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flolan fda

flolan fda
Flolan for Injection
Manufacturer: GlaxoSmithKline

DESCRIPTION
FLOLAN (epoprostenol sodium) for Injection is a sterile sodium salt formulatedfor intravenous (IV) administration flolan fda. Each vial of FLOLAN contains epoprostenolsodium 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 flolan fda. Sodium hydroxidemay have been added to adjust pH flolan fda.

Epoprostenol (PGI 2 , PGX, prostacyclin), a metabolite of arachidonic acid,is a naturally occurring prostaglandin with potent vasodilatory activity andinhibitory activity of platelet aggregation flolan fda.

Epoprostenol is (5Z,9(alpha),11(alpha),13 E ,15 S )-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oicacid flolan fda.

Epoprostenol sodium has a molecular weight of 374.45 and a molecular formulaof C 20 H 31 NaO 5 flolan fda.

FLOLAN is a white to off-white powder that must be reconstituted with STERILEDILUENT for FLOLAN flolan fda. STERILE DILUENT for FLOLAN is supplied in glass vials containing50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added toadjust pH), and Water for Injection, USP flolan fda.

The reconstituted solution of FLOLAN has a pH of 10.2 to 10.8 and is increasinglyunstable at a lower pH flolan fda.

CLINICAL PHARMACOLOGY
General: Epoprostenol has 2 major pharmacological actions: (1) direct vasodilationof pulmonary and systemic arterial vascular beds, and (2) inhibition of plateletaggregation flolan fda. In animals, the vasodilatory effects reduce right- and left-ventricularafterload and increase cardiac output and stroke volume flolan fda. The effect of epoprostenolon heart rate in animals varies with dose flolan fda. At low doses, there is vagally mediatedbradycardia, but at higher doses, epoprostenol causes reflex tachycardia inresponse to direct vasodilation and hypotension flolan fda. No major effects on cardiacconduction have been observed flolan fda. Additional pharmacologic effects of epoprostenolin animals include bronchodilation, inhibition of gastric acid secretion, anddecreased gastric emptying flolan fda.

Pharmacokinetics: Epoprostenol is rapidly hydrolyzed at neutral pH in bloodand is also subject to enzymatic degradation flolan fda. Animal studies using tritium-labeledepoprostenol have indicated a high clearance (93 mL/kg/min), small volume ofdistribution (357 mL/kg), and a short half-life (2.7 minutes) flolan fda. During infusionsin animals, steady-state plasma concentrations of tritium-labeled epoprostenolwere reached within 15 minutes and were proportional to infusion rates flolan fda.

No available chemical assay is sufficiently sensitive and specific to assessthe in vivo human pharmacokinetics of epoprostenol flolan fda. The in vitro half-life ofepoprostenol 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 beno greater than 6 minutes flolan fda. The in vitro pharmacologic half-life of epoprostenolin human plasma, based on inhibition of platelet aggregation, was similar formales (n = 954) and females (n = 1,024) flolan fda.

Tritium-labeled epoprostenol has been administered to humans in order to identifythe metabolic products of epoprostenol flolan fda. Epoprostenol is metabolized to 2 primarymetabolites: 6-keto-PGF 1(alpha) (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1(alpha) (enzymatically formed), both of which have pharmacological activityorders of magnitude less than epoprostenol in animal test systems flolan fda. The recoveryof radioactivity in urine and feces over a 1-week period was 82% and 4% of theadministered dose, respectively flolan fda. Fourteen additional minor metabolites havebeen isolated from urine, indicating that epoprostenol is extensively metabolizedin humans flolan fda.

CLINICAL TRIALS IN PULMONARY HYPERTENSION
Acute Hemodynamic Effects: Acute intravenous infusions of FLOLAN for up to 15minutes in patients with secondary and primary pulmonary hypertension producedose-related increases in cardiac index (CI) and stroke volume (SV) and dose-relateddecreases in pulmonary vascular resistance (PVR), total pulmonary resistance(TPR), and mean systemic arterial pressure (SAPm) flolan fda. The effects of FLOLAN onmean pulmonary artery pressure (PAPm) were variable and minor flolan fda.

Chronic Infusion in Primary Pulmonary Hypertension (PPH): Hemodynamic Effects:Chronic continuous infusions of FLOLAN in patients with PPH were studied in2 prospective, open, randomized trials of 8 and 12 weeks' duration comparingFLOLAN plus conventional therapy to conventional therapy alone flolan fda. Dosage of FLOLANwas determined as described in DOSAGE AND ADMINISTRATION and averaged 9.2 ng/kg/minat study's end flolan fda. Conventional therapy varied among patients and included someor all of the following: anticoagulants in essentially all patients; oral vasodilators,diuretics, and digoxin in one half to two thirds of patients; and supplementaloxygen in about half the patients flolan fda. Except for 2 New York Heart Association (NYHA)functional Class II patients, all patients were either functional Class IIIor Class IV flolan fda. As results were similar in the 2 studies, the pooled results aredescribed flolan fda. Chronic hemodynamic effects were generally similar to acute effects flolan fda. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, meanright atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) wereobserved in patients who received FLOLAN chronically compared to those who didnot flolan fda. Table 1 illustrates the treatment-related hemodynamic changes in thesepatients after 8 or 12 weeks of treatment flolan fda.

Table 1 flolan fda. Hemodynamics During Chronic Administration of
FLOLAN in Patients With PPH Hemodynamic
Parameter Baseline Mean Change from Baseline at End of Treatment Period *
FLOLAN
(N = 52) Standard Therapy
(N = 54) FLOLAN
(N = 48) Standard Therapy
(N = 41)
CI
(L/min/m 2 ) 2.0 2.0 0.3 **/* -0.1
PAPm
(mm Hg) 60 60 -5 **/* 1
PVR
(Wood U) 16 17 -4 **/* 1
SAPm
(mm Hg) 89 91 -4 -3
SV
(mL/beat) 44 43 6 **/* -1
TPR
(Wood U) 20 21 -5 **/* 1
*At 8 weeks: FLOLAN N = 10, conventional therapy N = 11 (N is the number ofpatients with hemodynamic data) flolan fda.
At 12 weeks: FLOLAN N = 38, conventional therapy N = 30 (N is the number ofpatients with hemodynamic data) flolan fda.
**/* Denotes statistically significant difference between FLOLAN and conventionaltherapy groups flolan fda.
CI = cardiac index, PAPm = mean pulmonary arterial pressure, PVR = pulmonaryvascular resistance, SAPm = mean systemic arterial pressure, SV = stroke volume,TPR = total pulmonary resistance flolan fda.

These hemodynamic improvements appeared to persist when FLOLAN was administeredfor at least 36 months in an open, nonrandomized study flolan fda.

Clinical Effects: Statistically significant improvement was observed in exercisecapacity, as measured by the 6-minute walk test in patients receiving continuousintravenous FLOLAN plus conventional therapy (N = 52) for 8 or 12 weeks comparedto those receiving conventional therapy alone (N = 54) flolan fda. Improvements were apparentas early as the first week of therapy flolan fda. Increases in exercise capacity were accompaniedby statistically significant improvement in dyspnea and fatigue, as measuredby the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index flolan fda.

Survival was improved in NYHA functional Class III and Class IV PPH patientstreated with FLOLAN for 12 weeks in a multicenter, open, randomized, parallelstudy flolan fda. At the end of the treatment period, 8 of 40 (20%) patients receivingconventional therapy alone died, whereas none of the 41 patients receiving FLOLANdied (p = 0.003) flolan fda.

Chronic Infusion in Pulmonary Hypertension Associated with the SclerodermaSpectrum of Diseases (PH/SSD): Hemodynamic Effects: Chronic continuous infusionsof FLOLAN in patients with PH/SSD were studied in a prospective, open, randomizedtrial of 12 weeks' duration comparing FLOLAN plus conventional therapy (N =56) to conventional therapy alone (N = 55) flolan fda. Except for 5 NYHA functional ClassII patients, all patients were either functional Class III or Class IV flolan fda. Dosageof FLOLAN was determined as described in DOSAGE AND ADMINISTRATION and averaged11.2 ng/kg/min at study's end flolan fda. Conventional therapy varied among patients andincluded some or all of the following: anticoagulants in essentially all patients,supplemental oxygen and diuretics in two thirds of the patients, oral vasodilatorsin 40% of the patients, and digoxin in a third of the patients flolan fda. A statisticallysignificant increase in CI, and statistically significant decreases in PAPm,RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients whoreceived FLOLAN chronically compared to those who did not flolan fda. Table 2 illustratesthe treatment-related hemodynamic changes in these patients after 12 weeks oftreatment flolan fda.

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