Skip to Content

VELETRI 1.5 MG POWDER FOR SOLUTION FOR INFUSION

Active substance(s): EPOPROSTENOL / EPOPROSTENOL / EPOPROSTENOL

View full screen / Print PDF » Download PDF ⇩

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Veletri 1.5 mg, Powder for Solution for Infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1.593 mg epoprostenol sodium equivalent to 1.5 mg epoprostenol
One mL of reconstituted solution contains 0.3 mg epoprostenol (as epoprostenol sodium)
(1.5mg epoprostenol in 5 mL of solvent).
Excipient(s) with known effect: sodium, (0.03 mg for 0.5 mg/vial and 0.09 mg for
1.5 mg/vial)

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder for solution for infusion
White to off-white powder
For the pH of the diluted solution see section 4.4

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Veletri is indicated for:
Pulmonary Arterial Hypertension
Veletri is indicated for the treatment of pulmonary arterial hypertension (PAH)
(idiopathic or heritable PAH and PAH associated with connective tissue diseases) in
patients with WHO Functional Class III–IV symptoms to improve exercise capacity
(see section 5.1).
Renal Dialysis

Veletri is indicated for use in haemodialysis in emergency situations when use of
heparin carries a high risk of causing or exacerbating bleeding or when heparin is
otherwise contraindicated (see section 5.1).

4.2

Posology and method of administration

Posology
Pulmonary Arterial Hypertension
Veletri is only indicated for continuous infusion by intravenous route.
Treatment should only be initiated and monitored by a physician experienced in the
treatment of pulmonary arterial hypertension.
Short-term (acute) dose ranging:
This procedure should be conducted in a hospital with adequate resuscitation
equipment.
A short-term dose-ranging procedure administered via either a peripheral or central
venous line is required to determine the long-term infusion rate. The infusion is
initiated at 2 ng/kg/min and increased by increments of 2 ng/kg/min every 15 min or
longer until maximum haemodynamic benefit or dose-limiting pharmacological
effects are elicited.
If the initial infusion rate of 2 ng/kg/min is not tolerated, a lower dose that is tolerated
by the patient should be identified.
Long-term continuous infusion:
Long-term continuous infusion of Veletri should be administered through a central
venous catheter. Temporary peripheral i.v. infusions may be used until central access
is established. Long-term infusions should be initiated at 4 ng/kg/min less than the
maximum tolerated infusion rate determined during short-term dose-ranging. If the
maximum tolerated infusion rate is 5 ng/kg/min or less, the long-term infusion should
be started at 1 nanogram/kg/min.
Dosage adjustments:
Changes in the long-term infusion rate should be based on persistence, recurrence or
worsening of the patient’s symptoms of pulmonary arterial hypertension or the
occurrence of adverse reactions due to excessive doses of Veletri.
In general, the need for increases in dose from the initial long-term dose should be
expected over time. Increases in dose should be considered if symptoms of pulmonary
arterial hypertension persist, or recur after improving. The infusion rate 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 min. Following establishment of
a new infusion rate, the patient should be observed, and erect and supine blood

