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Medication Safety Issues
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(e poe PROST en ole)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of idiopathic pulmonary arterial hypertension (IPAH); pulmonary hypertension associated with the scleroderma spectrum of disease (SSD) in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy
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
B
Pregnancy Considerations
Teratogenic effects were not reported in animal studies. There are no adequate and well-controlled studies in pregnant women. Pregnant women with IPAH are encouraged to avoid pregnancy.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to epoprostenol or to structurally-related compounds; chronic use in patients with heart failure due to severe left ventricular systolic dysfunction; patients who develop pulmonary edema during dose initiation
Warnings/Precautions
Concerns related to adverse effects:
• Pulmonary edema: Some patients with primary pulmonary hypertension have developed pulmonary edema during dosing adjustment, which may be associated with pulmonary veno-occlusive disease.
• Rebound pulmonary hypertension: Abrupt interruptions or large sudden reductions in dosage may result in rebound pulmonary hypertension. Avoid abrupt withdrawal.
Disease-related concerns:
• Conditions that increase bleeding risk: Epoprostenol is an inhibitor of platelet aggregation. Use with caution in patients with risk factors for bleeding.
Concurrent drug therapy issues:
• Anticoagulants: During chronic use, unless contraindicated, anticoagulants should be coadministered to reduce the risk of thromboembolism.
Other warnings/precautions:
• Infection: Chronic continuous I.V. infusion of epoprostenol via a chronic indwelling central venous catheter has been associated with local infections and serious blood stream infections.
Adverse Reactions
Note: Adverse events reported during dose initiation and escalation include flushing (58%), headache (49%), nausea/vomiting (32%), hypotension (16%), anxiety/nervousness/agitation (11%), chest pain (11%), dizziness, abdominal pain, bradycardia, musculoskeletal pain, dyspnea, back pain, diaphoresis, dyspepsia, hypoesthesia/paresthesia, and tachycardia are also reported. The following adverse events have been reported during chronic administration for IPAH. Although some may be related to the underlying disease state, anxiety, diarrhea, flu-like syndrome, flushing, headache, jaw pain, nausea, nervousness, and vomiting are clearly contributed to epoprostenol.
>10%:
Cardiovascular: Chest pain (52% to 67%), palpitation (63%), tachycardia (35% to 43%), flushing (23% to 42%), arrhythmia (27%), bradycardia (15%), hypotension (13%)
Central nervous system: Dizziness (83%), headache (46% to 83%), chills/fever/sepsis/flu-like syndrome (13% to 25%), anxiety/nervousness/tremor (7% to 21%), depression/depression psychotic (13%)
Dermatologic: Skin ulcer (39%), eczema/rash/urticaria (25%)
Gastrointestinal: Nausea/vomiting (41% to 67%), anorexia (66%), diarrhea (37% to 50%), weight loss (27%)
Hematologic: Hemorrhage (11% to 19%)
Hepatic: Ascites (23%)
Local: Injection site reactions: Infection (21%), pain (13%)
Neuromuscular & skeletal: Weakness (87% to 100%), pain/neck pain/arthralgia (84%), jaw pain (54% to 75%), arthritis (52%), myalgia (44%), musculoskeletal pain (35%; predominantly involving legs and feet), back pain (13%), hypoesthesia/hyperparesthesia/paresthesia (5% to 12%)
Respiratory: Dyspnea (90%)
Miscellaneous: Diaphoresis (41%)
1% to 10%:
Cardiovascular: Supraventricular tachycardia (8%), cerebrovascular accident (4%), MI (4%)
Central nervous system: Insomnia (9%), seizure (4%), somnolence (4%)
Dermatologic: Rash (10%), pruritus (4%)
Endocrine & metabolic: Hypokalemia (6%), hyperkalemia (4%)
Gastrointestinal: Abdominal pain (14%), constipation (4% to 6%), weight gain (6%), flatulence (5%), abdominal enlargement (4%)
Genitourinary: Urinary tract infection (7%)
Hematologic: Thrombocytopenia (4%)
Ocular: Amblyopia (8%), vision abnormality (4%)
Renal: Hematuria (5%)
Respiratory: Epistaxis (4% to 9%), pleural effusion (4% to 7%), pharyngitis (5%), pneumonia (5%), pneumothorax (4%), pulmonary edema (4%)
<1%, postmarketing, and/or case reports: Anemia, hepatic failure, hypersplenism, hyperthyroidism, pancytopenia, pulmonary embolism, splenomegaly
Drug Interactions
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. Risk C: Monitor therapy
Antihypertensives: Prostacyclin Analogues may enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Antiplatelet Agents: Prostacyclin Analogues may enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Storage
Prior to use, store vials at 15°C to 25°C (59°F to 77°F); do not freeze. Protect from light. Following reconstitution, solution must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) if not used immediately; do not freeze. Protect from light. Discard if refrigerated for >48 hours. During use, a single reservoir of solution may be used at room temperature for a total duration of 8 hours, or used with a cold pouch for administration up to 24 hours. Cold packs should be changed every 12 hours.
Reconstitution
Reconstitute only with provided sterile diluent. See table.
Preparation of Epoprostenol Infusion
Note: Only prepare with sterile diluent provided.
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 a sufficient volume of supplied 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 to a sufficient volume of supplied 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 to a sufficient volume of supplied 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 to a sufficient volume of supplied diluent to make a total of 100 mL.
Table has been converted to the following text.
Preparation of Epoprostenol Infusion
Note: Only prepare with sterile diluent provided.
To make 100 mL of solution with the following concentrations:
3000 ng/mL: 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.
5000 ng/mL: 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.
10,000 ng/mL: 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.
15,000 ng/mL: 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.
Compatibility
Only prepare with sterile diluent provided. Do not mix or administer with any other drugs or solutions prior to or during administration.
