- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy, and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyPulmonary Arterial HypertensionEpoprostenol is only indicated for continuous infusion by intravenous route.Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension.
Short-term (acute) dose ranging:This procedure should be conducted in a hospital with adequate resuscitation equipment.A short-term dose-ranging procedure administered via either a peripheral or central venous line is required to determine the long-term infusion rate. The infusion rate is initiated at 2 nanograms/kg/min and increased by increments of 2 nanograms/kg/min every 15 min or longer until maximum haemodynamic benefit or dose-limiting pharmacological effects are elicited.If the initial infusion rate of 2 nanograms/kg/min is not tolerated, a lower dose which is tolerated by the patient should be identified.
Long-term continuous infusion:Long-term continuous infusion of Flolan should be administered through a central venous catheter. Temporary peripheral i.v. infusions may be used until central access is established. Long-term infusions should be initiated at 4 nanograms/kg/min less than the maximum tolerated infusion rate determined during short-term dose-ranging. If the maximum tolerated infusion rate is 5 nanograms/kg/min or less, then the long-term infusion should be started at 1 nanograms/kg/min .
Dosage adjustments:Changes in the long-term infusion rate should be based on persistence, recurrence or worsening of the patient's symptoms of pulmonary arterial hypertension or the occurrence of adverse reaction due to excessive doses of 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 pulmonary arterial hypertension persist, or recur after improving. The infusion rate should be increased by 1 to 2 nanograms/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be of at least 15 min. Following establishment of a new infusion rate, the patient should be observed, and erect and supine blood pressure and heart rate monitored for several hours to ensure that the new dose is tolerated.During long-term infusion, the occurrence of dose-related pharmacological events similar to those observed during the dose-ranging period may necessitate a decrease in infusion rate, but the adverse reactions may occasionally resolve without dosage adjustment. Dosage decreases should be made gradually in 2 nanograms/kg/min decrements every 15 min or longer until the dose-limiting effects resolve. Abrupt withdrawal of Flolan or sudden large reductions in infusion rates should be avoided due to the risk of potential fatal rebound effect (see section 4.4). Except in life-threatening situations (e.g. unconsciousness, collapse, etc) infusion rates of Flolan should be adjusted only under the direction of a physician.Renal DialysisFlolan is suitable for continuous infusion only, either intravascularly or into the blood supplying the dialyser.The following schedule of infusion has been found effective in adults:Prior to dialysis: 4 nanograms/kg/min intravenously for 15 mins During dialysis: 4 nanograms/kg/min into the arterial inlet of the dialyserThe 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.
ElderlyThere is no specific information on the use of Flolan in patients over 65 years for renal dialysis or pulmonary arterial hypertension. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal (in the case of pulmonary arterial hypertension) or cardiac function and of concomitant disease or other medicine therapy.
Paediatric populationThe safety and efficacy of epoprostenol in children younger than 18 years have not yet been established.
Method of administration
Preparation of Flolan intravenous injectable solution:Reconstituted solutions, prepared in real time, must not be administered over more than 12 hours when they are used at room temperature (between 15°C and 25°C). They should be kept under 25°C and protected from light.It is possible to refrigerate Flolan reconstituted solutions, before they are used at room temperature, ranging between 2°C and 8°C and without exceeding 40 hour storage. In this case, the solutions should not be used over more than 8 hours when administered at room temperature.The reconstituted solution should be examined prior to administration. Its use is forbidden in the presence of a discoloration or particles.For further instructions on reconstitution and dilution of the medicinal product before administration, (see section 6.6).Epoprostenol must not be administered as a bolus injection.
PregnancyThere is a limited amount of data from the use of epoprostenol in pregnant women.Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).Given the absence of alternative medicines, epoprostenol can be used in those women who choose to continue their pregnancy, despite the known risk of pulmonary arterial hypertension during pregnancy.
BreastfeedingIt is unknown if epoprostenol or its metabolites are excreted in human milk. A risk to the breastfeeding child cannot be excluded. Breast-feeding should be discontinued during treatment with Flolan.
