Epoprostenol Sodium 0.5 mg Powder and Solvent for Solution for Infusion

Epoprostenol Sodium 0.5 mg Powder and Solvent for Solution for Infusion:

Each vial contains epoprostenol sodium equivalent to 0.5 mg epoprostenol.

Excipient(s): contains 0.051 mmol sodium (1.18 mg).

Solvent for Epoprostenol Sodium 0.5 mg Powder and Solvent for Solution for Infusion:

Each vial contains 50ml sterile glycine buffer solution.

Excipient(s): contains 1.25 mmol sodium ( 28,82 mg).

For a full list of excipients, see section 6.1.

One ml of reconstituted concentrate solution contains epoprostenol (as epoprostenol sodium) 10 000 nanogram.

Powder and solvent for solution for infusion

− White to almost white freeze dried powder

− Clear solution (pH 10.3-10.8)

Epoprostenol is indicated for:

- renal dialysis when use of heparin carries a high risk of causing or exacerbating bleeding or when heparin is otherwise contraindicated

Epoprostenol is only indicated for continuous infusion, either by intravenous route.

Epoprostenol must not be administered as a bolus injection.

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 must be carried out using sterile techniques, immediately prior to clinical use.

The powder for solution for infusion must be reconstituted using only the sterile glycine buffer provided.

Prior to dialysis: 4 nanogram/kg/min intravenously during 15 min.

During dialysis: 4 nanogram/kg/min into the arterial inlet of the dialyser.

The infusion should be stopped at the end of dialysis.

The recommended dose for renal dialysis should be exceeded only with careful monitoring of patient blood pressure.

Use in children:

There is no specific information available on the use of epoprostenol for renal dialysis in children.

Use in elderly:

There is no specific information available on the use of epoprostenol for renal dialysis in elderly patients.

Renal dialysis

In renal dialysis Epoprostenol Sodium 0.5 mg Powder and Solvent for Solution for Infusion and glycine buffer diluent 50 ml should be used.

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 Epoprostenol Sodium 0.5 mg Powder and Solvent for Solution for Infusion and shake gently until the powder has dissolved.

3. Draw up the resulting solution into the syringe, re-inject it into the remaining volume of the Glycine buffer diluent solution and mix thoroughly.

The concentrated solution of 50 ml contains 10,000 nanograms per ml epoprostenol. Only this concentrated solution is suitable for further dilution prior to use.

When Epoprostenol Sodium 0.5 mg Powder and Solvent for Solution for Infusion is reconstituted with 50 ml of 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. Epopostenol 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.

The infusion rate may be calculated from the following formula:

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

Examples:

Epoprostenol may be administered in diluted form (1) or as the concentrated solution (2):

1. Diluted solution: A commonly used dilution is:

10 ml concentrated solution + 40 ml physiological saline (0.9%)

Resultant concentration = 2,000 nanogram/ml epoprostenol

Flow rates in ml/hr

2. Concentrated solution: 10,000 ng/ml epoprostenol

Flow rates in ml/hr

Epoprostenol is contraindicated in patients:

• with known hypersensitivity to the drug.

• with congestive heart failure arising from severe left ventricular dysfunction.

• who develop pulmonary oedema during dose-ranging.

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 .

As epoprostenol is a potent vasodilator, blood pressure and heart rate should be monitored during infusion as hypotension, tachycardia and bradycardia may occur. The change is thought to depend on both the basal heart rate and the concentration of epoprostenol administered. The cardiovascular effect disappear within 30 minutes after ended administration. 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 pronounced in overdose and may result in loss of consciousness. (See section 4.9)

Elevated serum glucose levels have been reported during infusion of epoprostenol in man but are not common.

Epoprostenol is an inhibitor of platelet aggregation, therefore an increased risk for haemorrhagic complications should be considered, particularly for patients with other risk factors for bleeding (see section 4.5 Interactions with other medicinal products and other forms of interaction)

Acetate buffer in the dialysis bath may enhance the hypotensive effect of epoprostenol during renal dialysis.