pressure and heart rate monitored for several hours to ensure that the new dose is
tolerated.
During long-term infusion, the occurrence of dose-related pharmacological events
similar to those observed during the dose-ranging period may necessitate a decrease in
infusion rate, but the adverse reactions may occasionally resolve without dosage
adjustment. Dosage decreases should be made gradually in 2 ng/kg/min decrements
every 15 min or longer until the dose-limiting effects resolve. Abrupt withdrawal of
Veletri or sudden large reductions in infusion rates should be avoided due to the risk
of potentially fatal rebound effect (see section 4.4). Except in life-threatening
situations (e.g. unconsciousness, collapse, etc.), infusion rates of Veletri should be
adjusted only under the direction of a physician.
Renal Dialysis
Veletri is suitable for continuous infusion only, either intravascularly or into the blood
supplying the dialyser.
The following schedule of infusion has been found effective in adults:
Prior to dialysis: 4 ng/kg/min intravenously for 15 mins
During dialysis: 4 ng/kg/min into the arterial inlet of the dialyser
The infusion should be stopped at the end of dialysis.
The recommended dose for renal dialysis should be exceeded only with careful
monitoring of patient blood pressure.
Elderly
There is no specific information on the use of Veletri in patients over 65 years for
renal dialysis or pulmonary arterial hypertension. In general, dose selection for an
elderly patient should be made carefully, reflecting the greater frequency of decreased
hepatic, renal (in the case of pulmonary arterial hypertension) or cardiac function and
of concomitant disease or other medicine therapy.
Paediatric population
The safety and efficacy of Veletri in children have not yet been established.
Method of administration
Veletri long-term administration is administered via intravenous route through central
venous catheter using an ambulatory infusion pump. The patient must be adequately
trained in all aspects of care of the central venous catheter, in the aseptic preparation
of the Veletri intravenous injectable solution, and in the preparation and change of the
drug delivery reservoir of the infusion pump, and the extension set.
Suitable ambulatory pumps to be used for the administration of VELETRI are provided in
section 6.6.

Reduction of the risk of catheter-related blood-stream infection

Particular attention should be given to the recommendations in section 4.4 and the
following as this should help to reduce the risk of catheter-related blood-stream
infections.
The care of the central venous catheter and the catheter exit site should follow
established medical principles.
Only extension sets with an in-line 0.22 micron filter placed between the infusion
pump and the central venous catheter must be used. It is recommended to use filters
with a hydrophilic polyethersulfone membrane. The extension set and the in-line filter
must be changed at least every 48 hours (see section 6.6).
Preparation of Veletri intravenous injectable solution:
The reconstituted solution should be examined prior to further dilution. Its use is
forbidden in the presence of discolouration or particles. Reconstituted solutions
should be immediately further diluted to the final concentration.
For further instructions on reconstitution and dilution of the medicinal product before
administration, see section 6.6.
Veletri must not be administered as a bolus injection.
4.3

Contraindications
Veletri is contraindicated in patients:

4.4



with known hypersensitivity to the active substance or to any of the excipients
listed in section 6.1.



with congestive heart failure arising from severe left ventricular dysfunction.



Veletri must not be used chronically in patients who develop pulmonary oedema
during dose-ranging.

Special warnings and precautions for use

The pH of the diluted “ready-to-use solution” decreases with dilution, and ranges
from 12.0 for a concentration of 90,000 ng/mL, 11.7 for a concentration of
45,000 ng/mL to 11.0 for a concentration of 3,000 ng/mL. Therefore, peripheral
intravenous use should be restricted to short duration only, using low concentrations.
Because of the high pH of the final infusion solutions, care should be taken to avoid
extravasation during their administration and consequent risk of tissue damage.
The medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e.
essentially sodium free.
Veletri is a potent pulmonary and systemic vasodilator. The cardiovascular effects
during infusion disappear within 30 min of the end of administration.

