VELETRI Powder for solution for infusion Ref.[9383] Active ingredients: Epoprostenol

Pharmacotherapeutic group: Antithrombotic Agents; Platelet aggregation inhibitors excl. heparin
ATC code: B01AC09

The pH value of VELETRI is higher than the pH of other epoprostenol products.

Compared to other epoprostenol diluted solutions, which are buffered with glycine, VELETRI contains l-arginine, at lower buffering capacity. This leads to a broader range of pH values of the diluted solution. The pH decreases with dilution from 12.0 at a concentration of 90,000 ng/mL, 11.7 at a concentration of 45,000 ng/mL to 11.0 at a concentration of 3,000 ng/mL.

The studies described below under subheading “Pharmacodynamic effects” refer to studies performed with a solution of epoprostenol buffered with glycine and with a pH between 10.3 and 10.8 (Flolan).

Mechanism of action

Epoprostenol Sodium, the monosodium salt of epoprostenol, a naturally occurring prostaglandin produced by the intima of blood vessels. Epoprostenol is the most potent inhibitor of platelet aggregation known. It is also a potent vasodilator.

Many of the actions of epoprostenol are exerted via the stimulation of adenylate cyclase, which leads to increased intracellular levels of cyclic adenosine 3’5' monophosphate (cAMP). A sequential stimulation of adenylate cyclase, followed by activation of phosphodiesterase, has been described in human platelets. Elevated cAMP levels regulate intracellular calcium concentrations by stimulating calcium removal, and thus platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depends.

Pharmacodynamic effects

An infusion of 4 ng/kg/min for 30 minutes has been shown to have no significant effect on heart rate or blood pressure, although facial flushing may occur at this level.

Pulmonary Arterial Hypertension

Intravenous epoprostenol infusions of up to 15 minutes have been found to 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) in patients with idiopathic or heritable PAH were variable and minor.

Renal Dialysis

The effects of epoprostenol on platelet aggregation is dose-related when between 2 and 16 ng/kg/min is administered intravenously, and significant inhibition of aggregation induced by adenosine diphosphate is observed at doses of 4 ng/kg/min and above.

Effects on platelets have been found to disappear within 2 hours of discontinuing the infusion, and haemodynamic changes due to epoprostenol to return to baseline within 10 minutes of termination of 60 minutes infusion at 1 to 16 ng/kg/min.

Higher circulating doses of epoprostenol (20 ng/kg/min) disperse circulating platelet aggregates and increase by up to two-fold the cutaneous bleeding time.

Epoprostenol potentiates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor.

Clinical efficacy and safety

Pulmonary Arterial Hypertension

Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomised trials of 8 and 12 weeks' duration (N=25 and N=81, respectively) comparing epoprostenol plus conventional therapy to conventional therapy alone. 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 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described. The combined baseline 6-minute walk test (6MWT) median value for the conventional therapy group and epoprostenol plus conventional therapy group was 266 meters and 301 meters, respectively.

Improvements from baseline in cardiac index (0.33 vs. -0.12 L/min/m²), stroke volume (6.01 vs. -1.32 mL/beat), arterial oxygen saturation (1.62 vs. -0.85%), mean pulmonary artery pressure (-5.39 vs. 1.45 mm Hg), mean right atrial pressure (-2.26 vs. 0.59 mm Hg), total pulmonary resistance (-4.52 vs. 1.41 Wood U), pulmonary vascular resistance (-3.60 vs. 1.27 Wood U), and systemic vascular resistance (-4.31 vs. 0.18 Wood U) were statistically different between patients who received epoprostenol chronically and those who did not. Mean systemic arterial pressure was not significantly different between the 2 groups (-4.33 vs. -3.05 mm Hg). These haemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, non-randomised study.

Statistically significant improvement was observed in exercise capacity (p=0.001), as measured by the 6MWT 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] combined week 8 and 12 change from baseline – median: 49 vs. -4 meters; mean: 55 vs. -4 meters). Improvements were apparent as early as the first week of therapy. At the end of the treatment period in the 12-week study, survival was improved in NYHA functional Class III and Class IV patients. Eight of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p=0.003).

Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomised trial of 12 weeks' duration comparing epoprostenol plus conventional therapy (N=56) to conventional therapy alone (N=55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. 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. The primary efficacy endpoint for the study was improvement in the 6MWT. The median baseline value for the conventional therapy group and epoprostenol plus conventional therapy group was 240 meters and 270 meters, respectively. 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.

Over 12 weeks, a statistical difference (p<0.001) in the change from baseline for the 6MWT was observed in the group receiving epoprostenol and conventional therapy as compared to the group receiving conventional therapy alone (median: 63.5 vs. -36.0 meters; mean: 42.9 vs. -40.7 meters).

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 dyspnoea, as measured by the Borg Dyspnea Index. 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.

Renal Dialysis

Six heparin-controlled studies and five emergency studies explored the place of epoprostenol in the general management of renal dialysis, using different techniques. Primary measurements of efficacy included intradialytic removal of BUN and creatinine, intradialytic removal of fluid (ultrafiltration), and clotting within the extracorporeal circuit.

Major clotting (dialysis permanently suspended, or requiring changing of artificial kidney) occurred in approximately 9% (N=56) of all epoprostenol dialyses and in <1% (N=1) of heparin dialyses in major controlled studies and emergency studies. Most epoprostenol dialyses (67%) that required replacement of artificial kidney were completed subsequently with epoprostenol without clotting. However, 9 of 27 epoprostenol dialyses were unsuccessful following multiple attempts.

Independent of technical difficulties, which occurred rarely with either treatment, major dialysis-limiting clotting did not occur in 93% of all epoprostenol dialyses and 99% of all heparin dialyses.

Minor clotting (sufficient to require intervention, but not permanently suspending dialysis or requiring changing of the artificial kidney) was reported more frequently during epoprostenol than during heparin dialyses. None of the dialyses using heparin and 5% (N=32) of dialyses using epoprostenol had minor clotting.

Visible clotting (not necessitating intervention) was reported in another 31% of epoprostenol dialyses and 5% of heparin dialyses.

To establish that renal dialysis patients at increased risk of haemorrhage bleed less frequently with epoprostenol than heparin, 2 major prospectively controlled studies were conducted. Each patient was randomly assigned to a sequence of heparin or epoprostenol dialyses and received up to 6 dialyses per entry in one study and up to 3 dialyses per entry in another study.

Bleeding risk was defined as:

• Very high risk – presence of active bleeding at the time of dialysis initiation
• High risk – having had within 3 days prior to dialysis an active bleed that stopped at the pre-dialysis phase; or having incurred surgical or traumatic wounds within 3 days prior to dialysis

Twelve patients at very high risk of haemorrhage received 35 epoprostenol dialyses and 11 patients received 28 heparin dialyses in major controlled studies. Sixteen patients received 24 epoprostenol dialyses in emergency studies.

In major controlled studies, when all dialyses were combined for each treatment (heparin or epoprostenol), more heparin patients bled during the day prior to dialysis (N=13/17 vs. 8/23), dialysis day (N=25/28 vs. 16/35) and the day following dialysis (N=16/24 vs. 5/24) than epoprostenol patients during the same time periods.

Those patients who continued to bleed were evaluated for changes in bleeding severity. Severity of bleeding in those patients was improved more frequently with epoprostenol the day prior to dialysis and on dialysis day (pre-dialysis: N=4/8; dialysis: N=6/16) than with heparin (predialysis: N=4/13; dialysis: N=4/25). However, the reverse was observed for post-dialysis days with epoprostenol (N=1/5) compared to heparin (N=8/16). Bleeding severity worsened during only 1 dialysis day with epoprostenol (N=1/16) whereas severity worsened during 5 dialysis days (N=5/25) and 2 predialysis days (N=2/13) with heparin.

Patients who did not have clear evidence of bleeding just prior to their first study dialysis but who bled within 3 days prior were classified as high risk of haemorrhage. Nineteen patients received 51 heparin dialyses, and 19 received 44 epoprostenol dialyses in major controlled studies.

When all dialyses were combined, slightly more epoprostenol patients appeared to bleed during the pre-dialysis (N=12/25 vs. 8/32), dialysis (23/44 vs. 14/51) and post-dialysis (8/34 vs. 5/44) days compared to heparin patients during the same periods.