Veletri Safety Profile

Contraindications

Congestive heart failure: 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.

Pulmonary veno-occlusive disease: Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Veletri should not be used chronically in patients who develop pulmonary edema during dose initiation.

Hypersensitivity: Veletri is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds. Hypersensitivity reactions, including anaphylaxis, have been reported with epoprostenol use.

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. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. 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.

Reconstitution and dilution

Veletri must be reconstituted and diluted only as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Veletri must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration

Do not freeze reconstituted solutions of Veletri. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 5 days, or if held at room temperature for more than 48 hours.

Adverse events during dose initiation and escalation

The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing but also included chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia.

Chronic use and dose adjustment

During chronic use, Veletri is delivered continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, anticoagulant therapy should be administered 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, aseptic technique must be used in the reconstitution and administration of Veletri as well as in routine catheter care. Even brief interruptions in the delivery of Veletri may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia.

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, standing and supine blood pressure and heart rate should be monitored closely for several hours.

Abrupt withdrawal (including interruptions in drug delivery) or a sudden large reduction in Veletri dose may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. Abrupt withdrawal should be avoided.

Drug interactions

Additional reductions in blood pressure may occur when Veletri is administered with diuretics, antihypertensive agents, or other vasodilators. When 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.

Adverse events during chronic administration

Interpretation of adverse events is complicated by the clinical features of Idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH^*) and pulmonary arterial hypertension associated with connective tissue disease (PAH/CTD), which are similar to some of the pharmacologic effects of epoprostenol (eg, dizziness, syncope). Adverse events probably 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 headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness.

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.