FertilityThere are no data on the effects of epoprostenol on fertility in humans. Reproductive studies in animals have shown no effects on fertility (see section 5.3).
|Infections and Infestations|
|Common||Sepsis, septicaemia (mostly related to delivery system for Flolan)1|
|Blood and Lymphatic System Disorders|
|Common||Decreased platelet count, bleeding at various sites (e.g. pulmonary, gastrointestinal, epistaxis, intracranial, post-procedural, retroperitoneal)|
|Nervous System Disorders|
|Very common||Facial flushing (seen even in the anaesthetised patient)|
|Respiratory, thoracic and mediastinal disorders|
|Very common||Nausea, vomiting, diarrhoea|
|Common||Abdominal colic, sometimes reported as abdominal discomfort|
|Skin and Subcutaneous Tissue Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|Very common||Jaw pain|
|General Disorders and Administration Site Conditions|
|Very common||Pain (unspecified)|
|Common||Pain at the injection site*, chest pain|
|Very rare||Erythema over the infusion site*, occlusion of the long i.v. catheter*, lassitude, chest tightness|
|Unknown||Blood glucose increased|
|* Associated with the delivery system for Flolan|
|1 Catheter-related infections caused by organisms not always considered pathogenic (including micrococcus) have been reported.|
|2 Tachycardia has been reported as a response to Flolan at doses of 5 nanograms/kg/min and below.|
|3 Bradycardia, sometimes accompanied by orthostatic hypotension, has occurred in healthy volunteers at doses of Flolan 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 Flolan equivalent to 30 nanograms/kg/min in healthy conscious volunteers.|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Mechanism of actionEpoprostenol Sodium, the monosodium salt of epoprostenol, a naturally occurring prostaglandin produced by the intima of blood vessels. Epoprostenol is the most potent inhibitor of platelet aggregation known. It is also a potent vasodilator.Many of the actions of epoprostenol are exerted via the stimulation of adenylate cyclase, which leads to increased intracellular levels of cyclic adenosine 3'5' monophosphate (cAMP). A sequential stimulation of adenylate cyclase, followed by activation of phosphodiesterase, has been described in human platelets. Elevated cAMP levels regulate intracellular calcium concentrations by stimulating calcium removal, and thus platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depends.
Pharmacodynamic effectsInfusion of 4 nanograms/kg/min for 30 minutes have been shown to have no significant effect on heart rate or blood pressure, although facial flushing may occur at these levels.
Pulmonary Arterial HypertensionIntravenous epoprostenol infusions of up to 15 minutes have been found to produce dose-related increases in cardiac index (CI) and stroke volume (SV), and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR) and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary artery pressure (PAPm) in patients with PPH were variable and minor.Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomised trials of 8 and 12 weeks' duration (N=25 and N=81, respectively) comparing epoprostenol plus conventional therapy to conventional therapy alone. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described. The combined baseline 6-minute walk test median values for the conventional therapy group and epoprostenol plus conventional therapy group was 266 meters and 301 meters, respectively.Improvements from baseline in cardiac index (0.33 vs. -0.12 L/min/m2), stroke volume (6.01 vs. -1.32 mL/beat), arterial oxygen saturation (1.62 vs. -0.85%), mean pulmonary artery pressure (-5.39 vs. 1.45 mm Hg), mean right atrial pressure (-2.26 vs. 0.59 mm Hg), total pulmonary resistance (-4.52 vs. 1.41 Wood U), pulmonary vascular resistance (-3.60 vs. 1.27 Wood U), and systemic vascular resistance (-4.31 vs. 0.18 Wood U) were statistically different between patients who received epoprostenol chronically and those who did not. Mean systemic arterial pressure was not significantly different between the two groups (-4.33 vs. -3.05 mm Hg). These haemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, nonrandomized study.Statistically significant improvement was observed in exercise capacity (p=0.001), as measured by the 6MWT in patients receiving continuous intravenous epoprostenol plus conventional therapy (N=52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N=54) (combined week 8 and 12 change from baseline median: 49 vs. -4 meters; mean: 55 vs. -4 meters). Improvements were apparent as early as the first week of therapy. At the end of the treatment period in the 12 weeks study, survival was improved in NYHA functional Class III and Class IV patients. Eight of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p=0.003).Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomised trial of 12 weeks' duration comparing epoprostenol plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. The primary efficacy endpoint for the study was improvement in the 6MWT. The median baseline value for the conventional therapy group and epoprostenol plus conventional therapy group was 240 meters and 270 meters, respectively. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not. Over 12 weeks, a statistical difference (p<0.001) in the change from baseline for the 6MWT was observed in the group receiving epoprostenol and conventional therapy as compared to the group receiving conventional therapy alone (median: 63.5 vs. -36.0 meters; mean: 42.9 vs. -40.7 meters). Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnoea, as measured by the Borg Dyspnea Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened. No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.
Renal DialysisThe effects of epoprostenol on platelet aggregation is dose-related when between 2 and 16 nanograms/kg/min is administered intravenously, and significant inhibition of aggregation induced by adenosine diphosphate is observed at doses of 4 nanograms/kg/min and above.Effects on platelets have been found to disappear within 2 hours of discontinuing the infusion, and haemodynamic changes due to epoprostenol to return to baseline within 10 minutes of termination of 60 minutes infusion at 1 to 16 nanograms/kg/min.Higher circulating doses of epoprostenol (20 nanograms/kg/min) disperse circulating platelet aggregates and increase by up to two fold the cutaneous bleeding time.Epoprostenol potentiates the anticoagulant activity of heparin by approximately 50%, possibly reducing the release of heparin neutralising factor.Six heparin-controlled studies and five emergency studies explored the place of epoprostenol in the general management of renal dialysis, using different techniques. Primary measurements of efficacy included intradialytic removal of BUN and creatinine, intradialytic removal of fluid (ultrafiltration), and clotting within the extracorporeal circuit.Major clotting (dialysis permanently suspended, or requiring changing of artificial kidney) occurred in approximately 9% (n=56) of all epoprostenol dialyses and in <1% (n=1) of heparin dialyses in major controlled studies and emergency studies. Most epoprostenol dialyses (67%) that required replacement of artificial kidney were completed subsequently with epoprostenol without clotting. However, 9 of 27 epoprostenol dialyses were unsuccessful following multiple attempts.Independent of technical difficulties which occurred rarely with either treatment, major dialysis-limiting clotting did not occur in 93% of all epoprostenol dialyses and 99% of all heparin dialyses.Minor clotting (sufficient to require intervention, but not permanently suspending dialysis or requiring changing of the artificial kidney) was reported more frequently during epoprostenol than during heparin dialyses. None of the dialyses using heparin and 5% (n=32) of dialyses using epoprostenol had minor clotting. Visible clotting (not necessitating intervention) was reported in another 31% of epoprostenol dialyses and 5% of heparin dialyses. To establish that renal dialysis patients at increased risk of haemorrhage bleed less frequently with epoprostenol than heparin, 2 major prospectively controlled studies were conducted. Each patient was randomly assigned to a sequence of heparin or epoprostenol dialyses and received up to 6 dialyses per entry in one study and up to 3 dialyses per entry in another study.Bleeding risk was defined as: • Very high risk presence of active bleeding at the time of dialysis initiation • High risk having had within 3 days prior to dialysis an active bleed that stopped at the pre-dialysis phase; or having incurred surgical or traumatic wounds within 3 days prior to dialysisTwelve patients at very high risk of haemorrhage received 35 epoprostenol dialyses and 11 patients received 28 heparin dialyses in major controlled studies. Sixteen patients received 24 epoprostenol dialyses in emergency studies.In major controlled studies, when all dialyses were combined for each treatment (heparin or epoprostenol), more heparin patients bled during the day prior to dialysis (N=13/17 vs. 8/23), dialysis day (N=25/28 vs. 16/35) and the day following dialysis (N=16/24 vs. 5/24) than epoprostenol patients during the same time periods.Those patients who continued to bleed were evaluated for changes in bleeding severity. Severity of bleeding in those patients was improved more frequently with epoprostenol the day prior to dialysis and on dialysis day (predialysis: N=4/8; dialysis: N=6/16) than with heparin (predialysis: N=4/13; dialysis: N=4/25). However, the reverse was observed for postdialysis days with epoprostenol (N=1/5) compared to heparin (N=8/16). Bleeding severity worsened during only 1 dialysis day with epoprostenol (N=1/16) whereas severity worsened during 5 dialysis days (N=5/25) and 2 predialysis days (N=2/13) with heparin. Patients who did not have clear evidence of bleeding just prior to their first study dialysis, but who bled within 3 days prior were classified as high risk of haemorrhage. Nineteen patients received 51 heparin dialyses and 19 received 44 epoprostenol dialyses in major controlled studies.When all dialyses were combined, slightly more epoprostenol patients appeared to bleed during the predialysis (N=12/25 vs. 8/32), dialysis (23/44 vs. 14/51) and postdialysis (8/34 vs. 5/44) days compared to heparin patients during the same periods.
Powder for solution for infusion:MannitolGlycineSodium ChlorideSodium Hydroxide (for pH adjustment)
Solvent for parenteral use:GlycineSodium ChlorideSodium Hydroxide (for pH adjustment)Water for Injection
|Powder and Solvent for solution for infusion:||3 years.|
In use shelf life reconsititued/solvent solution for infusion:Reconstituted solutions must not be administered over more than 12 hours when they are used at room temperature (between 15°C and 25°C). They should be kept under 25°C and protected from light. Where the infusion pump allows the use of a cold pouch, the solution may be used over a 24 hour period, provided the cold pouch is changed as necessary throughout the day.It is possible to refrigerate Flolan reconstituted solutions, before they are used at room temperature, ranging between 2°C and 8°C and without exceeding 40 hour storage. In this case, the solutions should not be used over more than 8 hours when administered at room temperature.
Powder for solution for infusion:Do not store vials above 25°C. Protect from light. Keep dry. Do not freeze. Store in the original package.
Solvent for parenteral use:Store the solvent below 25°C. Do not freeze. Protect from light. Store in the original package.The solvent contains no preservative; consequently a vial should be used once only and then discarded.Reconstitution and dilution should be carried out immediately prior to use (see section 4.2, section 6.3 and Section 6.6).Freshly prepared epoprostenol solutions for the treatment of pulmonary arterial hypertension should be used within 12 hours at 25°C, or stored for up to 40 hours at between 2 to 8°C and then used within 8 hours at 25°C. The maximum storage and in-use time when maintained between 2 and 8°C must not exceed 48 hours. Where the infusion pump allows the use of a cold pouch, the solution in the infusion pump must be used within a 24 hour period, provided that the cold pouch is changed as necessary throughout the day.
Powder for solution for infusion:Clear (type 1) glass vials with synthetic butyl rubber stoppers and an aluminium collar with a snap-off top.
Solvent for parenteral use:Clear (type 1) glass vials with synthetic butyl rubber stoppers and an external aluminium collar with a plastic flip-top cover.Pack sizes:Pulmonary Arterial HypertensionThere are four packs available for use in the treatment of pulmonary arterial hypertension, as follows:• One 0.5 mg powder vial and one or two solvent vials and a filter unit.• One 1.5 mg powder vial and one or two solvent vials and a filter unit.• One 0.5 mg powder vial.• One 1.5 mg powder vial.Renal DialysisOnly the 0.5 mg pack is suitable for use in renal dialysis.Not all pack sizes may be marketed.
Renal DialysisThe pack suitable for use in renal dialysis contains 0.5 mg freeze-dried Flolan plus 50 mL solvent.
