Epoprostenol

FULL PRESCRIBING INFORMATION

Indications and Usage for Epoprostenol

Epoprostenol is indicated for:

• the long-term intravenous treatment of primary pulmonary hypertension


• and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy


• [see CLINICAL STUDIES: Clinical Trials in Pulmonary Hypertension (14.1)].

Epoprostenol Dosage and Administration

Important Note: Epoprostenol for Injection must be reconstituted only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Reconstituted solutions of Epoprostenol for Injection must not be diluted or administered with other parenteral solutions or medications [see WARNINGS AND PRECAUTIONS: General (5.1)].

Dosage

Continuous chronic infusion of Epoprostenol should be prepared as directed [see Reconstitution (2.4)], and administered through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Chronic infusion of Epoprostenol should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted [see Dosage Adjustments (2.2)]. If dose-limiting pharmacologic effects occur, then the infusion rate should be decreased to the point that the pharmacologic effects of Epoprostenol are 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 PH/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 to 3 ng/kg/min every 3 weeks.

Dosage Adjustments

Changes in the chronic infusion rate should be based 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. In general, increases in dose from the initial chronic dose should be expected.

Increments in dose should be considered if symptoms of pulmonary hypertension persist or recur after improving. The infusion should be increased by 1- 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 a new chronic infusion rate, the patient should be observed, and standing and supine blood pressure and heart rate monitored 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. Dosage decreases should be made gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of Epoprostenol or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of Epoprostenol 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.

Administration

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

The ambulatory infusion pump used to administer Epoprostenol 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. 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. A multi-lumen catheter should be considered if other intravenous therapies are routinely administered.

Reconstitution

Epoprostenol for Injection is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Epoprostenol for Injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

Prior to use, Epoprostenol for Injection solutions reconstituted with 5 mL diluent must be protected from light and can be refrigerated at 2° to 8°C (36° to 46°F) for as long as 5 days or held at up to 25°C (77°F) for up to 48 hours prior to use. Do not freeze reconstituted solutions of Epoprostenol for Injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 5 days, or if held at room temperature for more than 48 hours.

During use, a single reservoir of diluted solution of Epoprostenol for Injection prepared as directed can be administered at room temperature for up to 24 hours. (If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.) Do not expose this solution to direct sunlight.

A concentration for the solution of Epoprostenol 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, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 1 are directions for preparing different concentrations of Epoprostenol for up to a 24-hour period.

Table 1: Reconstitution and Dilution Instructions

To make 100 mL of solution with Final Concentration (ng/mL) of:	Directions:
* Higher concentrations may be prepared for patients who receive Epoprostenol long-term.
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:

Infusion Rate (mL/hr) =	[Dose (ng/kg/min) × Weight (kg) × 60 min/hr]
	Final Concentration (ng/mL)

Tables 2 and 3 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 to be used. These 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. For infusion/dose rates lower than those listed in Tables 2 and 3, 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. If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.

Table 2: Infusion Rates for Epoprostenol at a Concentration of 15,000 ng/mL

	Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	4	6	8	10	12	14	16
	Infusion Delivery Rate (mL/hr)
20	---	---	---	---	1.0	1.1	1.3
30	---	---	1.0	1.2	1.4	1.7	1.9
40	---	1.0	1.3	1.6	1.9	2.2	2.6
50	---	1.2	1.6	2.0	2.4	2.8	3.2
60	1.0	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	5.0	5.8
100	1.6	2.4	3.2	4.0	4.8	5.6	6.4

Table 3: Infusion Rates for Epoprostenol at a Concentration of 30,000 ng/mL

Dose or Drug Delivery Rate (ng/kg/min)
Patient weight (kg)	6	8	10	12	14	16
30	---	---	---	---	---	1.0
40	---	---	---	1.0	1.1	1.3
50	---	---	1.0	1.2	1.4	1.6
60	---	1.0	1.2	1.4	1.7	1.9
70	---	1.1	1.4	1.7	2.0	2.2
80	1.0	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	2.0	2.4	2.8	3.2

Dosage Forms and Strengths

Epoprostenol for Injection contains Epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) Epoprostenol and is supplied as a sterile lyophilized material in a 10 mL vial with a red flip-off seal.