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; subject to some enzymatic degradation; forms one active metabolite and 13 inactive metabolites
Half-life elimination: 6 minutes
Excretion: Urine (84%); feces (4%)
Dosage
Children (unlabeled use) and Adults: I.V.: Initial: 1-2 ng/kg/minute, increase dose in increments of 1-2 ng/kg/minute every 15 minutes or longer until dose-limiting side effects are noted or tolerance limit to epoprostenol is observed. 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).
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.
Dose adjustment:
Increase dose in 1-2 ng/kg/minute increments at intervals of at least 15 minutes if symptoms persist or recur following improvement. In clinical trials, dosing increases occurred at intervals of 24-48 hours.
Decrease dose in 2 ng/kg/minute decrements at intervals of at least 15 minutes in case of dose-limiting pharmacologic events. Avoid abrupt withdrawal or sudden large dose reductions.
Lung transplant: In patients receiving lung transplants, epoprostenol may be tapered after the initiation of cardiopulmonary bypass.
Administration: I.V.
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 pump used in the most recent clinical trial was CADD-1 HFX 5100 (Pharmacia Deltec). Immediate access to back up pump, infusion sets and medication is essential to prevent treatment interruptions. Assess patient's and family's ability to manage a central venous catheter in the home setting. Clinicians should routinely review with patient the importance of infection control practices for the management of a central venous catheter.
Administration: I.V. Detail
When given on an ongoing basis, must be infused through a central venous catheter. Peripheral infusion may be used temporarily until central line is established. Infuse using an infusion pump. Avoid abrupt withdrawal (including interruptions in delivery) or sudden large reductions in dosing.
pH: 10.2-10.8
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, diarrhea, weight loss, nervousness, dizziness (use caution when driving or engaging in activities requiring alertness) 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; chest pain; palpitations; irregular, slow or fast pulse; flushing; loss of sensation; 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
Nursing: Physical Assessment/Monitoring
Institutional: Continuous pulmonary and hemodynamic arterial monitoring, protimes. Noninstitutional: Avoid sudden rate reduction or abrupt withdrawal or interruption of therapy. When adjustment in rate is made, monitor blood pressure (standing and supine) and pulse for several hours to ensure tolerance to new rate. Monitor for bleeding. Monitor (or teach appropriate caregiver or patient to monitor) vital signs on 3 times/day basis. Monitor for improved pulmonary function and improved quality of life. Be alert for any infusion pump malfunction. Assess for signs of overdose (eg, hypoxia, flushing, tachycardia, fever, chills, anxiety, acute headache, tremor, vomiting, diarrhea).
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 0.5 mg, 1.5 mg [provided with 50 mL sterile diluent]
Flolan®: 0.5 mg, 1.5 mg
References
Badesch DB, Abman SH, Ahearn GS, et al, “Medical Therapy for Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guideline,” Chest, 2004, 126(1 Suppl):35-62.
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, 21;132(6):425-34.
Barst RJ, Maislin G, and Fishman AP, “Vasodilator Therapy for Primary Pulmonary Hypertension in Children,” Circulation, 1999, 99(9):1197-208.
Barst RJ, Rubin LJ, Long WA, et al, “A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) With Conventional Therapy for Primary Pulmonary Hypertension. The Primary Pulmonary Hypertension Study Group,” N Engl J Med, 1996, 334(5):296-302.
Cremona G and Higenbottam T, “Role of Prostacyclin in the Treatment of Primary Pulmonary Hypertension,” Am J Cardiol, 1995, 75(3):67A-71A.
Higenbottam TW, Spiegelhalter D, Scott JP, et al, “Prostacyclin (Epoprostenol) and Heart-Lung Transplantation as Treatments for Severe Pulmonary Hypertension,” Br Heart J, 1994, 70:366-70.
Jones DK, Higenbottam TW, and Wallwork J, “Treatment of Primary Pulmonary Hypertension Intravenous Epoprostenol (Prostacyclin),” Br Heart J 1987, 57(3):270-8.
McLaughlin VV, Genthner DE, Panella MM, et al, “Reduction in Pulmonary Vascular Resistance With Long-Term Epoprostenol (Prostacyclin) Therapy in Primary Pulmonary Hypertension,” N Engl J Med, 1998, 338(5):273-7.
McLaughlin VV, Shillington A, and Rich S, “Survival in Primary Pulmonary Hypertension: The Impact of Epoprostenol Therapy,” Circulation, 2002, 106(12):1477-82.
Nakayama T, Shimada H, Takatsuki S, et al, “Efficacy and Limitations of Continuous Intravenous Epoprostenol Therapy for Idiopathic Pulmonary Arterial Hypertension in Japanese Children,” Circ J, 2007, 71(11):1785-90.
Rosenzweig EB and Barst RJ, “Idiopathic Pulmonary Arterial Hypertension in Children,” Curr Opin Pediatr, 2005, 17(3):372-80.
Rosenzweig EB, Kerstein D, and Barst RJ, "Long-Term Prostacyclin for Pulmonary Hypertension With Associated Congenital Heart Defects," Circulation, 1999, 99(14):1858-65.
Rosenzweig EB, Widlitz AC, and Barst RJ, “Pulmonary Arterial Hypertension in Children,” Pediatr Pulmonol, 2004, 38(1):2-22.
Sitbon O, Humbert M, Nunes H, et al, “Long-Term Intravenous Epoprostenol Infusion in Primary Pulmonary Hypertension - Prognostic Factors and Survival,” J Am Coll Cardiol, 2002, 40(40):780-8.
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.
Widlitz A and Barst RJ, “Pulmonary Arterial Hypertension in Childrenl,”Eur Respir J, 2003, 21(1):155-76.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
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