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FLOLAN 0.5MG INJECTION

Active substance(s): EPOPROSTENOL SODIUM / EPOPROSTENOL SODIUM

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Flolan 0.5 mg powder and solvent for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Epoprostenol 0.5 mg powder for solution for infusion:
Each vial contains epoprostenol sodium equivalent to 0.5 mg epoprostenol.
One ml of reconstituted concentrate solution contains epoprostenol (as epoprostenol
sodium) 10,000 nanogram (0.5 mg epoprostenol in 50 ml of solvent).
Excipients with known effect:
The amount of sodium present in the reconstituted concentrate solution equals 73 mg
approximately.
The amount of sodium present in the powder for solution for infusion equals 3 mg
approximately per vial.
The amount of sodium present in the solvent for parenteral use equals 70 mg
approximately per vial.
For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Powder and solvent for solution for infusion.
Powder for solution for infusion:
- White or off-white freeze dried powder
Solvent for parenteral use:
-

Clear, colourless solution (pH 11.7 – 12.3)

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Flolan is indicated for:
Pulmonary Arterial Hypertension

Flolan 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

Flolan 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

Epoprostenol 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 rate is
initiated at 2 nanograms/kg/min and increased by increments of 2 nanograms/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 nanograms/kg/min is not tolerated, a lower dose which
is tolerated by the patient should be identified.
Long-term continuous infusion:
Long-term continuous infusion of Flolan 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 nanograms/kg/min less
than the maximum tolerated infusion rate determined during short-term dose-ranging.
If the maximum tolerated infusion rate is 5 nanograms/kg/min or less, then the longterm infusion should be started at 1 nanograms/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
reaction due to excessive doses of Flolan.
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 nanograms/kg/min increments at intervals sufficient to allow
assessment of clinical response; these intervals should be of 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 nanograms/kg/min
decrements every 15 min or longer until the dose-limiting effects resolve. Abrupt
withdrawal of Flolan or sudden large reductions in infusion rates should be avoided
due to the risk of potential fatal rebound effect (see section 4.4). Except in lifethreatening situations (e.g. unconsciousness, collapse, etc) infusion rates of Flolan
should be adjusted only under the direction of a physician.
Renal Dialysis

Flolan 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 nanograms/kg/min intravenously for 15 mins
During dialysis: 4 nanograms/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 Flolan 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 epoprostenol in children younger than 18 years have not
yet been established.
Method of administration
Precautions to be taken before handling or administering the medicinal product
Pulmonary Arterial Hypertension
Freshly prepared solutions for infusion (either as a concentrated solution or a further
diluted solution) can be administered immediately or stored for up to 8 days at 2°C to
8°C prior to administration. Following this preparation or storage, the solution for

infusion should be used within 72 hours at up to 25°C, or 48 hours at up to 30ºC, or
24 hours at up to 35 ºC, or 12 hours at up to 40 ºC.
Renal Dialysis

Freshly prepared solutions for infusion (either as a concentrated solution or a further
diluted solution) can be administered for up to 12 hours at up to 25°C.
The reconstituted solution should be examined prior to administration. Its use is
forbidden in the presence of a discoloration or particles.
For instructions on reconstitution and dilution of the medicinal product before
administration, see section 6.6.
Epoprostenol must not be administered as a bolus injection.
4.3

Contraindications

Flolan is contraindicated in patients:

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



4.4

with congestive heart failure arising from severe left ventricular dysfunction.

