EPOPROSTENOL SODIUM - epoprostenol sodium injection 
STERILE DILUENT FOR EPOPROSTENOL SODIUM - water injection 
Teva Parenteral Medicines, Inc

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PRESCRIBING INFORMATION

Rx only

DESCRIPTION

Epoprostenol sodium for injection is a sterile sodium salt formulated for intravenous (IV) administration. Each vial of epoprostenol sodium for injection contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.

Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation.

Epoprostenol is (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid.

Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of C20H31NaO5. The structural formula is:

Epoprostenol sodium for injection is a white to off-white powder that must be reconstituted with STERILE DILUENT for epoprostenol sodium for injection. STERILE DILUENT for epoprostenol sodium for injection is supplied in glass vials containing 50 mL of 94 mg glycine,73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection, USP.

The reconstituted solution of epoprostenol sodium for injection has a pH of 11.0 to 11.8 and is increasingly unstable at a lower pH.

CLINICAL PHARMACOLOGY

General

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

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.

CLINICAL TRIALS IN PULMONARY HYPERTENSION

Acute Hemodynamic Effects

Acute intravenous infusions of epoprostenol for up to 15 minutes in patients with secondary and primary pulmonary hypertension 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 artery pressure (PAPm) were variable and minor.

Chronic Infusion in Primary Pulmonary Hypertension (PPH)

Hemodynamic Effects

Chronic continuous infusions of epoprostenol in patients with PPH 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 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 1 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 PPH patients 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 Pulmonary Hypertension Associated with the Scleroderma Spectrum of Diseases (PH/SSD)