EPOPROSTENOL 1.5 MG POWDER FOR SOLUTION FOR INFUSION - summary of medicine characteristics

Epoprostenol 1.5 mg powder for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Epoprostenol 1.5 mg:

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).

Excipient(s) with known effect: sodium.

Each 1.5 mg vial contains 17.26 mg sodium.

For the full list of excipients, see section 6.1.

Powder for solution for infusion

White to off-white powder

For the pH of the diluted solution see section 4.4. The osmolality of the diluted solution is between 150 and 350 mOsm/kg.

4.1 Therapeutic indications

Epoprostenol is indicated for:

Pulmonary arterial hypertension

Epoprostenol 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

Epoprostenol 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 epoprostenol 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 doseranging. If the maximum tolerated infusion rate is 5 nanograms/kg/min or less, then 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 reaction due to excessive doses of epoprostenol.

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 epoprostenol 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 epoprostenol should be adjusted only under the direction of a physician.

Renal dialysis

Epoprostenol 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 epoprostenol in patients over 65 years for pulmonary arterial hypertension or renal dialysis. 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

Epoprostenol 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 epoprostenol 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 Epoprostenol 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 epoprostenol 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 further diluted to the final concentration within one hour of reconstitution.

For further 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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Congestive heart failure arising from severe left ventricular dysfunction

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

4.4 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.

Epoprostenol is a potent pulmonary and systemic vasodilator. The cardiovascular effects during infusion disappear within 30 min of the end of administration.

Epoprostenol 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 epoprostenol, 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

epoprostenol.

Epoprostenol may either decrease or increase heart rate. The change is thought to depend on both the basal heart rate and the concentration of epoprostenol administered.

The effects of epoprostenol 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).

This medicine contains less than 1 mmol sodium (23 mg) per maximum daily dose, that is to say essentially ‘sodium- free’.

Pulmonary arterial hypertension

Some patients with pulmonary arterial hypertension have developed pulmonary oedema during dose-ranging, which may be associated with pulmonary venoocclusive disease. Epoprostenol must not be used chronically in patients who develop pulmonary edema 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, increase dyspnoea, and may lead to death (see section 4.2).

Epoprostenol is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with epoprostenol 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 epoprostenol may result in rapid symptomatic deterioration. The decision to administer epoprostenol for pulmonary arterial hypertension should be based upon the patients understanding that there is a high likelihood that therapy with epoprostenol 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 epoprostenol may be enhanced by the use of acetate buffer in the dialysis bath during renal dialysis.

During renal dialysis with epoprostenol, it should be ensured that the cardiac output increases more than minimally so that delivery of oxygen to peripheral tissue is not diminished.

Epoprostenol 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 epoprostenol is administered to patients receiving concomitant anticoagulants standard anticoagulant monitoring is advisable.

The vasodilator effects of epoprostenol may augment or be augmented by concomitant use of other vasodilators.

As reported with other prostaglandin analogues, epoprostenol may reduce the thrombolytic efficacy of tissue plasminogen activator (t-PA) by increasing hepatic clearance of t-PA.

When NSAIDS or other drugs affecting platelet aggregation are used concomitantly, there is the potential for epoprostenol to increase the risk of bleeding.

Patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with epoprostenol which although transient, may be clinically significant in patients prone to digoxin toxicity.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of epoprostenol in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Given the absence of alternative medicinal products, 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 whether epoprostenol or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with epoprostenol.

Fertility

There are no or limited 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 epoprostenol used in renal dialysis on the ability to drive or operate machinery.

4.8 UNDESIRABLE EFFECTS

Adverse events are listed in the following table by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (> 1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (> 1/10,000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

* Associated with the delivery system for epoprostenol_________­________________________­____

1 Cathether-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 nanograms/kg/min and below.___________­________________________­____________________

3 Bradycardia, sometimes accompanied by orthostatic hypotension, has occurred in healthy volunteers at doses of epoprostenol 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 epoprostenol 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The main feature of overdose is likely to be hypotension.

In general, events seen after overdose of epoprostenol 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

Infusion of 4 nanograms/kg/min for 30 minutes have 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, nonrandomised 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

Glycine

Sucrose

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.

The diluted solution of Epoprostenol (pH 12) must not be used with administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG).

This product is compatible with polyvinyl chloride reservoir.

