time off Epoprostenol Generic Name: Epoprostenol sodium Dosage Form: injection, powder, for solution Overview Side Effects Dosage Professional Interactions More Pregnancy Warnings User Reviews Support Group Q & A Pricing & Coupons Indications and Usage for Epoprostenol Epoprostenol sodium for injection is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Trials establishing effectiveness included predominantly (97%) patients with New York Heart Association (NYHA) Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (49%) or PAH associated with connective tissue diseases (51%). Slideshow Can Prescription Drugs Lead to Weight Gain? Epoprostenol Dosage and Administration Reconstitution Each vial is for single dose only; discard any unused diluent or unused reconstituted solution. Select a concentration for the solution of Epoprostenol sodium for injection 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 below [see Dosage and Administration (2.4)] . Using aseptic technique, reconstitute Epoprostenol sodium for injection only with STERILE DILUENT for Epoprostenol sodium for injection. Table 1 gives directions for preparing several different concentrations of Epoprostenol sodium for injection. See Table 2 for storage and administration time limits for the reconstituted Epoprostenol sodium for injection. Table 1. Reconstitution and Dilution Instructions for Epoprostenol Sodium for Injection Using STERILE DILUENT for Epoprostenol Sodium for Injection. * Higher concentrations may be prepared for patients who receive Epoprostenol sodium for injection long-term. To make 100 mL of solution with final concentration of: Directions: 3,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of sterile diluent. Withdraw 3 mL and add to sufficient sterile 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 diluent. Withdraw entire vial contents and add sufficient sterile 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 diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 15,000 ng/mL * Dissolve contents of one 1.5-mg vial with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. Table 2. Storage and Administration Limits for Reconstituted Epoprostenol Sodium for Injection When Using STERILE DILUENT for Epoprostenol Sodium for Injection Stability When used at room temperature, (15 C to 25 C; 59 F to 77 F) reconstituted solutions: • are stable for up to 8 hours following reconstitution or removal from refrigerated storage • may be stored for up to 40 hours refrigerated at 2 C to 8 C (36 F to 46 F) before use. When used with a cold pack, reconstituted solutions: • are stable for up to 24 hours use • may be stored refrigerated at 2 C to 8 C (36 F to 46 F) before use as long as the total time of refrigerated storage and infusion does not exceed 48 hours • Change cold packs every 12 hours. • Reconstituted solutions can be used immediately. Refrigerate at 2 C to 8 C (36 F to 46 F) if not used immediately. • Protect from light. • Do not freeze reconstituted solutions. Dosage Initiate intravenous infusions of Epoprostenol sodium for injection at 2 ng/kg/min. Alter the infusion 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. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output may occur. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated. 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 vasodilatory reactions. In general, expect progressive increases in dose. If dose-related adverse reactions occur, make dose decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve [see Adverse Reactions ( 6.1 )] . Avoid abrupt withdrawal of Epoprostenol sodium for injection or sudden large reductions in infusion rates [see Warnings and Precautions ( 5.2 )] . Following establishment of a new chronic infusion rate, measure standing and supine blood pressure for several hours. Taper doses of Epoprostenol sodium for injection after initiation of cardiopulmonary bypass in patients receiving lung transplants. Administration Initiate Epoprostenol in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use. Administer continuous chronic infusion of Epoprostenol sodium for injection through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Do not administer bolus injections of Epoprostenol sodium for injection. The ambulatory infusion pump used to administer Epoprostenol sodium 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 sodium for injection. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Use a 60-inch microbore non-di-(2-ethylhexyl)phthalate (DEHP) extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22-micron filter. To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Do not administer or dilute reconstituted solutions of Epoprostenol sodium for injection with other parenteral solutions or medications. Consider a multi-lumen catheter if other intravenous therapies are routinely administered. Select a concentration for the solution of Epoprostenol sodium for injection 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. When administered chronically, prepare Epoprostenol sodium for injection in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of STERILE DILUENT for Epoprostenol sodium for injection. Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of Epoprostenol sodium for injection. Infusion rates may be calculated using the following formula: Infusion Rate (mL/h) = [Dose (ng/kg/min) Weight (kg) 60 min/h] Final Concentration (ng/mL) Example calculations for infusion rates are as follows: Example 1: for a 60-kg person at the recommended initial dose of 2 ng/kg/min using a 3,000-ng/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [2 (ng/kg/min) 60 (kg) 60 ( min/h) ] = 2.4 (mL/h) 3,000 (ng/mL) Example 2: for a 70-kg person at a dose of 16 ng/kg/min using a 15,000-ng/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [16 (ng/kg/min) 70 (kg) 60 ( min/h) ] = 4.48 (mL/h) 15,000 (ng/mL) Dosage Forms and Strengths For injection: 0.5 mg or 1.5 mg of Epoprostenol, freeze-dried powder in a single-dose vial for reconstitution with the supplied diluent. Contraindications Epoprostenol is contraindicated in patients with heart failure caused by reduced left ventricular ejection fraction [see Clinical Studies ( 14.3 )] . Epoprostenol is contraindicated in patients with a hypersensitivity to the drug or any of its ingredients. Warnings and Precautions Pulmonary Edema If the patient develops pulmonary edema during initiation with Epoprostenol, discontinue therapy and do not readminister. Consider the possibility of associated pulmonary veno-occlusive disease in such patients. Rebound Pulmonary Hypertension following Abrupt Withdrawal Avoid abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of Epoprostenol because symptoms associated with rebound pulmonary hypertension (e.g., dyspnea, dizziness, and asthenia) may occur. In clinical trials, one Class III patient's death was judged attributable to the interruption of Epoprostenol. Vasodilation Epoprostenol is a potent pulmonary and systemic vasodilator and can cause hypotension and other reactions such as flushing, nausea, vomiting, dizziness, and headache. Monitor blood pressure and symptoms regularly during initiation and after dose change [see Dosage and Administration ( 2.2 )]. Increased Risk for Bleeding Epoprostenol is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding [see Clinical Pharmacology ( 12.3 )] . 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions are shown in Table 3 and are generally related to vasodilatory effects. Table 3. Adverse Reactions Occurring in Patients with Idiopathic or Heritable PAH and with PAH Associated with Scleroderma Spectrum of Diseases (PAH/SSD) Occurring ≥10% More Frequently on Epoprostenol than Conventional Therapy Adverse Reaction Idiopathic or Heritable PAH PAH/SSD Epoprostenol (n = 52) Conventional Therapy (n = 54) Epoprostenol (n = 56) Conventional Therapy (n = 55) Body as a whole Jaw pain 54% 0% 75% 0% Nonspecific musculoskeletal pain 35% 15% 84% 65% Headache 83% 33% 46% 5% Chills/fever/sepsis/flu-like symptoms 25% 11% 13% 11% Cardiovascular system Flushing 42% 2% 23% 0% Hypotension 27% 31% 13% 0% Tachycardia 35% 24% 43% 42% Digestive system Anorexia 25% 30% 66% 47% Nausea/Vomiting 67% 48% 41% 16% Diarrhea 37% 6% 50% 5% Skin and Appendages Skin ulcer - - 39% 24% Eczema/rash/urticaria 10% 13% 25% 4% Musculoskeletal system Myalgia 44% 31% - - Nervous system Anxiety/hyperkinesias/nervousness /tremor 21% 9% 7% 5% Hyperesthesia/hypesthesia/paresthesia 12% 2% 5% 0% Dizziness 83% 70% 59% 76% Adverse Events Attributable to the Drug Delivery System Chronic infusions of Epoprostenol are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks duration, the local infection rate was about 18%, and the rate for pain was about 11%. During long-term follow-up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with Epoprostenol. Postmarketing Experience The following events have been identified during postapproval use of Epoprostenol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic Anemia, hypersplenism, pancytopenia, splenomegaly, thrombocytopenia. Endocrine and Metabolic Hyperthyroidism. Gastrointestinal Hepatic failure. Respiratory, Thoracic, and Mediastinal Pulmonary embolism. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Epoprostenol should be used during pregnancy only if clearly needed. Animal Data Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100 mcg/kg/day (600 mcg/m 2 /day in rats, 2.5 times the recommended human dose, and 1,180 mcg/m 2 /day in rabbits, 4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to Epoprostenol. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Epoprostenol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical trials of Epoprostenol in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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. Overdosage Signs and Symptoms Hypoxemia, hypotension, and respiratory arrest leading to death have been reported in clinical practice following overdosage of Epoprostenol. Excessive doses of Epoprostenol were associated with flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea during clinical trials. One patient with PAH/SSD accidentally received 50 mL of an unspecified concentration of Epoprostenol. The patient vomited and became unconscious with an initially unrecordable blood pressure. Epoprostenol was discontinued and the patient regained consciousness within seconds. Single intravenous doses of Epoprostenol at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia. Treatment Discontinue or reduce dose of Epoprostenol. Epoprostenol 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 (PGI 2 , 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,13 E ,15 S )-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 C 20 H 31 NaO 5 . 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. Epoprostenol - Clinical Pharmacology 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. Pharmacodynamics Acute Hemodynamic Effects Acute intravenous infusions of Epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or 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 artery pressure (PAPm) were variable and minor. In humans, hemodynamic changes due to Epoprostenol (e.g., increased heart rate, facial flushing) returned to baseline within 10 minutes of termination of 60-minute infusions of 1 to 16 ng/kg/min. This pharmacodynamic behavior is consistent with a short in vivo half-life and rapid clearance in man, as suggested by the results of animal and in vitro studies. 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. Drug Interactions Additional reductions in blood pressure may occur when Epoprostenol is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is a potential for Epoprostenol to increase the risk of bleeding. However, patients receiving infusions of Epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding. Pharmacokinetics Absorption/Distribution Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of Epoprostenol. 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. Metabolism 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-PGF 1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF 1α (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. Elimination 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. Drug Interactions In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide in whom therapy with Epoprostenol was initiated, apparent oral clearance values for furosemide (n = 23) were decreased by 13% on the second day of therapy and returned to baseline values by Day 87. The change in furosemide clearance value is not likely to be clinically significant. In a pharmacokinetic substudy in patients with congestive heart failure receiving digoxin in whom therapy with Epoprostenol was initiated, apparent oral clearance values for digoxin (n = 30) were decreased by 15% on the second day of therapy and returned to baseline values by Day 87. Clinical significance of this interaction is not known. Nonclinical Toxicology 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/m 2 /day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m 2 /day, IV] based on body surface area). Clinical Studies 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 with conventional therapy alone. Dosage of Epoprostenol was determined as described in Dosage and Administration ( 2 ) and averaged 9.2 ng/kg/min at trials 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 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 trials, 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 with those who did not. Table 4 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment. Table 4. Hemodynamics during Chronic Administration of Epoprostenol in Patients with Idiopathic or Heritable PAH * At 8 weeks: Epoprostenol n = 10, conventional therapy n = 11 (n is the number of patients with hemodynamic data). At 12 weeks: Epoprostenol n = 38, conventional therapy n = 30 (n is the number of patients with hemodynamic data). † Denotes statistically significant difference between group receiving Epoprostenol and group receiving conventional therapy. CI = Cardiac index, PAPm = Mean pulmonary arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure, SV = Stroke volume, TPR = Total pulmonary resistance. Hemodynamic Parameter Baseline Mean Change from Baseline at End of Treatment Period * Epoprostenol (n = 52) Standard Therapy (n = 54) Epoprostenol (n = 48) Standard Therapy (n = 41) CI (L/min/m 2 ) 2.0 2.0 0.3 † -0.1 PAPm (mm Hg) 60 60 -5 † 1 PVR (Wood U) 16 17 -4 † 1 SAPm (mm Hg) 89 91 -4 -3 SV (mL/beat) 44 43 6 † -1 TPR (Wood U) 20 21 -5 † 1 These hemodynamic improvements appeared to persist when Epoprostenol was administered for at least 36 months in an open, nonrandomized trial. The acute hemodynamic response to Epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of Epoprostenol. Clinical Effects A 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 with 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, respectively. 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 trial. 