Epoprostenol (Systemic)


VA CLASSIFICATION
Primary: CV402

Commonly used brand name(s): Flolan.

Other commonly used names are
Prostacyclin {03}, PGI 2 {02}, and PGX {01} .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive (pulmonary)—

vasodilator—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hypertension, pulmonary (treatment)—Epoprostenol is indicated for the long-term intravenous treatment of primary pulmonary hypertension (PPH) in patients with New York Heart Association (NYHA) Class III and Class IV heart failure {01}{43}. Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of PPH {01}. The diagnosis of PPH should be carefully established by standard clinical tests to exclude secondary causes of pulmonary hypertension {01}.

Hypertension, pulmonary, secondary to scleroderma spectrum of disease (treatment)—Epoprostenol is indicated for the long-term intravenous treatment of pulmonary hypertension associated with the scleroderma spectrum of disease in patients with New York Heart Association (NYHA) Class III and Class IV heart failure who do not respond adequately to conventional therapy{39}{40}{42}{43}.

[Hypertension, pulmonary, secondary to congenital diaphragmatic hernia (treatment)]1
[Hypertension, pulmonary, secondary to congenital heart disease (treatment)]1—Epoprostenol is indicated for intravenous use in the treatment of pulmonary hypertension secondary to congenital heart disease (Evidence rating: III) {27} {28} and to serve as a bridge to other therapy, such as extracorporeal membrane oxygenation (ECMO), in patients with pulmonary hypertension secondary to congenital diaphragmatic hernia (Evidence rating: III) {15}.

Acceptance not established
Epoprostenol has been used intravenously for the treatment of pulmonary hypertension after cardiac surgery (Evidence rating: III) {14} {16} {17} {26}.

Intravenous epoprostenol has been reported to be effective in improving ulcer healing or in alleviating associated symptoms, such as pain, that occur in patients with peripheral vascular disease (PVD) (Evidence rating: III) {19} {20} {22} {23} {25} and in decreasing the severity, frequency, and duration of attacks that occur with Raynaud's phenomenon (Evidence rating: III) {08} {09} {11} {24}.

Aerosolized epoprostenol has been used to achieve selective pulmonary vasodilation by inhalation in the treatment of pulmonary hypertension in children (Evidence rating: III) {12} {13} and to improve arterial oxygenation in patients with acute respiratory distress syndrome (ARDS) (Evidence rating: III) {06} {07}.

Unaccepted
Epoprostenol has been investigated for the long-term treatment of patients with class IIIB or class IV congestive heart failure with decreased left ventricular ejection fraction {05}. In a randomized, controlled clinical trial called the FIRST study, an increased risk of death in patients treated with epoprostenol prompted early termination of the trial {05}. It was determined that chronic intravenous epoprostenol therapy in these patients is not associated with improvement in distance walked, quality of life, or morbid events, and is associated with an increased risk of death (Evidence rating: I) {05}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Prostaglandin {01}.
Molecular weight—
    Epoprostenol sodium: 374.46 {03}

Mechanism of action/Effect:

Prostaglandins are present in most body tissues and fluids and mediate many biological functions {02}. Approximately 90 prostaglandins have been identified {02}. Prostacyclin (epoprostenol) is a member of the family of prostaglandins that is derived from arachidonic acid {02}. The therapeutic effects of epoprostenol in the treatment of primary pulmonary hypertension (PPH) appear to be due primarily to its vasodilating effects {01}, but also may be attributed to its ability to inhibit platelet aggregation, which may help limit thrombus formation {02}. Vasodilation occurs in pulmonary and systemic arterial vascular beds as a result of a direct relaxation of vascular smooth muscle by epoprostenol {02}. In animals, low doses of epoprostenol cause a vagally mediated bradycardia and higher doses cause a reflex tachycardia in response to hypotension caused by the direct vasodilation {01}. In patients with PPH, epoprostenol increases cardiac output and decreases pulmonary vascular resistance, mean systemic arterial pressure, and mean pulmonary artery pressure {35}.


