Epoprostenol

FDA Drug Information • Also known as: Epoprostenol, Veletri

Brand Names: Epoprostenol, Veletri
Drug Class: Prostacycline Vasodilator [EPC]
Route: INTRAVENOUS
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Epoprostenol sodium is the sodium salt of epoprostenol, formulated as a sterile lyophilized powder for intravenous (IV) administration. Each vial of epoprostenol for injection contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 50 mg arginine and 100 mg sucrose. Sodium hydroxide is 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 (5 Z ,9a,11a,13 E ,15 S )-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid. Epoprostenol sodium has a molecular weight of 374.5 and a molecular formula of C 20 H 31 NaO 5 . The structural formula is: Epoprostenol for injection is a white to off-white lyophilized powder or cake. It is reconstituted with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. The reconstituted solution of epoprostenol for injection has a pH ranging from 11 to 13 and is increasingly unstable at a lower pH. Epoprostenol Structural Formula

What Is Epoprostenol Used For?

1 INDICATIONS AND USAGE 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. Epoprostenol for injection is a prostacyclin vasodilator 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. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Important Note: Reconstitute Epoprostenol for Injection only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not dilute reconstituted solutions of epoprostenol for injection or administer it with other parenteral solutions or medications [see Dosage and Administration (2.4) ].

Dosage - Infusion of epoprostenol for injection 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. ( 2.1 ) - If symptoms of pulmonary hypertension persist or recur after improving - the infusion should be increased 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. ( 2.2 )

Administration - Epoprostenol for injection is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. ( 2.3 ) - Do not mix with any other parenteral medications or solutions prior to or during administration. ( 2.4 )

Reconstitution - Reconstituted in vial with only 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9% Injection. - Epoprostenol for injection solution reconstituted and immediately diluted to the final concentration in the drug delivery reservoir can be administered per the conditions of use as outlined in Table 1. ( 2.4 ) - Solution for chronic delivery should be prepared in a drug delivery reservoir appropriate for the infusion pump. ( 2.4 ) 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS

Most common adverse reactions during: - Dose Initiation and Escalation: Nausea, vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia ( 6.1 ) - Chronic Dosing: Headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. 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 8 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency. Table 8: 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 Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of epoprostenol (e.g., dizziness, syncope). Adverse events which may be 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 hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during epoprostenol therapy, and a role for the drug in these events cannot be excluded. Adverse Events during Chronic Administration for Idiopathic or Heritable PAH In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 9 lists adverse events that occurred at a rate at least 10% greater on epoprostenol than on conventional therapy in controlled trials for idiopathic or heritable PAH. Table 9: Adverse Events Regardless of Attribution Occurring in Patients with Idiopathic or Heritable PAH 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...

Drug Interactions

7 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 the 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. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen. In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with epoprostenol was initiated, apparent oral clearance values for furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the second day of therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be clinically significant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with epoprostenol, which may be clinically significant in patients prone to digoxin toxicity.

Diuretics, antihypertensive agents, or other vasodilators: reduction in blood pressure ( 7 )

Antiplatelet agents or anticoagulants: increase the risk of bleeding ( 7 )

Patients on digoxin: elevations of digoxin concentrations clinically significant in patients prone to digoxin toxicity ( 7 )

Contraindications

4 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.

Congestive heart failure due to severe left ventricular systolic dysfunction ( 4 )

Pulmonary edema (4)

Hypersensitivity to the drug or to structurally related compounds ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary 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 ( see Clinical Considerations ). In animal reproduction studies, pregnant rats and rabbits received epoprostenol sodium during organogenesis at exposures of 2.5 and 4.8 times the maximum recommended human dose (MRHD), respectively, and there was no effect on the fetus ( see Data ). 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data Embryo-fetal development studies have been performed in rats and rabbits during organogenesis. Epoprostenol sodium doses up to 100 mcg/kg/day, a dose that was maternally toxic in rabbits but not in rats, (600 mcg/m 2 /day in rats, 2.5 times the MRHD, and 1,180 mcg/m 2 /day in rabbits, 4.8 times the MRHD based on body surface area), had no effect on the fetus. In a postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at a male and female toxic dose of up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the MRHD based on body surface area). There was no effect on growth and development of the offspring.

Overdosage

10 OVERDOSAGE Signs and symptoms of excessive doses of epoprostenol during clinical trials are the expected dose-limiting pharmacologic effects of epoprostenol, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of epoprostenol. One patient with secondary pulmonary hypertension 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. In clinical practice, fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of epoprostenol. 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.