2.1 Reconstitution

Each vial is for single use only; discard any unused diluent or unused reconstituted solution.

Select a concentration for the solution of FLOLAN 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 below [see Dosage and Administration (2.3)].

Using aseptic technique, reconstitute FLOLAN only with pH 12 STERILE DILUENT for FLOLAN. Table 1 gives directions for preparing several different concentrations of FLOLAN. See storage and administration time limits for the reconstituted FLOLAN below.

Storage and Administration Limits for Reconstituted FLOLAN

•

Freshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2°C to 8°C (36°F to 46°F) for no longer than 8 days can be administered up to:

•

48 hours at up to 25°C (77°F).

•

36 hours at up to 30°C (86°F).

•

24 hours at up to 35°C (95°F).

•

12 hours at up to 40°C (104°F).

 

Discard any unused solution after these times.

•

Reconstituted solutions can be used immediately. Refrigerate at 2°C to 8°C (36°F to 46°F) if not used immediately.

•

Protect from light.

•

Do not freeze reconstituted solutions.

2.2 Dosage

Initiate intravenous infusions of FLOLAN at 2 ng/kg/min. Alter the infusion 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.

During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output may occur. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse vasodilatory reactions. In general, expect progressive increases in dose.

If dose-related adverse reactions occur, make dose decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve [see Adverse Reactions (6.1, 6.2)]. Avoid abrupt withdrawal of FLOLAN or sudden large reductions in infusion rates [see Warnings and Precautions (5.2)].

Following establishment of a new chronic infusion rate, measure standing and supine blood pressure for several hours.

Taper doses of FLOLAN after initiation of cardiopulmonary bypass in patients receiving lung transplants.

2.3 Administration

Initiate FLOLAN in a setting with adequate personnel and equipment for physiologic monitoring and emergency care.

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Administer continuous chronic infusion of FLOLAN through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Do not administer bolus injections of FLOLAN.

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. Use a 60-inch microbore non-di-(2-ethylhexyl)phthalate (DEHP) extension set with proximal antisyphon valve, low-priming volume (0.9 mL), and in-line 0.22-micron filter.

Preparation and administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG) may become damaged when used with FLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN and therefore must not be used.

Consult the manufacturer of the sets to confirm that they are considered compatible with highly alkaline solutions, such as FLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN.

To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets.

Do not administer or dilute reconstituted solutions of FLOLAN with other parenteral solutions or medications. Consider a multi‑lumen catheter if other intravenous therapies are routinely administered.

Select a concentration for the solution of FLOLAN 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. When administered chronically, prepare FLOLAN in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of pH 12 STERILE DILUENT for FLOLAN.

Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long‑term administration of FLOLAN.

Infusion rates may be calculated using the following formula:

5.1 Pulmonary Edema

If the patient develops pulmonary edema during initiation with FLOLAN, discontinue therapy and do not readminister. Consider the possibility of associated pulmonary veno-occlusive disease in such patients.

5.2 Rebound Pulmonary Hypertension following Abrupt Withdrawal

Avoid abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of FLOLAN because symptoms associated with rebound pulmonary hypertension (e.g., dyspnea, dizziness, and asthenia) may occur. In clinical trials, one Class III patient's death was judged attributable to the interruption of FLOLAN.

5.3 Vasodilation

FLOLAN is a potent pulmonary and systemic vasodilator and can cause hypotension and other reactions such as flushing, nausea, vomiting, dizziness, and headache. Monitor blood pressure and symptoms regularly during initiation and after dose change [see Dosage and Administration (2.2)].

5.4 Increased Risk for Bleeding

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 Clinical Pharmacology (12.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions are shown in Table 2 and are generally related to vasodilatory effects.

PAH = Pulmonary Arterial Hypertension, SSD = Scleroderma Spectrum of Diseases.

Adverse Events Attributable to the Drug Delivery System

Chronic infusions of FLOLAN are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks’ duration, the local infection rate was about 18% and the rate for pain was about 11%. During long‑term follow‑up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with FLOLAN.

6.2 Postmarketing Experience

The following events have been identified during postapproval use of FLOLAN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic

Anemia, hypersplenism, pancytopenia, splenomegaly, thrombocytopenia.

Cardiac

High output cardiac failure.

Endocrine and Metabolic

Hyperthyroidism.

Gastrointestinal

Hepatic failure.

Respiratory, Thoracic, and Mediastinal

Pulmonary embolism.

8.1 Pregnancy

Risk Summary

Limited published data from case series and case reports have not established an association with FLOLAN and major birth defects, miscarriage or adverse maternal or fetal outcomes when FLOLAN is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). In animal reproduction studies, pregnant rats and rabbits received epoprostenol sodium during organogenesis at exposures of 2.5 and 4.8 times the maximum recommended human dose (MRHD), respectively, and there was no effect on the fetus (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.

