DESCRIPTION

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 0.5mg (500,000ng) or 1.5mg (1,500,000ng) epoprostenol, 3.76mg glycine, 2.93mg sodium chloride, and 50mg mannitol. Sodium hydroxide may have been added to adjust pH.

Epoprostenol (PGI2, 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,9α,11α,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 C20H31NaO5. 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 50mL of 94mg glycine, 73.3mg 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.

CLINICAL PHARMACOLOGY

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.

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 (93mL/kg/min), small volume of distribution (357mL/kg), and a short half-life (2.7minutes). During infusions in animals, steady-state plasma concentrations of tritium-labeled epoprostenol were reached within 15minutes 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 6minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6minutes. 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-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (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.

CLINICAL TRIALS IN PULMONARY ARTERIAL HYPERTENSION (PAH)

Acute Hemodynamic Effects

Acute intravenous infusions of FLOLAN for up to 15minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of FLOLAN on mean pulmonary artery pressure (PAPm) were variable and minor.

Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects

Chronic continuous infusions of FLOLAN in patients with idiopathic or heritable PAH were studied in 2prospective, open, randomized trials of 8 and 12weeks’ duration comparing FLOLAN plus conventional therapy to conventional therapy alone. Dosage of FLOLAN was determined as described in DOSAGE AND ADMINISTRATION and averaged 9.2ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional ClassII patients, all patients were either functional ClassIII or ClassIV. As results were similar in the 2 studies, the pooled results are described. Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received FLOLAN chronically compared to those who did not. Table1 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12weeks of treatment.

* At 8weeks: FLOLAN N=10, conventional therapy N=11 (N is the number of patients with hemodynamic data).

At 12weeks: FLOLAN N=38, conventional therapy N=30 (N is the number of patients with hemodynamic data).

† Denotes statistically significant difference between FLOLAN and conventional therapy groups.

CI = cardiac index, PAPm = mean pulmonary arterial pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure, SV = stroke volume, TPR = total pulmonary resistance.
 

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

Clinical Effects

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous FLOLAN plus conventional therapy (N=52) for 8 or 12weeks compared to those receiving conventional therapy alone (N=54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index.

Survival was improved in NYHA functional ClassIII and ClassIV patients with idiopathic or heritable PAH treated with FLOLAN for 12weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40(20%) patients receiving conventional therapy alone died, whereas none of the 41patients receiving FLOLAN died (p =0.003).

Chronic Infusion in PAH/Scleroderma Spectrum of Diseases (SSD)

Hemodynamic Effects

Chronic continuous infusions of FLOLAN in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12weeks’ duration comparing FLOLAN plus conventional therapy (N=56) to conventional therapy alone (N=55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of FLOLAN was determined as described in DOSAGE AND ADMINISTRATION and averaged 11.2ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12weeks of treatment were observed in patients who received FLOLAN chronically compared to those who did not. Table2 illustrates the treatment-related hemodynamic changes in these patients after 12weeks of treatment.

* Denotes statistically significant difference between FLOLAN and conventional therapy groups (N is the number of patients with hemodynamic data).

CI = cardiac index, PAPm = mean pulmonary arterial pressure, RAPm = mean right arterial pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure.

Clinical Effects

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous FLOLAN plus conventional therapy for 12weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with FLOLAN compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with FLOLAN and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with FLOLAN and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12weeks were not available for 5patients treated with FLOLAN and 7patients treated with conventional therapy alone.

No statistical difference in survival over 12weeks was observed in PAH/SSD patients treated with FLOLAN as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving FLOLAN died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.

No controlled clinical trials with FLOLAN have been performed in patients with pulmonary hypertension associated with other diseases.

INDICATIONS AND USAGE

FLOLAN is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) 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.

CONTRAINDICATIONS

A large study eva luating the effect of FLOLAN on survival in NYHA ClassIII and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471patients 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.

WARNINGS

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.

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 ClassIII patient's death was judged attributable to the interruption of FLOLAN. Avoid abrupt withdrawal.

Sepsis

See ADVERSE REACTIONS: Adverse Events Attributable to the Drug Delivery System.

PRECAUTIONS

General

FLOLAN should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. Carefully establish the diagnosis of idiopathic or heritable PAH or PAH/CTD.

FLOLAN is a potent pulmonary and systemic vasodilator. Initiate FLOLAN in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

FLOLAN is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding (see PRECAUTIONS: Drug Interactions).

During chronic use, deliver FLOLAN continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving FLOLAN to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of FLOLAN and 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. Intravenous therapy with FLOLAN will likely be needed for prolonged periods, possibly years, so consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump.

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. Adjust dosage of FLOLAN during chronic use 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, monitor standing and supine blood pressure and heart rate closely for several hours.

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. Patients must adhere to sterile technique 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.

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. In clinical 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to eva luate 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 FLOLAN by subcutaneous injection at doses up to 100mcg/kg/day (600mcg/m2/day, 2.5times the recommended human dose [4.6ng/kg/min or 245.1mcg/m2/day, IV] based on body surface area).

Pregnancy

Pregnancy Category B. Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100mcg/kg/day (600mcg/m2/day in rats, 2.5times the recommended human dose, and 1,180mcg/m2/day in rabbits, 4.8times 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.

Labor and Delivery

The use of FLOLAN during labor, vaginal delivery, or cesarean section has not been adequately studied in humans.

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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.

ADVERSE REACTIONS

During clinical trials, adverse events were classified as follows: (1)adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.

Adverse Events During Dose Initiation and Escalation

During early clinical trials, FLOLAN was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of FLOLAN. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table3 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.

Adverse Events During Chronic Administration

Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of FLOLAN (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to FLOLAN. These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during FLOLAN therapy, and a role for the drug in these events cannot be excluded.

Adverse Events During Chronic Administration for Idiopathic or Heritable PAH

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table4 lists adverse events that occurred at a rate at least 10% greater on FLOLAN in controlled trials.

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving FLOLAN.

Adverse Events During Chronic Administration for PAH/SSD

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table5 lists adverse events that occurred at a rate at least 10% greater on FLOLAN in the controlled trial.

Table 5. Adverse Events Regardless of Attribution Occurring in Patients with PAH/SSD With ≥10% Difference Between FLOLAN and Conventional Therapy Alone

Adverse Event	FLOLAN (n = 56)	Conventional Therapy (n = 55)
Occurrence More Common With FLOLAN
Cardiovascular
Flushing	23%	0%
Hypotension	13%	0%
Gastrointestinal
Anorexia	66%	47%
Nausea/vomiting	41%	16%
Diarrhea	50%	5%
Musculoskeletal
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