2.1 Dosage

Prepare continuous chronic infusion of epoprostenol for injection as directed, and administer through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of epoprostenol for injection at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until epoprostenol for injection is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, use a lower dose.

In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 ng/kg/min to 3 ng/kg/min every 3 weeks.

2.2 Dosage Adjustments

Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient’s symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of epoprostenol for injection. In general, expect increases in dose from the initial chronic dose.

Consider increments in dose if symptoms of pulmonary hypertension persist or recur. Adjust the infusion by 1 ng/kg/min to 2 ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2 ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve [see Adverse Reactions (6.1and6.2)]. Avoid abrupt withdrawal of epoprostenol for injection or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of epoprostenol for injection should be adjusted only under the direction of a physician.

In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.

2.3 Administration

Epoprostenol for injection, once prepared as directed [see Dosage and Administration (2.4)], is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, epoprostenol for injection may be administered peripherally.

Infusion sets with an in-line 0.22 micron filter should be used.

The ambulatory infusion pump used to administer epoprostenol for injection should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2 ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver epoprostenol for injection. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

2.4 Reconstitution

Epoprostenol for Injection is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not reconstitute or mix epoprostenol for injection with any other parenteral medications or solutions prior to or during administration. Each vial is for single-dose only; discard any unused solution.

Use after reconstitution and immediate dilution to final concentration

Use at room temperature (77°F/25°C)

Epoprostenol for Injectionsolution reconstituted with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection,and immediately diluted to the final concentration in the drug delivery reservoir can be administered at room temperature per the conditions of use as outlined in Table 1.

Use at higher temperatures >77°F up to 104°F (>25° to 40°C)

Temperatures greater than 77°F and up to 86°F (>25°C to 30°C): A single reservoir of fully diluted solution of 60,000 ng/mL or above of epoprostenol for injectionprepared as directed can be administered (either immediately or after up to 8 days storage at 36° to 46°F (2° to 8°C)) for up to 48 hours. For diluted solutions of less than 60,000 ng/mL, pump reservoirs should be changed every 24 hours.

Temperatures up to 104°F (40°C):Fully diluted solutions of 60,000 ng/mL or above of epoprostenol for injection, prepared as directed, can be immediately administered for periods up to 24 hours.

Do not expose this solution to direct sunlight.

A concentration for the solution of epoprostenol for injectionshould be selected that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. Epoprostenol for injection, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 2 are directions for preparing different concentrations of epoprostenol for injection.

Each vial is for single-dose; discard any unused solution.

Table 2: Reconstitution and Dilution Instructions

* Higher concentrations may be prepared for patients who receive epoprostenol for injection long-term.
To make 100 mL of solution with Final Concentration (ng/mL) of:	Directions:
Using the 0.5 mg vial
3,000 ng/mL	Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, USP. Withdraw 3 mL of the vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
5,000 ng/mL	Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. 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	Dissolve contents of two 0.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
Using the 1.5 mg vial
15,000 ng/mL*	Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
30,000 ng/mL*	Dissolve contents of two 1.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.

 

Infusion rates may be calculated using the following formula:

Tables 3 to 7 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of epoprostenol for injection to be used. These tables may be used to select the most appropriate concentration of epoprostenol for injection 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. For infusion/dose rates lower than those listed in Tables 3 to 7, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half-life of epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of epoprostenol for injection.

Table 3: Infusion Rates for Epoprostenol for Injection at a Concentration of 3,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	2	3	4	5
	Infusion Delivery Rate (mL/hr)
20	---	1.2	1.6	2
30	1.2	1.8	2.4	3
40	1.6	2.4	3.2	4
50	2	3	4	---
60	2.4	3.6	---	---
70	2.8	---	---	---
80	3.2	---	---	---
90	3.6	---	---	---
100	4	---	---	---

Table 4: Infusion Rates for Epoprostenol for Injection at a Concentration of 5,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	2	4	6	8	10	12	14
	Infusion Delivery Rate (mL/hr)
20	---	1	1.4	1.9	2.4	2.9	3.4
30	---	1.4	2.2	2.9	3.6	---	---
40	1	1.9	2.9	3.8	---	---	---
50	1.2	2.4	3.6	---	---	---	---
60	1.4	2.9	---	---	---	---	---
70	1.7	3.4	---	---	---	---	---
80	1.9	3.8	---	---	---	---	---
90	2.2	---	---	---	---	---	---
100	2.4	---	---	---	---	---	---

Table 5: Infusion Rates for Epoprostenol for Injection at a Concentration of 10,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	4	6	8	10	12	14	16
	Infusion Delivery Rate (mL/hr)
20	---	---	1	1.2	1.4	1.7	1.9
30	---	1.1	1.4	1.8	2.2	2.5	2.9
40	1	1.4	1.9	2.4	2.9	3.4	3.8
50	1.2	1.8	2.4	3	3.6	---	---
60	1.4	2.2	2.9	3.6	---	---	---
70	1.7	2.5	3.4	---	---	---	---
80	1.9	2.9	3.8	---	---	---	---
90	2.2	3.2	---	---	---	---	---
100	2.4	3.6	---	---	---	---	---

