UK/H/2736 - Medicines and Healthcare products Regulatory Agency

PAR Epoprostenol GEBRO 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion UK/H/2736/01-02/DC

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Public Assessment Report

Decentralised Procedure

Epoprostenol GEBRO 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion

(epoprostenol sodium)

UK/H/2736/01-2/DC

UK licence numbers: PL 33028/0006-7

Drehm Pharma GmbH


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LAY SUMMARY On 18th October 2010, the MHRA granted Drehm Pharma Marketing Authorisations (licences) for the medicinal products, Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion (PL 33028/0006-7). These are prescription-only medicines (POM). Epoprostenol belongs to a group of medicines used to prevent blood clots (anticoagulants). Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion have two separate uses; they can be used during kidney dialysis (to stop your blood from clotting), or they can be used to treat primary and secondary pulmonary hypertension, where epoprostenol widens the blood vessels in the lungs and so lowers the blood pressure in your lungs. This effect is known as a vasodilator action. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion outweigh the risks; hence Marketing Authorisations have been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 28 Module 4: Labelling Page 46 Module 5: Scientific Discussion Page 56 1 Introduction Page 56 2 About the product Page 58 3 Quality aspects Page 59 4 Pre-clinical aspects Page 62 5 Clinical aspects Page 62 6 Overall conclusions Page 64 Module 6 Steps taken after initial procedure Page 65


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Module 1

Information about Initial Procedure

Product Name

Epoprostenol GEBRO Sodium 0.5 mg Powder and Solvent for Solution for Infusion Epoprostenol GEBRO Sodium 1.5 mg Powder and Solvent for Solution for Infusion

Type of Application

Generic, Article 10.1

Active Substance

Epoprostenol sodium

Form

Powder and solvent for solution for infusion

Strength

0.5 mg and 1.5 mg

MA Holder

Drehm Pharma GmbH Hietzinger Hauptstrasse 37/2, 1130 Vienna Austria

Reference Member State (RMS)

UK

Concerned Member State / s (CMS)

Austria, Hungary, Spain

Procedure Number

UK/H/2736/01-02/DC

Timetable

Day 210 – 19th August 2010


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Module 2

Summary of Product Characteristics

The UK Summary of Product Characteristics (SmPC) for Epoprostenol GEBRO 0.5 mg Powder and Solvent for Solution for Infusion (PL 33028/0006) is as follows:

1 NAME OF THE MEDICINAL PRODUCT

Epoprostenol GEBRO 0.5 mg Powder and Solvent for Solution for Infusion 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 vial contains 0.531 mg Epoprostenol Sodium, corresponding to 0.5 mg Epoprostenol. Each vial of solvent contains 50 ml of a sterile glycine buffer solution containing approximately 55 mg sodium.

When 1 vial with 500 microgram epoprostenol is reconstituted with 50 ml of sterile buffer, the resultant concentration is 10,000 nanograms per ml.

Excipients: contains 0.05 mmol sodium (1.15 mg) per vial.

For a full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM

Powder and solvent for solution for infusion. White lyophilised powder cake in colourless glass-vials, and a clear, colourless solution in 50 ml glass vials. When 500 microgram epoprostenol powder is reconstituted with 50 ml of the Glycine Buffer Diluent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Haemodialysis Epoprostenol GEBRO is indicated for use in renal dialysis when use of heparin carries a high risk of causing or exacerbating bleeding or when heparin is otherwise contraindicated. Primary and secondary pulmonary hypertension Epoprostenol GEBRO is also indicated for the intravenous long-term treatment of primary pulmonary hypertension (PPH) in New York Heart Association (NYHA) functional Class III and Class IV patients who do not respond adequately to conventional therapy, and secondary pulmonary hypertension (SPH) in the scleroderma spectrum of diseases (SSD) due to intrinsic precapillary pulmonary vascular disease in patients with NYHA functional class III and IV. There are limited data on long-term use.

4.2 Posology and method of administration

Epoprostenol GEBRO must be reconstituted only with specific sterile diluent for Epoprostenol. For information regarding reconstitution, dilution and calculation of dose, please see section 6.6 .

After reconstitution Epoprostenol GEBRO is a colourless solution, practically free of particles.

Epoprostenol GEBRO is suitable for continuous infusion only, either intravascular or into the blood supplying the dialyser.

Epoprostenol GEBRO is not to be used for bolus administration.


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Renal Dialysis: Adults: The following general schedule of infusion has been found effective in adults: Prior to dialysis: 4 nanograms/kg/min intravenously for 15 minutes. 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 appropriate patient monitoring. Children and the elderly: There is no specific information available on the use of Epoprostenol for renal dialysis in children or in elderly patients. Primary and Secondary Pulmonary Hypertension: Adults: The following schedules have been found effective: Short-term (acute) dose ranging: 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 minutes 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 well tolerated, a lower dosage has to be determined.

During acute dose ranging in clinical trials, the mean maximum tolerated dose was 8.6±0.3 nanograms/kg/min. Long-term continuous infusion: Long-term continuous infusion of Epoprostenol GEBRO should be administered through a central venous catheter. Temporary peripheral intravenous 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 less than 5 nanograms/kg/min; the long-term infusion should be started at one-half the maximum tolerated infusion rate. Dosage adjustments: Changes in the long-term infusion rate should be based on persistence, recurrence or worsening of the patient's symptoms of PPH or the occurrence of adverse events due to excessive doses of Epoprostenol GEBRO.

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 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 minutes.

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 event may occasionally resolve without dosage adjustment.

Dosage decreases should be made gradually in 2 nanograms/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of Epoprostenol GEBRO or sudden large reductions in infusion rates should be avoided.

Except in life-threatening situations (e.g. unconsciousness, collapse, etc) infusion rates of Epoprostenol GEBRO should be adjusted only under the direction of a physician.


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Oral anticoagulation was continued in the PPH clinical trial population in addition to continuous intravenous Epoprostenol administration and was well tolerated. Concurrent oral anticoagulation is recommended. Children: There is limited information on the use of Epoprostenol for PPH/SPH in children. Elderly: There is limited information on the use of Epoprostenol in patients over 65. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

4.3 Contraindications

Epoprostenol GEBRO is contraindicated in patients with known hypersensitivity to the drug.

Epoprostenol GEBRO is contraindicated in patients with congestive heart failure arising from severe left ventricular dysfunction.

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

4.4 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.

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

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 the concentration of epoprostenol administered. Hypotension may occur during infusions of Epoprostenol.

The effects of Epoprostenol on heart rate may be masked by concomitant use of drugs which affect cardiovascular reflexes.

If excessive hypotension occurs during administration of Epoprostenol, the dose should be reduced or the infusion discontinued. Hypotension may be profound with overdose and may result in loss of consciousness (see section 4.9).

Short-term dose-ranging with Epoprostenol must be performed in a hospital setting with adequate personnel and equipment for haemodynamic monitoring and emergency care.

Elevated serum glucose levels have been reported during infusion of Epoprostenol. Renal Dialysis: 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.

During renal dialysis with Epoprostenol there is a need for careful haematological monitoring and it should be ensured that cardiac output is adequately maintained so that delivery of oxygen to peripheral tissues is not diminished.

Haemorrhagic complications have not been encountered with Epoprostenol but the possibility should be considered when the drug is administered to patients with spontaneous or drug-induced haemorrhagic diatheses. When Epoprostenol is used alone, measurements such as activated whole blood clotting time may not be reliable.

The hypotensive effect of Epoprostenol may be enhanced by the use of acetate buffer in the dialysis bath during renal dialysis. Primary and Secondary Pulmonary Hypertension: The hazards of Epoprostenol treatment are considered to outweigh the risks of the disease in patients with functional capacity of New York Heart Association (NYHA) Class I and Class II. Epoprostenol therapy should therefore not be initiated in these patients.


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Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of this disorder.

Some patients with primary pulmonary hypertension have developed pulmonary oedema during dose-ranging, which may be associated with pulmonary veno-occlusive disease. 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 receive Epoprostenol for PPH and SPH should be based upon the 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 intravenous catheter and infusion pump should be carefully considered.

The enclosed Glycine Buffer Diluent contains no preservative; consequently a vial should be used once only and then discarded.

This medicinal product contains approximately 2.43 mmol (or 56 mg) sodium after reconstitution with 50 ml of the Glycine Buffer Diluent.

To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction

When Epoprostenol GEBRO is administered to patients receiving concomitant anticoagulants standard anticoagulant monitoring is advisable as there may be potentiation of effect.

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

The vasodilator effect of Epoprostenol GEBRO may augment or be augmented by concomitant use of other vasodilators.

The effects of Epoprostenol GEBRO on heart-rate may be masked by concomitant use of drugs which affect cardiovascular reflexes.

Epoprostenol GEBRO may reduce the thrombolytic efficacy of tissue plasminogen activator (t-PA) by increasing hepatic clearance of t-PA.

4.6 Pregnancy and lactation

Pregnancy There are no or limited amount of data from the use of epoprostenol sodium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Epoprostenol during pregnancy. Lactation It is not known whether epoprostenol is excreted in breast milk. A risk to the newborns /infants cannot be excluded. Breast-feeding should be discontinued during treatment with Epoprostenol. Fertility Epoprostenol had no effect on male or female fertility in animals (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects

Adverse reactions are listed below by system organ class and frequency. The following terminologies have been used in order to classify the occurrence of undesirable effects


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− Very Common: (≥1/10) − Common: (≥1/100 to <1/10) − Uncommon: (≥1/1,000 to <1/100) − Rare: (≥1/10,000 to <1/1,000) − Very Rare: (<1/10,000), not known (cannot be estimated from the available data)

The interpretation of adverse events during long term administration of Epoprostenol is complicated by the clinical features of the underlying disease being treated.

Infections and infestations Very common: Sepsis, septicaemia*

Blood and lymphatic system disorders Common: Decreased platelet count

Psychiatric disorders Common: Anxiety, nervousness Very Rare: Agitation

Nervous system disorders Very Common: Headache

Cardiac disorders Common: Tachycardia has been reported as a response to Epoprostenol at doses of 5 nanograms/kg/min and below.] 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.

Vascular Disorders Very Common: Facial flushing (seen even in the anaesthetised patient) Very Rare: Pallor

Gastrointestinal Disorders Very Common: Nausea, vomiting Common: Abdominal colic, sometimes reported as abdominal discomfort Uncommon: Dry mouth

Skin and subcutaneous tissue disorders Very Rare: Sweating

Musculoskeletal and connective tissue disorders Very Common: Jaw pain

General disorders and administration site conditions Rare: Local infection*, chest pain Very Rare: Reddening over the infusion site*, occlusion of the long i.v. catheter*, pain at the injection site*, lassitude, chest tightness * Associated with the delivery system for epoprostenol.

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. 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.


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5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Epoprostenol GEBRO is 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.

Infusions of 4ng/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. Renal Dialysis: 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 this platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depend.

The effect 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 4ng/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-minute infusions at 1-16 ng/kg/min.

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

Epoprostenol potentates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor. Primary and Secondary Pulmonary Hypertension:

Intravenous Epoprostenol GEBRO 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 GEBRO on mean pulmonary artery pressure (PAPm) in patients with PPH were variable and minor.

Chronic haemodynamic effects are generally similar to acute effects. During chronic infusion cardiac index (CI), stroke volume (SV) and arterial oxygen saturation are increased and mean systemic arterial pressure (SAPm), right atrial pressure, total pulmonary resistance (TPR) and systemic vascular resistance are decreased.

