Epoprostenol

Epoprostenol for injection is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

Important Note:

[see

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 Injection

solution 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.

Table 1: Maximum Duration of Administration (hours) at Room Temperature (77°F/25°C) of Fully Diluted Solutions in the Drug Delivery ReservoirShort excursions at 104°F (40°C) are permitted for up to:

2 hours for concentrations below 15,000 ng/mL

4 hours for concentrations between 15,000 ng/mL and 60,000 ng/mL

8 hours for concentrations above 60,000 ng/mL

Final concentration range	Immediate administration	If stored for up to 8 days at 36° to 46°F (2° to 8°C)
0.5 mg vial
≥3,000 ng/mL and <15,000 ng/mL	48 hours	24 hours
1.5 mg vial
≥15,000 ng/mL and <60,000 ng/mL	48 hours	48 hours
≥60,000 ng/mL	72 hours	48 hours

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 injection

prepared 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 injection

should 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

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/mLHigher concentrations may be prepared for patients who receive epoprostenol for injection long-term.	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

].

Epoprostenol for Injection

Limited published data from case series and case reports with epoprostenol have not established a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes when used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• •Do not abruptly lower the dose or withdraw dosing. All dosing initiation and changes should be closely monitored. (
  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.
  )