Contraindications

A large study evaluating the effect of Epoprostenol on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving Epoprostenol plus conventional therapy than in those receiving conventional therapy alone. The chronic use of Epoprostenol in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.

Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Epoprostenol should not be used chronically in patients who develop pulmonary edema during dose initiation.

Epoprostenol is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

Warnings and Precautions

General

Epoprostenol for Injection must be reconstituted only as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Epoprostenol for Injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration. [See Reconstitution (2.4)]

Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. The diagnosis of pulmonary hypertension should be carefully established.

Dose Initiation

Epoprostenol is a potent pulmonary and systemic vasodilator. Dose initiation with Epoprostenol must be performed in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation in controlled PPH clinical trials was performed during right heart catheterization. In clinical trials, dose initiation was performed without cardiac catheterization. The risk of cardiac catheterization in patients with pulmonary hypertension should be carefully weighed against the potential benefits. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, dose reduction should be considered, but such an increase does not imply that chronic treatment is contraindicated.

Chronic Use and Dose Adjustment

During chronic use, Epoprostenol is delivered continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, anticoagulant therapy should be administered to PPH and PH/SSD patients receiving Epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. 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. 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. The decision to initiate therapy with Epoprostenol should be based upon the understanding that there is a high likelihood that intravenous therapy with Epoprostenol will be needed indefinitely, and the patient's ability to accept and care for a permanent intravenous catheter and infusion pump should be carefully considered.

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. Dosage of Epoprostenol during chronic use should be adjusted 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)]. Following dosage adjustments, standing and supine blood pressure and heart rate should be monitored closely for several hours.

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. Abrupt withdrawal should be avoided.

Sepsis

See ADVERSE REACTIONS, Adverse Events Attributable to the Drug Delivery System (6.1).

Adverse Reactions

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.

Adverse Events During Dose Initiation and Escalation

During early clinical trials, Epoprostenol was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of Epoprostenol. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 4 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.

Table 4: Adverse Events During Dose Initiation and Escalation

Adverse Events Occurring in ≥1% of Patients	Epoprostenol (n = 391)
Flushing	58%
Headache	49%
Nausea/vomiting	32%
Hypotension	16%
Anxiety, nervousness, agitation	11%
Chest pain	11%
Dizziness	8%
Bradycardia	5%
Abdominal pain	5%
Musculoskeletal pain	3%
Dyspnea	2%
Back pain	2%
Sweating	1%
Dyspepsia	1%
Hypesthesia/paresthesia	1%
Tachycardia	1%

Adverse Events During Chronic Administration for PPH

Interpretation of adverse events is complicated by the clinical features of PPH and PH/SSD, which are similar to some of the pharmacologic effects of Epoprostenol (e.g., dizziness, syncope). Adverse events probably related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to Epoprostenol. These include headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness.

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% different in the 2 groups in controlled trials for PPH.

Table 5: Adverse Events Regardless of Attributions Occurring in Patients With PPH With ≥ 10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event	Epoprostenol (n = 52)	Conventional Therapy (n = 54)
Occurrence More Common With Epoprostenol
General
Chills/fever/sepsis/flu-like symptoms	25%	11%
Cardiovascular
Tachycardia	35%	24%
Flushing	42%	2%
Gastrointestinal
Diarrhea	37%	6%
Nausea/vomiting	67%	48%
Musculoskeletal
Jaw pain	54%	0%
Myalgia	44%	31%
Nonspecific musculoskeletal pain	35%	15%
Neurological
Anxiety/nervousness/tremor	21%	9%
Dizziness	83%	70%
Headache	83%	33%
Hypesthesia, hyperesthesia, paresthesia	12%	2%
Occurrence More Common With Standard Therapy
Cardiovascular
Heart failure	31%	52%
Syncope	13%	24%
Shock	0%	13%
Respiratory
Hypoxia	25%	37%

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving Epoprostenol.

Table 6 lists additional adverse events reported in PPH patients receiving Epoprostenol plus conventional therapy or conventional therapy alone during controlled clinical trials.