5.2 Pharmacokinetic properties

Intravenously administered epoprostenol sodium is rapidly distributed from blood to tissue. At normal physiological pH and temperature, it breaks down spontaneously to 6-oxo-prostaglandin F1a, although there is some enzymatic degradation to other products. The half-life for this process in man is expected to be no more than 6 minutes, and may be as short as 2-3 minutes, as estimated from in vitro rates of degradation of epoprostenol in human whole blood.

Pharmacokinetic studies in animals have shown the whole body distribution to be 1015ml/kg, and the whole body clearance to be 4.27ml/kg/sec. Following intravenous injection of radiolabelled epoprostenol, the highest concentrations are found in the liver, kidneys and small intestine. Steady-state plasma concentrations are reached within 15 minutes and are proportional to infusion rates. Extensive clearance by the liver has been demonstrated, with approximately 80% being removed in a single pass. Urinary excretion of the metabolites of epoprostenol accounts for between 40% and 90% of the administered dose, with biliary excretion accounting for the remainder. Urinary excretion is greater than 95% complete within 25 hours of dosing. Tissue levels decline rapidly with no evidence of accumulation.

Following the administration of radiolabelled epoprostenol to humans, the urinary and faecal recoveries of radioactivity were 82% and 4% respectively. At least 16 compounds were found, 10 of


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which were structurally identified. Unlike many other prostaglandins, epoprostenol is not metabolised during passage through the pulmonary circulation.

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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Fertility: A study in which male and female rats were dosed subcutaneously for 74 or 63 days respectively, with 0, 10, 30 or 100mg/kg/day, showed no effects on fertility.

There was no evidence of mutagenicity in the Ames test, micronucleus assay or DNA elution.

Carcinogenicity: Oncology studies have not been performed. 6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder for solution for infusion: Mannitol Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment)

Solvent: Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Water for injection

6.2 Incompatibilities

Epoprostenol GEBRO must be reconstituted using only the sterile buffer provided. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Powder for solution for infusion: 18 months

Solvent: 2 years

Protect infusion bags from light during infusion. Renal Dialysis: When reconstituted with the Glycine Buffer Diluent and diluted with physiological saline as instructed (see 6.6, Instructions for Use/Handling, Renal Dialysis), freshly prepared Epoprostenol solutions should be used within a maximum time frame of 12 hours at 25°C. Primary and Secondary Pulmonary Hypertension: When reconstituted and diluted with the Glycine Buffer Diluent as instructed (see 6.6, Instructions for Use/Handling, Primary Pulmonary Hypertension), freshly prepared Epoprostenol solutions should be infused immediately. If not used immediately, in-use storage times are the responsibility of the user and should not be longer than 24 hours at 2-8°C.

Where the solution is held in an ambulatory infusion pump system, a cold pouch must be used to maintain the temperature of the solution at 2-8°C for the full administration period. Epoprostenol GEBRO solution may then be used over a 24 hour period provided that the cold pouch is changed as necessary throughout the day.

Where an ambulatory cold pouch system cannot be used the maximum administration time at 25°C is 12 hours for freshly prepared solutions.


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6.4 Special precautions for storage

Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C Solvent: Keep the vial in the outer carton in order to protect from light. Store below 25°C For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Each pack unit contains - one vial Epoprostenol GEBRO 0.5mg, containing a white freeze-dried powder cake packed in a

15 ml clear glass vial Type I with grey lyo stopper and aluminium caps with blue flip-off inserts. - one 50ml sterile Glycine buffer solution, pH 10.5 in a clear glass vial - one single unit sterile filter device for aseptic preparation of infusion solution

6.6 Special precautions for disposal

Reconstitution and dilution: 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 GEBRO 0.5 mg must be carried out using sterile techniques, immediately prior to clinical use.

Reconstitution time should be below 30 seconds.

After reconstitution Epoprostenol GEBRO is a colourless solution, practically free of particles. Renal dialysis Reconstitution: 1. Use only the Glycine Buffer Diluent provided for reconstitution. 2. Withdraw approximately 10 ml of the Glycine Buffer Diluent into a sterile syringe, inject the

contents of the syringe into the vial containing 0.5 mg 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 Glycine Buffer Diluent solution and mix thoroughly.

This solution is now referred to as the concentrated solution and contains 10,000 nanograms per ml epoprostenol. Only this concentrated solution is suitable for further dilution prior to use. When 0.5 mg epoprostenol powder is reconstituted with 50 ml of the Glycine Buffer Diluent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg. Dilution: For administration using a pump capable of delivering small volume constant infusions, suitable aliquots of concentrated solution may be diluted with sterile physiological saline.

It may be diluted with physiological saline (0.9%), provided a ratio of 6 volumes of saline to 1 volume of concentrated solution is not exceeded; e.g. 50 ml of concentrated solution further diluted with a maximum of 300 ml saline.

Other common intravenous fluids are unsatisfactory for the dilution of the concentrated solution as the required pH is not attained. Epoprostenol solutions are less stable at low pH.

Prior to using the concentrated solution, or the diluted form, a filtration step is needed. To filter, draw the reconstituted product into a large syringe and then attach the sterile filter provided to the syringe.


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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.

When reconstituted and diluted as directed above, epoprostenol infusion solutions have a pH of approximately 10 and will retain 90% of their initial potency for approximately 12 hours at 25°C. CALCULATION OF INFUSION RATE: The infusion rate may be calculated by the following formula: Infusion rate = dosage (ng/kg/min) x bodyweight (kg) (ml/min) concentration of solution (ng/ml) Infusion rate (ml/hr) = Infusion rate (ml/min) x 60 Infusion rate formulae - examples When used in renal dialysis Epoprostenol GEBRO 0.5 mg may be administered as the concentrated solution (a) or in diluted form (b). a. Using concentrated solution i.e. 10,000 ng/ml epoprostenol.

Concentration of solution = 10,000 ng/ml epoprostenol

Dosage (ng/kg/min) Bodyweight (kilograms)

30 40 50 60 70 80 90 100

1 0.18 0.24 0.30 0.36 0.42 0.48 0.54 0.60

2 0.36 0.48 0.60 0.72 0.84 0.96 1.08 1.20

3 0.54 0.72 0.90 1.08 1.26 1.44 1.62 1.80

4 0.72 0.96 1.20 l.44 1.68 1.92 2.16 2.40

5 0.90 1.20 1.50 1.80 2.10 2.40 2.70 3.00

Flow rates in ml/hr b. Using concentrated solution, diluted: 10ml concentrated solution + 40 ml physiological saline (0.9%). To give a final total volume of 50 ml. Resultant concentration = 2,000 nanograms/ml epoprostenol.



30 40 50 60 70 80 90 100

1 0.90 1.20 1.50 1.80 2.10 2.40 2.70 3.00

2 1.80 2.40 3.00 3.60 4.20 4.80 5.40 6.00

3 2.70 3.60 4.50 5.40 6.30 7.20 8.10 9.00

4 3.60 4.80 6.00 7.20 8.40 9.60 10.80 12.00

5 4.50 6.00 7.50 9.00 10.50 12.00 13.50 15.00

Flow rates in ml/hr


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Primary and secondary Pulmonary Hypertension The following pack unit is available for use in the treatment of primary pulmonary hypertension:

One vial containing sterile freeze-dried epoprostenol sodium equivalent to 0.5 mg epoprostenol supplied with one 50 ml vial of sterile Glycine Buffer Diluent solution.

Initially a pack unit containing diluent buffer must be used. During chronic epoprostenol 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 epoprostenol.

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: This should be carried out according to the instructions given for renal dialysis. Where a pack containing 0.5 mg epoprostenol is reconstituted with 50 ml sterile diluent the resultant concentration is 10,000 nanograms per ml. Dilution: Epoprostenol GEBRO 0.5 mg may be used either as concentrated solution or in a diluted form for the treatment of PPH/SPH. Only the Glycine Buffer Diluent provided may be used for the further dilution of reconstituted Epoprostenol GEBRO 0.5 mg. Physiological saline must not be used when Epoprostenol GEBRO 0.5 mg is to be used for the treatment of primary pulmonary hypertension. Concentrations commonly used in the treatment of primary or secondary pulmonary hypertension are as follows: − 15,000 ng/ml – 3vials of 0.5mg epoprostenol or one vial of 1.5mg epoprostenol reconstituted and

diluted to a total volume of 100ml in the Glycine Buffer Diluent. − 10,000 ng/ml – two vials containing 0.5mg epoprostenol reconstituted and diluted to a total volume

of 100ml in the Glycine Buffer Diluent. The maximum recommended concentration for administration in primary pulmonary hypertension is 60,000ng/ml.

Epoprostenol GEBRO 0.5 mg must not be administered with other parenteral solutions or medications when used for primary or secondary pulmonary 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 pump cassette using firm but not excessive pressure; the typical time taken for filtration of 50 ml of concentrated solution is 70 seconds.

Remove the filter from the syringe and draw up the additional volume of the Glycine Buffer Diluent required to achieve the desired dilution.

Refit the filter to the syringe and dispense the additional buffer through this into the concentrated Epoprostenol GEBRO 0.5 mg solution in the cassette.

Mix well.

The filter unit must be used for the dilution of one pack only and then discarded.

The ambulatory pump used to administer Epoprostenol GEBRO 0.5 mg should (1) be small and lightweight, (2) be able to adjust infusion rates in ng/kg/min increments, (3) have occlusion, end of infusion, and low battery alarms, (4) be accurate to ± 6% of the programmed rate (5) be positive pressure driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Epoprostenol GEBRO 0.5 mg, and (6) include a cold pouch system. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Protect infusion bags from light during infusion. CALCULATION OF INFUSION RATE: The infusion rate may be calculated from the formula given above for renal dialysis. An example of a concentration commonly used in primary or secondary pulmonary hypertension is shown below.


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Infusion rates for a concentration of 15,000 nanograms/ml: Concentration of solution = 15,000 ng/ml epoprostenol


30 40 50 60 70 80 90 100

4 1.0 1.1 1.3 1.4 1.6

6 1.0 1.2 1.4 1.7 1.9 2.2 2.4

8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2

10 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0

12 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

14 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6

16 1.9 2.6 3.2 3.8 4.5 5.1 5.8 6.4

Flow rates in ml/hr

7 MARKETING AUTHORISATION HOLDER

Drehm Pharma GmbH Hietzinger Hauptstrasse 37/2, 1130 Vienna Austria Telephone: +43 1 879 52 45 11 Telefax: +43 1 879 52 45 3 E-Mail: [email protected]

8 MARKETING AUTHORISATION NUMBER(S)

PL 33028/0006 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/10/2010 10 DATE OF REVISION OF THE TEXT

18/10/2010


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Summary of Product Characteristics

The UK Summary of Product Characteristics (SmPC) for Epoprostenol GEBRO 1.5 mg Powder and Solvent for Solution for Infusion (PL 33028/0007) is as follows: 1 NAME OF THE MEDICINAL PRODUCT

Epoprostenol GEBRO 1.5 mg Powder and Solvent for Solution for Infusion 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 vial contains 1.593 mg Epoprostenol Sodium, corresponding to 1.5 mg Epoprostenol. Each vial of solvent contains 50 ml of a sterile glycine buffer solution containing approximately 55 mg sodium. When 1 vial with 1.5 mg epoprostenol is reconstituted with 50 ml sterile diluent, the resultant concentration is 30,000 nanograms per ml. Excipients: contains 0.05 mmol sodium (1.15 mg) per vial. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for solution for infusion. White lyophilised powder cake in colourless glass-vials, and a clear, colourless solution in 50 ml glass vials. When 1.5 mg epoprostenol powder is reconstituted with 50 ml of the Glycine Buffer Diluent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Haemodialysis Epoprostenol GEBRO is indicated for use in renal dialysis when use of heparin carries a high risk of causing or exacerbating bleeding or when heparin is otherwise contraindicated. Primary and secondary pulmonary hypertension Epoprostenol GEBRO is also indicated for the intravenous long-term treatment of primary pulmonary hypertension (PPH) in New York Heart Association (NYHA) functional Class III and Class IV patients who do not respond adequately to conventional therapy, and secondary pulmonary hypertension (SPH) in the scleroderma spectrum of diseases (SSD) due to intrinsic precapillary pulmonary vascular disease in patients with NYHA functional class III and IV. There are limited data on long-term use.