Other actions/effects:

Epoprostenol in animals also causes bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying {01}.

Biotransformation:

Epoprostenol is extensively metabolized by rapid hydrolysis at neutral pH in blood and by enzymatic degradation {01}. Two primary metabolites, 6-keto-PGF 1-alpha, formed by spontaneous degradation, and 6,15-diketo-13,14-dihydro-PGF 1-alpha, formed enzymatically, have been found to be less pharmacologically active than epoprostenol {01}. Fourteen additional minor metabolites also have been identified {01}.

Half-life:


In vitro in human blood at 37 °C and pH 7.4:

Approximately 6 minutes {01}.


Elimination:
    Renal—82% {01}.
    Fecal—4% {01}.


Precautions to Consider

Carcinogenicity

Long-term studies to evaluate the carcinogenic potential of epoprostenol have not been done {01}.

Mutagenicity

No evidence of mutagenicity was found in a micronucleus test in rats {01}. Although no evidence of mutagenicity was found in either the Ames test or DNA elution tests, the significance of the outcome of these tests is uncertain due to the instability of epoprostenol {01}.

Pregnancy/Reproduction
Fertility—
No evidence of impaired fertility was found in rats given daily doses of epoprostenol by subcutaneous injection at doses of up to 100 mcg per kg of body weight (mcg/kg) {01}. This dose represents 600 mcg per square meter of body surface area (mcg/m 2) per day, which is 2.5 times the recommended human dose of 4.6 nanograms per kg of body weight per minute (nanograms/kg/min) or 245.1 mcg/m 2 per day, given intravenously, based on body surface area {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done and use of epoprostenol during pregnancy is not recommended unless absolutely necessary {01}. No evidence of impaired fertility or harm to the fetus was found in reproductive studies in pregnant rats or rabbits given daily doses of up to 100 mcg/kg {01}. In rats, this dose is equivalent to 600 mcg/m 2, or 2.5 times the recommended human dose {01} and in rabbits, this dose is equivalent to 1180 mcg/m 2, or 4.8 times the recommended human dose, based on body surface area {01}.

FDA Pregnancy Category B {01}.

Labor—

Studies to evaluate the use of epoprostenol during labor, vaginal delivery, or caesarean section have not been done {01}.

Breast-feeding

It is not known whether epoprostenol is distributed into breast milk {01}. Caution should be used when epoprostenol is administered to mothers who are nursing {01}.

Pediatrics

Although information on the use of epoprostenol in pediatric patients is limited, some studies suggest that pediatric patients tolerate higher doses of epoprostenol than do adult patients; however, other studies have found no significant difference in dose tolerance {10} {14} {15} {16} {29}.


Geriatrics


No information is available on the relationship of age to the effects of epoprostenol in geriatric patients. Epoprostenol was not studied in a sufficient number of patients 65 years of age and older to determine whether the elderly respond differently than younger patients {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anticoagulants{01} or
Nonsteroidal anti-inflammatory drugs (NSAIDs){04} or
Platelet aggregation inhibitors (see Appendix II ){04}    (concurrent use with epoprostenol may increase the risk of bleeding {01} {04}; however, patients in clinical trials who were taking anticoagulants did not have evidence of increased bleeding {01})


Antihypertensive agents{01} or
Diuretic agents{01} or
Vasodilators, other{01}    (concurrent use with epoprostenol may further reduce blood pressure {01})


Digoxin{34}    (it has been speculated that epoprostenol may increase gastrointestinal blood flow [a factor that affects digoxin absorption] and consequently increase digoxin bioavailability {34})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Platelet counts{01}    (thrombocytopenia has occurred with administration of epoprostenol {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» New York Heart Association (NYHA) Class III and IV congestive heart failure due to severe left ventricular systolic dysfunction{01}    (increased risk of death with long-term use of epoprostenol {01})


