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Flolan

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Flolan

Flolan

INDICATIONS

FLOLAN (epoprostenol sodium) is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

DOSAGE AND ADMINISTRATION

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

Dosage

Administer continuous chronic infusion of FLOLAN (epoprostenol sodium) through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) . 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 FLOLAN (epoprostenol sodium) or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of FLOLAN (epoprostenol sodium) only under the direction of a physician.

In patients receiving lung transplants, doses of FLOLAN (epoprostenol sodium) were tapered after the initiation of cardiopulmonary bypass.

Administration

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

The ambulatory infusion pump used to administer FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) . 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 25°C (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 FLOLAN (epoprostenol sodium) between 2° and 8°C for 12 hours.

Reconstitution

FLOLAN (epoprostenol sodium) is stable only when reconstituted with STERILE DILUENT for FLOLAN (epoprostenol sodium) . FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of FLOLAN (epoprostenol sodium) .

Table 6: Reconstitution and Dilution Instructions

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 FLOLAN. Withdraw 3 mL and add to sufficient STERILE DILUENT for FLOLAN 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 FLOLAN. Withdraw entire vial contents and add sufficient STERILE DILUENT for FLOLAN 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 FLOLAN. Withdraw entire vial contents and add sufficient STERILE DILUENT for FLOLAN 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 FLOLAN. Withdraw entire vial contents and add sufficient STERILE DILUENT for FLOLAN to make a total of 100 mL.
* Higher concentrations may be required for patients who receive FLOLAN long-term.

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) x Weight (kg) x 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 FLOLAN (epoprostenol sodium) to be used. These tables may be used to select the most appropriate concentration of FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) .

Table 7: Infusion Rates for FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) are stable until the date indicated on the package when stored at 15° to 25°C (59° to 77°F) and protected from light in the carton. Unopened vials of STERILE DILUENT for FLOLAN (epoprostenol sodium) are stable until the date indicated on the package when stored at 15° to 25°C (59° to 77°F).

Prior to use, reconstituted solutions of FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) . 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) 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 FLOLAN (epoprostenol sodium) . 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 FLOLAN (epoprostenol sodium) 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.

HOW SUPPLIED

FLOLAN (epoprostenol sodium) for Injection is supplied as a sterile freeze-dried powder in 17-mL flint glass vials with gray butyl rubber closures, individually packaged in a carton.

17-mL vial containing epoprostenol sodium equivalent to 0.5 mg (500,000 ng), carton of 1 (NDC 0173-0517-00).

17-mL vial containing epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng), carton of 1 (NDC 0173-0519-00).

Store the vials of FLOLAN (epoprostenol sodium) at 15° to 25°C (59° to 77°F). Protect from light.

The STERILE DILUENT for FLOLAN (epoprostenol sodium) is supplied in flint glass vials containing 50-mL diluent with fluororesin-faced butyl rubber closures.

50-mL of STERILE DILUENT for FLOLAN (epoprostenol sodium) , tray of 2 vials (NDC 0173-0518-01).

Store the vials of STERILE DILUENT for FLOLAN (epoprostenol sodium) at 15° to 25°C (59° to 77°F). DO NOT FREEZE.

GlaxoSmithKline, Research Triangle Park, NC 27709. March 2011

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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