Veletri is a potent inhibitor of platelet aggregation, therefore an increased risk for
haemorrhagic complications should be considered, particularly for patients with other
risk factors for bleeding (see section 4.5).
If excessive hypotension occurs during administration of Veletri, the dose should be
reduced or the infusion discontinued. Hypotension may be profound in overdose and
may result in loss of consciousness (see section 4.9).
Blood pressure and heart rate should be monitored during administration of Veletri.
Veletri may either decrease or increase heart rate. The change is thought to depend on
both the basal heart rate and the infusion rate of Veletri administered.
The effects of Veletri on heart rate may be masked by concomitant use of drugs which
affect cardiovascular reflexes.
Extreme caution is advised in patients with coronary artery disease.
Elevated serum glucose levels have been reported (see section 4.8).
The solvent contains no preservative; consequently a vial should be used once only
and then discarded.
This medicinal product contains sodium, which should be taken into consideration by
patients on a controlled sodium diet.
Pulmonary Arterial Hypertension
Some patients with pulmonary arterial hypertension have developed pulmonary
oedema during dose-ranging, which may be associated with pulmonary venoocclusive disease. Veletri must not be used chronically in patients who develop
pulmonary oedema during dose initiation (see section 4.3).
Abrupt withdrawal or interruption of infusion must be avoided, except in lifethreatening situations. An abrupt interruption of therapy can induce a rebound of
pulmonary arterial hypertension, resulting in dizziness, asthenia, increased dyspnoea,
and may lead to death (see section 4.2).
Veletri is infused continuously through a permanent indwelling central venous
catheter via a small, portable infusion pump. Thus, therapy with Veletri requires
commitment by the patient to sterile drug reconstitution, drug administration, care of
the permanent central venous catheter, and access to intense and ongoing patient
education.
Aseptic conditions must be adhered to in preparing the drug and in the care of the
catheter. Even brief interruptions in the delivery of Veletri may result in rapid
symptomatic deterioration. The decision to administer Veletri for pulmonary arterial
hypertension should be based upon the patient’s understanding that there is a high
likelihood that therapy with Veletri will be needed for prolonged periods, possibly

years, and the patient’s ability to accept and care for a permanent i.v. catheter and
infusion pump should be carefully considered.
Renal Dialysis
The hypotensive effect of Veletri may be enhanced by the use of acetate buffer in the
dialysis bath during renal dialysis.
During renal dialysis with Veletri, it should be ensured that the cardiac output
increases more than minimally so that delivery of oxygen to peripheral tissue is not
diminished.
Veletri is not a conventional anticoagulant. Epoprostenol has been successfully used
instead of heparin in renal dialysis, but in a small proportion of dialyses clotting has
developed in the dialysis circuit, requiring termination of dialysis. When epoprostenol
is used alone, measurements such as activated whole blood clotting time may not be
reliable.
4.5

Interaction with other medicinal products and other forms of interaction

When Veletri is administered to patients receiving concomitant anticoagulants,
standard anticoagulant monitoring is advisable.
The vasodilator effects of Veletri may augment or be augmented by concomitant use
of other vasodilators.
As reported with other prostaglandin analogues, Veletri may reduce the thrombolytic
efficacy of tissue plasminogen activator (t-PA) by increasing hepatic clearance of tPA.
When NSAIDs or other drugs affecting platelet aggregation are used concomitantly,
there is the potential for Veletri to increase the risk of bleeding.
Patients on digoxin may show elevations of digoxin concentrations after initiation of
therapy with Veletri, which – although transient – may be clinically significant in
patients prone to digoxin toxicity.
4.6

Fertility, pregnancy and lactation

Pregnancy
There is limited data from the use of epoprostenol in pregnant women.
Animal studies did not indicate harmful effects with respect to reproductive toxicity
(see section 5.3).
Given the absence of alternative medicines, epoprostenol can be used in women who
choose to continue their pregnancy, despite the known risk of pulmonary arterial
hypertension during pregnancy.

Breast-feeding
It is unknown if epoprostenol or its metabolites are excreted in human milk. A risk to
the breastfeeding child cannot be excluded. Breastfeeding should be discontinued
during treatment with Veletri.
Fertility
There are no data on the effects of epoprostenol on fertility in humans. Reproductive
studies in animals have shown no effects on fertility (see section 5.3).
4.7

Effects on ability to drive and use machines
Pulmonary arterial hypertension and its therapeutic management may affect the
ability to drive and operate machinery.
There are no data regarding the effect of Veletri used in renal dialysis on the ability to
drive or operate machinery.