Risk-benefit should be considered when the following medical problems exist
Pulmonary edema, development of{01} or
Pulmonary veno-occlusive disease{01}    (some patients with primary pulmonary hypertension have developed pulmonary edema during dosage titration with epoprostenol, which may be associated with pulmonary veno-occlusive disease {01}; epoprostenol should not be used as long-term treatment in patients who develop pulmonary edema during dosage titration {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure determinations, standing and supine{01} and
» Heart rate determinations{01}    (following dosage adjustments, standing and supine blood pressure and heart rate should be monitored closely for several hours {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
With acute dosage titration
Incidence more frequent
    
Flushing (redness of face)—incidence 58%{01}
    
headache —incidence 49%{01}
    
hypotension (dizziness, lightheadedness or fainting)—incidence 16%{01}
    
nausea and/or vomiting —incidence 32%{01}

Note: Flushing, headache, hypotension, nausea, and vomiting are the most common adverse and dose-limiting side/adverse effects that occur with initial epoprostenol administration and are related to the vasodilating effects of epoprostenol {01}.



With chronic administration
Incidence more frequent
    
Anxiety and/or nervousness —incidence 21%{01}
    
diarrhea —incidence 37%{01}
    
dizziness —incidence 83%{01}
    
flushing (redness of face)—incidence 42%{01}
    
headache —incidence 83%{01}
    
influenza-like symptoms and/or sepsis{01} (chills; confusion; delirium; dizziness, lightheadedness, or fainting; fast heartbeat; fever; rapid, shallow breathing)
    
local infection at the catheter site{01}
    
jaw pain (with chewing){37} —incidence 54%{01}
    
musculoskeletal pain{01} (muscle or skeletal pain)
    
pain at injection site{01}
    
tachycardia (fast heartbeat)—incidence 35%{01}
    
thrombocytopenia{01} (may cause unusual bleeding such as nosebleeds or bleeding gums or bruising)

Note: Epoprostenol is used with an infusion pump and delivered through an indwelling central venous catheter {01}. This form of delivery has been associated with the following side/adverse effects and incidences: Local infection occurred in 21% of patients, pain at the injection site occurred in 13% of patients, and sepsis was reported at least once during the course of treatment in 14% of patients and occurred at a rate of 0.32 infections per patient per year in patients treated with epoprostenol {01}. In one study, a lower incidence of sepsis was attributed to the education of the patients and referring physicians about the use of sterile technique in mixing the medications and to the early detection of any serious infection {35}.


Incidence less frequent
    
Hypesthesia, hypoesthesia, or paresthesia{01} (altered or abnormal touch sensation or sensitivity)




Those indicating the need for medical attention if they occur after abrupt withdrawal or after a sudden large reduction in dosage of epoprostenol
    
Symptoms associated with rebound pulmonary hypertension, including asthenia{01} (weakness), dizziness{01}
dyspnea{01} (difficult or labored breathing), and fainting{41}

Note: Because epoprostenol is metabolized rapidly, brief interruptions in the delivery or a sudden large reduction in the dosage may result in rebound pulmonary hypertension {01}. In clinical trials, the interruption of epoprostenol was considered to be the cause of death of one patient with NYHA Class III primary pulmonary hypertension {01}.





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Diarrhea{01}
    
flushing{01} (redness of face or neck)
    
headache{01}
    
hypotension, severe{01} (lightheadedness or fainting)
    
nausea{01}
    
tachycardia{01} (fast heartbeat)
    
vomiting{01}

Note: Vomiting, unconsciousness, and an initially unrecordable blood pressure occurred in a patient with secondary pulmonary hypertension who unintentionally received 50 mL of an unspecified concentration of epoprostenol {01}. The epoprostenol was discontinued and the patient regained consciousness seconds later {01}. No fatal events have been reported following overdosage of epoprostenol {01}.



