Epoprostenol sodium is available as a lyophilized powder in vials containing 0.5 mg (500,000 ng) and 1.5 mg (1,500,000 ng) of epoprostenol.2879; 2880; 2881 Several different formulations of epoprostenol sodium products are available; instructions for reconstitution and administration may differ, and epoprostenol stability may vary depending on formulation-specific factors.2879; 2880; 2881
Epoprostenol sodium (Flolan, Glaxo; generic, Teva) vials also contain glycine 3.76 mg, sodium chloride 2.93 mg, and mannitol 50 mg.2879; 2881 Sodium hydroxide may have been added during manufacturing to adjust the pH.2879; 2881 These epoprostenol sodium vials must be reconstituted and further diluted using only a special diluent that is recommended by the manufacturer.2879; 2881 Flolan must be reconstituted only with one of 2 special diluents, which are labeled as either “sterile diluent for Flolan” (in a 50-mL glass vial) or “pH 12 sterile diluent for Flolan” (in a 50-mL plastic vial).2879 The choice of which of these 2 special diluents is used in the reconstitution and dilution of Flolan affects the drug's stability.2879 (See Stability.) Epoprostenol sodium (Teva) must be reconstituted only with the sterile diluent that is labeled as “sterile diluent for epoprostenol sodium for injection” (in a 50-mL glass vial).2881 Regardless of the formulation, these vials of special diluent contain glycine 94 mg, sodium chloride 73.3 mg, and sodium hydroxide to adjust the pH in water for injection.2879; 2881
Epoprostenol sodium (Veletri, Actelion) has a differing formulation.2880 In addition to epoprostenol sodium, vials of Veletri contain sucrose 100 mg, arginine 50 mg, and sodium hydroxide to adjust the pH.2880 Vials of this formulation may be reconstituted with either sterile water for injection or sodium chloride 0.9% and further diluted with the same diluent used for reconstitution.2880
Each 0.5-mg (500,000-ng) or 1.5-mg (1,500,000-ng) vial of any formulation of epoprostenol sodium should be reconstituted with 5 mL of an appropriate diluent.2879; 2880; 2881 The reconstituted solutions must be diluted prior to administration to provide a final concentration that is compatible with the maximum and minimum flow rates of the infusion pump, the reservoir capacity, and other infusion pump-specific criteria as stated by the manufacturers.2879; 2880; 2881 In general, a 3000- to 10,000-ng/mL concentration of epoprostenol is sufficient to accommodate infusion rates of 2 to 16 ng/kg/min in adults, although higher concentrations may be required for some patients.2879; 2880; 2881
The manufacturers’ instructions for preparing various concentrations of epoprostenol from the reconstituted solution using the identical diluent that was used for reconstitution are as follows:2879; 2880; 2881
For 3000 ng/mL, withdraw 3 mL from one 0.5-mg (500,000-ng) vial and add a sufficient amount of diluent to make a total of 100 mL.
For 5000 ng/mL, withdraw the entire contents of one 0.5-mg (500,000-ng) vial and add a sufficient amount of diluent to make a total of 100 mL.
For 10,000 ng/mL, withdraw the entire contents of two 0.5-mg (500,000-ng) vials and add a sufficient amount of diluent to make a total of 100 mL.
For 15,000 ng/mL, withdraw the entire contents of one 1.5-mg (1,500,000-ng) vial and add a sufficient amount of diluent to make a total of 100 mL.
For 30,000 ng/mL, withdraw the entire contents of two 1.5-mg (1,500,000-ng) vials and add a sufficient amount of diluent to make a total of 100 mL.2880
The manufacturers state that higher concentrations of the drug may be prepared for those receiving long-term therapy.2879; 2880; 2881
pH
Sterile diluent for Flolan has a pH ranging from 10.2 to 10.8; pH 12 sterile diluent for Flolan has a pH ranging from 11.7 to 12.3.2879
Reconstituted solutions of epoprostenol (Teva) prepared with the provided sterile diluent for epoprostenol sodium for injection have a pH ranging from 11 to 11.8.2881
Reconstituted solutions of Veletri have a pH ranging from 11 to 13.2880
Trade Name(s)
Flolan, Veletri
Following reconstitution and dilution to the selected final concentration, epoprostenol solution is administered by continuous intravenous infusion through a central venous catheter using an ambulatory infusion pump.2879; 2880; 2881 The drug may be given temporarily by peripheral infusion until a central line can be established.2879; 2880; 2881 The pump reservoirs used should be made of polyvinyl chloride (PVC), polypropylene, or glass.2879; 2880; 2881
Epoprostenol solutions prepared with sterile diluent for Flolan or sterile diluent for epoprostenol sodium for injection must be used with a cold pouch if not administered within 8 hours of reconstitution or removal from refrigeration.2879; 2881 (See Stability.)
Epoprostenol Sodium (Flolan, Glaxo)
Intact vials of the Flolan formulation of epoprostenol sodium should be stored at 15 to 25°C in the carton to protect from light.2879 Intact vials of sterile diluent for Flolan and pH 12 sterile diluent for Flolan also should be stored at 15 to 25°C and should not be frozen.2879 Flolan must be reconstituted and diluted only with one of these 2 diluents; the reconstituted epoprostenol solutions should not be diluted or administered with other parenteral solutions or medications.2879 If not used immediately following preparation, these solutions of epoprostenol should be refrigerated at 2 to 8°C and protected from light.2879 The solutions should not be frozen; any solution that has been frozen should be discarded.2879 Solutions should be visually inspected for particulate matter and discoloration and should not be used if either is noted.2879 Vials are for single dose only; any unused solution or diluent should be discarded.2879
Epoprostenol solutions prepared with sterile diluent for Flolan are stable for up to 8 hours when used at 15 to 25°C following reconstitution.2879 These solutions may be stored for up to 40 hours at 2 to 8°C prior to use and are stable for up to 8 hours when used at 15 to 25°C following removal from refrigeration; solutions should be discarded after more than 40 hours of refrigerated storage.2879 Solutions prepared with sterile diluent for Flolan must be used with a cold pouch if not administered within 8 hours.2879 These solutions may be stored for up to 24 hours at 2 to 8°C prior to use and are stable for up to 24 hours when used with a cold pouch that is changed every 12 hours.2879 Solutions may be stored at 2 to 8°C prior to use as long as the total combined time of refrigerated storage and infusion does not exceed 48 hours; solutions should be discarded after more than 48 hours of refrigerated storage.2879
Epoprostenol solutions prepared with pH 12 sterile diluent for Flolan may be administered for up to 72 hours at up to 25°C, 48 hours at up to 30°C, 24 hours at up to 35°C, or 12 hours at up to 40°C, either immediately following preparation or following refrigerated storage at 2 to 8°C for up to 8 days; these solutions do not require the use of a cold pouch during administration.2879 Solutions prepared with pH 12 sterile diluent for Flolan should be discarded after 8 days of refrigerated storage.2879
Epoprostenol Sodium (Teva)
Intact vials of this formulation of epoprostenol sodium should be stored at 20 to 25°C in the carton to protect from light.2881 Intact vials of sterile diluent for epoprostenol sodium for injection also should be stored at 20 to 25°C and should not be frozen.2881 This epoprostenol sodium formulation must be reconstituted and diluted only with sterile diluent for epoprostenol sodium for injection; the reconstituted epoprostenol solutions should not be diluted or administered with other parenteral medications or solutions.2881 If not used immediately following preparation, these solutions of epoprostenol should be refrigerated at 2 to 8°C and protected from light.2881 The solutions should not be frozen; any solution that has been frozen should be discarded.2881 Solutions should be visually inspected for particulate matter and discoloration and should not be used if either is noted.2881 Vials are for single dose only; any unused solution or diluent should be discarded.2881
Epoprostenol solutions prepared with sterile diluent for epoprostenol sodium for injection are stable for up to 8 hours when used at 15 to 25°C following reconstitution.2881 These solutions may be stored for up to 40 hours at 2 to 8°C prior to use and are stable for up to 8 hours when used at 15 to 25°C following removal from refrigeration; solutions should be discarded after more than 40 hours of refrigerated storage.2881 Solutions prepared with sterile diluent for epoprostenol sodium for injection must be used with a cold pouch if not administered within 8 hours.2881 These solutions may be stored for up to 24 hours at 2 to 8°C prior to use and are stable for up to 24 hours when used with a cold pouch that is changed every 12 hours.2881 Solutions may be stored at 2 to 8°C prior to use as long as the total combined time of refrigerated storage and infusion does not exceed 48 hours; solutions should be discarded after more than 48 hours of refrigerated storage.2881
Epoprostenol Sodium (Veletri, Actelion)
Intact vials of the Veletri formulation of epoprostenol sodium should be stored at 20 to 25°C in the carton and protected from direct sunlight.2880 The manufacturer states that this formulation of epoprostenol sodium is stable only when reconstituted and diluted as directed with sterile water for injection or sodium chloride 0.9%; the drug should not be mixed with any other drugs or solutions prior to or during administration.2880 Solutions should be visually inspected for particulate matter and discoloration and should not be used if either is noted.2880 Vials are for single use only; any unused solution should be discarded.2880
For administration at 25°C, reconstituted and diluted epoprostenol solutions of 3000 to less than 15,000 ng/mL (prepared as directed using 0.5-mg [500,000-ng] vials) may be administered for a maximum duration of 48 hours beginning immediately after reconstitution and dilution or a maximum duration of 24 hours after storage under refrigeration at 2 to 8°C for up to 8 days.2880 Solutions of 15,000 to less than 60,000 ng/mL (prepared as directed using 1.5-mg [1,500,000-ng] vials) may be administered at 25°C for a maximum duration of 48 hours beginning either immediately after reconstitution and dilution or after storage under refrigeration at 2 to 8°C for up to 8 days.2880 Solutions of 60,000 ng/mL or more (prepared using 1.5-mg [1,500,000-ng] vials) may be administered at 25°C for a maximum duration of 72 hours beginning immediately after reconstitution and dilution or a maximum duration of 48 hours after storage under refrigeration at 2 to 8°C for up to 8 days.2880 Short excursions at 40°C are permitted for up to 2, 4, or 8 hours for solutions of less than 15,000 ng/mL, 15,000 to 60,000 ng/mL, or greater than 60,000 ng/mL, respectively.2880
Epoprostenol solutions of 60,000 ng/mL or more (prepared using 1.5-mg [1,500,000-ng] vials) may be administered at temperatures greater than 25°C up to 30°C for a maximum duration of 48 hours, either beginning immediately after reconstitution and dilution or after refrigeration at 2 to 8°C for up to 8 days.2880 Such solutions also may be administered at temperatures up to 40°C for a maximum duration of 24 hours immediately after reconstitution and dilution.2880 For solutions with a concentration less than 60,000 ng/mL, the pump reservoir should be changed every 24 hours.2880
pH Effects
Epoprostenol is best stabilized in basic solutions,2882 and the reconstituted solution becomes increasingly unstable at pH values below the respective normal ranges of each formulation.2880; 2881 Veletri uses arginine as a buffer, which provides a higher pH than that provided by the glycine buffer in other epoprostenol sodium products (Glaxo, Teva) and likely contributes to the relative improvement in stability.2879; 2880; 2881; 2882 Flolan prepared with the provided pH 12 sterile diluent for Flolan results in a reconstituted solution with a higher pH than if prepared with the alternative provided sterile diluent for Flolan and demonstrates increased stability as a result.2879
Light Effects
Epoprostenol sodium (Flolan, Glaxo; generic, Teva) as unopened vials and reconstituted solutions should be protected from light during storage.2879; 2881 The manufacturer of Veletri notes that this formulation of epoprostenol sodium should not be exposed to direct sunlight either in the unopened vial during storage or in solution.2880
Filtration
A 60-inch microbore non-diethylhexyl phthalate (non-DEHP) extension set with proximal antisyphon valve, low priming volume (0.9 mL), and inline 0.22-µm filter was used during trials with epoprostenol2880; 2881 and is recommended for Flolan administration.2879 Infusion sets with an inline 0.22-µm filter should be used for the administration of Veletri.2880
For a list of references cited in the text of this monograph, search the monograph titled References.