Reconstitution:1. Use only the solvent provided for reconstitution.2. Withdraw approximately 10 mL of the solvent into a sterile syringe, inject it into the vial containing 0.5 mg freeze-dried Flolan powder 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 solvent and mix thoroughly.This solution is now referred to as the concentrated solution and contains 10,000 nanograms/mL Flolan. Only this concentrated solution is suitable for further dilution prior to use.When 0.5 mg Flolan powder for i.v. infusion is reconstituted with 50 mL of solvent, the final injection has a pH of approximately 10.5 and a sodium ion content of approximately 56 mg.
Dilution:The concentrated solution is normally further diluted before use. It may be diluted with sodium chloride 0.9% w/v solution, provided a ratio of 6 volumes of sodium chloride 0.9% w/v solution to 1 volume of concentrated solution is not exceeded e.g. 50 mL of concentrated solution further diluted with a maximum of 300 mL sodium chloride 0.9% w/v solution.Other common i.v. fluids are unsatisfactory for the dilution of concentrated solution as the required pH is not attained. Flolan solutions are less stable at low pH.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 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/h) = Infusion rate (mL/min) x 60Infusion rate formulae - examplesWhen used in renal dialysis Flolan may be administered as the concentrated solution (a) or in diluted form (b).a. Using concentrated solution, i.e. 10,000 nanograms/mL Flolan:
|Dosage (nanograms/ kg/min)||Bodyweight (kg)|
|Flow rates in mL/h|
|Dosage (nanograms/ kg/min)||Bodyweight (kg)|
|Flow rates in mL/h|
Pulmonary Arterial HypertensionThere are four packs available for use in the treatment of pulmonary arterial hypertension, as follows:• One vial containing sterile, freeze-dried Flolan equivalent to 0.5 mg Flolan, supplied with one or two 50 mL vials of solvent and a filter unit.• One vial containing sterile, freeze-dried Flolan equivalent to 1.5 mg Flolan, supplied with one or two 50 mL vials of solvent and a filter unit.• One vial containing sterile, freeze-dried Flolan equivalent to 0.5 mg Flolan supplied alone.• One vial containing sterile, freeze-dried Flolan equivalent to 1.5 mg Flolan supplied alone.Initially a pack containing solvent for parenteral use must be used. During chronic Flolan 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 Flolan.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 Flolan is reconstituted with 50 mL solvent the resultant concentration is 30,000 nanograms/mL.
Dilution:Flolan may be used either as concentrated solution or in a diluted form for the treatment of pulmonary arterial hypertension. Only the solvent provided may be used for the further dilution of reconstituted Flolan. Sodium chloride 0.9% w/v solution must not be used when Flolan is to be used for the treatment of pulmonary arterial hypertension. Flolan must not be administered with other parenteral solutions or medications when used for pulmonary arterial 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 solvent 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.Concentrations commonly used in the treatment pulmonary arterial hypertension are as follows:• 5,000 nanograms/mL - One vial containing 0.5 mg Flolan reconstituted and diluted to a total volume of 100 mL in solvent.• 10,000 nanograms/mL - Two vials containing 0.5 mg Flolan reconstituted and diluted to a total volume of 100 mL in solvent.• 15,000 nanograms/mL - 1.5 mg Flolan reconstituted and diluted to a total volume of 100mL in solvent.
Calculation of infusion rate:The infusion rate may be calculated from the formula given above for renal dialysis. Examples for some concentrations commonly used in pulmonary arterial hypertension are shown below.Infusion rates for a concentration of 5,000 nanograms/mL
|Example For Dosing Using a Concentration of 5,000 nanograms/mL|
|Dosage (nanograms/kg/ min)||Bodyweight (kg)|
|Flow rates in mL/h|
|Example For Dosing Using a Concentration of 15,000 nanograms/mL|
|Dosage (nanograms/kg/ min)||Bodyweight (kg)|
|Flow rates in mL/h|
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