Treatment of overdose
It is recommended that the dosage of epoprostenol be reduced {01}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Epoprostenol (Systemic) .

In providing consultation, consider emphasizing the following» selected information ( = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Other medical problems, especially NYHA Class III and IV congestive heart failure due to severe left ventricular systolic dysfunction

Proper use of this medication
Following instructions from the physician or nurse on the preparation and administration of epoprostenol

» Reconstituting epoprostenol only with epoprostenol sterile diluent and not mixing epoprostenol with any other parenteral medications or solutions prior to or during administration {01}

» Using sterile technique when reconstituting epoprostenol and in caring for the central venous catheter {01}

» Avoiding interruptions in administration of epoprostenol

» Proper dosing
Missed dose: Epoprostenol is administered by continuous intravenous infusion and should not be stopped abruptly

» Proper storage

Precautions while using this medication
Making regular visits to the physician to check progress

» Reporting any signs of infection at the catheter site or the sudden development of a fever

Avoiding the use of saunas, hot baths, and sunbathing or other situations that may promote vasodilation because of risk of severe hypotension {04}

» Not stopping epoprostenol suddenly without consulting physician

Carrying a medical identification card stating use of epoprostenol


Side/adverse effects
Signs of potential side effects, especially flushing, headache, hypotension, nausea and/or vomiting, anxiety and/or nervousness, diarrhea, dizziness, influenza-like symptoms and/or sepsis, local infection at the catheter site, jaw pain (with chewing), musculoskeletal pain, injection site pain, tachycardia, thrombocytopenia, hypesthesia, hypoesthesia, paresthesia, aesthenia, dyspnea, or fainting


General Dosing Information
Dosage titration with epoprostenol must be performed in a setting with adequate personnel and equipment for monitoring and emergency care {01}.

Although acute dosage titration in clinical trials was performed during right heart catheterization using a pulmonary artery catheter, in uncontrolled studies, acute dosage titration was performed without cardiac catheterization {01}. The risks associated with cardiac catheterization in patients with primary pulmonary hypertension (PPH) should be carefully weighed against the potential benefits {01}. During acute dosage titration, asymptomatic increases in pulmonary artery pressure coinciding with increases in cardiac output occurred rarely {01}. In such cases, a dosage reduction should be considered {01}.

Unless contraindicated, anticoagulant therapy should be administered to PPH patients receiving epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale {01}.

In patients receiving lung transplants, it is recommended that the dose of epoprostenol be tapered after the initiation of cardiopulmonary bypass {01}.


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

Epoprostenol is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump {01}{43}. However, during dosage titration, epoprostenol may be administered peripherally {01}{43}. Epoprostenol is not to be used for bolus administration {04}{43}. If other intravenous medications are regularly administered, use of a multilumen catheter should be considered {01}{43}.

In order to reduce the risk of infection, aseptic technique must be used in the reconstitution and administration of epoprostenol as well as in routine catheter care {01}{43}. In one study, a lower incidence of sepsis was attributed to the education of the patients and referring physicians about the use of sterile technique in mixing the medications and the early detection of any serious infection {35}.

In order to avoid symptoms associated with rebound pulmonary hypertension, epoprostenol should not be withdrawn abruptly or the infusion rate suddenly reduced {01}{43}. To avoid potential interruptions in delivery of epoprostenol, a backup infusion pump and intravenous infusion sets should be accessible {01}{43}. Infusion rates of epoprostenol should be adjusted only under the direction of a physician except in a life-threatening situation, such as unconsciousness or collapse {01}{43}.

