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Drug Information for EPOPROSTENOL (GeneraMedix Inc ): DOSAGE AND ADMINISTRATION
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Important Note: Epoprostenol for Injection must be reconstituted only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Reconstituted solutions of Epoprostenol for Injection must not be diluted or administered with other parenteral solutions or medications (see WARNINGS AND PRECAUTIONS: General (5.1 ).
Continuous chronic infusion of epoprostenol should be prepared as directed [see Reconstitution(2.4)], and administered through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Chronic infusion of epoprostenol should be initiated at 2 ng/kg/min and increased 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 (2.2).]. If dose-limiting pharmacologic effects occur, then the infusion rate should be decreased to the point that the pharmacologic effects of epoprostenol are 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, use a lower dose.
In the controlled 12-week trial in PH/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.
2.2 Dosage Adjustments
Changes in the chronic infusion rate should be based 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. In general, increases in dose from the initial chronic dose should be expected.
Increments in dose should be considered if symptoms of pulmonary hypertension persist or recur after improving. The infusion should be increased 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, the patient should be observed, and standing and supine blood pressure and heart rate monitored 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. Dosage decreases should be made gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of epoprostenol or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of epoprostenol should be adjusted only under the direction of a physician.
In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.
Epoprostenol, once prepared as directed [see Reconstitution (2.4)], is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, epoprostenol may be administered peripherally.
The ambulatory infusion pump used to administer epoprostenol 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. 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 potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. A multi-lumen catheter should be considered if other intravenous therapies are routinely administered.
Epoprostenol for Injection is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Epoprostenol must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
Prior to use, epoprostenol solutions reconstituted with 5 mL diluent must be protected from light and can be refrigerated at 2° to 8°C (36° to 46°F) for as long as 5 days or held at up to 25°C (77 oF) for up to 48 hours prior to use. Do not freeze reconstituted solutions of Epoprostenol for Injection. Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 5 days, or if held at room temperature for more than 48 hours.
During use, a single reservoir of diluted solution of Epoprostenol for Injection prepared as directed can be administered at room temperature for up to 24 hours. (If lower concentrations are chosen, pump reservoirs should be changed every 12 hours when administered at room temperature.) Do not expose this solution to direct sunlight.
A concentration for the solution of epoprostenol should be selected 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. Epoprostenol, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 1 are directions for preparing different concentrations of epoprostenol for up to a 24-hour period.
Table 1: Reconstitution and Dilution Instructions To make 100 mL of solution with Final Concentration (ng/mL) of: Directions:
* Higher concentrations may be required for patients who receive epoprostenol long-term.
15,000 ng/mL* Dissolve contents of one 1.5 mg vial with5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume ofthe identical diluent to make a total of 100 mL. 30,000 ng/mL* Dissolve contents of two 1.5 mg vials each with5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL.
Infusion rates may be calculated using the following formula:
Infusion Rate (mL/hr) = [Dose (ng/kg/min) x Weight (kg) x 60 min/hr]
Final Concentration (ng/mL)
Tables 2 and 3 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 to be used. These tables may be used to select the most appropriate concentration of epoprostenol 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. For infusion/dose rates lower than those listed in Tables 2 and 3, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half life of epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of epoprostenol. If concentrations lower than 15,000 ng/mL are prepared, the pump reservoirs should be changed every 12 hours when administered at room temperature.
Table 2: Infusion Rates for Epoprostenol at a Concentration of 15,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight(kg) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 20 – – – – 1.0 1.1 1.3 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 Table 3: Infusion Rates for Epoprostenol at a Concentration of 30,000 ng/mL Dose or Drug Delivery Rate (ng/kg/min) Patient weight (kg) 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 30 – – – – – 1.0 40 – – – 1.0 1.1 1.3 50 – – 1.0 1.2 1.4 1.6 60 – 1.0 1.2 1.4 1.7 1.9 70 – 1.1 1.4 1.7 2.0 2.2 80 1.0 1.3 1.6 1.9 2.2 2.6 90 1.1 1.4 1.8 2.2 2.5 2.9 100 1.2 1.6 2.0 2.4 2.8 3.2
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