Epoprostenol is not a conventional anticoagulant, successfully used instead of heparin in renal dialysis, and in isolated cases, clotting has developed in the dialysis circuit, requiring termination of dialysis. When epoprostenol is used alone, measurements such as activated whole blood clotting time may not be reliable.

During renal dialysis 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 never been observed but the possibility should be considered in patients with spontaneous or drug-induced haemorrhagic diatheses.

Glycine buffer diluent contains no preservative, consequently a vial should be used once only and then discarded.

This medicinal product contains sodium. See section 2. To be taken into consideration by patients on a controlled sodium date.

The effect of heparin and other anticoagulants may be enhanced by epoprostenol. In case of concomitant use of heparin or other anticoagulants, standard anticoagulant monitoring is advisable.

The vasodilating effects of epoprostenol may be increased by concomitant use of other vasodilators (e.g. metoprolol, enalapril, nitroglycerin).

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

Concomitant administration of non-steroidal anti-inflammatory drugs (NSAIDs) or other drugs affecting platelets aggregation may increase the risk of bleeding.

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

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

Fertility

Animal studies did not indicate harmful effects with respect to fertility. However, the relevance of these animal findings to man is unknown.

Pregnancy

Animal studies did not indicate harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. However, the relevance of these animal findings to man is unknown.

In the absence of adequate experience of administration of epoprostenol to pregnant women, the potential benefit to the mother must be weighed against the unknown risks to the foetus.

Lactation

It is not known whether epoprostenol or its metabolites are excreted in human milk.

A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue/abstain from the breast-feeding or to discontinue/abstain from epoprostenol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

Adverse events 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

Blood and Lymphatic System Disorders

Metabolism and nutrition disorders

Psychiatric Disorders

Nervous System Disorders

Cardiac Disorders

Bradycardia, sometimes accompanied by orthostatic hypotension, has occurred in healthy volunteers at doses of epoprostenol greater than 5 nanograms/kg/minute. 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.

Hypotension

Vascular Disorders

Respiratory, thoracic and mediastinal disorders

Not known: pulmonary oedema

Gastrointestinal Disorders

Skin and Subcutaneous Tissue Disorders

Musculoskeletal and Connective Tissue Disorders

General Disorders and Administration Site Conditions

* Related to equipment and administration system.

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.

ATC Code: B01AC09

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

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

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. During infusion in animals, steady-state plasma concentrations of tritium-labelled epoprostenol 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.

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

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

Carcinogenicity: Oncology studies have not been performed.

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

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

In-use shelf life reconstituted/diluted solution for infusion:

From a physico-chemical point of view :

- Storage / use refrigerated: Reconstituted solutions may be kept at 2° to 8°C for no more than 48 hours

- Storage / use at room temperature: When administered at room temperature (up to 25°C), reconstituted solutions may be used for no longer than 12 hours.

- Storage refrigerated, use at room temperature: Prior to use at room temperature, constituted solutions may be stored refrigerated for no longer than 40 hours. In this case, solutions may be used for no longer than 8 hours.

From a microbiological point of view:

− The product should be used immediately.If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Powder for solution for infusion: Keep the vial in the outer carton in order to protect from light.

Solvent: Do not freeze.

For storage conditions of the reconstituted / diluted medicinal product, see section 6.3.

Powder for solution for infusion: 15 ml colourless glass type I vials closed with rubber stopper and aluminium/propylene cap

Solvent: 55 ml colourless glass type I vials closed with rubber stopper and aluminium/propylene cap.

Pack sizes:

- 1, 2, 3, 4, 5, 6 or 10 packs containing 1 vial with powder for solution for infusion, 1 vial with solvent and 1 filter;

- 1, 2, 3, 4, 5, 6 or 10 packs containing 1 vial with powder for solution for infusion, 2 vials with solvent and 1 filter.

Not all pack sizes may be marketed

Any unused product or waste material should be disposed of in accordance with local requirements.

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 04416/0915

20/05/2010

November 2010