The infusion pump minimum and maximum flow rates and reservoir capacity should be compatible with the concentration of the epoprostenol solution used {01}. The infusion pump should also have the following features:    • Small, lightweight, and portable {01}{43}
   • Adjustable infusion rates in 2 nanograms per kg of body weight per minute increments {01}{43}
   • Alarm capability for detecting occlusion, end of infusion, and low battery {01}{43}
   • Accuracy to ± 6% of the programmed rate {01}{43}
   • Continuous or pulsatile positive pressure driven with intervals between pulses no greater than 3 minutes at the programmed rate {01}{43}
   • Polyvinyl chloride, polypropylene, or glass reservoir {01}{43}
Infusion pumps used in clinical trials were the CADD-1 HFX 5100, Walk-Med 410 C, and the Auto Syringe AS2F {01}.

In clinical trials, a cold pouch with frozen gel packs was used to maintain the temperature of epoprostenol at between 2 and 8 °C for 12 hours {01}.

EPOPROSTENOL SODIUM FOR INJECTION

Usual adult dose
Primary pulmonary hypertension and
pulmonary hypertension secondary to scleroderma spectrum of disease


Acute dosage titration:
The initial long-term infusion rate of epoprostenol is determined by acute dosage titration {01}{43}. The infusion rate should be initiated at 2 nanograms per kg of body weight per minute and increased in increments of 2 nanograms per kg of body weight per minute every fifteen minutes, or longer, until dose-limiting side/adverse effects, such as flushing, headache, hypotension, nausea, and/or vomiting, occur {01}{43}. It is common in clinical practice to reduce the frequency of dose increases to once daily to possibly decrease the number of associated side effects {36}. In clinical trials, the mean maximum dose that did not induce dose-limiting side/adverse effects during acute dosage titration was 8.6 ± 0.3 nanograms per kg of body weight per minute {01}. If asymptomatic increases in pulmonary artery pressure occur with increases in cardiac output, a dosage reduction should be considered {01}.



Continuous long-term infusion:
Epoprostenol should be administered by continuous, long-term infusion through a central venous catheter {01}{43}. Peripheral intravenous infusions may be used temporarily until a central venous catheter is in place {01}{43}. Long-term infusions of epoprostenol should be initiated at an infusion rate that is 4 nanograms per kg of body weight per minute less than the maximally tolerated rate determined during acute dosage titration {01}. If the maximally tolerated infusion rate is less than 5 nanograms per kg of body weight per minute, the long-term infusion rate should be started at one half the maximally tolerated infusion rate {01}. In clinical trials, the mean initial long-term infusion rate was 5 nanograms per kg of body weight per minute {01}. Changes in the long-term infusion rate should be based on the persistence, recurrence, or worsening of primary pulmonary hypertension (PPH) symptoms and the occurrence of side/adverse effects associated with epoprostenol administration {01}. However, a more aggressive treatment strategy directed at maintaining patients at the highest dose tolerated (as assessed by side effects), even with clinical improvement, also has been used {35}.

The dose of epoprostenol is usually increased from the initial long-term dose {01}. In a controlled twelve-week clinical trial, the mean starting dose of epoprostenol of 5.2 nanograms per kg of body weight per minute (4 nanograms per kg of body weight per minute less than the new tolerated dose) was increased to 9.2 nanograms per kg of body weight per minute by the end of week twelve {01}. This dose was 1.6 nanograms per kg of body weight per minute less than the mean nontolerated dose {01}.

An increase in the dose should be considered if symptoms of PPH persist or recur after an initial improvement {01}. The infusion should be increased by 1 to 2 nanograms per kg of body weight per minute increments at intervals of no less than every fifteen minutes in order to allow assessment of the clinical response {01}{43}. Standing and supine blood pressure, heart rate, and symptomatic evidence of intolerance should be monitored at the new dose for several hours {01}{43}.

If dose-related side/adverse effects occur during long-term infusion, the infusion rate may need to be decreased {01}{43}. Occasionally, the dose-related side/adverse effects may resolve without a dosage adjustment {01}{43}. If a decrease in dosage is required, it should be made gradually, in 2 nanograms per kg of body weight per minute decrements every fifteen minutes or longer until the dose-related side/adverse effects resolve {01}{43}. Sudden, large reductions in infusion rates should be avoided {01}{43}.

