Flolan 1.5mg Injection

Epoprostenol sodium equivalent to 1.5 mg epoprostenol.

Sterile freeze-dried powder for solution for infusion.

Flolan 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.

Flolan is also indicated for the intravenous 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. There are limited data on long term use.

Flolan is not to be used for bolus administration.

Flolan (epoprostenol sodium) must be reconstituted only with specific sterile diluent for Flolan. (See section 6.6 Instructions for use/handling).

Renal Dialysis:

Flolan is suitable for continuous infusion only, either intravascularly or into the blood supplying the dialyser.

The following general schedule of infusion has been found effective in adults:

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

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.

Children and the elderly:

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

Primary Pulmonary Hypertension:

The following schedules have been found effective:

Adults

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 nanogram/kg/min and increased by increments of 2 nanogram/kg/min every 15 minutes or longer until maximum haemodynamic benefit or dose-limiting pharmacological effects are elicited.

During acute dose ranging in clinical trials, the mean maximum tolerated dose was 8.6±0.3 nanogram/kg/min.

Long-term continuous infusion:

Long-term continuous infusion of Flolan 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 nanogram/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 nanogram/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 Flolan.

In general, the need for increases in dose from the initial long-term dose should be expected over time. Increases in dose should be considered if symptoms of PPH persist, or recur after improving. The infusion rate should be increased by 1 to 2 nanogram/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 nanogram/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of Flolan or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (eg. unconsciousness, collapse, etc) infusion rates of Flolan 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 Flolan administration and was well tolerated. Concurrent oral anticoagulation is recommended.

Children

There is limited information on the use of Flolan for PPH in children.

Elderly

There is limited information on the use of Flolan 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.

Flolan is contraindicated in patients with known hypersensitivity to the drug.

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

Flolan should not be used chronically in patients 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.

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

Epoprostenol is a potent inhibitor of platelet aggregation, therefore, an increased risk for haemorrhagic complications should be considered, particularly for patients with other risk factors for bleeding (see sections 4.5 and 4.8).

Blood pressure and heart rate should be monitored during administration of Flolan. Flolan may either decrease or increase heart rate. The change is thought to depend on both the basal rate and the concentration of epoprostenol administered. Hypotension may occur during infusions of Flolan. If excessive hypotension occurs during administration of flolan, the dose should be reduced or the infusion discontinued. Hypotension may be profound in overdose and may result in loss of consciousness (see section 4.9).

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

Elevated serum glucose levels have been reported during infusion of Flolan in man but these are not inevitable.

Renal Dialysis:

The hypotensive effect of Flolan may be enhanced by the use of acetate buffer in the dialysis bath during 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. When Epoprostenol is used alone, measurements such as activated whole blood clotting time may not be reliable.

During renal dialysis with Flolan there is a need for careful haematological monitoring and it should be ensured that cardiac output increases more than minimally so that delivery of oxygen to peripheral tissues is not diminished.

Primary Pulmonary Hypertension:

The hazards of Flolan 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. Flolan therapy should therefore not be initiated in these patients.

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

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

Some patients with primary pulmonary hypertension have developed pulmonary oedema during dose-ranging, which may be associated with pulmonary veno-occlusive disease.

Abrupt withdrawal or interruption of infusion must be avoided, except in life-threatening situations. An abrupt interruption of therapy can induce a rebound of pulmonary hypertension resulting in dizziness, asthenia, increase dyspnoea, and may lead to death (see section 4.2 Posology and method of administration).

Flolan is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with Flolan requires commitment by the patient to sterile drug reconstitution, drug administration, care of the permanent central venous catheter, and access to intense and ongoing patient education.

Sterile technique must be adhered to in preparing the drug and in the care of the catheter. Even brief interruptions in the delivery of Flolan may result in rapid symptomatic deterioration. The decision to receive Flolan for PPH should be based upon the understanding that there is a high likelihood that therapy with Flolan will be needed for prolonged periods, possibly years, and the patient's ability to accept and care for a permanent intravenous catheter and infusion pump should be carefully considered.

GlaxoSmithKline Glycine Buffer Diluent contains no preservative, consequently a vial should be used once only and then discarded.

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

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

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

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

Patients on digoxin have shown elevations of digoxin concentrations after initiation of therapy with Flolan. This may be clinically relevant in patients prone to digoxin toxicity. Monitoring of digoxin levels is therefore advisable until digoxin levels are clinically stable in patients receiving treatment with Flolan and digoxin.

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 unknown if 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 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.

There are no data regarding the effect of Flolan used in renal dialysis on the ability to drive or operate machinery.

PPH and its therapeutic management may affect the ability to drive and operate machinery.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as follows: very common 1/10 (10%); common 1/100 and <1/10 (1% and <10%); uncommon 1/1000 and <1/100 (0.1% and <1%); rare 1/10,000 and <1/1000 (0.01% and <0.1%); very rare <1/10,000 (< 0.01%), unknown (cannot be estimated from the available data).