6.3 Shelf life

2 years

In use shelf life reconstituted/di­luted solution for infusion

The reconstituted solution should be further diluted to the final concentration within one hour of reconstitution.

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.

Stability during administration:

For Solutions > 3000 ng/ml and < 15,000 ng/ml:

Freshly prepared solution for infusion can be administered immediately or stored in the reservoir of ambulatory pump up to 8 days at 2° C to 8° C prior to administration.

Freshly prepared solution can be administered for up to 48 hours at room temperature (25° C)

Solution that has been stored in the reservoir of ambulatory pump at 2° C to 8° C for up to 8 days can be administered for up to 24 hours at room temperature (25° C).

Discard any unused solution after this time.

Freshly prepared solution for infusion can be administered immediately or stored in the reservoir of ambulatory pump up to 8 days at 2° C to 8° C prior to administration.

Freshly prepared solution can be administered for up to 48 hours at room temperature (25° C)

Solution that has been stored in the reservoir of ambulatory pump at 2° C to 8° C for up to 8 days can be administered for up to 48 hours at room temperature (25° C).

Discard any unused solution after this time.

6.4 Special precautions for storage

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

The reconstituted solution should be further diluted to the final concentration within one hour of reconstitution (see sections 6.3 and 6.6).

Epoprostenol 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

Epoprostenol is packed in a 10 ml colourless glass type I vial closed with a rubber stopper and an aluminium flip-off cap.

Pack sizes:

Pulmonary arterial hypertension

There are two packs 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

Only the 0.5 mg pack is suitable for use in renal dialysis.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The following portable infusion pumps have been shown to be suitable for Epoprostenol:

– CADD-Legacy 1

– CADD-Legacy PLUS

Manufactured by Smiths Medical.

Pump accessories found to be compatible with the administration of Epoprostenol 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 antisiphon 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 epoprostenol 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 of epoprostenol must be carried out under aseptic conditions.

Renal dialysis

There is one pack available for use in the treatment of renal dialysis, as follows:

– One vial containing sterile, freeze-dried epoprostenol equivalent to 0.5 mg epoprostenol.

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 epoprostenol 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 further diluted to the final concentration within one hour of reconstitution. Further dilution should be performed with the same diluent as used for reconstitution of the sterile, lyophilised powder.

Calculation of infusion rate

The infusion rate may be calculated from the following formula:

Inftision rate (ml/mln)

Infusion rate (ml/h) = Infusion rate (ml/min) x 60

A commonly used dilution is 2000 ng/ml epoprostenol:

Pulmonary arterial hypertension

There are two packs available for use in the treatment of pulmonary arterial hypertension, as follows:

– One vial containing sterile, freeze-dried epoprostenol equivalent to 0.5 mg epoprostenol.

– One vial containing sterile, freeze-dried epoprostenol equivalent to 1.5 mg epoprostenol.

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 Epoprostenol 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 further diluted to the final concentration within one hour of reconstitution. Further dilution should be performed with the same diluent as used for reconstitution of the sterile, lyophilised powder.

Epoprostenol when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Only extension sets with an inline 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 15,000ng/ml.

Table 1 provides examples for preparing frequently used concentrations of epoprostenol solutions. Each vial is for single use only.

Table 1: Frequently used concentrations – Examples of reconstitution and dilution

Epoprostenol 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

Do not expose the fully diluted solution to direct sunlight.

Calculation of infusion rate

Infusion rates may be calculated using the following formula:

T „ ,        . ,, , _ Dosage £ng/ks/tnta.) x bodyweight (kg)

Infusion rata (ml/min) = — ---——----———-,———

Concentration of solution ¡ng/ml;

Infusion rate (ml/h) = Infusion rate (ml/min) x 60

Examples for some concentrations commonly used in pulmonary arterial hypertension are shown below.

Table 3: Infusion Rates for epoprostenol at a concentration of 5000 ng/ml

Table 4: Infusion Rates for epoprostenol at a concentration of 15,000 ng/ml

Table 5: Infusion Rates for epoprostenol at a concentration of 30,000 ng/ml

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

7 MARKETING AUTHORISATION HOLDER

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp The Netherlands

8 MARKETING AUTHORISATION NUMBER(S)

PL 31750/0138

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

04/09/2018