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/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) with conventional therapy alone (n = 55). Except for 5 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. 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 to 3 ng/kg/min every 3 weeks. 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 with those who did not. Table 5 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment. Table 5. Hemodynamics during Chronic Administration of Epoprostenol in Patients with PAH/SSD * Denotes statistically significant difference between group receiving Epoprostenol and group receiving conventional therapy (n is the number of patients with hemodynamic data). Hemodynamic Parameter Baseline Mean Change from Baseline at 12 Weeks Epoprostenol (n = 56) Conventional Therapy (n = 55) Epoprostenol (n = 50) Conventional Therapy (n = 48) CI (L/min/m 2 ) 1.9 2.2 0.5 * -0.1 PAPm (mm Hg) 51 49 -5 * 1 RAPm (mm Hg) 13 11 -1 * 1 PVR (Wood U) 14 11 -5 * 1 SAPm (mm Hg) 93 89 -8 * -1 CI = Cardiac index, PAPm = Mean pulmonary arterial pressure, RAPm = Mean right arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure. 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 with 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 with 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. No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with Epoprostenol as compared with 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. Increased Mortality in Patients with Heart Failure Caused by Severe Left Ventricular Systolic Dysfunction A large trial 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 heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated. How Supplied/Storage and Handling How Supplied Epoprostenol sodium for injection is supplied as a sterile freeze-dried powder in 10 mL flint glass vials with gray butyl rubber closures, individually packaged in a carton. NDC 0703- 1985-01 10 mL vial containing Epoprostenol sodium equivalent to 0.5 mg (500,000 ng), carton of 1. NDC 0703- 1995-01 10 mL vial containing Epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng), carton of 1. The STERILE DILUENT for Epoprostenol Sodium for Injection is supplied in flint glass vials containing 50 mL diluent with butyl rubber closures. NDC 0703- 9258-09 50 mL of STERILE DILUENT for Epoprostenol Sodium for Injection, tray of 2 vials. Storage and Handling Proper storage and handling are essential to maintain the potency of Epoprostenol sodium for injection. Unopened vials of Epoprostenol sodium for injection powder are stable until the date indicated on the package when stored at room temperature, 20 C to 25 C (68 F to 77 F) [see USP Controlled Room Temperature] and protected from light in the carton. Unopened vial of STERILE DILUENT for Epoprostenol sodium for injection are stable until the date indicated on the package when stored at room temperature, 20 C to 25 C (68 F to 77 F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise patients: • Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for Epoprostenol sodium for injection. • Reconstituted solution prepared with STERILE DILUENT for Epoprostenol sodium for injection must be used with a cold pouch if not administered within 8 hours. • Epoprostenol sodium for injection is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with Epoprostenol sodium for injection requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of Epoprostenol sodium for injection may result in rapid symptomatic deterioration. A patient s decision to receive Epoprostenol sodium for injection should be based upon the understanding that there is a high likelihood that therapy with Epoprostenol sodium for injection will be needed for prolonged periods, possibly years. Consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump. • To adjust infusion rates of Epoprostenol sodium for injection only under the direction of a physician. • To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. • To contact their healthcare providers if any unusual bruising or bleeding develops. Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. C 7/2017 PATIENT INFORMATION Epoprostenol Sodium ( e poe pros te nol soe dee um ) for Injection Read this Patient Information before you start taking Epoprostenol sodium for injection and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is Epoprostenol sodium for injection? Epoprostenol sodium for injection is a prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of the lungs. Epoprostenol sodium for injection can improve your ability to be physically active. It is not known if Epoprostenol sodium for injection is safe and effective in children. Who should not use Epoprostenol sodium for injection? Do not use Epoprostenol sodium for injection if you: • have certain types of heart failure. Talk to your healthcare provider before using Epoprostenol sodium for injection if you have hear largely
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