4.2 Posology and method of administration

Epoprostenol GEBRO must be reconstituted only with specific sterile diluent for Epoprostenol. For information regarding reconstitution, dilution and calculation of dose, please see section 6.6 . After reconstitution Epoprostenol GEBRO is a colourless solution, practically free of particles. Epoprostenol GEBRO is suitable for continuous infusion only, either intravascular or into the blood supplying the dialyser. Epoprostenol GEBRO is not to be used for bolus administration.


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Renal Dialysis: Adults: The following general schedule of infusion has been found effective in adults: Prior to dialysis: 4 nanograms/kg/min intravenously for 15 minutes. 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 appropriate patient monitoring. Children and the elderly: There is no specific information available on the use of Epoprostenol for renal dialysis in children or in elderly patients. Primary and Secondary Pulmonary Hypertension: Adults: The following schedules have been found effective: Short-term (acute) dose ranging: 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 minutes 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 well tolerated, a lower dosage has to be determined. During acute dose ranging in clinical trials, the mean maximum tolerated dose was 8.6±0.3 nanograms/kg/min. Long-term continuous infusion: Long-term continuous infusion of Epoprostenol GEBRO should be administered through a central venous catheter. Temporary peripheral intravenous 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 less than 5 nanograms/kg/min; the long-term infusion should be started at one-half the maximum tolerated infusion rate. Dosage adjustments: Changes in the long-term infusion rate should be based on persistence, recurrence or worsening of the patient's symptoms of PPH or the occurrence of adverse events due to excessive doses of Epoprostenol GEBRO. 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 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 minutes. 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 event may occasionally resolve without dosage adjustment.


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Dosage decreases should be made gradually in 2 nanograms/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of Epoprostenol GEBRO or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g. unconsciousness, collapse, etc) infusion rates of Epoprostenol GEBRO should be adjusted only under the direction of a physician. Oral anticoagulation was continued in the PPH clinical trial population in addition to continuous intravenous Epoprostenol administration and was well tolerated. Concurrent oral anticoagulation is recommended. Children: There is limited information on the use of Epoprostenol for PPH/SPH in children. Elderly: There is limited information on the use of Epoprostenol in patients over 65. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

4.3 Contraindications

Epoprostenol GEBRO is contraindicated in patients with known hypersensitivity to the drug. Epoprostenol GEBRO is contraindicated in patients with congestive heart failure arising from severe left ventricular dysfunction. Epoprostenol GEBRO should not be used chronically in patients who develop pulmonary oedema during dose-ranging.

4.4 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. Epoprostenol is a potent pulmonary and systemic vasodilator. The cardiovascular effects during infusion disappear within 30 minutes of the end of administration. 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 the concentration of epoprostenol administered. Hypotension may occur during infusions of Epoprostenol. The effects of Epoprostenol on heart rate may be masked by concomitant use of drugs which affect cardiovascular reflexes. If excessive hypotension occurs during administration of Epoprostenol, the dose should be reduced or the infusion discontinued. Hypotension may be profound with overdose and may result in loss of consciousness (see section 4.9). Short-term dose-ranging with Epoprostenol must be performed in a hospital setting with adequate personnel and equipment for haemodynamic monitoring and emergency care. Elevated serum glucose levels have been reported during infusion of Epoprostenol. Renal Dialysis: 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. During renal dialysis with Epoprostenol there is a need for careful haematological monitoring and it should be ensured that cardiac output is adequately maintained so that delivery of oxygen to peripheral tissues is not diminished.


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Haemorrhagic complications have not been encountered with Epoprostenol but the possibility should be considered when the drug is administered to patients with spontaneous or drug-induced haemorrhagic diatheses. When Epoprostenol is used alone, measurements such as activated whole blood clotting time may not be reliable. The hypotensive effect of Epoprostenol may be enhanced by the use of acetate buffer in the dialysis bath during renal dialysis. Primary and Secondary Pulmonary Hypertension: The hazards of Epoprostenol treatment are considered to outweigh the risks of the disease in patients with functional capacity of New York Heart Association (NYHA) Class I and Class II. Epoprostenol therapy should therefore not be initiated in these patients. Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of this disorder. Some patients with primary pulmonary hypertension have developed pulmonary oedema during dose-ranging, which may be associated with pulmonary veno-occlusive disease. 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 receive Epoprostenol for PPH and SPH should be based upon the 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 intravenous catheter and infusion pump should be carefully considered. The enclosed Glycine Buffer Diluent contains no preservative; consequently a vial should be used once only and then discarded. This medicinal product contains approximately 2.43 mmol (or 56 mg) sodium after reconstitution with 50 ml of the Glycine Buffer Diluent. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

When Epoprostenol GEBRO is administered to patients receiving concomitant anticoagulants standard anticoagulant monitoring is advisable as there may be potentiation of effect. When NSAIDS or other drugs affecting platelets aggregation are used concomitantly, there is the potential for Epoprostenol GEBRO to increase the risk of bleeding. The vasodilator effect of Epoprostenol GEBRO may augment or be augmented by concomitant use of other vasodilators. The effects of Epoprostenol GEBRO on heart-rate may be masked by concomitant use of drugs which affect cardiovascular reflexes. Epoprostenol GEBRO may reduce the thrombolytic efficacy of tissue plasminogen activator (t-PA) by increasing hepatic clearance of t-PA.

4.6 Pregnancy and lactation

Pregnancy There are no or limited amount of data from the use of epoprostenol sodium in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Epoprostenol during pregnancy.


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Lactation It is not known whether epoprostenol is excreted in breast milk. A risk to the newborns /infants cannot be excluded. Breast-feeding should be discontinued during treatment with Epoprostenol. Fertility Epoprostenol had no effect on male or female fertility in animals (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects

Adverse reactions are listed below by system organ class and frequency. The following terminologies have been used in order to classify the occurrence of undesirable effects − Very Common: (≥1/10) − Common: (≥1/100 to <1/10) − Uncommon: (≥1/1,000 to <1/100) − Rare: (≥1/10,000 to <1/1,000) − Very Rare: (<1/10,000), not known (cannot be estimated from the available data)

The interpretation of adverse events during long term administration of Epoprostenol is complicated by the clinical features of the underlying disease being treated. Infections and infestations Very common: Sepsis, septicaemia* Blood and lymphatic system disorders Common: Decreased platelet count Psychiatric disorders Common: Anxiety, nervousness Very Rare: Agitation Nervous system disorders Very Common: Headache Cardiac disorders Common: Tachycardia has been reported as a response to Epoprostenol at doses of 5 nanograms/kg/min and below.] 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. Vascular Disorders Very Common: Facial flushing (seen even in the anaesthetised patient) Very Rare: Pallor Gastrointestinal Disorders Very Common: Nausea, vomiting Common: Abdominal colic, sometimes reported as abdominal discomfort Uncommon: Dry mouth Skin and subcutaneous tissue disorders Very Rare: Sweating


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Musculoskeletal and connective tissue disorders Very Common: Jaw pain General disorders and administration site conditions Rare: Local infection*, chest pain Very Rare: Reddening over the infusion site*, occlusion of the long i.v. catheter*, pain at the injection site*, lassitude, chest tightness * Associated with the delivery system for epoprostenol.

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. 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 Epoprostenol GEBRO is 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. Infusions of 4ng/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. Renal Dialysis: 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 this platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depend. The effect 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 4ng/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-minute infusions at 1-16 ng/kg/min. Higher doses of epoprostenol sodium (20 nanograms/kg/min) disperse circulating platelet aggregates and increase by up to two fold the cutaneous bleeding time. Epoprostenol potentates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor. Primary and Secondary Pulmonary Hypertension: Intravenous Epoprostenol GEBRO 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 GEBRO on mean pulmonary artery pressure (PAPm) in patients with PPH were variable and minor.


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Chronic haemodynamic effects are generally similar to acute effects. During chronic infusion cardiac index (CI), stroke volume (SV) and arterial oxygen saturation are increased and mean systemic arterial pressure (SAPm), right atrial pressure, total pulmonary resistance (TPR) and systemic vascular resistance are decreased.

5.2 Pharmacokinetic properties

Intravenously administered epoprostenol sodium is rapidly distributed from blood to tissue. At normal physiological pH and temperature, it breaks down spontaneously to 6-oxo-prostaglandin F1a, although there is some enzymatic degradation to other products. The half-life for this process in man is expected to be no more than 6 minutes, and may be as short as 2-3 minutes, as estimated from in vitro rates of degradation of epoprostenol in human whole blood. Pharmacokinetic studies in animals have shown the whole body distribution to be 1015ml/kg, and the whole body clearance to be 4.27ml/kg/sec. Following intravenous injection of radiolabelled epoprostenol, the highest concentrations are found in the liver, kidneys and small intestine. Steady-state plasma concentrations are reached within 15 minutes and are proportional to infusion rates. Extensive clearance by the liver has been demonstrated, with approximately 80% being removed in a single pass. Urinary excretion of the metabolites of epoprostenol accounts for between 40% and 90% of the administered dose, with biliary excretion accounting for the remainder. Urinary excretion is greater than 95% complete within 25 hours of dosing. Tissue levels decline rapidly with no evidence of accumulation. Following the administration of radiolabelled epoprostenol to humans, the urinary and faecal recoveries of radioactivity were 82% and 4% respectively. At least 16 compounds were found, 10 of which were structurally identified. Unlike many other prostaglandins, epoprostenol is not metabolised during passage through the pulmonary circulation. 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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction. Fertility: A study in which male and female rats were dosed subcutaneously for 74 or 63 days respectively, with 0, 10, 30 or 100mg/kg/day, showed no effects on fertility. There was no evidence of mutagenicity in the Ames test, micronucleus assay or DNA elution. Carcinogenicity: Oncology studies have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder for solution for infusion: Mannitol Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Solvent: Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Water for injection

6.2 Incompatibilities

Epoprostenol GEBRO must be reconstituted using only the sterile buffer provided. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.


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6.3 Shelf life

Powder for solution for infusion: 18 months Solvent: 2 years Protect infusion bags from light during infusion. Renal Dialysis: When reconstituted with the Glycine Buffer Diluent and diluted with physiological saline as instructed (see 6.6, Instructions for Use/Handling, Renal Dialysis), freshly prepared Epoprostenol solutions should be used within a maximum time frame of 12 hours at 25°C. Primary and Secondary Pulmonary Hypertension: When reconstituted and diluted with the Glycine Buffer Diluent as instructed (see 6.6, Instructions for Use/Handling, Primary Pulmonary Hypertension), freshly prepared Epoprostenol solutions should be infused immediately. If not used immediately, in-use storage times are the responsibility of the user and should not be longer than 24 hours at 2-8°C. Where the solution is held in an ambulatory infusion pump system, a cold pouch must be used to maintain the temperature of the solution at 2-8°C for the full administration period. Epoprostenol GEBRO solution may then be used over a 24 hour period provided that the cold pouch is changed as necessary throughout the day. Where an ambulatory cold pouch system cannot be used the maximum administration time at 25°C is 12 hours for freshly prepared solutions.

