A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Flolan Indications, Dosage, Storage, Stability - Epoprostenol sodium
Flolan Indications, Dosage, Storage, Stability - Epoprostenol sodium
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 2ng/kg per
minute 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, 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 per minute is not
tolerated, a lower dose which 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 2.2ng/kg per minute. During the
first seven days of treatment, the dose was increased daily to a mean dose of
4.1 mg/kg per minute on Day of treatment. The dose was increased daily to a
mean dose of 4.1 mg/kg per minute on Day 7 of treatment. At the end of week
12, the mean dose was 11.2 ng/kg per minute. The mean incremental increase was
2 to 3 ng/kg per minute 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-per-minute 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 – 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 remove without dosage adjustment. Dosage decreases should be made
gradually in 2-ng/kg-per-minute 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 cardipulmonary 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-per-minute
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" 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 andintravenous 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 note 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
which 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 8gives 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:
|
|
3000 ng/mL
|
Dissolve contents of one 0.5.mg vial with 5 mL of STERILE
DILUENT for FLOLAN. Withdraw 3mL And add to sufficient STERILE DILUENT
for FLOLAN to make a total of 100 mL.
|
|
5000 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, 3000 ng/mL and 10,000 ng/mL are satisfactory concentrations
to deliver between 2 to 16 ng/kg per minute 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/hrl
Final Concentration (ng/m)
Tables 9 through 12 provide infusion delivery rates for doses
up to 16 ng/kg per minute based upon patient weight, drug delivery rate, and
concentration of the solution of FOLAN 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 which 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 3000
ng/mL
|
Patient
|
Dose or Drug Delivery Rate (ng/kg per minute)
|
|
Weight(kg)
|
2
|
4
|
6
|
8
|
10
|
12
|
14
|
16
|
| |
Infusion Delivery Rate (mL/hr)
|
|
10
|
…
|
…
|
1.2
|
1.6
|
20
|
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 5000
ng/mL
|
Patient
|
Dose of Drug Delivery Rate (ng/kg per minute)
|
|
Weight(kg)
|
2
|
4
|
6
|
8
|
10
|
12
|
14
|
16
|
| |
Infusion Delivery Rate (mL/hr)
|
|
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.
|
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 per minute)
|
|
Weight(kg)
|
4
|
6
|
8
|
10
|
12
|
14
|
16
|
| |
Infusion Delivery Rate (mL/hr)
|
|
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 per minute)
|
|
Weight(kg)
|
4
|
6
|
8
|
10
|
12
|
14
|
16
|
| |
Infusion Delivery Rate (mL/hr)
|
|
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 two 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 2o to 8oC (36o to 46oF) 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 three equal portions. Two of the portions are stored refrigerated
at 2° to8°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 l (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 50-mL flint glass
vials with fluororesin-faced butyl rubber closures.
50-mL vial of STERILE DILUENT for FLOLAN, tray of 4 (NDC 0173-0518-00).
Store the vials of STERILE DUILENT for FLOLAN at 15° to 25°C
(59° to 77°F), DO NOT FREEZE.
US Patent Nos. 4,335,139; 4,539,33; and 4,883,812 (Use Patent)
Licensed Under US Patent No. 4,338,325
Glaxo Wellcome Inc., Reasearch Triangle Park,
NC 27709, ©Copyright 1996, 1999 Glaxo Wellcome Inc. All rights reserved.
Sterile Diluent for FLOLAN manufactured by Catalytica Pharmaceuticals, Inc.
Greenville, NC 27834 ForGlaxo Wellcome Inc. Research Triangle Park, NC 27709
October 1999 RL-xxx
top