4.8

Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are
defined as follows: very common ≥ 1/10 (≥ 10%); common ≥ 1/100 and < 1/10 (≥ 1%
and < 10%); uncommon ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1%); rare ≥ 1/10,000
and < 1/1000 ( ≥ 0.01% and < 0.1%); very rare < 1/10,000 (< 0.01%) and not known
(cannot be estimated from the available data).
Infections and Infestations
Sepsis, septicaemia (mostly related to delivery system for Veletri)1
Common
Blood and Lymphatic System Disorders
Decreased platelet count, bleeding at various sites (e.g. pulmonary,
Common
gastrointestinal, epistaxis, intracranial, post-procedural,
retroperitoneal)
Splenomegaly, Hypersplenism
Unknown
Endocrine Disorders
Very rare
Hyperthyroidism
Psychiatric Disorders
Common
Anxiety, nervousness
Very rare
Agitation
Nervous System Disorders
Very common
Headache
Cardiac Disorders
Common
Tachycardia2, bradycardia3,
Vascular Disorders
Very common
Facial flushing (seen even in the anaesthetised patient)
Common
Hypotension
Very rare
Pallor

Not known
Ascites
Respiratory, thoracic and mediastinal disorders
Unknown
Pulmonary oedema
Gastrointestinal Disorders
Very common
Nausea, vomiting, diarrhoea
Common
Abdominal colic, sometimes reported as abdominal discomfort
Uncommon
Dry mouth
Skin and Subcutaneous Tissue Disorders
Common
Rash
Uncommon
Sweating
Musculoskeletal and Connective Tissue Disorders
Very common
Jaw pain
Common
Arthralgia
General Disorders and Administration Site Conditions
Very common
Pain (unspecified)
Common
Pain at the injection site*, chest pain
Rare
Local infection*
Very rare
Erythema over the infusion site*, occlusion of the long i.v. catheter*,
lassitude, chest tightness
Investigations
Unknown
Blood glucose increased
* Associated with the delivery system for epoprostenol
1
Catheter-related infections caused by organisms not always considered pathogenic (including
micrococcus) have been reported.
2
Tachycardia has been reported as a response to epoprostenol at doses of 5 ng/kg/min and below.
3
Bradycardia, sometimes accompanied by orthostatic hypotension, has occurred in healthy volunteers
at doses of epoprostenol greater than 5 ng/kg/min. Bradycardia associated with a considerable fall in
systolic and diastolic blood pressure has followed i.v. administration of a dose of epoprostenol
equivalent to 30 ng/kg/min in healthy conscious volunteers.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the national reporting system (see details below).
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9

Overdose
The main feature of overdose is likely to be hypotension.
In general, events seen after overdose of Veletri represent exaggerated
pharmacological effects of the drug (e.g. hypotension and complications of
hypotension).
If overdose occurs, reduce the dose or discontinue the infusion and initiate
appropriate supportive measures as necessary; for example, plasma volume expansion
and/or adjustment to pump flow.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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 postdialysis (8/34 vs. 5/44) days compared to heparin patients during the same periods.

5.2

Pharmacokinetic properties
Due to the chemical instability, high potency and short half-life of epoprostenol, no
precise and accurate assay has been identified as appropriate for quantifying
epoprostenol in biological fluids.
Intravenously administered epoprostenol is rapidly distributed from blood to tissue.
At normal physiological pH and temperature, epoprostenol breaks down
spontaneously to 6-oxo-prostaglandin F1 alpha, although there is some enzymatic
degradation to other products.
Following the administration of radiolabelled epoprostenol to humans, at least 16
metabolites were found, 10 of which were structurally identified.
Unlike many other prostaglandins, epoprostenol is not metabolised during passage
through the pulmonary circulation.
The half-life for the spontaneous breakdown to 6-oxo-prostaglandin F1 alpha in man
is expected to be no more than 6 minutes, and may be as short as 2 to 3 minutes, as
estimated from in vitro rates of degradation of epoprostenol in human whole blood.
Following the administration of radiolabelled epoprostenol to humans, the urinary
and faecal recoveries of radioactivity were 82% and 4%, respectively.