6.4 Special precautions for storage

Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C Solvent: Keep the vial in the outer carton in order to protect from light. Store below 25°C For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Each pack unit contains - one vial Epoprostenol GEBRO 1.5mg, a white freeze-dried powder cake packed in a 15ml clear

glass vial Type I with grey lyo stopper and aluminium caps with red flip-off inserts. - two 50ml sterile Glycine buffer solution, pH 10.5 in a clear glass vial - one single unit sterile filter device for aseptic preparation of infusion solution

6.6 Special precautions for disposal

Reconstitution and dilution: 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 GEBRO 1.5 mg must be carried out using sterile techniques, immediately prior to clinical use. Reconstitution time should be below 30 seconds. After reconstitution Epoprostenol GEBRO is a colourless solution, practically free of particles. Renal dialysis Reconstitution: 1. Use only the Glycine Buffer Diluent provided for reconstitution.


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2. Withdraw approximately 10 ml of the Glycine Buffer Diluent into a sterile syringe, inject the contents of the syringe into the vial containing 1.5 mg freeze-dried epoprostenol and shake gently until the powder has dissolved.


This solution is now referred to as the concentrated solution and contains 30,000 nanograms per ml epoprostenol. Only this concentrated solution is suitable for further dilution prior to use. When 1.5 mg epoprostenol powder is reconstituted with 50 ml of the Glycine Buffer Diluent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg. Dilution: For administration using a pump capable of delivering small volume constant infusions, suitable aliquots of concentrated solution may be diluted with sterile physiological saline. It may be diluted with physiological saline (0.9%), provided a ratio of 6 volumes of saline to 1 volume of concentrated solution is not exceeded; e.g. 50 ml of concentrated solution further diluted with a maximum of 300 ml saline. Other common intravenous fluids are unsatisfactory for the dilution of the concentrated solution as the required pH is not attained. Epoprostenol solutions are less stable at low pH. Prior to using the concentrated solution, or the diluted form, a filtration step is needed. To filter, draw the reconstituted product into a large 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. When reconstituted and diluted as directed above, epoprostenol infusion solutions have a pH of approximately 10 and will retain 90% of their initial potency for approximately 12 hours at 25°C. CALCULATION OF INFUSION RATE: The infusion rate may be calculated by the following formula: Infusion rate = dosage (ng/kg/min) x bodyweight (kg) (ml/min) concentration of solution (ng/ml) Infusion rate (ml/hr) = Infusion rate (ml/min) x 60 Infusion rate formulae - examples When used in renal dialysis Epoprostenol GEBRO 1.5 mg may be administered as the concentrated solution (a) or in diluted form (b). a. Using concentrated solution i.e. 30,000 ng/ml epoprostenol. Concentration of solution = 30,000 ng/ml epoprostenol


30 40 50 60 70 80 90 100

1 n/a* n/a* n/a* n/a* n/a* n/a* 0.18 0.20

2 n/a* n/a* 0.20 0.24 0.28 0.32 0.36 0.40

3 0.18 0.24 0.30 0.36 0.42 0.48 0.54 0.60

4 0.24 0.32 0.40 0.48 0.56 0.64 0.72 0.80


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5 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00

Flow rates in ml/hr * Very low flow rates required. Diluted solutions in physiological saline should be considered. b. Using concentrated solution, diluted: 10ml concentrated solution + 50 ml physiological saline (0.9%). To give a final total volume of 60 ml. Resultant concentration = 5,000 nanograms/ml epoprostenol. Concentration of solution = 5,000 ng/ml epoprostenol


30 40 50 60 70 80 90 100

1 0.4 0.5 0.6 0.7 0.9 1.0 1.1 1.2

2 0.7 1.0 1.2 1.4 1.7 1.9 2.2 2.4

3 1.1 1.5 1.8 2.2 2.5 2.9 3.2 3.6

4 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

5 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0

Flow rates in ml/hr Primary and Secondary Pulmonary Hypertension The following pack is available for use in the treatment of primary pulmonary hypertension: One vial containing sterile freeze-dried epoprostenol sodium equivalent to 1.5 mg epoprostenol supplied with two 50 ml vial of sterile Glycine Buffer Diluent solution. Initially a pack containing diluent buffer must be used. During chronic epoprostenol therapy the final concentration of solution may be increased by the addition of a second vial of freeze dried epoprostenol. 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: This should be carried out according to the instructions given for renal dialysis. Where a pack containing 1.5 mg epoprostenol is reconstituted with 50 ml sterile diluent the resultant concentration is 30,000 nanograms per ml. Dilution: Epoprostenol GEBRO 1.5 mg may be used either as concentrated solution or in a diluted form for the treatment of PPH/SPH. Only the Glycine Buffer Diluent provided may be used for the further dilution of reconstituted Epoprostenol GEBRO 1.5 mg. Physiological saline must not be used when Epoprostenol GEBRO 1.5 mg is to be used for the treatment of primary or secondary pulmonary hypertension. Concentrations commonly used in the treatment of primary pulmonary or secondary hypertension are as follows:

− 30,000 ng/ml - 1.5mg epoprostenol reconstituted to a total volume of 50 ml in the Glycine Buffer Diluent

− 15,000 ng/ml – 1.5mg epoprostenol reconstituted and diluted to a total volume of 100ml in the Glycine Buffer Diluent.


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The maximum recommended concentration for administration in primary pulmonary or secondary hypertension is 60,000ng/ml. Epoprostenol GEBRO 1.5 mg must not be administered with other parenteral solutions or medications when used for primary pulmonary 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 pump cassette using firm but not excessive pressure; the typical time taken for filtration of 50 ml of concentrated solution is 70 seconds. Remove the filter from the syringe and draw up the additional volume of the Glycine Buffer Diluent required to achieve the desired dilution. Refit the filter to the syringe and dispense the additional buffer through this into the concentrated Epoprostenol GEBRO 1.5 mg solution in the cassette. Mix well. The filter unit must be used for the dilution of one pack only and then discarded. The ambulatory pump used to administer Epoprostenol GEBRO 1.5 mg should (1) be small and lightweight, (2) be able to adjust infusion rates in ng/kg/min increments, (3) have occlusion, end of infusion, and low battery alarms, (4) be accurate to ± 6% of the programmed rate (5) be positive pressure driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Epoprostenol GEBRO 1.5 mg, and (6) include a cold pouch system The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Protect infusion bags from light during infusion. CALCULATION OF INFUSION RATE: The infusion rate may be calculated from the formula given above for renal dialysis. An example of a concentration commonly used in primary or secondary pulmonary hypertension is shown below. Infusion rates for a concentration of 15,000 nanograms/ml: Concentration of solution = 15,000 ng/ml epoprostenol


30 40 50 60 70 80 90 100

4 1.0 1.1 1.3 1.4 1.6

6 1.0 1.2 1.4 1.7 1.9 2.2 2.4

8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2

10 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0

12 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

14 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6

16 1.9 2.6 3.2 3.8 4.5 5.1 5.8 6.4

Flow rates in ml/hr


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7 MARKETING AUTHORISATION HOLDER

Drehm Pharma GmbH Hietzinger Hauptstrasse 37/2 A-1130 Vienna Austria Telephone: +43 1 879 52 45 11 Telefax: +43 1 879 52 45 3 E-Mail: [email protected]

8 MARKETING AUTHORISATION NUMBER(S)

PL 33028/0007 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/10/2010 10 DATE OF REVISION OF THE TEXT

18/10/2010


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Module 3

Product Information Leaflet text – PL 33028/0006

PACKAGE LEAFLET: INFORMATION FOR THE USER

Epoprostenol Gebro 0.5 mg Powder and Solvent for Solution for Infusion

Epoprostenol (as sodium)

Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor, nurse or pharmacist. In this leaflet: 1. What Epoprostenol Gebro is and what it is used for 2. Before you are given Epoprostenol Gebro 3. How Epoprostenol Gebro is given 4. Possible side effects 5. Storing Epoprostenol Gebro 6. Further information 1. WHAT EPOPROSTENOL GEBRO IS AND WHAT IT IS USED FOR This medicine contains epoprostenol. Epoprostenol Gebro has two separate uses. It can be used during kidney dialysis to stop your blood from clotting), or it can be used to treat primary and secondary pulmonary hypertension – where Epoprostenol Gebro widens the blood vessels in the lungs and so lowers the blood pressure in your lungs. 2. BEFORE YOU ARE GIVEN EPOPROSTENOL Gebro Do not use Epoprostenol Gebro - if you are allergic (hypersensitive) to epoprostenol or any of the other ingredients of

Epoprostenol Gebro (listed in Section 6) - if you have heart failure that makes you short of breath. This may be worse when lying flat and

can also cause swollen legs or feet due to a build-up of fluid. If you are unsure, talk to your doctor or nurse before having Epoprostenol Gebro. Take special care with Epoprostenol Gebro Your doctor needs to know before you are given Epoprostenol Gebro if: you have a tendency to bleed easily e.g. haemophilia. If you are unsure, talk to your doctor or nurse. This medicine can affect your blood pressure and heart rate and therefore your doctor will monitor these. Taking other medicines Please tell your doctor, nurse or pharmacist if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because epoprostenol can affect the way some medicines work. Also, some other medicines can affect the way epoprostenol works.


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In particular, tell your doctor, nurse or pharmacist if you are taking: • Medicines to prevent blood clots, such as heparin, warfarin or aspirin. • Medicines for high blood pressure such as doxazocin. • Medicines for angina, such as glyceryl trinitrate or other nitrate medicines. • Anti-inflammatory pain killers (also called 'NSAIDs') such as inuprofen. • Medicines for heart failure or irregular heartbeats, such as digoxin. • Medicines used to treat primary pulmonary hypertension, such as sildenafil,

sitaxentan, bosentan. Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines The effects of epoprostenol on driving and using machinery have not been studied. Important information about some of the ingredients of Epoprostenol Gebro This medicinal product contains 2.43 mmol (or 56 mg milligram) sodium (salt) per dose. To be taken into consideration by patients on a controlled sodium (salt) diet. 3. HOW EPOPROSTENOL GEBRO IS GIVEN • Epoprostenol Gebro will not be given by quick injection; instead it will be given slowly into your

vein over a long period of time. • Your doctor will decide how much Epoprostenol Gebro is right for you and how long you should

use it for. • The amount you are given is based on your body weight. • Your dose may be increased or decreased depending on how you respond to treatment.

Dosage Kidney dialysis: Adults: The usual starting dose for adults is 4 nanograms of epoprostenol for each kilogram of body weight, for each minute it is given.

• Before your dialysis, Epoprostenol Gebro may be given as a slow injection into your vein. • During dialysis, Epoprostenol Gebro will be slowly injected into the blood going into the

dialysis machine. Epoprostenol Gebro will not be given after the end of your dialysis. Children and the elderly: There is no specific information available on the use of Epoprostenol Gebro for kidney dialysis in children or in elderly patients. Primary and Secondary Pulmonary Hypertension: Adults:

• The usual starting dose for adults is 2 nanograms of epoprostenol for each kilogram of your body weight for each minute it is given

• This dose is then increased every 15 minutes until the best dose is found for you. The best dose will relieve your symptoms but cause the fewest possible side-effects.

Once the correct dose has been found, a permanent tube or line will be fitted. Your doctor will then continue to give you this dose through a pump. There are only certain pumps which can be used. Your doctor will make sure you are using the right one.


