1. Name Of The Medicinal Product
Flolan 0.5mg Injection
2. Qualitative And Quantitative Composition
Epoprostenol Sodium 0.5mg
3. Pharmaceutical Form
Freeze-Dried Powder
4. Clinical Particulars
4.1 Therapeutic Indications
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 contra-indicated.
Route of administration
By continuous infusion, either intravascularly or into the blood supplying the dialyser.
4.2 Posology And Method Of Administration
Flolan is suitable for continuous infusion only, either intravascularly or into the blood supplying the dialyser.
The following schedule of infusion has been found effective in adults:
Prior to dialysis: 4 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 doses should be exceeded only with careful monitoring of patient blood pressure.
Use in children: There is no specific information on the use of Flolan in children.
Use in the elderly: There is no specific information available on the use of Flolan in elderly patients.
Reconstitution:
Only the GlaxoSmithKline Glycine Buffer Diluent provided for the purpose should be used. The enclosed filter unit must be used once only and then discarded after use.
To reconstitute Flolan, a strict aseptic technique must be used. Particular care should be taken in calculating dilutions, and in diluting Flolan the following procedure is recommended:
1. Withdraw approximately 10 ml of the sterile GlaxoSmithKline Glycine Buffer Diluent into a sterile syringe.
2. Inject the contents of the syringe into the vial containing Flolan and shake gently until the powder has dissolved.
3. Draw up all the Flolan solution into the syringe.
4. Re-inject the entire contents into the residue of the original 50 ml of sterile GlaxoSmithKline Glycine Buffer Diluent.
5. Mix well. This solution is now referred to as the concentrated solution and contains Flolan 10,000 nanograms per millilitre. When 0.5mg Flolan powder for intravenous infusion is reconstituted with 50 ml sterile GlaxoSmithKline Glycine Buffer Diluent solution, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56mg. The concentrated solution is normally further diluted before use. 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. For administration using a pump capable of delivering small volume constant infusions, suitable aliquots of concentrated solution may be diluted with sterile physiological saline.
6. Before further dilution, draw up the concentrated solution into a larger syringe.
7. The filter provided should then be attached to the syringe and the concentrated solution is dispensed by filtration using firm but not excessive pressure. The typical time taken for filtration of 50 ml of solution is 70 seconds.
When reconstituted and diluted as directed, Flolan infusion solutions have a pH of approximately 10 and will retain 90% of their initial potency for approximately 12 hours at 25°C.
Infusion rate guidance
In general, the infusion rate may be calculated by the following formula:
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Examples:
Flolan may be administered in diluted form (1) or as the concentrated solution (2)
1. Diluted: A commonly used dilution is:
10ml concentrated solution + 40 ml physiological saline (0.9%).
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Flow rates in mls/hr
2. Using concentrated solution ie 10,000 ng/ml epoprostenol.
Bodyweight (kilograms)
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Flow rates in mls/hr
4.3 Contraindications
- Flolan is contra-indicated in patients with known hypersensitivity to the drug.
Flolan is contraindicated in patients with congestive heart failure arising from severe left ventricular dysfunction.
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.
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 Flolan is used alone, measurements such as activated whole blood clotting time may not be reliable.
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 heart 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 epoprostenol in man but these are not inevitable.
The hypotensive effect of Flolan may be enhanced by the use of acetate buffer in the dialysis bath during renal dialysis.
During renal dialysis with Flolan 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
When Flolan is administered to patients receiving concomitant anticoagulants standard anticoagulant monitoring is advisable as there may be potentiation of effect.
The vasodilator effect of Flolan may augment or be augmented by concomitant use of other 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 platelet aggregation are used concomitantly, there is the potential for epoprostenol to increase the risk of bleeding.
Patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with 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.
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
There are no data regarding the effect of epoprostenol used in renal dialysis on the ability to drive or operate machinery.
4.8 Undesirable Effects
Adverse events are listed below by system organ class and frequency. Frequencies are defined as follows: very common
The interpretation of adverse events during long term administration of Flolan is complicated by the clinical features of the underlying disease being treated.
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* Associated with the delivery system for Flolan
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Flolan 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.
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.
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
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
FREEZE-DRIED POWDER
Glycine BP 3.76 mg
Sodium chloride EP 2-932 mg
Mannitol BP 50.0 mg
Sodium hydroxide BP (quantity not fixed - used to adjust pH)
*Water for injections EP
*Water for injections is used during manufacture but is not present in the finished product, but removed during the freeze-drying process.
6.2 Incompatibilities
None known.
6.3 Shelf Life
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6.4 Special Precautions For Storage
Store below 25°C.
Store unopened vial in outer carton to protect from light and moisture.
Do not freeze.
Reconstitution and dilution should be carried out immediately prior to use (see section 4.2).
Freshly prepared epoprostenol solutions for renal dialysis should be used within 12 hours at 25°C. Any unused solution should be discarded after 12 hours.
6.5 Nature And Contents Of Container
0.5 mg freeze dried powder is contained in glass vials with synthetic butyl rubber plugs and aluminium collars.
6.6 Special Precautions For Disposal And Other Handling
Refer to section 4.2 Posology and method of administration
7. Marketing Authorisation Holder
Glaxo Wellcome UK Ltd
Trading as GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
United Kingdom
8. Marketing Authorisation Number(S)
Flolan 0.5 mg Injection PL 10949/0310
GlaxoSmithKline Glycine Buffer Diluent PL 10949/0311
9. Date Of First Authorisation/Renewal Of The Authorisation
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10. Date Of Revision Of The Text
25 November 2011
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