Table 6: Infusion Rates for Epoprostenol for Injection at a Concentration of 15,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	4	6	8	10	12	14	16
	Infusion Delivery Rate (mL/hr)
20	---	---	---	---	1	1.1	1.3
30	---	---	1	1.2	1.4	1.7	1.9
40	---	1	1.3	1.6	1.9	2.2	2.6
50	---	1.2	1.6	2	2.4	2.8	3.2
60	1	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	---
80	1.3	1.9	2.6	3.2	3.8	---	---
90	1.4	2.2	2.9	3.6	---	---	---
100	1.6	2.4	3.2	4	---	---	---

Table 7: Infusion Rates for Epoprostenol for Injection at a Concentration of 30,000 ng/mL

Patient weight (kg)	Dose or Drug Delivery Rate (ng/kg/min)
	6	8	10	12	14	16
30	---	---	---	---	---	1
40	---	---	---	1	1.1	1.3
50	---	---	1	1.2	1.4	1.6
60	---	1	1.2	1.4	1.7	1.9
70	---	1.1	1.4	1.7	2	2.2
80	1	1.3	1.6	1.9	2.2	2.6
90	1.1	1.4	1.8	2.2	2.5	2.9
100	1.2	1.6	2	2.4	2.8	3.2

 

5.1 Dose Initiation

Epoprostenol is a potent pulmonary and systemic vasodilator. Initiate epoprostenol in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

5.2 Chronic Use and Dose Adjustment

During chronic use, deliver epoprostenol continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of epoprostenol and in routine catheter care. Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of epoprostenol may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with epoprostenol will likely be needed for prolonged periods, possibly years, so consider the patient’s capacity to accept and care for a permanent intravenous catheter and infusion pump.

Based on clinical trials, the acute hemodynamic response (reduction in pulmonary artery resistance) to epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of epoprostenol. Adjust dosage of epoprostenol during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol [see Dosage and Administration (2.2)]. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.

5.3 Withdrawal Effects

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III primary pulmonary hypertension patient’s death was judged attributable to the interruption of epoprostenol. Avoid abrupt withdrawal.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.

6.2 Post-Marketing Experience

In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of epoprostenol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to epoprostenol.

Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly.

Cardiac: High output cardiac failure (consider dose reduction) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), andWarnings and Precautions (5.3)].

Endocrine and Metabolic: Hyperthyroidism

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of epoprostenol in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation.

12.2 Pharmacodynamics

In animals, the vasodilatory effects reduce right- and left-ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.

12.3 Pharmacokinetics

Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and a short half-life (2.7 minutes). During infusions in animals, steady-state plasma concentrations of tritium-labeled epoprostenol were reached within 15 minutes and were proportional to infusion rates.

No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n = 954) and females (n = 1,024).

Tritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a 1-week period was 82% and 4% of the administered dose, respectively. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were also negative, although the instability of epoprostenol makes the significance of these tests uncertain. Fertility was not impaired in rats given epoprostenol by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m2/day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m2/day, IV] based on body surface area).

14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)

Acute Hemodynamic Effects

Acute intravenous infusions of epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary arterial pressure (PAPm) were variable and minor.

Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects

Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing epoprostenol plus conventional therapy to conventional therapy alone. Dosage of epoprostenol was determined as described in DOSAGE AND ADMINISTRATION (2) and averaged 9.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described.

Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received epoprostenol chronically compared to those who did not. Table 11 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment.

These hemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, nonrandomized study.

Clinical Effects

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous epoprostenol plus conventional therapy (N = 52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N = 54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index.

Survival was improved in NYHA functional Class III and Class IV patients with idiopathic or heritable PAH treated with epoprostenol for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p = 0.003).

Chronic Infusion in PAH/Scleroderma Spectrum of Diseases (SSD)

Hemodynamic Effects

Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing epoprostenol plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of epoprostenol was determined as described in DOSAGE AND ADMINISTRATION (2) and averaged 11.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not. Table 12 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.

Clinical Effects

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous epoprostenol plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12 weeks were not available for 5 patients treated with epoprostenol and 7 patients treated with conventional therapy alone.

No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.

No controlled clinical trials with epoprostenol have been performed in patients with pulmonary hypertension associated with other diseases.

16.1 How Supplied

Epoprostenol for injection is supplied as a sterile white to off-white lyophilized powder or cake in 10 mL vials.

10 mL vial with a white flip-off seal containing epoprostenol sodium equivalent to 0.5 mg (500,000 ng) epoprostenol, is packaged in carton of 1 vial (NDC 67457-587-10).

10 mL vial with a light blue flip-off seal containing epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) epoprostenol, is packaged in carton of 1 vial (NDC 67457-588-10).

Store the vials of epoprostenol for injection at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

16.2 Storage and Stability

Unopened vials of epoprostenol for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F).The unopened vial should be kept in the carton and not exposed to direct sunlight.

Use after reconstitution and immediate dilution to final concentration can be found in DOSAGE AND ADMINISTRATION (2.4) Reconstitution, Table 1: Maximum duration of administration (hours) at room temperature (77°F /25°C) of fully diluted solutions in the drug delivery reservoir.

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.