Flolan must not be used chronically in patients who develop pulmonary oedema
during dose-ranging.
Special warnings and precautions for use

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.
Flolan is a potent pulmonary and systemic vasodilator. The cardiovascular effects
during infusion disappear within 30 min of the end of administration.
Flolan 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 Flolan, 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 Flolan.
Flolan may either decrease or increase heart rate. The change is thought to depend on
both the basal heart rate and the concentration of Flolan administered.
The effects of Flolan 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. Flolan 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).
Flolan is infused continuously through a permanent indwelling central venous catheter
via a small, portable infusion pump. Thus, therapy with Flolan 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.
Sterile technique must be adhered to in preparing the drug and in the care of the
catheter. Even brief interruptions in the delivery of Flolan may result in rapid
symptomatic deterioration. The decision to administer Flolan for pulmonary arterial
hypertension should be based upon the patient’s understanding that there is a high
likelihood that therapy with Flolan 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 Flolan may be enhanced by the use of acetate buffer in the
dialysis bath during renal dialysis.
During renal dialysis with Flolan it should be ensured that the cardiac output increases
more than minimally so that delivery of oxygen to peripheral tissue is not diminished.
Flolan is not a conventional anticoagulant. Flolan 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 Flolan 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 Flolan is administered to patients receiving concomitant anticoagulants
standard anticoagulant monitoring is advisable.
The vasodilator effects of Flolan may augment or be augmented by concomitant use
of other vasodilators.

As reported with other prostaglandin analogues, Flolan 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 Flolan to increase the risk of bleeding.
Patients on digoxin may show elevations of digoxin concentrations after initiation of
therapy with Flolan, which although transient, may be clinically significant in patients
prone to digoxin toxicity.
4.6

Fertility, pregnancy and lactation

Pregnancy
There is a limited amount of data from the use of epoprostenol in pregnant women.
Animal studies did not indicate direct or indirect harmful effects with respect to
reproductive toxicity (see section 5.3).
Given the absence of alternative medicines, epoprostenol can be used in those 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. Breast-feeding should be discontinued
during treatment with Flolan.
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 Flolan 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
Common
Sepsis, septicaemia (mostly related to delivery system for
Flolan)1

Blood and Lymphatic System Disorders
Common
Decreased platelet count, bleeding at various sites (e.g.
pulmonary, gastrointestinal, epistaxis, intracranial, postprocedural, retroperitoneal)
Unknown
Splenomegaly, Hypersplenism
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 Flolan
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 Flolan at doses of 5
nanograms/kg/min and below.

3

Bradycardia, sometimes accompanied by orthostatic hypotension, has
occurred in healthy volunteers at doses of Flolan greater than 5
nanograms/kg/min. Bradycardia associated with a considerable fall in systolic
and diastolic blood pressure has followed i.v. administration of a dose of Flolan
equivalent to 30 nanograms/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 Yellow Card Scheme at: 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 Flolan 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
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 nanograms/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
these levels.

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 PPH were variable and minor.
Renal Dialysis
The effects of epoprostenol on platelet aggregation is dose-related when between 2
and 16 nanograms/kg/min is administered intravenously, and significant inhibition of
aggregation induced by adenosine diphosphate is observed at doses of 4
nanograms/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 nanograms/kg/min.
Higher circulating doses of epoprostenol (20 nanograms/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 median values 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 two 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, nonrandomized 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 weeks
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 (predialysis: N=4/8;
dialysis: N=6/16) than with heparin (predialysis: N=4/13; dialysis: N=4/25).
However, the reverse was observed for postdialysis 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 predialysis (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

Powder for solution for infusion:
Mannitol
Glycine
Sodium Chloride

Sodium Hydroxide (for pH adjustment)
Solvent for parenteral use:
Glycine
Sodium Chloride
Sodium Hydroxide (for pH adjustment)
Water for Injection
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

Unopened vials
Powder for solution for infusion:

3 years

Solvent for parenteral use:

24 months

Stability during administration
Reconstituted/diluted solutions using solvent for pulmonary arterial hypertension
For solutions ≤ 150,000 ng/mL:
Freshly prepared solutions for infusion (either as a concentrated solution or a further
diluted solution) can be administered immediately or stored for up to 8 days at 2°C to
8°C prior to administration. Following this preparation or storage, the solution for
infusion should be used within:


72 hours at up to 25°C or



48 hours at up to 30ºC or



24 hours at up to 35 ºC or



12 hours at up to 40 ºC

Discard any unused solution after this time.
For solutions >150,000ng/mL and ≤300,000ng/mL:
Reconstituted solutions that have been stored at 2 to 8°C for up to 7 days can be
administered for up to 24 hours at 25°C.
Freshly prepared reconstituted solutions, or solutions that have been stored at 2 to 8°C
for no longer than 5 days can be administered for up to:
• 48 hours at up to 25ºC