The following tables may be used to select the most appropriate concentration of epoprostenol that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume {01}{43}. More concentrated solutions administered at a higher infusion rate may be necessary with long-term administration of epoprostenol {01}.


Infusion rates for epoprostenol at a concentration of 3000 nanograms per mL 
Patient weight (kg)   Dose or drug delivery rate (nanograms per kg of body weight per minute) 
2   10  12  14  16 
Infusion delivery rate (mL per hour [mL/hr]) 
10  —  —  1.2  1.6  2.4  2.8  3.2 
20  —  1.6  2.4  3.2  4.8  5.6  6.4 
30  1.2  2.4  3.6  4.8  7.2  8.4  9.6 
40  1.6  3.2  4.8  6.4  9.6  11.2  12.8 
50  10  12  14  16 
60  2.4  4.8  7.2  9.6  12  14.4  16.8  19.2 
70  2.8  5.6  8.4  11.2  14  16.8  19.6  22.4 
80  3.2  6.4  9.6  12.8  16  19.2  22.4  25.6 
90  3.6  7.2  10.8  14.4  18  21.6  25.2  28.8 
100  12  16  20  24  28  32 



Infusion rates for epoprostenol at a concentration of 5000 nanograms per mL 
Patient weight (kg)  Dose or drug delivery rate (nanograms per kg of body weight per minute) 
10  12  14  16 
Infusion delivery rate (mL/hr) 
10  —  —  —  1.2  1.4  1.7  1.9 
20  —  1.4  1.9  2.4  2.9  3.4  3.8 
30  —  1.4  2.2  2.9  3.6  4.3  5.8 
40  1.9  2.9  3.8  4.8  5.8  6.7  7.7 
50  1.2  2.4  3.6  4.8  7.2  8.4  9.6 
60  1.4  2.9  4.3  5.8  7.2  8.6  10.1  11.5 
70  1.7  3.4  6.7  8.4  10.1  11.8  13.4 
80  1.9  3.8  5.8  7.7  9.6  11.5  13.4  15.4 
90  2.2  4.3  6.5  8.6  10.8  13  15.1  17.3 
100  2.4  4.8  7.2  9.6  12  14.4  16.8  19.2 



Infusion rates for epoprostenol at a concentration of 10,000 nanograms per mL 
Patient weight (kg)  Dose or drug delivery rate (nanograms per kg of body weight per minute) 
10  12  14  16 
Infusion delivery rate (mL/hr)  
20  —  —  1.2  1.4  1.7  1.9 
30  —  1.1  1.4  1.8  2.2  2.5  2.9 
40  1.4  1.9  2.4  2.9  3.4  3.8 
50   1.2  1.8  2.4  3.6  4.2  4.8 
60  1.4  2.2  2.9  3.6  4.3  5.8 
70  1.7  2.5  3.4  4.2  5.9  6.7 
80  1.9  2.9  3.8  4.8  5.8  6.7  7.7 
90  2.2  3.2  4.3  5.4  6.5  7.6  8.6 
100  2.4  3.6  4.8  7.2  8.4  9.6 



Infusion rates for epoprostenol at a concentration of 15,000 nanograms per mL 
Patient weight (kg)  Dose or drug delivery rate (nanograms per kg of body weight per minute)  
10  12  14  16 
Infusion delivery rate (mL/hr) 
30  —  —  1.2  1.4  1.7  1.9 
40  —  1.3  1.6  1.9  2.2  2.6 
50  —  1.2  1.6  2.4  2.8  3.2 
60  1.4  1.9  2.4  2.9  3.4  3.8 
70  1.1  1.7  2.2  2.8  3.4  3.9  4.5 
80  1.3  1.9  2.6  3.2  3.8  4.5  5.1 
90  1.4  2.2  2.9  3.6  4.3  5.8 
100  1.6  2.4  3.2  4.8  5.6  6.4 




Usual adult prescribing limits
In clinical trials, the mean maximum dose during acute dose-ranging was 8.6 nanograms per kg of body weight per minute {29}. Mean long-term doses of 40 ± 15 nanograms per kg of body weight per minute have been used {35}.

Usual pediatric dose

Note: Information on dosing epoprostenol in pediatric patients is limited; however, children usually tolerate higher doses than adults {29}.

[Primary or secondary pulmonary hypertension]1


Acute dosage titration:
In a variety of studies and case reports, initial doses of intravenous epoprostenol have ranged from 1 to 25 nanograms per kg of body weight per minute {10} {14} {15} {18} {27} {28} {29} {30} {31} {32} {33}. In those studies and case reports in which the dose of epoprostenol was increased gradually, the most common dosing increments reported were by 5 nanograms per kg of body weight per minute, but ranged as high as by 15 nanograms per kg of body weight per minute, and the period of time or interval between dosage increases ranged from 5 to 30 minutes {10} {14} {15} {18} {27} {28} {29} {30} {31} {32} {33}. The initial dose, dosage increments, and time between increments in these studies were usually dependent upon the underlying disease state, whether or not the patient was anesthetized, the severity and tolerability of side effects that occurred, the level of response the clinician was trying to obtain, and whether or not other therapy, such as other vasodilators, inotropic agents, volume expanders, nitric oxide, or tolazoline, was used {10} {14} {15} {18} {27} {28} {30} {31} {32} {33}.



Continuous long-term infusion:
In pediatric patients with primary pulmonary hypertension and New York Heart Association (NYHA) Class III or Class IV heart failure, mean chronic infusion rates were not significantly different from those for adults {29}. See Usual adult dose .



Usual pediatric prescribing limits
In a study of sixty-three pediatric patients, the mean maximum dose used during acute dosage titration was 25 nanograms per kg of body weight per minute {29}. In this same study, mean maximum long-term doses tended to be slightly higher for pediatric patients than for adult patients, although the difference was not statistically significant {29}.

Strength(s) usually available
U.S.—


Epoprostenol sodium equivalent to 0.5 mg (500,000 nanograms) epoprostenol (Rx) [Flolan (17 mL vial) (3.76 mg glycine) (2.93 mg sodium chloride ) (50 mg mannitol) (sodium hydroxide) (Diluent—94 mg glycine, 73.5 mg sodium chloride, sodium hydroxide, water for injection)]{01}


Epoprostenol sodium equivalent to 1.5 mg (1,500,000 nanograms) of epoprostenol (Rx) [Flolan (17 mL vial) (3.76 mg glycine) (2.93 mg sodium chloride ) (50 mg mannitol) (sodium hydroxide) (Diluent—94 mg glycine, 73.5 mg sodium chloride, sodium hydroxide, water for injection)]{01}

Canada—


Epoprostenol sodium equivalent to 0.5 mg (500,000 nanograms) epoprostenol {04} (Rx) [Flolan (17 mL vial ) (3.76 mg glycine) ( 2.93 mg sodium chloride) (50 mg mannitol) (sodium hydroxide) (Diluent—94 mg glycine, 73.5 mg sodium chloride, sodium hydroxide, water for injection )]


Epoprostenol sodium equivalent to 1.5 mg (1,500,000 nanograms) of epoprostenol {04} (Rx) [Flolan ( 17 mL vial) (3.76 mg glycine) ( 2.93 mg sodium chloride) (50 mg mannitol) (sodium hydroxide) (Diluent—94 mg glycine, 73.5 mg sodium chloride, sodium hydroxide, water for injection )]

Packaging and storage:
Unopened vials

   • Store unopened vials of epoprostenol and the sterile diluent for epoprostenol at between 15 and 25 ºC (59 and 77 ºF) {01}{43}. Protect epoprostenol from light {01} and do not freeze diluent {38}.