5.3

Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to
reproduction and development. No long-term animal studies have been conducted to
determine the carcinogenic potential of epoprostenol.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sucrose
Arginine
Sodium hydroxide (for pH adjustment)

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3

Shelf life

3 years
In use shelf life reconstituted/diluted solution for infusion:
The reconstituted solution should be immediately further diluted to the final
concentration.
The diluted solution should be stored in the drug delivery reservoir in order to protect
from light and can be stored for up to 8 days at 2 to 8°C.
6.4

Special precautions for storage

This medicinal product (powder for solution for infusion) does not require any special
temperature storage conditions. Do not freeze.
The reconstituted solution should be immediately further diluted to the final
concentration. (see section 4.2, section 6.3 and section 6.6).
Veletri diluted to the final concentration in the drug delivery reservoir as directed can
be administered at room temperature (25°C) immediately after dilution or after
storage for up to 8 days at 2 to 8°C as per the conditions of use outlined in Table 2
section 6.6. Do not expose the fully diluted solution to direct sunlight.
6.5

Nature and contents of container

Powder for solution for infusion:
10 mL colourless glass type I vial closed with a rubber stopper and an aluminium flipoff cap (with a white disc for the 0.5 mg/vial strength, and a red disc for the 1.5
mg/vial strength).
Pack presentations:
Pulmonary Arterial Hypertension
There are 2 presentations available for use in the treatment of pulmonary arterial
hypertension, as follows:



One 0.5 mg powder vial.
One 1.5 mg powder vial.

Renal Dialysis
There is 1 presentation available for use in the treatment of renal dialysis, as follows:



One 0.5 mg powder vial.

Not all pack sizes may be marketed.
6.6

Special precautions for disposal and other handling




CADD-Legacy 1
CADD-Legacy PLUS

Manufactured by Smiths Medical.
Pump accessories found to be compatible with the administration of VELETRI include:



CADD disposable Medication Cassette Reservoir 50 mL; 100 mL from Smiths
Medical.
CADD extension set with in-line 0.2 micron filter (CADD extension set with male luer,
0.2- micron air-eliminating filter, clamp, and integral anti-siphon valve with male luer)
from Smiths Medical.

It is recommended that the infusion pump is not carried in permanent contact with the
skin in order to avoid temperature excursions of the cassette.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
The stability of solutions of Veletri is pH dependent.
The powder for solution for infusion must be reconstituted using either Sterile Water
for Injection or Sodium
Chloride 0.9% Injection solution.
Further dilution should be performed with the same diluent as used for reconstitution
of the sterile, lyophilised powder.
Reconstitution, dilution and calculation of infusion rate:
Particular care should be taken in the preparation of the infusion and in calculating the
rate of infusion. The procedure given below should be closely followed.
Reconstitution and dilution must be carried out under aseptic conditions.
Renal Dialysis
There is 1 pack available for use in the treatment of renal dialysis:

One vial containing sterile, freeze-dried Veletri equivalent to 0.5 mg Veletri
supplied alone.
Reconstitution:
Withdraw 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9%
Injection diluent into a sterile syringe, inject the contents of the syringe into the vial
containing Veletri and shake gently until the powder has dissolved. The reconstituted
solution should be examined prior to further dilution. Its use is forbidden in the
presence of discolouration or particles. Any unused reconstituted solution should be
disposed of in accordance with local requirements.
Dilution:

The reconstituted solution should be immediately further diluted to the final
concentration. Further dilution should be performed with the same diluent as used for
reconstitution of the sterile, lyophilised powder.
Calculation of infusion rate:
Infusion rates may be calculated using the following formula:
Infusion rate (mL/min) = Dosage (ng/kg/min) × bodyweight (kg)
Concentration of solution (ng/mL)
Infusion rate (mL/h) = Infusion rate (mL/min) × 60
A commonly used dilution is 2000 ng/mL Veletri:
Dosage (ng/
kg/min)
1
2
3
4
5