30

Children: There is limited information on the use of Epoprostenol Gebro for Primary and Secondary Pulmonary Hypertension in children. Elderly: There is limited information on the use of Epoprostenol Gebro in patients over 65. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Method of administration A short-term dose-ranging procedure administered via either a peripheral or central venous line is required to determine the long-term infusion rate. Long-term continuous infusion of Epoprostenol Gebro should be administered through a central venous catheter. If you are given more Epoprostenol Gebro than you need This can cause low blood pressure which can make you feel light-headed or faint. Your doctor or nurse will do whatever is necessary to correct this and may adjust your dose 4. POSSIBLE SIDE EFFECTS Like all medicines, Epoprostenol Gebro can cause side effects, although not everybody gets them. Tell your doctor or nurse immediately if:

• You get palpitations, chest pain, shortness of breath or sweating. • You feel dizzy or feel faint, especially on standing

These can be symptoms of an irregular heart beat or low blood pressure. Your doctor may check you regularly for these side effects. Other possible side effects include: Very common (affects more than 1 user in 10)

• Infection in the bloodstream, which may be due to the way this medicine is given. • Flushing (redness) of the face • Feeling sick (nausea) or being sick (vomiting) • Headache • Jaw pain

Common (affects 1 to 10 users in 100)

• Bleeding and/or bruising more easily than usual, for example from the nose or gums. Bleeding can be serious therefore tell your doctor or nurse as soon as possible if you think this applies to you.

• Feeling anxious or nervous • Stomach pain or discomfort which usually comes in waves (colic)

Uncommon (affects 1 to 10 users in 1,000)

• Dry mouth Rare (affects 1 to 10 users in 10,000) Infection at the injection site Very rare (affects less than 1 user in 10,000)

• Pain and redness at the injection site


31

• Pain or tightness in the chest • Pale skin • Feeling tired, weak or agitated • Sweating

If any of these side-effects gets serious or you notice any side-effects not listed in this leaflet, please tell your doctor or nurse. 5. STORING EPOPROSTENOL GEBRO Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C Solvent: Keep the vial in the outer carton in order to protect from light. Store below 25°C Keep out of the reach and sight of children. Do not use Epoprostenol Gebro after the expiry date which is stated on the bottle. The expiry date refers to the last day of that month. Shelf-life after reconstitution: Kidney Dialysis: When reconstituted with the Glycine Buffer Diluent and diluted with physiological saline as instructed (see information for medical or healthcare professionals below), freshly prepared Epoprostenol solutions should be used within a maximum time frame of 12 hours at 25°C. Primary and Secondary Pulmonary Hypertension: When reconstituted and diluted with the Glycine Buffer Diluent as instructed (see information for medical or healthcare professionals below), freshly prepared Epoprostenol solutions should be infused immediately. If not used immediately, in-use storage times are the responsibility of the user and should not be longer than 24 hours at 2-8°C. Where the solution is held in an ambulatory infusion pump system, a cold pouch must be used to maintain the temperature of the solution at 2-8°C for the full administration period. Epoprostenol Gebro solution may then be used over a 24 hour period provided that the cold pouch is changed as necessary throughout the day. Where an ambulatory cold pouch system cannot be used the maximum administration time at 25°C is 12 hours for freshly prepared solutions and 8 hours for solutions that have been stored prior to use. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.


32

6. FURTHER INFORMATION What Epoprostenol Gebro contains Powder for solution for infusion - The active substance is Epoprostenol (as Sodium).

1 vial contains 0.531 milligrams Epoprostenol Sodium, corresponding to 0.5 milligrams Epoprostenol.

- The other ingredients are: Powder for solution for infusion: Mannitol, Glycine, Sodium Chloride, Sodium Hydroxide (for

pH adjustment) Solvent: Glycine, Sodium Chloride, Sodium Hydroxide (for pH adjustment), Water for Injection Where 1 vial with 0.5 mg epoprostenol is reconstituted with 50 ml of sterile buffer, the resultant concentration is 10,000 nanograms per ml. Solvent Each vial of solvent contains 50 ml of a sterile glycine buffer solution containing approximately 55 milligram sodium. What Epoprostenol Gebro looks like and contents of the pack Epoprostenol Gebro is a white lyophilised powder cake packed in clear glass vials with grey lyo stopper and aluminium caps with blue flip-off inserts. The solvent is a clear, colourless solution packed in clear glass vials. After reconstitution Epoprostenol Gebro is a colourless solution, practically free of particles. Each pack unit contains

- one vial Epoprostenol Gebro 0.5mg, containing a white freeze-dried powder cake packed in a 15 ml clear glass vial Type I with grey lyo stopper and aluminium caps with blue flip-off inserts.

- one 50ml sterile Glycine buffer solution, pH 10.5 in a clear glass vial - one single unit sterile filter device for aseptic preparation of infusion solution

Marketing Authorisation Holder and Manufacturer <to be completed nationally> This medicinal product is authorised in the Member States of the EEA under the following names: UK: Epoprostenol Gebro 0.5 mg Powder and Solvent for Solution for Infusion Austria: Eprostil 0,5 mg Pulver und Lösungsmittel zur Herstellung einer Infusionslösung Hungary: Dynovas 0,5 mg Por és oldószer oldatos infúzióhoz Spain: Dynovas 0,5 mg Polvo y disolvente para solución para perfusión This leaflet was last approved in 08/2010


33

<----------------------------------------------------------------------------------------------------------------------> The following information is intended for medical or healthcare professionals only: Reconstitution and dilution: 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 Gebro 0.5 mg must be carried out using sterile techniques, immediately prior to clinical use. Reconstitution time should be below 30 seconds. After reconstitution Epoprostenol Gebro is a colourless solution, practically free of particles. Renal dialysis Reconstitution:

4. Use only the Glycine Buffer Diluent provided for reconstitution. 5. Withdraw approximately 10 ml of the Glycine Buffer Diluent into a sterile syringe, inject the



This solution is now referred to as the concentrated solution and contains 10,000 nanograms per ml epoprostenol. Only this concentrated solution is suitable for further dilution prior to use. When 0.5 mg epoprostenol powder is reconstituted with 50 ml of the Glycine Buffer Diluent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg. Dilution: For administration using a pump capable of delivering small volume constant infusions, suitable aliquots of concentrated solution may be diluted with sterile physiological saline. It may be diluted with physiological saline (0.9%), provided a ratio of 6 volumes of saline to 1 volume of concentrated solution is not exceeded; e.g. 50 ml of concentrated solution further diluted with a maximum of 300 ml saline. Other common intravenous fluids are unsatisfactory for the dilution of the concentrated solution as the required pH is not attained. Epoprostenol solutions are less stable at low pH. Prior to using the concentrated solution, or the diluted form, a filtration step is needed. To filter, draw the reconstituted product into a large 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. When reconstituted and diluted as directed above, epoprostenol infusion solutions have a pH of approximately 10 and will retain 90% of their initial potency for approximately 12 hours at 25°C. CALCULATION OF INFUSION RATE: The infusion rate may be calculated by the following formula: Infusion rate = dosage (ng/kg/min) x bodyweight (kg) (ml/min) concentration of solution (ng/ml)


34

Infusion rate (ml/hr) = Infusion rate (ml/min) x 60 Infusion rate formulae - examples When used in renal dialysis Epoprostenol Gebro 0.5 mg may be administered as the concentrated solution (a) or in diluted form (b). a. Using concentrated solution i.e. 10,000 ng/ml epoprostenol.



30 40 50 60 70 80 90 100

1 0.18 0.24 0.30 0.36 0.42 0.48 0.54 0.60

2 0.36 0.48 0.60 0.72 0.84 0.96 1.08 1.20

3 0.54 0.72 0.90 1.08 1.26 1.44 1.62 1.804 0.72 0.96 1.20 l.44 1.68 1.92 2.16 2.40

5 0.90 1.20 1.50 1.80 2.10 2.40 2.70 3.00

Flow rates in ml/hr b. Using concentrated solution, diluted: 10ml concentrated solution + 40 ml physiological saline (0.9%). To give a final total volume of 50 ml. Resultant concentration = 2,000 nanograms/ml epoprostenol.



30 40 50 60 70 80 90 100

1 0.90 1.20 1.50 1.80 2.10 2.40 2.70 3.00 2 1.80 2.40 3.00 3.60 4.20 4.80 5.40 6.00

3 2.70 3.60 4.50 5.40 6.30 7.20 8.10 9.00

4 3.60 4.80 6.00 7.20 8.40 9.60 10.80 12.00

5 4.50 6.00 7.50 9.00 10.50 12.00 13.50 15.00

Flow rates in ml/hr Primary and secondary Pulmonary Hypertension The following pack unit is available for use in the treatment of primary pulmonary hypertension: One vial containing sterile freeze-dried epoprostenol sodium equivalent to 0.5 mg epoprostenol supplied with one 50 ml vial of sterile Glycine Buffer Diluent solution.


35

Initially a pack unit containing diluent buffer must be used. During chronic epoprostenol 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 epoprostenol. 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: This should be carried out according to the instructions given for renal dialysis. Where a pack containing 0.5 mg epoprostenol is reconstituted with 50 ml sterile diluent the resultant concentration is 10,000 nanograms per ml. Dilution: Epoprostenol Gebro 0.5 mg may be used either as concentrated solution or in a diluted form for the treatment of PPH/SPH. Only the Glycine Buffer Diluent provided may be used for the further dilution of reconstituted Epoprostenol Gebro 0.5 mg. Physiological saline must not be used when Epoprostenol Gebro 0.5 mg is to be used for the treatment of primary pulmonary hypertension. Concentrations commonly used in the treatment of primary or secondary pulmonary hypertension are as follows:

− 15,000 ng/ml – 3vials of 0.5mg epoprostenol or one vial of 1.5mg epoprostenol reconstituted and diluted to a total volume of 100ml in the Glycine Buffer Diluent.

− 10,000 ng/ml – two vials containing 0.5mg epoprostenol reconstituted and diluted to a total volume of 100ml in the Glycine Buffer Diluent.

The maximum recommended concentration for administration in primary pulmonary hypertension is 60,000ng/ml. Epoprostenol Gebro 0.5 mg must not be administered with other parenteral solutions or medications when used for primary or secondary pulmonary 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 pump cassette using firm but not excessive pressure; the typical time taken for filtration of 50 ml of concentrated solution is 70 seconds. Remove the filter from the syringe and draw up the additional volume of The Glycine Buffer Diluent required to achieve the desired dilution. Refit the filter to the syringe and dispense the additional buffer through this into the concentrated Epoprostenol Gebro 0.5 mg solution in the cassette. Mix well. The filter unit must be used for the dilution of one pack only and then discarded. The ambulatory pump used to administer Epoprostenol Gebro 0.5 mg should (1) be small and lightweight, (2) be able to adjust infusion rates in ng/kg/min increments, (3) have occlusion, end of infusion, and low battery alarms, (4) be accurate to ± 6% of the programmed rate (5) be positive pressure driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Epoprostenol Gebro 0.5 mg, and (6) include a cold pouch system. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Protect infusion bags from light during infusion.