Reconstituted solutions

   • Prior to use (if not used immediately), refrigerate reconstituted solutions of epoprostenol at between 2 and 8 ºC (36 and 46 ºF) {01}{43}. When stored or in use, reconstituted epoprostenol must be insulated from temperatures higher than 25 ºC (77 ºF) and below 0 ºC (32 ºF), and must not be exposed to direct sunlight {01}.
   • Reconstituted solutions may be kept either in refrigerated storage or in a cold pouch or a combination of the two, for no more than 48 hours {01}. Reconstituted solutions that have been refrigerated for more than 48 hours should be discarded {01}{43}.
   • Reconstituted solutions of epoprostenol should not be frozen, and any reconstituted solution that has been frozen should be discarded {01}{43}.



Preparation of dosage form:
Epoprostenol must be reconstituted using only the specific sterile diluent for epoprostenol {01}. Do not reconstitute or mix epoprostenol with any other parenteral medications or solutions prior to or during administration {01}.

Epoprostenol, when administered long-term, should be prepared in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL {01}.

To make 100 mL of solution with a final concentration of:
3000 nanograms per mL



• Dissolve contents of one 0.5-mg vial with 5 mL of sterile diluent for epoprostenol {01}{43}. Withdraw 3 mL and add to sufficient sterile diluent for epoprostenol to make a total of 100 mL {01}{43}.


5000 nanograms per mL



• Dissolve contents of one 0.5-mg vial with 5 mL of sterile diluent for epoprostenol {01}{43}. Withdraw entire vial contents and add sufficient sterile diluent for epoprostenol to make a total of 100 mL {01}{43}.


10,000 nanograms per mL



• Dissolve contents of two 0.5-mg vials each with 5 mL of sterile diluent for epoprostenol {01}{43}. Withdraw entire vial contents and add sufficient sterile diluent for epoprostenol to make a total of 100 mL {01}{43}.


15,000 nanograms per mL



• Dissolve contents of one 1.5-mg vial with 5 mL of sterile diluent for epoprostenol {01}{43}. Withdraw entire vial contents and add sufficient sterile diluent for epoprostenol to make a total of 100 mL {01}{43}. Higher concentrations may be required for patients who receive epoprostenol long-term {01}.


More than one solution strength may be required to accommodate the range of infusions anticipated during acute dosage titration {01}. Generally, 3000 nanograms per mL and 10,000 nanograms per mL are satisfactory concentrations to deliver 2 to 16 nanograms per kg of body weight per minute in adults {01}. Infusion rates may be calculated using the following formula:

Infusion rate (mL per hour) = [Dose (nanograms per kg of body weight per minute) × Weight (kg) × 60 minutes per hour] ÷ Final concentration (nanograms per mL)


Stability:
A single reservoir of reconstituted solution of epoprostenol can be administered at room temperature (15 to 25 ºC [59 to 77 ºF]) over a period of no longer than 8 hours (refrigerated storage should not exceed 40 hours in this case) {01}.

If used with a cold pouch (two frozen 6-ounce gel packs in a cold pouch, changed every 12 hours), epoprostenol may be administered over a period of no longer than 24 hours (refrigerated storage should not exceed 24 hours in this case) {01}{43}.

Consistent with the 48-hour period, a two-day supply (200 mL) of epoprostenol may be reconstituted, dividing each 100 mL daily supply into three equal portions, and refrigerating two of the portions until they are used {01}.

Parenteral drug products should be inspected visually for particulate matter and discoloration {01}. If either occurs, epoprostenol should not be administered {01}.

Incompatibilities:
Epoprostenol should not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration {01}{43}.



Developed: 12/05/1998
Revised: 09/04/2000



References
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  1. Product Information: Flolan®, epoprostenol sodium. Glaxo Wellcome, Mississauga, Ontario, (PI revised 8/1999) reviewed 8/2000.
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