Table 6: Adverse Events Regardless of Attribution Occurring In Patients with PPH With <10% Difference between Epoprostenol and Conventional Therapy

Adverse Event	Epoprostenol (n = 52)	Conventional Therapy (n = 54)
General
Asthenia	87%	81%
Cardiovascular
Angina pectoris	19%	20%
Arrhythmia	27%	20%
Bradycardia	15%	9%
Supraventricular tachycardia	8%	0%
Pallor	21%	30%
Cyanosis	31%	39%
Palpitation	63%	61%
Cerebrovascular accident	4%	0%
Hemorrhage	19%	11%
Hypotension	27%	31%
Myocardial ischemia	2%	6%
Gastrointestinal
Abdominal Pain	27%	31%
Anorexia	25%	30%
Ascites	12%	17%
Constipation	6%	2%
Metabolic
Edema	60%	63%
Hypokalemia	6%	4%
Weight reduction	27%	24%
Weight gain	6%	4%
Musculoskeletal
Arthralgia	6%	0%
Bone pain	0%	4%
Chest pain	67%	65%
Neurological
Confusion	6%	11%
Convulsion	4%	0%
Depression	37%	44%
Insomnia	4%	4%
Respiratory
Cough increase	38%	46%
Dyspnea	90%	85%
Epistaxis	4%	2%
Pleural effusion	4%	2%
Skin and Appendages
Pruritus	4%	0%
Rash	10%	13%
Sweating	15%	20%
Special Senses
Amblyopia	8%	4%
Vision abnormality	4%	0%

Adverse Events During Chronic Administration for PH/SSD

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 7 lists adverse events that occurred at a rate at least 10% different in the 2 groups in the controlled trial for patients with PH/SSD.

Table 7: Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With ≥10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event	Epoprostenol (n = 56)	Conventional Therapy (n = 55)
Occurrence More Common With Epoprostenol
Cardiovascular
Flushing	23%	0%
Hypotension	13%	0%
Gastrointestinal
Anorexia	66%	47%
Nausea/vomiting	41%	16%
Diarrhea	50%	5%
Musculoskeletal
Jaw pain	75%	0%
Pain/neck pain/arthralgia	84%	65%
Neurological
Headache	46%	5%
Skin and Appendages
Skin ulcer	39%	24%
Eczema/rash/urticaria	25%	4%
Occurrence More Common With Conventional Therapy
Cardiovascular
Cyanosis	54%	80%
Pallor	32%	53%
Syncope	7%	20%
Gastrointestinal
Ascites	23%	33%
Esophageal reflux/gastritis	61%	73%
Metabolic
Weight decrease	45%	56%
Neurological
Dizziness	59%	76%
Respiratory
Hypoxia	55%	65%

Table 8 lists additional adverse events reported in PH/SSD patients receiving Epoprostenol plus conventional therapy or conventional therapy alone during controlled clinical trials.

Table 8: Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With <10% Difference Between Epoprostenol and Conventional Therapy Alone

Adverse Event*	Epoprostenol (n = 56)	Conventional Therapy (n = 55)
* Adverse events that occurred in at least 2 patients in either treatment group.
General
Asthenia	100%	98%
Hemorrhage/hemorrhage injection site/hemorrhage rectal	11%	2%
Infection/rhinitis	21%	20%
Chills/fever/sepsis/flu-like symptoms	13%	11%
Blood and Lymphatic
Thrombocytopenia	4%	0%
Cardiovascular
Heart failure/heart failure right	11%	13%
Myocardial Infarction	4%	0%
Palpitation	63%	71%
Shock	5%	5%
Tachycardia	43%	42%
Vascular disorder peripheral	96%	100%
Vascular disorder	95%	89%
Gastrointestinal
Abdominal enlargement	4%	0%
Abdominal pain	14%	7%
Constipation	4%	2%
Flatulence	5%	4%
Metabolic
Edema/edema peripheral/edema genital	79%	87%
Hypercalcemia	48%	51%
Hyperkalemia	4%	0%
Thirst	0%	4%
Musculoskeletal
Arthritis	52%	45%
Back pain	13%	5%
Chest pain	52%	45%
Cramps leg