36

CALCULATION OF INFUSION RATE: The infusion rate may be calculated from the formula given above for renal dialysis. An example of a concentration commonly used in primary or secondary pulmonary hypertension is shown below. Infusion rates for a concentration of 15,000 nanograms/ml:



30 40 50 60 70 80 90 100

4 1.0 1.1 1.3 1.4 1.6

6 1.0 1.2 1.4 1.7 1.9 2.2 2.4

8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2

10 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0

12 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

14 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6

16 1.9 2.6 3.2 3.8 4.5 5.1 5.8 6.4

Flow rates in ml/hr


37

Product Information Leaflet text – PL 33028/0007

PACKAGE LEAFLET: INFORMATION FOR THE USER

Epoprostenol Gebro 1.5 mg Powder and Solvent for Solution for Infusion

Epoprostenol (as sodium)

Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor, nurse or pharmacist. In this leaflet: 1. What Epoprostenol Gebro is and what it is used for 2. Before you are given Epoprostenol Gebro 3. How Epoprostenol Gebro is given 4. Possible side effects 5. Storing Epoprostenol Gebro 6. Further information 1. WHAT EPOPROSTENOL GEBRO IS AND WHAT IT IS USED FOR This medicine contains epoprostenol. Epoprostenol Gebro has two separate uses. It can be used during kidney dialysis (sto stop your blood from clotting), or it can be used to treat primary and secondary pulmonary hypertension – where Epoprostenol Gebro widens the blood vessels in the lungs and so lowers the blood pressure in your lungs. 2. BEFORE YOU ARE GIVEN EPOPROSTENOL GEBRO Do not use Epoprostenol Gebro - if you are allergic (hypersensitive) to epoprostenol or any of the other ingredients of

Epoprostenol Gebro (listed in Section 6) - if you have heart failure that makes you short of breath. This may be worse when lying flat and

can also cause swollen legs or feet due to a build-up of fluid. If you are unsure, talk to your doctor or nurse before having Epoprostenol Gebro. Take special care with Epoprostenol Gebro Your doctor needs to know before you are given Epoprostenol Gebro if you have a tendency to bleed easily e.g. haemophilia. If you are unsure, talk to your doctor or nurse. This medicine can affect your blood pressure and heart rate and therefore your doctor will monitor these. Taking other medicines Please tell your doctor, nurse or pharmacist if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because epoprostenol can affect the way some medicines work. Also, some other medicines can affect the way epoprostenol works. In particular, tell your doctor, nurse or pharmacist if you are taking:

• Medicines to prevent blood clots, such as heparin, warfarin or aspirin.


38

• Medicines for high blood pressure such as doxazocin. • Medicines for angina, such as glyceryl trinitrate or other nitrate medicines. • Anti-inflammatory pain killers (also called 'NSAIDs') such as ibuprofen. • Medicines for heart failure or irregular heartbeats, such as digoxin. • Other medicines used to treat primary pulmonary hypertension, such as sildenafil,

sitaxentan, bosentan. Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines The effects of epoprostenol on driving and using machinery have not been studied. Important information about some of the ingredients of Epoprostenol Gebro This medicinal product contains 2.43 mmol (or 56 milligram) sodium (salt) per dose. To be taken into consideration by patients on a controlled sodium (salt) diet. 3. HOW EPOPROSTENOL GEBRO IS GIVEN • Epoprostenol Gebro will not be given by quick injection; instead it will be given slowly into your

vein over a long period of time. • Your doctor will decide how much Epoprostenol Gebro is right for you and how long you should

use it for. • The amount you are given is based on your body weight. • Your dose may be increased or decreased depending on how you respond to treatment.

Dosage Kidney dialysis: Adults: The usual starting dose for adults is 4 nanograms of epoprostenol for each kilogram of body weight, for each minute it is given.

• Before your dialysis, Epoprostenol Gebro may be given as a slow injection into your vein. • During dialysis, Epoprostenol Gebro will be slowly injected into the blood going into the

dialysis machine. Epoprostenol Gebro will not be given after the end of your dialysis. Children and the elderly: There is no specific information available on the use of Epoprostenol Gebro for kidney dialysis in children or in elderly patients. Primary and Secondary Pulmonary Hypertension: Adults:

• The usual starting dose for adults is 2 nanograms of epoprostenol for each kilogram of your body weight for each minute it is given

• This dose is then increased every 15 minutes until the best dose is found for you. The best dose will relieve your symptoms but cause the fewest possible side-effects.

Once the correct dose has been found, a permanent tube or line will be fitted. Your doctor will then continue to give you this dose through a pump. There are only certain pumps which can be used. Your doctor will make sure you are using the right one.


39

Children: There is limited information on the use of Epoprostenol Gebro for Primary and Secondary Pulmonary Hypertension in children. Elderly: There is limited information on the use of Epoprostenol Gebro in patients over 65. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Method of administration A short-term dose-ranging procedure administered via either a peripheral or central venous line is required to determine the long-term infusion rate. Long-term continuous infusion of Epoprostenol Gebro should be administered through a central venous catheter. If you are given more Epoprostenol Gebro than you need This can cause low blood pressure which can make you feel light-headed or faint. Your doctor or nurse will do whatever is necessary to correct this and may adjust your dose. 4. POSSIBLE SIDE EFFECTS Like all medicines, Epoprostenol Gebro can cause side effects, although not everybody gets them. Tell your doctor or nurse immediately if:

• You get palpitations, chest pain, shortness of breath or sweating. • You feel dizzy or feel faint, especially on standing

These can be symptoms of an irregular heart beat or low blood pressure. Your doctor may check you regularly for these side effects. Other possible side effects include: Very common (affects more than 1 user in 10)

• Infection in the bloodstream, which may be due to the way this medicine is given. • Flushing (redness) of the face • Feeling sick (nausea) or being sick (vomiting) • Headache • Jaw pain

Common (affects 1 to 10 users in 100)

• Bleeding and/or bruising more easily than usual, for example from the nose or gums. Bleeding can be serious therefore tell your doctor or nurse as soon as possible if you think this applies to you.

• Feeling anxious or nervous • Stomach pain or discomfort which usually comes in waves (colic)

Uncommon (affects 1 to 10 users in 1,000)

• Dry mouth Rare (affects 1 to 10 users in 10,000) Infection at the injection site Very rare (affects less than 1 user in 10,000)

• Pain and redness at the injection site • Pain or tightness in the chest


40

• Pale skin • Feeling tired, weak or agitated • Sweating

If any of these side-effects gets serious or you notice any side-effects not listed in this leaflet, please tell your doctor or nurse. 5. STORING EPOPROSTENOL GEBRO Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C Solvent: Keep the vial in the outer carton in order to protect from light. Store below 25°C Keep out of the reach and sight of children. Do not use Epoprostenol Gebro after the expiry date which is stated on the bottle. The expiry date refers to the last day of that month. Shelf-life after reconstitution: Kidney Dialysis: When reconstituted with the Glycine Buffer Diluent and diluted with physiological saline as instructed (see information for medical or healthcare professionals below), freshly prepared Epoprostenol solutions should be used within a maximum time frame of 12 hours at 25°C. Primary and Secondary Pulmonary Hypertension: When reconstituted and diluted with the Glycine Buffer Diluent as instructed (see information for medical or healthcare professionals below), freshly prepared Epoprostenol solutions should be infused immediately. If not used immediately, in-use storage times are the responsibility of the user and should not be longer than 24 hours at 2-8°C. Where the solution is held in an ambulatory infusion pump system, a cold pouch must be used to maintain the temperature of the solution at 2-8°C for the full administration period. Epoprostenol Gebro solution may then be used over a 24 hour period provided that the cold pouch is changed as necessary throughout the day. Where an ambulatory cold pouch system cannot be used the maximum administration time at 25°C is 12 hours for freshly prepared solutions and 8 hours for solutions that have been stored prior to use. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Epoprostenol Gebro contains Powder for solution for infusion - The active substance is Epoprostenol (as Sodium).

1 vial contains 1.593 milligrams Epoprostenol Sodium, corresponding to 1.5 milligrams Epoprostenol.


41

- The other ingredients are: Powder for solution for infusion: Mannitol, Glycine, Sodium Chloride, Sodium Hydroxide (for

pH adjustment) Solvent: Glycine, Sodium Chloride, Sodium Hydroxide (for pH adjustment), Water for Injection When 1 vial with 1.5 mg epoprostenol is reconstituted with 50 ml sterile diluent, the resultant concentration is 30,000 nanograms per ml. Solvent Each vial of solvent contains 50 ml of a sterile glycine buffer solution containing approximately 55 milligram sodium. What Epoprostenol Gebro looks like and contents of the pack Epoprostenol Gebro is a white lyophilised powder cake packed in clear glass vials with grey lyo stopper and aluminium caps with blue flip-off inserts. The solvent is a clear, colourless solution packed in clear glass vials. After reconstitution Epoprostenol Gebro is a colourless solution, practically free of particles. Each pack unit contains:

- one vial Epoprostenol Gebro 1.5 mg, a white freeze-dried powder cake packed in a 15ml clear glass vial Type I with grey lyo stopper and aluminium caps with red flip-off inserts.

- two 50ml sterile Glycine buffer solution, pH 10.5 in a clear glass vial - one single unit sterile filter device for aseptic preparation of infusion solution

Marketing Authorisation Holder and Manufacturer <to be completed nationally> This medicinal product is authorised in the Member States of the EEA under the following names: UK: Epoprostenol Gebro 1.5 mg Powder and Solvent for Solution for Infusion Austria: Dynovase 1,5 mg Pulver und Lösungsmittel zur Herstellung einer Infusionslösung Hungary: Dynovas 1,5 mg Por és oldószer oldatos infúzióhoz Spain: Dynovas 1,5 mg Polvo y disolvente para solución para perfusión This leaflet was last approved in 08/2010


42

<----------------------------------------------------------------------------------------------------------------------> The following information is intended for medical or healthcare professionals only: Reconstitution and dilution: 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 Gebro 1.5 mg must be carried out using sterile techniques, immediately prior to clinical use. Reconstitution time should be below 30 seconds. After reconstitution Epoprostenol Gebro is a colourless solution, practically free of particles. Renal dialysis Reconstitution:

4. Use only the Glycine Buffer Diluent provided for reconstitution. 5. Withdraw approximately 10 ml of the Glycine Buffer Diluent into a sterile syringe, inject the



This solution is now referred to as the concentrated solution and contains 30,000 nanograms per ml epoprostenol. Only this concentrated solution is suitable for further dilution prior to use. When 1.5 mg epoprostenol powder is reconstituted with 50 ml of the Glycine Buffer Diluent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg. Dilution: For administration using a pump capable of delivering small volume constant infusions, suitable aliquots of concentrated solution may be diluted with sterile physiological saline. It may be diluted with physiological saline (0.9%), provided a ratio of 6 volumes of saline to 1 volume of concentrated solution is not exceeded; e.g. 50 ml of concentrated solution further diluted with a maximum of 300 ml saline. Other common intravenous fluids are unsatisfactory for the dilution of the concentrated solution as the required pH is not attained. Epoprostenol solutions are less stable at low pH. Prior to using the concentrated solution, or the diluted form, a filtration step is needed. To filter, draw the reconstituted product into a large 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. When reconstituted and diluted as directed above, epoprostenol infusion solutions have a pH of approximately 10 and will retain 90% of their initial potency for approximately 12 hours at 25°C. CALCULATION OF INFUSION RATE: The infusion rate may be calculated by the following formula: Infusion rate = dosage (ng/kg/min) x bodyweight (kg) (ml/min) concentration of solution (ng/ml)


43

Infusion rate (ml/hr) = Infusion rate (ml/min) x 60 Infusion rate formulae - examples When used in renal dialysis Epoprostenol Gebro 1.5 mg may be administered as the concentrated solution (a) or in diluted form (b). a. Using concentrated solution i.e. 30,000 ng/ml epoprostenol.



30 40 50 60 70 80 90 100

1 n/a* n/a* n/a* n/a* n/a* n/a* 0.18 0.20

2 n/a* n/a* 0.20 0.24 0.28 0.32 0.36 0.40

3 0.18 0.24 0.30 0.36 0.42 0.48 0.54 0.60

4 0.24 0.32 0.40 0.48 0.56 0.64 0.72 0.80

5 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00

Flow rates in ml/hr * Very low flow rates required. Diluted solutions in physiological saline should be considered. b. Using concentrated solution, diluted: 10ml concentrated solution + 50 ml physiological saline (0.9%). To give a final total volume of 60 ml. Resultant concentration = 5,000 nanograms/ml epoprostenol.