• 24 hours at up to 35 ºC
Discard any unused solution after this time.
Reconstituted solutions using solvent for renal dialysis
Reconstitution and subsequent dilution should be carried out immediately prior to use
(see section 6.6).
Freshly prepared solutions for infusion (either as a concentrated solution or a further
diluted solution) can be administered for up to 12 hours at up to 25°C.
Discard any unused solution after this time.
6.4

Special precautions for storage

Powder for solution for infusion:
Do not store vials above 25°C. Protect from light. Keep dry. Do not freeze. Store in
the original package.
Solvent for parenteral use:
Do not store vials above 25°C. Do not freeze. Protect from light. Store in the original
package.
The solvent contains no preservative; consequently a vial should be used once only
and then discarded.
For storage conditions after reconstitution and dilution of the medicinal product, see
section 6.3.
6.5

Nature and contents of container

Powder for solution for infusion:
Clear (type 1) glass vials with synthetic butyl rubber stoppers and an aluminium collar
with a snap-off top.
Solvent for parenteral use:
Clear plastic vials with synthetic butyl rubber stoppers and an external aluminium
collar with a purple plastic flip-top cover.
Pack sizes:
Pulmonary Arterial Hypertension
There are three presentations available in 0.5 mg for use in the treatment of
pulmonary arterial hypertension, as follows:
• One 0.5 mg powder vial and one solvent vial and a filter unit.
• One 0.5 mg powder vial and two solvent vials and a filter unit.
• One 0.5 mg powder vial.
Renal Dialysis
There is only one presentation available for use in the treatment of renal dialysis, as
follows:
• One 0.5 mg powder vial and one solvent vial and a filter unit.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
The stability of solutions of Flolan is pH dependent. Only the solvent supplied should
be used for reconstitution of freeze-dried Flolan and only the recommended infusion
solutions, in the stated ratio, should be used for further dilution, otherwise the
required pH may not be maintained.
Reconstitution and dilution of Flolan must be carried out using aseptic technique,
ideally immediately prior to clinical use.
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.
Pulmonary Arterial Hypertension
There are three 0.5 mg packs available for use in the treatment of pulmonary arterial
hypertension, as follows:


One vial containing sterile, freeze-dried Flolan equivalent to 0.5 mg Flolan, supplied with
one 50 mL vial of solvent and a filter unit.



One vial containing sterile, freeze-dried Flolan equivalent to 0.5 mg Flolan, supplied with
two 50 mL vials of solvent and a filter unit.



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

There are also three 1.5 mg packs available for use in the treatment of pulmonary arterial
hypertension.

Initially a pack containing solvent for parenteral use must be used. During chronic
Flolan therapy the final concentration of solution may be increased by the addition of
a further 0.5 mg or 1.5 mg vial of freeze-dried Flolan.
Only vials of the same amount as that included in the initial starter pack may be used
to increase the final concentration of solution.

Reconstitution:
1. Use only the sterile solvent solution provided for reconstitution.
2. Withdraw approximately 10 mL of the sterile solvent solution into a sterile
syringe, inject it into the vial containing the freeze-dried epoprostenol and shake
gently until the powder has dissolved.
3. Draw up the resulting epoprostenol solution into the syringe, re-inject it into the
remaining volume of the sterile solvent solution and mix thoroughly.

This solution is now referred to as the concentrated solution.


Where a pack containing 0.5 mg epoprostenol is reconstituted with 50 mL sterile
solvent the resultant concentration is 10,000 nanograms/mL epoprostenol.