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

Infections and Infestations

Blood and Lymphatic System Disorders

Endocrine Disorders

Psychiatric Disorders

Nervous System Disorders

Cardiac Disorders

Vascular Disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal Disorders

Skin and Subcutaneous Tissue Disorders

Musculoskeletal and Connective Tissue Disorders

General Disorders and Administration Site Conditions

* Associated with the delivery system for Flolan

Symptoms and Signs

In general, events seen after overdose of epoprostenol represent exaggerated pharmacological effects of the drug (e.g. hypotension and complications of hypotension).

Treatment

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.

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

Infusions of 4 nanogram/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 potentiates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor.

Primary Pulmonary Hypertension:

Intravenous Flolan 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 Flolan 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.

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.

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.

Freeze-dried powder:

Glycine

Sodium Chloride

Mannitol

Sodium hydroxide

Flolan must be reconstituted using only the sterile buffer provided. Any further dilution must be performed using only the recommended solutions (see 6.6, instructions for use/handling)

FLOLAN freeze-dried powder: 3 years.

Renal Dialysis: When reconstituted with GlaxoSmithKline Glycine Buffer Diluent and diluted with physiological saline as instructed (see 6.6, Instructions for Use/Handling, Renal Dialysis), freshly prepared Flolan solutions should be used within 12 hours at 25°C.

Primary Pulmonary Hypertension: When reconstituted and diluted with GlaxoSmithKline Glycine Buffer Diluent as instructed (see 6.6, Instructions for Use/Handling, Primary Pulmonary Hypertension), freshly prepared Flolan 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. Flolan 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.

Store below 25°C.

Store unopened vial in outer carton to protect from light and moisture.

Do not freeze.

Any cold pouch used must be capable of maintaining the temperature of reconstituted Flolan between 2°C and 8°C for the full administration period.

The stability of solutions of Flolan is pH dependent. Only the diluent supplied should be used for reconstitution of freeze-dried Flolan and only the recommended infusion solutions, in the stated ratio, should be used for further dilution, otherwise the required pH may not be maintained.

Reconstitution and dilution should be carried out immediately prior to use (see Posology and method of administration, and instructions for use/handling).

GlaxoSmithKline Glycine Buffer Diluent contains no preservative, consequently a vial should be used once only and then discarded.

Freeze-dried powder in glass vials with synthetic butyl rubber plugs and aluminium collars.

Pack presentations:

Single 1.5 mg vial mg of freeze-dried powder (Non-marketed)

Single 1.5 mg vial of freeze-dried powder plus single vial of diluent

Single 1.5 mg vial of freeze-dried powder plus two vials of diluent (Non-marketed)

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

Renal dialysis

Reconstitution:-

1. Use only the GlaxoSmithKline Glycine Buffer Diluent provided for reconstitution.

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

3. Draw up the resulting Flolan solution into the syringe, re-inject it into the remaining volume of the GlaxoSmithKline Glycine Buffer Diluent solution and mix thoroughly.

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 0.5 mg Flolan powder is reconstituted with 50 ml of GlaxoSmithKline 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. Flolan 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, Flolan 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 from the following formula:-

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

Infusion rate formulae - examples

When used in renal dialysis Flolan may be administered as the concentrated solution (a) or in diluted form (b).

a. Using concentrated solution, i.e. 30 000 nanogram/ml epoprostenol:

* Very low flow rates required. Diluted solutions in physiological saline should be considered.

b. Diluted: A commonly used dilution is: -

10 ml concentrated solution plus 50 ml physiological saline (0.9%). To give a final total volume of 60 ml.

Resultant concentration = 5000 nanogram/ml epoprostenol:

Primary Pulmonary Hypertension

The following packs are 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 one 50 ml vial of sterile GlaxoSmithKline Glycine Buffer Diluent solution.

One vial containing sterile freeze-dried epoprostenol sodium equivalent to 1.5 mg epoprostenol supplied with two 50 ml vials of sterile GlaxoSmithKline Glycine Buffer Diluent (Non-Marketed).

One vial containing sterile freeze-dried epoprostenol sodium equivalent to 1.5 mg epoprostenol supplied alone (Non-Marketed).

Initially a pack containing diluent buffer must be used. During chronic Flolan therapy the final concentration of solution may be increased by the addition of a 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 1.5 mg epoprostenol is reconstituted with 50 ml sterile diluent the resultant concentration is 30,000 nanograms per ml.

Dilution:

Flolan may be used either as concentrated solution or in a diluted form for the treatment of PPH. Only GlaxoSmithKline Glycine Buffer Diluent provided may be used for the further dilution of reconstituted Flolan. Physiological saline must not be used when Flolan is to be used for the treatment of primary pulmonary hypertension.

Concentrations commonly used in the treatment of primary pulmonary hypertension are as follows:

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

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

The maximum recommended concentration for administration in primary pulmonary hypertension is 60,000ng/ml.

Flolan 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 GlaxoSmithKline 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 Flolan 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 Flolan 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 Flolan, and (6) include a cold pouch system The reservoir should be made of polyvinyl chloride, polypropylene, or glass.

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 pulmonary hypertension is shown below.

Infusion rates for a concentration of 15,000 nanogram/ml

GlaxoWellcome UK Ltd

Trading as GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

Flolan 1.5mg Injection PL10949/0312

GlaxoSmithKline Glycine Buffer Diluent PL 10949/0311

7^th March 2001

24 January 2012