Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2168
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FLOLAN (Powder)
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| dailymed-instance:dosage |
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).<br/>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.<br/>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.<br/>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.<br/>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 deliveryreservoir 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. 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.<br/>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.<br/>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.<br/>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.
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| dailymed-instance:descripti... |
FLOLAN (epoprostenol sodium) for Injection is a sterile
sodium salt formulated for intravenous (IV) administration. Each vial of FLOLAN
contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng)
or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg
sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added
to adjust pH. Epoprostenol (PGI, PGX, prostacyclin),
a metabolite of arachidonic acid, is a naturally occurring prostaglandin with
potent vasodilatory activity and inhibitory activity of platelet aggregation. Epoprostenol
is (5Z,9��,11��,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic
acid. Epoprostenol sodium has a molecular weight of
374.45 and a molecular formula of CHNaO.
The structural formula is: FLOLAN is a white to off-white
powder that must be reconstituted with STERILE DILUENT for FLOLAN. STERILE
DILUENT for FLOLAN is supplied in glass vials containing 50 mL of 94 mg
glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH),
and Water for Injection, USP. The reconstituted solution
of FLOLAN has a pH of 10.2 to 10.8 and is increasingly unstable at a lower
pH.
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| dailymed-instance:clinicalP... |
General: Epoprostenol has 2 major pharmacological actions: (1) direct
vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition
of platelet aggregation. In animals, the vasodilatory effects reduce right-
and left-ventricular afterload and increase cardiac output and stroke volume.
The effect of epoprostenol on heart rate in animals varies with dose. At low
doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol
causes reflex tachycardia in response to direct vasodilation and hypotension.
No major effects on cardiac conduction have been observed. Additional pharmacologic
effects of epoprostenol in animals include bronchodilation, inhibition of
gastric acid secretion, and decreased gastric emptying.<br/>Pharmacokinetics: Epoprostenol is rapidly hydrolyzed at neutral pH in blood
and is also subject to enzymatic degradation. Animal studies using tritium-labeled
epoprostenol have indicated a high clearance (93 mL/kg/min), small volume
of distribution (357 mL/kg), and a short half-life (2.7 minutes).
During infusions in animals, steady-state plasma concentrations of tritium-labeled
epoprostenol were reached within 15 minutes and were proportional to
infusion rates. No available chemical assay is sufficiently
sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol.
The in vitro half-life of epoprostenol in human blood at 37��C and pH
7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol
in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic
half-life of epoprostenol in human plasma, based on inhibition of platelet
aggregation, was similar for males (n = 954) and females (n = 1,024). Tritium-labeled
epoprostenol has been administered to humans in order to identify the metabolic
products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites:
6-keto-PGF(formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF(enzymatically
formed), both of which have pharmacological activity orders of magnitude less
than epoprostenol in animal test systems. The recovery of radioactivity in
urine and feces over a 1-week period was 82% and 4% of the administered dose,
respectively. Fourteen additional minor metabolites have been isolated from
urine, indicating that epoprostenol is extensively metabolized in humans.
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A large study evaluating the effect of FLOLAN on survival
in NYHA Class III and IV patients with congestive heart failure due to
severe left ventricular systolic dysfunction was terminated after an interim
analysis of 471 patients revealed a higher mortality in patients receiving
FLOLAN plus conventional therapy than in those receiving conventional therapy
alone. The chronic use of FLOLAN in patients with congestive heart failure
due to severe left ventricular systolic dysfunction is therefore contraindicated. Some
patients with pulmonary hypertension have developed pulmonary edema during
dose initiation, which may be associated with pulmonary veno-occlusive disease.
FLOLAN should not be used chronically in patients who develop pulmonary edema
during dose initiation. FLOLAN is also contraindicated
in patients with known hypersensitivity to the drug or to structurally related
compounds.
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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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General: FLOLAN should be used
only by clinicians experienced in the diagnosis and treatment of pulmonary
hypertension. The diagnosis of PPH or PH/SSD should be carefully established. FLOLAN
is a potent pulmonary and systemic vasodilator. Dose initiation with FLOLAN
must be performed in a setting with adequate personnel and equipment for physiologic
monitoring and emergency care. Dose initiation in controlled PPH clinical
trials was performed during right heart catheterization. In uncontrolled PPH
and controlled PH/SSD clinical trials, dose initiation was performed without
cardiac catheterization. The riskof cardiac catheterization in patients with
pulmonary hypertension should be carefully weighed against the potential benefits.
During dose initiation, asymptomatic increases in pulmonary artery pressure
coincident with increases in cardiac output occurred rarely. In such cases,
dose reduction should be considered, but such an increase does not imply that
chronic treatment is contraindicated. During chronic
use, FLOLAN is delivered continuously on an ambulatory basis through a permanent
indwelling central venous catheter. Unless contraindicated, anticoagulant
therapy should be administered to PPH and PH/SSD patients receiving FLOLAN
to reduce the risk of pulmonary thromboembolism or systemic embolism through
a patent foramen ovale. In order to reduce the risk of infection, aseptic
technique must be used in the reconstitution and administration of FLOLAN
as well as in routine catheter care. Because FLOLAN is metabolized rapidly,
even brief interruptions in the delivery of FLOLAN may result in symptoms
associated with rebound pulmonary hypertension including dyspnea, dizziness,
and asthenia. The decision to initiate therapy with FLOLAN should be based
upon the understanding that there is a high likelihood that intravenous therapy
with FLOLAN will be needed for prolonged periods, possibly years, and the
patient's ability to accept and care for a permanent intravenous catheter
and infusion pump should be carefully considered. Based
on clinical trials, the acute hemodynamic response to FLOLAN did not correlate
well with improvement in exercise tolerance or survival during chronic use
of FLOLAN. Dosage of FLOLAN during chronic use should be adjusted at the first
sign of recurrence or worsening of symptoms attributable to pulmonary hypertension
or the occurrence of adverse events associated with FLOLAN (see DOSAGE AND
ADMINISTRATION).Following dosage adjustments,
standing and supine blood pressure and heart rate should be monitored closely
for several hours.<br/>Information for Patients: Patients receiving FLOLAN
should receive the following information. FLOLAN
must be reconstituted only with STERILE DILUENT for FLOLAN. FLOLAN
is infused continuously through a permanent indwelling central venous catheter
via a small, portable infusion pump. Thus, therapy with FLOLAN requires commitment
by the patient to drug reconstitution, drug administration, and care of the
permanent central venous catheter. Sterile technique must be adhered to in
preparing the drug and in the care of the catheter, and even brief interruptions
in the delivery of FLOLAN may result in rapid symptomatic deterioration. A
patient's decision to receive FLOLAN should be based upon the understanding
that there is a high likelihood that therapy with FLOLAN will be needed for
prolonged periods, possibly years. The patient's ability to accept and care
for a permanent intravenous catheter and infusion pump should also be carefully
considered.<br/>Drug Interactions: Additional reductions
in blood pressure may occur when FLOLAN is administered with diuretics, antihypertensive
agents, or other vasodilators. When other antiplatelet agents or anticoagulants
are used concomitantly, there is the potential for FLOLAN to increase the
risk of bleeding. However, patients receiving infusions of FLOLAN in clinical
trials were maintained on anticoagulants without evidence of increased bleeding.
Inclinical trials, FLOLAN was used with digoxin, diuretics, anticoagulants,
oral vasodilators, and supplemental oxygen. In a pharmacokinetic
substudy in patients with congestive heart failure receiving furosemide or
digoxin in whom therapy with FLOLAN was initiated, apparent oral clearance
values for furosemide (n = 23) and digoxin (n = 30) were
decreased by 13% and 15%, respectively, on the second day of therapy and had
returned to baseline values by day 87. The change in furosemide clearance
value is not likely to be clinically significant. However, patients on digoxin
may show elevations of digoxin concentrations after initiation of therapy
with FLOLAN, which may be clinically significant in patients prone to digoxin
toxicity.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to
evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence
of mutagenicity. The Ames test and DNA elution tests were also negative, although
the instability of epoprostenol makes the significance of these tests uncertain.
Fertility was not impaired in rats given FLOLANby subcutaneous injection
at doses up to 100 mcg/kg/day (600 mcg/m/day, 2.5 times
the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m/day,
IV] based on body surface area).<br/>Pregnancy: Pregnancy Category B. Reproductive studies have been performed
in pregnant rats and rabbits at doses up to 100 mcg/kg/day (600 mcg/m/day
in rats, 2.5 times the recommended human dose, and 1,180 mcg/m/day
in rabbits, 4.8 times the recommended human dose based on body surface
area) and have revealed no evidence of impaired fertility or harm to the fetus
due to FLOLAN. There are, however, no adequate and well-controlled studies
in pregnant women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly
needed.<br/>Labor and Delivery: The use of FLOLAN during
labor, vaginal delivery, or cesarean section has not been adequately studied
in humans.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised
when FLOLAN is administered to a nursing woman.<br/>Pediatric use: Safety and effectiveness in pediatric patients have not
been established.<br/>Geriatric Use: Clinical studies of FLOLAN
in pulmonary hypertension did not include sufficient numbers of subjects aged
65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function and of concomitant disease or other drug therapy.
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| dailymed-instance:overdosag... |
Signs and symptoms of excessive doses of FLOLAN during clinical
trials are the expected dose-limiting pharmacologic effects of FLOLAN, including
flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea.
Treatment will ordinarily require dose reduction of FLOLAN. One
patient with secondary pulmonary hypertension accidentally received 50 mL
of an unspecified concentration of FLOLAN. The patient vomited and became
unconscious with an initially unrecordable blood pressure. FLOLAN was discontinued
and the patient regained consciousness within seconds. In clinical practice,
fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been
reported following overdosage of FLOLAN. Single intravenous
doses of FLOLAN at 10 and 50 mg/kg (2,703 and 27,027 times the recommended
acute phase human dose based on body surface area) were lethal to mice and
rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia,
loss of righting reflex, deep slow breathing, and hypothermia.
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| dailymed-instance:genericMe... |
epoprostenol sodium
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| dailymed-instance:fullName |
FLOLAN (Powder)
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| dailymed-instance:warning |
FLOLAN must be reconstituted only
as directed using STERILE DILUENT for FLOLAN. FLOLAN must not be reconstituted
or mixed with any other parenteral medications or solutions prior to or during
administration.<br/>Abrupt Withdrawal: Abrupt withdrawal (including interruptions in drug delivery)
or sudden large reductions in dosage of FLOLAN may result in symptoms associated
with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia.
In clinical trials, one Class III PPH patient's death was judged attributable
to the interruption of FLOLAN. Abrupt withdrawal should be avoided.<br/>Sepsis: See ADVERSE REACTIONS: Adverse Events Attributable to the
Drug Delivery System.
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| dailymed-instance:indicatio... |
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).
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FLOLAN
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