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Flolan (Epoprostenol Sodium) - Indications and Dosage

 
 



INDICATIONS AND USAGE

FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy (see CLINICAL TRIALS IN PULMONARY HYPERTENSION).

DOSAGE AND ADMINISTRATION

Important Note

FLOLAN must be reconstituted only with STERILE DILUENT for FLOLAN. Reconstituted solutions of FLOLAN must not be diluted or administered with other parenteral solutions or medications (see WARNINGS).

Dosage

Continuous chronic infusion of FLOLAN should be administered through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Chronic infusion of FLOLAN 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 and further increases in the infusion rate are not clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then the infusion rate should be decreased to an appropriate chronic infusion rate whereby the pharmacologic effects of FLOLAN 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, a lower dose that is tolerated by the patient should be identified.

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.

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 FLOLAN. 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 FLOLAN or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of FLOLAN should be adjusted only under the direction of a physician.

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

Administration

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

The ambulatory infusion pump used to administer FLOLAN 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. 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.

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 between 2° and 8°C for 12 hours.

Reconstitution

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

A concentration for the solution of FLOLAN 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. FLOLAN, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL. FLOLAN should be prepared using 2 vials of STERILE DILUENT for FLOLAN for use during a 24-hour period. Table 8 gives directions for preparing several different concentrations of FLOLAN.

Table 8. 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 9 through 12 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 to be used. These tables may be used to select the most appropriate concentration of FLOLAN 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.

Table 9. Infusion Rates for FLOLAN at a Concentration of 3,000 ng/mL

Patient

Dose or Drug Delivery Rate (ng/kg/min)

Weight (kg)

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 10. Infusion Rates for FLOLAN at a Concentration of 5,000 ng/mL

Patient

Dose or Drug Delivery Rate (ng/kg/min)

Weight (kg)

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 11. Infusion Rates for FLOLAN at a Concentration of 10,000 ng/mL

Patient

Dose or Drug Delivery Rate (ng/kg/min)

Weight (kg)

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 12. Infusion Rates for FLOLAN at a Concentration of 15,000 ng/mL

Patient

Dose or Drug Delivery Rate (ng/kg/min)

Weight (kg)

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 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 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 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. 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 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, reconstituted FLOLAN must be insulated from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and must not be exposed 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 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. 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 may be used for no longer than 24 hours. The gel packs should be changed 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, FLOLAN should not be administered.

HOW SUPPLIED

FLOLAN 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 at 15° to 25°C (59° to 77°F). Protect from light.

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

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

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

GlaxoSmithKline

Research Triangle Park, NC 27709

© 2002, GlaxoSmithKline. All rights reserved.

September 2002 RL-1139

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