Higher concentrations may be prepared for patients who receive epoprostenol long
term.
Only concentrated solutions are suitable for further dilution prior to use.
Dilution:
Flolan may be used either as concentrated solution or in a diluted form for the
treatment of pulmonary arterial hypertension. Only the solvent provided may be used
for the further dilution of reconstituted Flolan. Sodium chloride 0.9% w/v solution
must not be used when Flolan is to be used for the treatment of pulmonary arterial
hypertension. Flolan must not be administered with other parenteral solutions or
medications when used for pulmonary arterial hypertension.
To dilute the concentrated solution, draw it up into a larger syringe and then attach the
sterile filter provided to the syringe.
Dispense the concentrated solution directly into the solvent using firm but not
excessive pressure; the typical time taken for filtration of 50 mL of concentrated
solution is 70 seconds. Mix well.
The filter unit must be used once only and then discarded.
Concentrations commonly used in the treatment of pulmonary arterial hypertension
are as follows:


5,000 nanograms/mL - One vial containing 0.5 mg Flolan reconstituted and diluted to a
total volume of 100 mL in solvent.



10,000 nanograms/mL - Two vials containing 0.5 mg Flolan reconstituted and diluted
to a total volume of 100 mL in solvent.

Calculation of infusion rate:
The infusion rate may be calculated from the formula given above for renal dialysis.
Examples for some concentrations commonly used in pulmonary arterial hypertension
are shown below.
Infusion rates for a concentration of 5,000 nanograms/mL
Example For Dosing Using a Concentration of 5,000 nanograms/mL
Dosage
Bodyweight (kg)
(nanograms/kg/
min)
20
30
40
50
60
70
80
90
2
0.5
0.7
1.0
1.2
1.4
1.7
1.9
2.2
4
1.0
1.4
1.9
2.4
2.9
3.4
3.8
4.3
6
1.4
2.2
2.9
3.6
4.3
5.0
5.8
6.5
8
1.9
2.9
3.8
4.8
5.8
6.7
7.7
8.6
10
2.4
3.6
4.8
6.0
7.2
8.4
9.6
10.8
12
2.9
4.3
5.8
7.2
8.6
10.1 11.5 13.0
14
3.4
5.0
6.7
8.4
10.1 11.8 13.4 15.1
16
3.8
5.8
7.7
9.6
11.5 13.4 15.4 17.3
Flow rates in mL/h

100
2.4
4.8
7.2
9.6
12.0
14.4
16.8
19.2

Infusion rates for a concentration of 10,000 nanograms/mL

Example For Dosing Using a Concentration of 10,000 nanograms/mL
Dosage
Bodyweight (kg)
(nanograms/kg/
min)
20
30
40
50
60 70 80 90 100
2
0.2
0.4
0.5
0.6 0.7 0.8 1.0 1.1 1.2
4
0.5
0.7
1.0
1.2 1.4 1.7 1.9 2.2 2.4
6
0.7 1.1
1.4
1.8
2.2 2.5 2.9 3.2 3.6
8
1.0
1.4
1.9
2.4
2.9 3.4 3.8 4.3 4.8
10
1.2
1.8
2.4
3.0
3.6 4.2 4.8 5.4 6.0
12
1.4
2.2
2.9
3.6
4.3 5.0 5.8 6.5 7.2
14
1.7
2.5
3.4
4.2
5.0 5.9 6.7 7.6 8.4
16
1.9
2.9
3.8
4.8
5.8 6.7 7.7 8.6 9.6
Flow rates in mL/h
Higher infusion rates, and therefore, more concentrated solutions may be necessary
with long-term administration of Flolan.
Renal Dialysis
The pack suitable for use in renal dialysis contains 0.5 mg freeze-dried Flolan plus
50 mL solvent.

Reconstitution:

Ideally reconstitution should be carried out immediately prior to use.
The pack suitable for use in renal dialysis contains 0.5 mg freeze-dried epoprostenol
and one 50 mL sterile solvent.
1.

Use only the solvent provided for reconstitution.

2.

Withdraw approximately 10 mL of the solvent into a sterile syringe, inject it into the
vial containing 0.5 mg freeze-dried Flolan powder and shake gently until the powder has
dissolved.

3.

Draw up the resulting Flolan solution into the syringe, re-inject it into the remaining
volume of the solvent and mix thoroughly.

This solution is now referred to as the concentrated solution and contains 10,000
nanograms/mL Flolan. Only this concentrated solution is suitable for further dilution
prior to use.
When 0.5 mg Flolan powder for i.v. infusion is reconstituted with 50 mL of solvent,
the final injection has a pH of approximately 12 and a sodium ion content of
approximately 73 mg.
Dilution:
The concentrated solution is normally further diluted immediately prior to use. It may
be diluted with sodium chloride 0.9% w/v (saline) solution, in a ratio of 2.3 volumes
of saline to 1 volume of concentrated solution, e.g. 50 mL of concentrated solution
further diluted with 117 mL of saline.
Other common i.v. fluids are unsatisfactory for the dilution of concentrated solution
as the required pH is not attained. Flolan solutions are less stable at low pH.
To dilute the concentrated solution, draw it up into a larger syringe and then attach the
sterile filter provided to the syringe.
Dispense the concentrated solution directly into the chosen infusion solution using
firm but not excessive pressure; the typical time taken for filtration of 50 mL of
concentrated solution is 70 seconds. Mix well.
The filter unit must be used once only and then discarded.
For administration using a pump capable of delivering small volume constant
infusions, suitable aliquots of concentrated solution may be diluted with sterile
sodium chloride 0.9% w/v solution.
When reconstituted and diluted as directed above, Flolan infusion solutions will retain
90% of their initial potency for approximately 12 hours at 25°C.

Calculation of infusion rate:
The infusion rate may be calculated from the following formula:
Infusion rate
dosage (nanogram/kg/min) x bodyweight (kg)
=
(mL/min)
concentration of solution (nanogram/mL)
Infusion rate (mL/h) = Infusion rate (mL/min) x 60
Infusion rate formulae – examples
When used in renal dialysis Flolan may be administered as the concentrated solution
(a) or in diluted form (b).
a. Using concentrated solution, i.e. 10,000 nanograms/mL Flolan:
Example For Dosing Using a Concentration of 10,000 nanograms/mL
Dosage
Bodyweight (kg)
(nanograms/
kg/min)
30
40
50
60
70
80
90
1
0.18
0.24
0.30
0.36
0.42
0.48
0.54
2
0.36
0.48
0.60
0.72
0.84
0.96
1.08
3
0.54
0.72
0.90
1.08
1.26
1.44
1.62
4
0.72
0.96
1.20
1.44
1.68
1.92
2.16
5
0.90
1.20
1.50
1.80
2.10
2.40
2.70
Flow rates in mL/h

100
0.60
1.20
1.80
2.40
3.00

b. Diluted: A commonly used dilution is:
15 mL concentrated solution + 35 mL sodium chloride 0.9% w/v solution.
Resultant concentration = 3,000 nanograms/mL Flolan:
Example For Dosing Using a Concentration of 3,000 nanograms/mL
Dosage
Bodyweight (kg)
(nanograms/
kg/min)
30
40
50
60
70
80
90
1
0.60
0.80
1.00
1.20
1.40
1.60
1.80
2
1.20
1.60
2.00
2.40
2.80
3.20
3.60
3
1.80
2.40
3.00
3.60
4.20
4.80
5.40
4
2.40
3.20
4.00
4.80
5.60
6.40
7.20
5
3.00
4.00
5.00
6.00
7.00
8.00
9.00
Flow rates in mL/h

7

MARKETING AUTHORISATION HOLDER
GlaxoWellcome UK Ltd
Trading as GlaxoSmithKline UK

100
2.00
4.00
6.00
8.00
10.00

Stockley Park West
Uxbridge
Middlesex
UB11 1BT

8

MARKETING AUTHORISATION NUMBER(S)
Flolan 0.5 mg Injection

9

PL 10949/0310

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
First Authorisation
18.03.81
Renewal:
13.08.87, 23.04.91, 03.08.02

10

DATE OF REVISION OF THE TEXT
16/02/2017

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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.

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