30 40 50 60 70 80 90 100

1 0.4 0.5 0.6 0.7 0.9 1.0 1.1 1.2

2 0.7 1.0 1.2 1.4 1.7 1.9 2.2 2.4

3 1.1 1.5 1.8 2.2 2.5 2.9 3.2 3.6

4 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

5 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0

Flow rates in ml/hr Primary and Secondary Pulmonary Hypertension The following pack is available for use in the treatment of primary pulmonary hypertension: One vial containing sterile freeze-dried epoprostenol sodium equivalent to 1.5 mg epoprostenol supplied with two 50 ml vial of sterile Glycine Buffer Diluent solution.


44

Initially a pack containing diluent buffer must be used. During chronic epoprostenol therapy the final concentration of solution may be increased by the addition of a second vial of freeze dried epoprostenol. 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: This should be carried out according to the instructions given for renal dialysis. Where a pack containing 1.5 mg epoprostenol is reconstituted with 50 ml sterile diluent the resultant concentration is 30,000 nanograms per ml. Dilution: Epoprostenol Gebro 1.5 mg may be used either as concentrated solution or in a diluted form for the treatment of PPH/SPH. Only the Glycine Buffer Diluent provided may be used for the further dilution of reconstituted Epoprostenol Gebro 1.5 mg. Physiological saline must not be used when Epoprostenol Gebro 1.5 mg is to be used for the treatment of primary or secondary pulmonary hypertension. Concentrations commonly used in the treatment of primary pulmonary or secondary hypertension are as follows:

− 30,000 ng/ml - 1.5mg epoprostenol reconstituted to a total volume of 50 ml in the Glycine Buffer Diluent

− 15,000 ng/ml – 1.5mg epoprostenol reconstituted and diluted to a total volume of 100ml in the Glycine Buffer Diluent.

The maximum recommended concentration for administration in primary pulmonary or secondary hypertension is 60,000ng/ml. Epoprostenol Gebro 1.5 mg must not be administered with other parenteral solutions or medications when used for primary pulmonary 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 pump cassette using firm but not excessive pressure; the typical time taken for filtration of 50 ml of concentrated solution is 70 seconds. Remove the filter from the syringe and draw up the additional volume of the Glycine Buffer Diluent required to achieve the desired dilution. Refit the filter to the syringe and dispense the additional buffer through this into the concentrated Epoprostenol Gebro 1.5 mg solution in the cassette. Mix well. The filter unit must be used for the dilution of one pack only and then discarded. The ambulatory pump used to administer Epoprostenol Gebro 1.5 mg should (1) be small and lightweight, (2) be able to adjust infusion rates in ng/kg/min increments, (3) have occlusion, end of infusion, and low battery alarms, (4) be accurate to ± 6% of the programmed rate (5) be positive pressure driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Epoprostenol Gebro 1.5 mg, and (6) include a cold pouch system The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Protect infusion bags from light during infusion.


45

CALCULATION OF INFUSION RATE: The infusion rate may be calculated from the formula given above for renal dialysis. An example of a concentration commonly used in primary or secondary pulmonary hypertension is shown below. Infusion rates for a concentration of 15,000 nanograms/ml:



30 40 50 60 70 80 90 100

4 1.0 1.1 1.3 1.4 1.6

6 1.0 1.2 1.4 1.7 1.9 2.2 2.4

8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2

10 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0

12 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

14 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6

16 1.9 2.6 3.2 3.8 4.5 5.1 5.8 6.4

Flow rates in ml/hr


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Module 4

Labelling text

Epoprostenol GEBRO 0.5 mg Powder and Solvent for Solution for Infusion (PL 33028/0006)

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING FOLDING CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoprostenol Gebro 0.5 mg Powder and Solvent for Solution for Infusion Active substance: Epoprostenol 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 vial contains 0.531 mg Epoprostenol Sodium, corresponding to 0.5mg Epoprostenol. 3. LIST OF EXCIPIENTS Powder for solution for infusion: Mannitol Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Solvent: Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Water for injection See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and Solvent for Solution for Infusion This package contains: 1 vial 1 glycine buffers and 1 sterilisation filter unit 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use. Read the package leaflet before use.


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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY The sterile filter unit must be used for the dilution. 8. EXPIRY DATE EXP: Ready-for-use solutions containing Epoprostenol Sodium should be stored in cool conditions (2-8°C), and not longer than 24 hours. 9. SPECIAL STORAGE CONDITIONS Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C Solvent: Keep the vial in the outer carton in order to protect from light. Store below 25°C Use as directed by the physician. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE The containers are for single use only. Discard any unused portion. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: DREHM PHARMA GMBH Klostergasse 37/1/8 1180 Vienna AUSTRIA 12. MARKETING AUTHORISATION NUMBER(S) MA No.: PL 33028/0006 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY <Medicinal product subject to medical prescription.>


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15. INSTRUCTIONS ON USE Read the package leaflet before use. 16. INFORMATION IN BRAILLE <Justification for not including Braille accepted> MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS CLEAR GLASS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoprostenol Gebro 0.5 mg Powder for Infusion Epoprostenol Sodium 2. METHOD OF ADMINISTRATION For continuous infusion. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 vial contains 0.5 mg Epoprostenol Sodium 6. OTHER Store below 25° C. Keep the vial in the outer carton in order to protect from light. Only the original glycine buffer diluent should be used for reconstitution!


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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING CLEAR GLASS VIAL (Glycine Buffer) 1. NAME OF THE MEDICINAL PRODUCT Glycine – buffer solution 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 vial contains 50 ml glycine buffer solution. 3. LIST OF EXCIPIENTS Solvent: Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Water for injection See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution 50 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY For single use only. Only this glycine buffer diluent should be used for reconstitution! 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Keep the vial in the outer carton in order to protect from light. Store below 25°C


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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Discard any unused portion. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER DREHM PHARMA GMBH Klostergasse 37/1/8 1180 Vienna AUSTRIA 12. MARKETING AUTHORISATION NUMBER(S) MA number: PL 33028/0006 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY <Medicinal product subject to medical prescription.> 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE <Justification for not including Braille accepted>


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Labelling text

Epoprostenol GEBRO 1.5 mg Powder and Solvent for Solution for Infusion (PL 33028/0007)

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING FOLDING CARTON 1. NAME OF THE MEDICINAL PRODUCT Epoprostenol Gebro 1.5 mg Powder and Solvent for Solution for Infusion Active substance: Epoprostenol 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 vial contains 1.593 mg Epoprostenol Sodium, corresponding to 1.5mg Epoprostenol. 3. LIST OF EXCIPIENTS Powder for solution for infusion: Mannitol Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Solvent: Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Water for injection See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and Solvent for Solution for Infusion This package contains: 1 vial 2 glycine buffers and 1 sterilisation filter unit 5. METHOD AND ROUTE(S) OF ADMINISTRATION Intravenous use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children.


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7. OTHER SPECIAL WARNING(S), IF NECESSARY The sterile filter unit must be used for the dilution. 8. EXPIRY DATE EXP: Ready-for-use solutions containing Epoprostenol Sodium should be stored in cool conditions (2-8°C), and not longer than 24 hours. 9. SPECIAL STORAGE CONDITIONS Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C Solvent: Keep the vial in the outer carton in order to protect from light. Store below 25°C Use as directed by the physician. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE The containers are for single use only. Discard any unused portion. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Marketing Authorisation Holder: DREHM PHARMA GMBH Klostergasse 37/1/8 1180 Vienna AUSTRIA 12. MARKETING AUTHORISATION NUMBER(S) MA No.: PL 33028/0007 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY <Medicinal product subject to medical prescription.> 15. INSTRUCTIONS ON USE Read the package leaflet before use.


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16. INFORMATION IN BRAILLE <Justification for not including Braille accepted> MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS CLEAR GLASS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Epoprostenol Gebro 1.5 mg Powder for Infusion Epoprostenol Sodium 2. METHOD OF ADMINISTRATION For continuous infusion. 3. EXPIRY DATE EXP: 4. BATCH NUMBER Batch: 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 vial contains 1.5 mg Epoprostenol Sodium 6. OTHER Store below 25° C. Keep the vial in the outer carton in order to protect from light. Only the original glycine buffer diluent should be used for reconstitution!


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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING CLEAR GLASS VIAL (Glycine Buffer) 1. NAME OF THE MEDICINAL PRODUCT Glycine – buffer solution 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 vial contains 50 ml glycine buffer solution. 3. LIST OF EXCIPIENTS Solvent: Glycine Sodium Chloride Sodium Hydroxide (for pH adjustment) Water for injection See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Solution 50 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY For single use only. Only this glycine buffer diluent should be used for reconstitution! 8. EXPIRY DATE EXP: 9. SPECIAL STORAGE CONDITIONS Keep the vial in the outer carton in order to protect from light. Store below 25°C


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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE For single use only. Discard any unused portion. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER DREHM PHARMA GMBH Klostergasse 37/1/8 1180 Vienna AUSTRIA 12. MARKETING AUTHORISATION NUMBER(S) MA number: PL 33028/0007 13. BATCH NUMBER Batch: 14. GENERAL CLASSIFICATION FOR SUPPLY <Medicinal product subject to medical prescription.> 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE <Justification for not including Braille accepted>


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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Drehm Pharma GmbH Marketing Authorisations for the medicinal products Epoprostenol GEBRO 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion (PL 33028/0006-7, UK/H/2736/01-02/DC) on 18th October 2010. The products are prescription-only medicines. The products are licensed under the trade names, Epoprostenol GEBRO 0.5 mg and 1.5 mg Powder and Solvent for Solution for Infusion, but will be referred to by the generic names, Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion, in the remainder of this report. These are generic applications for Epoprostenol GEBRO 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion, submitted under Article 10.1 of 2001/83 EC, as amended. The applications refer to the EU originator products, Flolan 500, poeder enoplosmiddel voor oplossing voor infusie 500 microgram (RVG 14469) and Flolan 1500, poeder enoplosmiddel voor oplossing voor infusie 1500 microgram (RVG 23523), authorised to GlaxoSmithKline B.V., The Netherlands on 24th June 1992. The reference products have been authorised in the EU for more than 10 years, so the period of data exclusivity has expired. With the UK as the Reference Member State in this Decentralised Procedure, Drehm Pharma GmbH applied for Marketing Authorisations for Epoprostenol GEBRO 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion in Austria, Hungary and Spain. Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion are indicated for use in renal dialysis when use of heparin carries a high risk of causing or exacerbating bleeding or when heparin is otherwise contraindicated. These medicines are also indicated for the intravenous long-term treatment of primary pulmonary hypertension (PPH) in New York Heart Association (NYHA) functional Class III and Class IV patients who do not respond adequately to conventional therapy; and secondary pulmonary hypertension (SPH) in the scleroderma spectrum of diseases (SSD) due to intrinsic precapillary pulmonary vascular disease in patients with NYHA functional class III and IV. Epoprostenol sodium (ATC code – B01A C09), the monosodium salt of epoprostenol, is a naturally occurring prostaglandin produced by the intima of blood vessels. 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 this platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depend. The effect 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 4ng/kg/min and above. Epoprostenol potentiates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor. Epoprostenol is the most potent inhibitor of platelet aggregation known. It is also a potent vasodilator. 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-