Bodyweight (kg)
30
0.90
1.80
2.70
3.60
4.50

40
1.20
2.40
3.60
4.80
6.00

50
1.50
3.00
4.50
6.00
7.50

60
70
80
1.80
2.10
2.40
3.60
4.20
4.80
5.40
6.30
7.20
7.20
8.40
9.60
9.00
10.50
12.00
Flow rates in mL/h

90
2.70
5.40
8.10
10.80
13.50

100
3.00
6.00
9.00
12.00
15.00

Pulmonary Arterial Hypertension
There are 2 packs available for use in the treatment of pulmonary arterial
hypertension, as follows:

One vial containing sterile, freeze-dried Veletri equivalent to 0.5 mg Veletri
supplied alone.

One vial containing sterile, freeze-dried Veletri equivalent to 1.5 mg Veletri
supplied alone.
Reconstitution:
Withdraw 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9%
Injection diluent into a sterile syringe, inject the contents of the syringe into the vial
containing Veletri and shake gently until the powder has dissolved. The reconstituted
solution should be examined prior to further dilution. Its use is forbidden in the
presence of discolouration or particles. Any unused reconstituted solution should be
disposed of in accordance with local requirements.
Dilution:
The reconstituted solution should be immediately further diluted to the final
concentration. Further dilution should be performed with the same diluent as used for
reconstitution of the sterile, lyophilised powder.
Veletri when administered chronically, should be prepared in a drug delivery reservoir
appropriate for the infusion pump. Only extension sets with an in-line 0.22 micron
filter placed between the infusion pump and the catheter must be used. It is
recommended to use filters with a hydrophilic polyethersulfone membrane. The

extension set and the in-line filter must be changed at least every 48 hours (see section
4.4).
The vial containing 0.5 mg epoprostenol must be used for the preparation of solutions
with final concentrations below 15,000 ng/mL.
Table 1 provides examples for preparing frequently used concentrations of Veletri
solutions. Each vial is for single use only.
Table 1: Frequently used concentrations – Examples of Reconstitution and Dilution
Final Concentration (ng/mL)
3000 ng/mL

5000 ng/mL

10,000 ng/mL

15,000 ng/mL*

30,000 ng/mL*

30,000 ng/mL*

Directions:
Dissolve contents of one 0.5 mg vial with 5 mL of either
Sterile Water for Injection or Sodium Chloride 0.9%
Injection.
Withdraw 3 mL of the vial contents and add to a
sufficient volume of the identical diluent to make a total
of 100 mL.
Dissolve contents of one 0.5 mg vial with 5 mL of either
Sterile Water for Injection, or Sodium Chloride 0.9%
Injection.
Withdraw entire vial contents and add to a sufficient
volume of the identical diluent to make a total of
100 mL.
Dissolve contents of two 0.5 mg vials, each with 5 mL
of either Sterile Water for Injection or Sodium Chloride
0.9% Injection.
Withdraw entire vial contents and add to a sufficient
volume of the identical diluent to make a total of
100 mL.
Dissolve contents of one 1.5 mg vial with 5 mL of either
Sterile Water for Injection or Sodium Chloride 0.9%
Injection.
Withdraw entire vial contents and add to a sufficient
volume of the identical diluent to make a total of
100 mL.
Dissolve contents of two 1.5 mg vials, each with 5 mL
of either Sterile Water for Injection or Sodium Chloride
0.9% Injection.
Withdraw entire vial contents and add to a sufficient
volume of the identical diluent to make a total of
100 mL.
Dissolve contents of one 1.5 mg vial with 5 mL of either
Sterile Water for Injection or Sodium Chloride 0.9%
Injection.
Withdraw entire vial contents and add to a sufficient
volume of the identical diluent to make a total of 50 mL.

* Solutions with higher final concentrations may be necessary for patients who receive long-term administration of
Veletri.

