Epoprostenol Sodium

Epoprostenol Sodium Manufacturers

• Teva Parenteral Medicines, Inc.
  

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  Epoprostenol Sodium | Teva Parenteral Medicines, Inc.

  

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  Important Note: Epoprostenol sodium for injection must be reconstituted only with STERILE DILUENT for epoprostenol sodium for injection. Do not dilute reconstituted solutions of epoprostenol for injection or administer with other parenteral solutions or medications (see WARNINGS).

  Dosage

  Administer continuous chronic infusion of epoprostenol sodium for injection through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of epoprostenol sodium for injection at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then decrease the infusion rate until epoprostenol sodium for injection is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, identify a lower dose that is tolerated by the patient.

  In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

  Dosage Adjustments

  Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of epoprostenol sodium for injection. In general, expect increases in dose from the initial chronic dose.

  Consider increments in dose if symptoms of PAH persist or recur. Increase the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

  During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of epoprostenol sodium for injection or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of epoprostenol sodium for injection only under the direction of a physician.

  In patients receiving lung transplants, doses of epoprostenol sodium for injection were tapered after the initiation of cardiopulmonary bypass.

  Administration

  Epoprostenol sodium for injection is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, epoprostenol sodium for injection may be administered peripherally.

  The ambulatory infusion pump used to administer epoprostenol sodium for injection should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver epoprostenol sodium for injection. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

  To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

  To facilitate extended use at ambient temperatures exceeding 20° to 25°C (68° to 77°F), a cold pouch with frozen gel packs was used in clinical trials (see DOSAGE AND ADMINISTRATION: Storage and Stability). The cold pouches and gel packs used in clinical trials were obtained from Palco Labs, Palo Alto, California. Any cold pouch used must be capable of maintaining the temperature of reconstituted epoprostenol sodium for injection between 2° and 8°C for 12 hours.

  Reconstitution

  Epoprostenol sodium for injection is stable only when reconstituted with STERILE DILUENT for epoprostenol sodium for injection. Epoprostenol sodium for injection must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

   Select a concentration for the solution of epoprostenol sodium for injection that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. When administered chronically, prepare epoprostenol sodium for injection in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of STERILE DILUENT for epoprostenol sodium for injection for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of epoprostenol sodium for injection.

  Table 6. Reconstitution and Dilution Instructions * Higher concentrations may be required for patients who receive epoprostenol sodium for injection long-term. To make 100 mL of
  solution
  with Final Concentration
  (ng/mL) of: Directions: 3,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw 3 mL and add to sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL. 5,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw entire vial contents and add sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL. 10,000 ng/mL Dissolve contents of two 0.5-mg vials each with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw entire vial contents and add sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL. 15,000 ng/mL* Dissolve contents of one 1.5-mg vial with 5 mL of STERILE DILUENT for epoprostenol sodium for injection. Withdraw entire vial contents and add sufficient STERILE DILUENT for epoprostenol sodium for injection to make a total of 100 mL.

  Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Infusion rates may be calculated using the following formula:

  Infusion Rate (mL/hr) = [Dose (ng/kg/min) × Weight (kg) × 60 min/hr] Final Concentration (ng/mL)

  Tables 7 through 10 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of epoprostenol sodium for injection to be used. These tables may be used to select the most appropriate concentration of epoprostenol sodium for injection that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of epoprostenol sodium for injection.

  Table 7. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 3,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 2 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 10 ---- ---- 1.2 1.6 2.0 2.4 2.8 3.2 20 ---- 1.6 2.4 3.2 4.0 4.8 5.6 6.4 30 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6 40 1.6 3.2 4.8 6.4 8.0 9.6 11.2 12.8 50 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 60 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2 70 2.8 5.6 8.4 11.2 14.0 16.8 19.6 22.4 80 3.2 6.4 9.6 12.8 16.0 19.2 22.4 25.6 90 3.6 7.2 10.8 14.4 18.0 21.6 25.2 28.8 100 4.0 8.0 12.0 16.0 20.0 24.0 28.0 32.0 Table 8. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 5,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 2 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 10 ---- ---- ---- 1.0 1.2 1.4 1.7 1.9 20 ---- 1.0 1.4 1.9 2.4 2.9 3.4 3.8 30 ---- 1.4 2.2 2.9 3.6 4.3 5.0 5.8 40 1.0 1.9 2.9 3.8 4.8 5.8 6.7 7.7 50 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6 60 1.4 2.9 4.3 5.8 7.2 8.6 10.1 11.5 70 1.7 3.4 5.0 6.7 8.4 10.1 11.8 13.4 80 1.9 3.8 5.8 7.7 9.6 11.5 13.4 15.4 90 2.2 4.3 6.5 8.6 10.8 13.0 15.1 17.3 100 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2 Table 9. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 10,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 20 ---- ---- 1.0 1.2 1.4 1.7 1.9 30 ---- 1.1 1.4 1.8 2.2 2.5 2.9 40 1.0 1.4 1.9 2.4 2.9 3.4 3.8 50 1.2 1.8 2.4 3.0 3.6 4.2 4.8 60 1.4 2.2 2.9 3.6 4.3 5.0 5.8 70 1.7 2.5 3.4 4.2 5.0 5.9 6.7 80 1.9 2.9 3.8 4.8 5.8 6.7 7.7 90 2.2 3.2 4.3 5.4 6.5 7.6 8.6 100 2.4 3.6 4.8 6.0 7.2 8.4 9.6 Table 10. Infusion Rates for Epoprostenol Sodium for Injection at a Concentration of 15,000 ng/mL Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/h) 30 ---- ---- 1.0 1.2 1.4 1.7 1.9 40 ---- 1.0 1.3 1.6 1.9 2.2 2.6 50 ---- 1.2 1.6 2.0 2.4 2.8 3.2 60 1.0 1.4 1.9 2.4 2.9 3.4 3.8 70 1.1 1.7 2.2 2.8 3.4 3.9 4.5 80 1.3 1.9 2.6 3.2 3.8 4.5 5.1 90 1.4 2.2 2.9 3.6 4.3 5.0 5.8 100 1.6 2.4 3.2 4.0 4.8 5.6 6.4 Storage and Stability

  Unopened vials of epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] and protected from light in the carton. Unopened vials of STERILE DILUENT for epoprostenol sodium for injection are stable until the date indicated on the package when stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

  Prior to use, reconstituted solutions of epoprostenol sodium for injection must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately. Do not freeze reconstituted solutions of epoprostenol sodium for injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 48 hours.

  During use, a single reservoir of reconstituted solution of epoprostenol sodium for injection can be administered at room temperature for a total duration of 8 hours, or it can be used with a cold pouch and administered up to 24 hours with the use of 2 frozen 6 oz gel packs in a cold pouch. When stored or in use, insulate reconstituted epoprostenol sodium for injection from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.

  Use at Room Temperature

  Prior to use at room temperature, 15° to 25°C (59° to 77°F), reconstituted solutions of epoprostenol sodium for injection may be stored refrigerated at 2° to 8°C (36° to 46°F) for no longer than 40 hours. When administered at room temperature, reconstituted solutions may be used for no longer than 8 hours. This 48-hour period allows the patient to reconstitute a 2-day supply (200 mL) of epoprostenol sodium for injection. Each 100 mL daily supply may be divided into 3 equal portions. Two of the portions are stored refrigerated at 2° to 8°C (36° to 46°F) until they are used.

  Use with a Cold Pouch

  Prior to infusion with the use of a cold pouch, solutions may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours. When a cold pouch is employed during the infusion, reconstituted solutions of epoprostenol sodium for injection may be used for no longer than 24 hours. Change gel packs every 12 hours. Reconstituted solutions may be kept at 2° to 8°C (36° to 46°F), either in refrigerated storage or in a cold pouch or a combination of the two, for no more than 48 hours.

  Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.

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