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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. Chronic haemodynamic effects are generally similar to acute effects. During chronic infusion cardiac index (CI), stroke volume (SV) and arterial oxygen saturation are increased and mean systemic arterial pressure (SAPm), right atrial pressure, total pulmonary resistance (TPR) and systemic vascular resistance are decreased. The medicinal product is presented as a white lyophilised powder cake and a clear, colourless solvent (sterile glycine buffer solution). Prior to administration a filtration step is necessary after reconstitution with the sterile diluent. These medicines are not for self-administration; they will be administered to the patient by a qualified healthcare professional. No new pre-clinical or clinical efficacy studies were conducted, which is acceptable given that these are generic applications cross-referring to products that have been licensed for over 10 years. Bioequivalence studies are not necessary to support these applications for parenteral products. The applicant has provided assurance that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types at all sites responsible for the manufacture and assembly of these products. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. For manufacturing sites within the Community, the applicant has provided acceptable copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. The RMS considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The Marketing Authorisation Holder has provided adequate justification for not submitting a Risk Management Plan (RMP). As the applications are for generic versions of already authorised reference products, for which safety concerns requiring additional risk minimisation have not been identified, a risk minimisation system is not considered necessary. The reference products have been in use for many years and the safety profile of the active is well-established. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). These were applications for generic products and there is no reason to conclude that marketing of these products will change the overall use pattern of the existing market.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Epoprostenol GEBRO Sodium 0.5 mg Powder and Solvent for Solution for Infusion Epoprostenol GEBRO Sodium 1.5 mg Powder and Solvent for Solution for Infusion

Name(s) of the active substance(s) (INN)

Epoprostenol sodium

Pharmacotherapeutic classification (ATC code)

Antithrombotic agents

(B01A C09)

Pharmaceutical form and strength(s)

Powder and solvent for solution for infusion

0.5mg and 1.5g

Reference numbers for the Decentralised Procedure

UK/H/2736/01-02/DC

Reference Member State

United Kingdom

Member States concerned

AT, ES, HU

Marketing Authorisation Number(s)

PL 33028/0006-7

Name and address of the authorisation holder

Drehm Pharma GmbH Hietzinger Hauptstrasse 37/2, 1130 Vienna Austria


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III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 QUALITY ASPECTS

ACTIVE SUBSTANCE

Epoprostenol sodium

Nomenclature:

INN: Epoprostenol sodium

Chemical name: Sodium (5Z,13E,15S)-6,9α-epoxy-11α,15-dihydroxyprosta-5,13-dien-1-oate

Structure:

Molecular formula: C20H31NaO5

Molecular weight: 374.45 g/mol

CAS No: 61849-14-7

Physical form: A white or almost white, crystalline, hygroscopic powder

Solubility: Soluble in water and in ethanol, slightly soluble in acetonitrile The active substance, epoprostenol sodium, is not the subject of a European Pharmacopeia (Ph. Eur.) monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. Confirmation has been provided that the raw materials, intermediates and auxiliary agents used in synthesis of the active are not of animal, biological or genetically modified origin. Appropriate specifications have been provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided and comply with the proposed specifications. Satisfactory Certificates of Analysis have been provided for any reference standards used by the active substance manufacturers during validation studies. The active substance is stored in appropriate packaging. Specifications and Certificates of Analysis have been provided for the packaging materials used. The primary packaging in direct contact with the active substance satisfies Directive 2002/72/EC (as amended) and is suitable for contact with foodstuffs.


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Appropriate stability data have been generated by both active substance manufacturers for active substance stored in the proposed commercial packaging. These data demonstrate the stability of the active substance and appropriate retest periods have been applied. MEDICINAL PRODUCT

Description and Composition

The medicinal product is presented as a white lyophilised powder cake and a clear, colourless sterile diluent (solvent). Prior to administration a filtration step is necessary after reconstitution with the sterile diluent. The filter is the same as in the originator products. Technical drawings and validation of the filter chosen is provided. Results of compatibility studies of the chosen packaging materials with the sterile diluent and the reconstituted solution, including container closure integrity and extractable / leachables testing, were presented and accepted. Other ingredients consist of pharmaceutical excipients, namely mannitol, glycine, sodium chloride and sodium hydroxide (for pH adjustment) making up the powder; and glycine, sodium chloride, sodium hydroxide (for pH adjustment), and water for injections making up the solvent. Appropriate justification for the inclusion of each excipient has been provided. All excipients used comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for all excipients. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in or used in the manufacturing process for the proposed product. None of the excipients are sourced from genetically modified organisms. There were no novel excipients used and no overages. Pharmaceutical development

Details of the pharmaceutical development of the medicinal products have been supplied and are satisfactory. The aim was to obtain medicinal products pharmaceutically equivalent to the European originator products, Flolan 500 / 1500, poeder enoplosmiddel voor oplossing voor infusie 500 / 1500 microgram (GlaxoSmithKline B.V.). A comparative quality study between the reference and generic products was submitted and comparative dissolution profiles were deemed acceptable. Manufacture

A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the products and the method of manufacture. Process validation studies have been conducted and the results are satisfactory. Finished product specification

The finished product specifications are provided for both release and shelf life for the lyophilised powder cake for solution for infusion and for the reconstituted solution, and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Satisfactory batch analysis data are provided, and accepted, for both strengths of the medicinal product. Certificates of Analysis have been provided for any reference standards used.


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Container Closure System

The lyophilised powder cake for solution for infusion is presented in 15 ml clear, colourless glass type I vials closed with grey bromobutyl rubber stoppers and aluminium flip-off caps. Each vial contains epoprostenol sodium equivalent to 0.5 mg or 1.5 mg epoprostenol. The solvent is presented in colourless glass type I vials, also closed with grey bromobutyl rubber stoppers and aluminium flip-off caps. Each vial contains 50 ml sterile glycine buffer solution. Each pack licensed for marketing will contain 1 vial with the lyophilised powder cake for solution for infusion, 1 vial with solvent, 1 single unit sterile filter device for aseptic preparation of infusion solution and the package leaflet. The vials satisfy Directive 2002/72/EC (as amended), and are suitable for contact with parenteral preparations. Appropriate specifications and validation of the filter device have been provided. Specifications and Certificates of Analysis for all packaging components used have been provided and are satisfactory. Stability

Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 18 months has been set for the powder for solution for infusion and a shelf-life of 2 years has been set for the solvent; this is satisfactory. Storage instructions for the powder are ‘Keep the vial in the outer carton in order to protect from light. Keep the vial tightly closed in order to protect from moisture. Store below 25°C’. Storage conditions for the solvent are ‘Keep the vial in the outer carton in order to protect from light. Store below 25°C’. For full details of shelf-life and storage conditions for the reconstituted / diluted medicinal products, as well as instructions for reconstitution, dilution and infusion, refer to sections 6.3 and 6.6 of the SmPC. Bioequivalence Study

Bioequivalence studies are not necessary to support these applications for parenteral products. Quality Overall Summary

A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Product Information

The approved Summaries of Product Characteristics (SmPCs), and Patient Information Leaflet (PIL) and labelling texts are satisfactory. The MAH has submitted text versions only and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. The PIL user testing report has been evaluated and is accepted. Conclusion

All pharmaceutical issues have been resolved and the quality grounds for these applications are considered adequate. There are no objections to approval of Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion from a pharmaceutical point of view.


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III.2 PRE-CLINICAL ASPECTS

Specific non-clinical studies have not been performed, which is acceptable for these applications for generic versions of products that have been licensed for over 10 years. The non-clinical overview provides a satisfactory review of the pharmacodynamic, pharmacokinetic, and toxicological properties of epoprostenol, which is a widely used and well-known active substance. The CV of the non-clinical expert has been supplied. For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the EU reference products, Flolan 500, poeder enoplosmiddel voor oplossing voor infusie 500 microgram and Flolan 1500, poeder enoplosmiddel voor oplossing voor infusie 1500 microgram (GlaxoSmithKline B.V., The Netherlands). III.3 CLINICAL ASPECTS

INDICATIONS

Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion are indicated for use in renal dialysis when use of heparin carries a high risk of causing or exacerbating bleeding or when heparin is otherwise contraindicated. These medicines are also indicated for the intravenous long-term treatment of primary pulmonary hypertension (PPH) in New York Heart Association (NYHA) functional Class III and Class IV patients who do not respond adequately to conventional therapy; and secondary pulmonary hypertension (SPH) in the scleroderma spectrum of diseases (SSD) due to intrinsic precapillary pulmonary vascular disease in patients with NYHA functional class III and IV. The indications are accepted. POSOLOGY AND METHOD OF ADMINISTRATION

Full details concerning the posology are provided in the SmPCs. The posology is satisfactory. TOXICOLOGY

The toxicology of epoprostenol is well-known No new data have been submitted and none are required for these types of application. CLINICAL PHARMACOLOGY

The clinical pharmacology of epoprostenol is well known. No novel pharmacodynamic or pharmacokinetic data are supplied or required for these applications. Clinical efficacy

No new data are submitted and none are required for these types of application. Efficacy is reviewed in the clinical overview. The efficacy of epoprostenol is well-established from its extensive use in clinical practice. Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion are to be administered as an aqueous intravenous solution and contain the same active substance, in the same concentrations, as the currently authorised EU reference products, Flolan 500, poeder enoplosmiddel voor oplossing voor infusie 500 microgram and Flolan 1500, poeder enoplosmiddel voor oplossing voor infusie 1500 microgram (GlaxoSmithKline B.V., The Netherlands). Thus, in accordance with the “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 rev. 1/Corr), the applicant is not required to submit a bioequivalence study.


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Clinical safety

No new safety data have been submitted and none are required for applications of this type. No new or unexpected safety concerns arose from these applications. Safety is reviewed in the clinical overview. The safety profile of epoprostenol is well-known. PRODUCT INFORMATION:

Summary of Product Characteristics (SmPC)

The approved SmPCs are satisfactory. Product Information Leaflet (PIL)

The final PIL texts are in line with the approved SmPCs and are satisfactory. Labelling

The labelling texts are satisfactory. Clinical overview

A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified expert. The CV of the clinical expert has been supplied. CONCLUSIONS

For generic applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the EU reference products, Flolan 500, poeder enoplosmiddel voor oplossing voor infusie 500 microgram and Flolan 1500, poeder enoplosmiddel voor oplossing voor infusie 1500 microgram (GlaxoSmithKline B.V., The Netherlands). Sufficient clinical information has been submitted to support these applications. All issues have been adequately addressed by the applicant. When used as indicated, Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion have a favourable benefit-to-risk ratio. The granting of Marketing Authorisations was therefore recommended on medical grounds.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY

The important quality characteristics of Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRE-CLINICAL

No new pre-clinical data were submitted and none are required for applications of this type. EFFICACY

The applicant’s Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion have been demonstrated to be generic versions of the EU reference products, Flolan 500, poeder enoplosmiddel voor oplossing voor infusie 500 microgram and Flolan 1500, poeder enoplosmiddel voor oplossing voor infusie 1500 microgram (GlaxoSmithKline B.V., The Netherlands). No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE

The approved SmPCs are satisfactory. The final PIL texts are in line with the SmPCs. The leaflet texts have been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the leaflet texts meet the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The approved labelling texts are satisfactory. The MAH has submitted text versions only for the PILs and labelling, and has committed to submitting mock-up livery to the relevant regulatory authorities for approval before packs are marketed. BENEFIT-RISK ASSESSMENT

The quality of the products is acceptable and no new pre-clinical or clinical safety concerns have been identified. The qualitative and quantitative assessment supports the claim that the applicant’s Epoprostenol 0.5 mg & 1.5 mg Powder and Solvent for Solution for Infusion and the EU reference products, Flolan 500, poeder enoplosmiddel voor oplossing voor infusie 500 microgram and Flolan 1500, poeder enoplosmiddel voor oplossing voor infusie 1500 microgram (GlaxoSmithKline B.V.) are interchangeable. Extensive clinical experience with epoprostenol is considered to have demonstrated the therapeutic value of the active substance. The risk: benefit ratio is considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted

Application type

Scope Outcome

UK/H/2736 - Medicines and Healthcare products Regulatory Agency

Documents

Transcript of UK/H/2736 - Medicines and Healthcare products Regulatory Agency