failure symptoms and exercise tolerance, but an increase in mortality.

Dental Health: Effects on Dental Treatment:

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

Anxiety, nervousness are common; may cause confusion, insomnia, or depression

Mental Health: Effects on Psychiatric Treatment:

Hypotensive effects may be exacerbated by low potency antipsychotics (chlorpromazine) and TCAs

Dosage Forms:

Injection, powder for reconstitution, as sodium: 0.5 mg, 1.5 mg [provided with 50 mL sterile diluent]

International Brand Names:

Flolan® (BE, CA, CH, DK, ES, FR, GB, IL, IT, NL, NO, PL, SG)

References

Cremona G and Higenbottam T, "Role of Prostacyclin in the Treatment of Primary Pulmonary Hypertension,"Am J Cardiol, 1995, 75(3):67A-71A.

Jones DK, Higenbottam TW, and Wallwork J, "Treatment of Primary Pulmonary Hypertension Intravenous Epoprostenol (Prostacyclin),"Br Heart J 1987, 57(3):270-8.

Rich S, "Prostacyclin and Primary Pulmonary Hypertension,"Ann Intern Med, 1994, 121(6):463-4.

Rich S, "The Medical Treatment of Primary Pulmonary Hypertension. Proven and Promising Strategies,"Chest, 1994, 105(2 Suppl):17-20.

Sueta CA, Gheorghiade M, Adams KF, et al, "Safety and Efficacy of Epoprostenol in Patients With Severe Congestive Heart Failure. Epoprostenol Multicenter Research Group,"Am J Cardiol, 1995, 75(3):34A-43A.

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