Data

Animal Data: Embryo-fetal development studies have been performed in rats and rabbits during organogenesis. Epoprostenol sodium doses up to 100 mcg/kg/day, a dose that was maternally toxic in rabbits but not in rats (600 mcg/m2/day in rats, 2.5 times the MRHD, and 1,180 mcg/m2/day in rabbits, 4.8 times the MRHD based on body surface area), had no effect on the fetus.

In a postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at a male and female toxic dose of up to 100 mcg/kg/day (600 mcg/m2/day, 2.5 times the MRHD based on body surface area). There was no effect on growth and development of the offspring.

8.2 Lactation

Risk Summary

There are no data on the presence of epoprostenol in either human or animal milk, the effects on the breastfed infant, or the effect on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLOLAN and any potential adverse effects on the breastfed child from epoprostenol or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials of FLOLAN in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

12.1 Mechanism of Action

Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds and (2) inhibition of platelet aggregation.

12.2 Pharmacodynamics

Acute Hemodynamic Effects

Acute intravenous infusions of FLOLAN for up to 15 minutes in patients with idiopathic or heritable PAH or 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.

In humans, hemodynamic changes due to epoprostenol (e.g., increased heart rate, facial flushing) returned to baseline within 10 minutes of termination of 60-minute infusions of 1 to 16 ng/kg/min. This pharmacodynamic behavior is consistent with a short in vivo half-life and rapid clearance in humans, as suggested by the results of animal and in vitro studies.

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.

Drug Interaction Studies

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 a 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.

12.3 Pharmacokinetics

Absorption/Distribution

Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. 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.

Metabolism

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.

Elimination

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.

Drug Interaction Studies

In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide in whom therapy with FLOLAN was initiated, apparent oral clearance values for furosemide (n = 23) were decreased by 13% on the second day of therapy and returned to baseline values by Day 87. The change in furosemide clearance value is not likely to be clinically significant.

In a pharmacokinetic substudy in patients with congestive heart failure receiving digoxin in whom therapy with FLOLAN was initiated, apparent oral clearance values for digoxin (n = 30) were decreased by 15% on the second day of therapy and returned to baseline values by Day 87. Clinical significance of this interaction is not known.

13.1 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.

In a fertility/postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at an adult toxic dose of up to 100 mcg/kg/day (600 mcg/m2/day, 2.5 times the MRHD based on body surface area). There was no effect on fertility in female or male rats.

14.1 Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects

Chronic continuous infusions of FLOLAN in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing FLOLAN plus conventional therapy with conventional therapy alone. Dosage of FLOLAN was determined as described in Dosage and Administration (2) and averaged 9.2 ng/kg/min at trials’ 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 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 trials, 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 with those who did not. Table 3 illustrates the treatment‑related hemodynamic changes in these patients after 8 or 12 weeks of treatment.

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

The acute hemodynamic response to FLOLAN did not correlate well with improvement in exercise tolerance or survival during chronic use of FLOLAN.

Clinical Effects

A 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 12 weeks compared with 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, respectively.

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

14.2 Chronic Infusion in PAH/SSD

Hemodynamic Effects

Chronic continuous infusions of FLOLAN in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing FLOLAN plus conventional therapy (n = 56) with conventional therapy alone (n = 55). Except for 5 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. In the controlled 12-week trial in PAH/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.

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 12 weeks of treatment were observed in patients who received FLOLAN chronically compared with those who did not. Table 4 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.

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 12 weeks compared with 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 with 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.

No statistical difference in survival over 12 weeks was observed in patients with PAH/SSD treated with FLOLAN as compared with 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.

14.3 Increased Mortality in Patients with Heart Failure Caused by Severe Left Ventricular Systolic Dysfunction

A large trial 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 heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.

16.1 How Supplied

FLOLAN for injection is supplied as a sterile freeze‑dried powder in 17‑mL flint glass vials with gray butyl rubber closures.

pH 12 STERILE DILUENT for FLOLAN is supplied in plastic vials containing 50‑mL diluent with fluororesin‑faced butyl rubber closures with aluminum overseal and lavender plastic flip-off cap.

16.2 Storage and Handling

Proper storage and handling are essential to maintain the potency of FLOLAN for injection.

Unopened vials of FLOLAN powder are stable until the date indicated on the package when stored at room temperature, 15°C to 25°C (59°F to 77°F) and protected from light in the carton.

Unopened vials of pH 12 STERILE DILUENT for FLOLAN are stable until the date indicated on the package when stored at room temperature, 15°C to 25°C (59°F to 77°F). DO NOT FREEZE.