Veletri diluted to the final concentration in the drug delivery reservoir as directed can
be administered immediately at room temperature (25°C) or, if stored, for up to 8 days
at 2 to 8°C as per the conditions of use outlined in Table 2.
Table 2: Maximum duration of administration (hours) at room temperature (25°C) of
fully diluted solutions stored in the drug delivery reservoir
Final concentration range

3000 ng/mL and <15,000 ng/mL
15,000 ng/mL

Immediate
administration
*
48 hours
48 hours

If stored for up
to 8 days at 2 to
8°C*
24 hours
48 hours

Do not expose the fully diluted solution to direct sunlight.

Calculation of infusion rate:
Infusion rates may be calculated using the following formula:
Infusion rate (mL/min) = Dosage (ng/kg/min) × bodyweight (kg)
Concentration of solution (ng/mL)
Infusion rate (mL/h) = Infusion rate (mL/min) × 60
Examples for some concentrations commonly used in pulmonary arterial hypertension
are shown below.
Table 3: Infusion Rates for Veletri at a Concentration of 5000 ng/mL
Example For Dosing Using a Concentration of 5000 ng/mL
Dosage (ng/kg/
Bodyweight (kg)
min)
10
20
30
40
50
60
70
1.0
1.2
1.4
1.7
2
1.0
1.4
1.9
2.4
2.9
3.4
4
1.4
2.2
2.9
3.6
4.3
5.0
6
1.0
1.9
2.9
3.8
4.8
5.8
6.7
8
1.2
2.4
3.6
4.8
6.0
7.2
8.4
10
1.4
2.9
4.3
5.8
7.2
8.6
10.1
12
1.7
3.4
5.0
6.7
8.4
10.1 11.8
14
1.9
3.8
5.8
7.7
9.6
11.5 13.4
16
Flow rates in mL/h

80
1.9
3.8
5.8
7.7
9.6
11.5
13.4
15.4

90
2.2
4.3
6.5
8.6
10.8
13.0
15.1
17.3

100
2.4
4.8
7.2
9.6
12.0
14.4
16.8
19.2

Table 4: Infusion Rates for Veletri at a Concentration of 15,000 ng/mL
Example For Dosing Using a Concentration of 15,000 ng/mL
Dosage (ng/
Bodyweight (kg)
kg/min)
30
40
50
60
70
80
4
1.0
1.1
1.3

90
1.4

100
1.6

6
8
10
12
14
16

1.0
1.2
1.4
1.7
1.9

1.0
1.3
1.6
1.9
2.2
2.6

1.2
1.6
2.0
2.4
2.8
3.2

1.4
1.7
1.9
2.2
2.4
2.8
2.9
3.4
3.4
3.9
3.8
4.5
Flow rates in mL/h

1.9
2.6
3.2
3.8
4.5
5.1

2.2
2.9
3.6
4.3
5.0
5.8

2.4
3.2
4.0
4.8
5.6
6.4

Table 5: Infusion Rates for Veletri at a Concentration of 30,000 ng/mL
Example For Dosing Using a Concentration of 30,000 ng/mL
Dosage
Bodyweight (kg)
(ng/kg/ min)
30
40
50
60
70
80
1.0
6
1.0
1.1
1.3
8
1.0
1.2
1.4
1.6
10
1.0
1.2
1.4
1.7
1.9
12
1.1
1.4
1.7
2.0
2.2
14
1.0
1.3
1.6
1.9
2.2
2.6
16
Flow rates in mL/h

90
1.1
1.4
1.8
2.2
2.5
2.9

100
1.2
1.6
2.0
2.4
2.8
3.2

Higher dosages, and therefore, more concentrated solutions may be necessary with
long-term administration of Veletri.

7

MARKETING AUTHORISATION HOLDER
Actelion Registration Ltd
Chiswick Tower 13th Floor
389 Chiswick High Road
London W4 4AL
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 18900/0008

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/04/2013

10

DATE OF REVISION OF THE TEXT
12/05/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide