Note-information provided is for both products unless otherwise noted.
Indications: Epoprostenol is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity.
Mechanism: Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation.
Dosing:
- 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.
- 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.
- 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. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer (Flolan), or until the dose-limiting effects resolve. (Flolan/Veletri)
- Epoprostenol 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.
- Do not mix with any other parenteral medications or solutions prior to or during administration.
- (Flolan) During use, a single reservoir of reconstituted solution of can be administered at room temperature for a total duration of 8 hours, or it can be used with a cold pouch and administered up to 24 hours with the use of 2 frozen 6-oz gel packs in a cold pouch. When stored or in use, insulate reconstituted FLOLAN from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.
Efficacy:
Idiopathic/Heritable PAH:
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 to conventional therapy alone. The average dose of epoprostenol in these studies was 9.2 ng/kg/min.
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. 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. 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 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).
PAH/Scleroderma Spectrum of Diseases:
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) to conventional therapy alone (n=55).Dosage of epoprostenol averaged 11.2 ng/kg/min at study’s end.
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 to those who did not. 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 to 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.
At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to 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 to 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.
Adverse Events (most common by phase of treatment):
- Dose Initiation and Escalation phase: Nausea, vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia
- Chronic Dosing phase: (Veletri) Headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness. (Flolan) hypotension, bradycardia, tachycardia, pulmonary edema, bleeding, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation.
Warnings:
- Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension.
- Veletri-reconstitute only as directed, with Sterile Water for Injection or Sodium Chloride 0.9% Injection.
- Flolan-reconstitute only as directed using STERILE DILUENT for FLOLAN. FLOLAN must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
- Do not abruptly lower the dose or withdraw dosing. All dosing initiation and changes should be closely monitored.
Contraindications:
- Congestive heart failure due to severe left ventricular systolic dysfunction
- Pulmonary edema
- Hypersensitivity to the drug or to structurally related compounds
Metabolism/Drug interactions:
- Digoxin-increased digoxin levels with concomitant use
- Diuretics, antihypertensive agents, or other vasodilators: reduction in blood pressure
- Antiplatelet agents or anticoagulants: increase the risk of bleeding
Access Program: none, however product only available through specialty pharmacy with an accompanying Rx and patient enrollment form.
Patient Enrollment forms: http://www.veletri.com/pdf/Accredo_PAH_Enrollment_Form.pdf
http://www.accredo.com/referral/PAH.pdf
Full US Prescribing Information can be found here:
Veletri: http://www.veletri.com/pdf/veletri_full_prescribing_information_2nd_gen.pdf
Flolan: http://us.gsk.com/products/assets/us_flolan.pdf
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