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Prescribing Information

Chronic Infusion in PAH/SDD:

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 to conventional therapy alone. Except for the five NYHA functional Class II patients, all patients were either functional Class III or Class IV. The patients principally had pulmonary vascular manifestations of the collagen-vascular disease, with minimal evidence of interstitial lung disease and with total lung capacities greater than 60% of the predicted normal. Dosage of EPOPROSTENOL was determined as described in DOSAGE AND ADMINISTRATION and averaged 11.2 ng/kg per minute at study end. Conventional therapy varied among patients and included 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, RAP, PVR, and SAPm were observed in patients who received EPOPROSTENOL chronically compared to those who did not. Table 2 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.

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 to those receiving conventional therapy alone. Improvements were apparent as early as 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. By 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. No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with EPOPROSTENOL. At the end of the treatment period, 4 of 56 (7%) patients receiving EPOPROSTENOL died, whereas 5 of 55 (9%) patients receiving conventional therapy died.

IMPORTANT SAFETY INFORMATION

Contraindications

VELETRI is contraindicated in patients with congestive heart failure due to severe left ventricular systolic dysfunction.

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

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

Indication

VELETRI® (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 (CTD).

Dose Initiation

VELETRI is a potent pulmonary and systemic vasodilator. Initiate VELETRI in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

Chronic Use and Dose Adjustment

During chronic use, deliver VELETRI continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving VELETRI to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of VELETRI and in routine catheter care.

Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of VELETRI may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with VELETRI will likely be needed for prolonged periods, possibly years, so consider the patient’s capacity to accept and care for a permanent intravenous catheter and infusion pump.

Dosage of VELETRI 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. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of VELETRI may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. Abrupt withdrawal should be avoided.

Adverse Events

The most common and dose-limiting adverse events during dose initiation and escalation (≥1%) were 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%), and tachycardia (1%).

Adverse events occurring in patients with idiopathic or heritable PAH with ≥10% difference between epoprostenol and conventional therapy alone were chills/fever/sepsis/flu-like symptoms (25% vs 11%), tachycardia (35% vs 24%), flushing (42% vs 2%), diarrhea (37% vs 6%), nausea/vomiting (67% vs 48%), jaw pain (54% vs 0%), myalgia (44% vs 31%), nonspecific musculoskeletal pain (35% vs 15%), anxiety/nervousness/tremor (21% vs 9%), dizziness (83% vs 70%), headache (83% vs 33%), and hypesthesia/hyperesthesia/paresthesia (12% vs 2%).

Adverse events occurring in patients with PAH/CTD with ≥10% difference between epoprostenol and conventional therapy alone were flushing (23% vs 0%), hypotension (13% vs 0%), anorexia (66% vs 47%), nausea/vomiting (41% vs 16%), diarrhea (50% vs 5%), jaw pain (75% vs 0%), pain/neck pain/arthralgia (84% vs 65%), headache (46% vs 5%), skin ulcer (39% vs 24%), and eczema/rash/urticaria (25% vs 4%).

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

Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure.

Drug Interactions

Additional reductions in blood pressure may occur when VELETRI is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for VELETRI 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.

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