ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions are dizziness, jaw pain, headache, musculoskeletal pain, and nausea/vomiting, and are generally associated with vasodilation. (6)To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and are generally related to vasodilatory effects.Table 2. Adverse Reactions Occurring in Patients with Idiopathic or Heritable PAH and with PAH Associated with Scleroderma Spectrum of Diseases (PAH/SSD) Occurring >=10% More Frequently on FLOLAN than Conventional TherapyAdverse ReactionIdiopathic or HeritablePAHPAH/SSDFLOLANConventional TherapyFLOLANConventional Therapy(n 52)(n 54)(n 56)(n 55)Body as wholeJaw pain54%0%75%0%Nonspecific musculoskeletal pain35%15%84%65%Headache83%33%46%5%Chills/fever/sepsis/flu-like symptoms25%11%13%11%Cardiovascular systemFlushing42%2%23%0%Hypotension27%31%13%0%Tachycardia35%24%43%42%Digestive systemAnorexia25%30%66%47%Nausea/Vomiting67%48%41%16%Diarrhea37%6%50%5%Skin and AppendagesSkin ulcer--39%24%Eczema/rash/urticaria10%13%25%4%Musculoskeletal SystemMyalgia44%31%--Nervous systemAnxiety/hyperkinesias/nervousness/tremor21%9%7%5%Hyperesthesia/hypesthesia/paresthesia12%2%5%0%Dizziness83%70%59%76%Adverse Events Attributable to the Drug Delivery SystemChronic infusions of FLOLAN are delivered using 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 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 population of uncertain size, it is not always possible to estimate reliably their frequency or establish causal relationship to drug exposure.Blood and LymphaticAnemia, hypersplenism, pancytopenia, splenomegaly, thrombocytopenia.CardiacHigh output cardiac failure.Endocrine and MetabolicHyperthyroidism.Gastrointestinal Hepatic failure.Respiratory, Thoracic, and MediastinalPulmonary embolism.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere 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 mothers clinical need for FLOLAN and any potential adverse effects on the breastfed child from epoprostenol or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate carcinogenic potential. 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 fertility/postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Epoprostenol has major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds and (2) inhibition of platelet aggregation.. 12.2 Pharmacodynamics. Acute Hemodynamic EffectsAcute 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 to 16 ng/kg/min. This pharmacodynamic behavior is consistent with 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 StudiesAdditional 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 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/DistributionEpoprostenol 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 high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and 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.MetabolismTritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to primary metabolites: 6-keto-PGF1 (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1 (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 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.EliminationThe in vitro half-life of epoprostenol in human blood at 37C and pH 7.4 is approximately minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than minutes.Drug Interaction StudiesIn 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Chronic Infusion in Idiopathic or Heritable PAH. Hemodynamic EffectsChronic continuous infusions of FLOLAN in patients with idiopathic or heritable PAH were studied in prospective, open, randomized trials of 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 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 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 illustrates the treatment-related hemodynamic changes in these patients after or 12 weeks of treatment.Table 3. Hemodynamics during Chronic Administration of FLOLAN in Patients with Idiopathic or Heritable PAHa At weeks: FLOLAN = 10, conventional therapy = 11 (n is the number of patients with hemodynamic data). At 12 weeks: FLOLAN = 38, conventional therapy = 30 (n is the number of patients with hemodynamic data). Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy. CI Cardiac index, PAPm Mean pulmonary arterial pressure, PVR Pulmonary vascular resistance, SAPm Mean systemic arterial pressure, SV Stroke volume, TPR Total pulmonary resistance.BaselineMean Change from Baseline at End of Treatment Perioda HemodynamicParameterFLOLAN(n 52)Standard Therapy(n 54)FLOLAN(n 48)Standard Therapy(n 41)CI(L/min/m2)2.02.00.3b -0.1PAPm(mm Hg)6060-5b 1PVR(Wood U)1617-4b 1SAPm(mm Hg)8991-4-3SV(mL/beat)44436b -1TPR(Wood U)2021-5b 1These 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 EffectsA 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 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 multicenter, open, randomized, parallel trial. At the end of the treatment period, 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 EffectsChronic continuous infusions of FLOLAN in patients with PAH/SSD were studied in prospective, open, randomized trial of 12 weeks duration comparing FLOLAN plus conventional therapy (n 56) with conventional therapy alone (n 55). Except for 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 mean starting dose of 2.2 ng/kg/min. During the first days of treatment, the dose was increased daily to mean dose of 4.1 ng/kg/min on Day of treatment. At the end of Week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was to ng/kg/min every 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 third of the patients. 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 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.Table 4. Hemodynamics during Chronic Administration of FLOLAN in Patients with PAH/SSDa Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy (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.BaselineMean Change from Baseline at 12 WeeksHemodynamicParameterFLOLAN(n 56)Conventional Therapy(n 55)FLOLAN(n 50)Conventional Therapy(n 48)CI(L/min/m2)1.92.20.5a -0.1PAPm(mm Hg)5149-5a 1RAPm(mm Hg)1311-1a 1PVR(Wood U)1411-5a 1SAPm(mm Hg)9389-8a -1Clinical EffectsStatistically 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, of 56 (7%) patients receiving FLOLAN died, whereas 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. 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 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. FLOLAN is contraindicated in patients with heart failure caused by reduced left ventricular ejection fraction [see Clinical Studies (14.3)].FLOLAN is contraindicated in patients with hypersensitivity to the drug or any of its ingredients.. oHeart failure with reduced ejection fraction. (4)oHypersensitivity to FLOLAN or any of its ingredients. (4). oHeart failure with reduced ejection fraction. (4). oHypersensitivity to FLOLAN or any of its ingredients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. FLOLAN (epoprostenol sodium) for injection is sterile sodium salt that is white or off-white powder 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, 50 mg mannitol, and 2.93 mg sodium chloride. Sodium hydroxide may have been added to adjust pH.Epoprostenol (PGI2, PGX, prostacyclin), metabolite of arachidonic acid, is naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation. The chemical name of epoprostenol is (5Z,9,11,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid. Epoprostenol sodium has molecular weight of 374.45 and molecular formula of C20H31NaO5. The structural formula is:FLOLAN must be reconstituted with pH 12 STERILE DILUENT for FLOLAN.pH 12 STERILE DILUENT for FLOLAN is supplied in plastic vials each containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust the pH to 11.7 to 12.3), and Water for Injection. The stability of reconstituted solutions of FLOLAN is pH-dependent and is greater at higher pH.. epoprostenol sodium chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oInitiate intravenous infusion through central venous catheter at ng/kg/min. (2.2, 2.3)oChange dose in 1-to 2-ng/kg/min increments at intervals of at least 15 minutes based on clinical response. (2.2)oAvoid sudden large dose reductions. (2.2, 5.2). oInitiate intravenous infusion through central venous catheter at ng/kg/min. (2.2, 2.3). oChange dose in 1-to 2-ng/kg/min increments at intervals of at least 15 minutes based on clinical response. (2.2). oAvoid sudden large dose reductions. (2.2, 5.2). 2.1 Reconstitution. Each vial is for single use only; discard any unused diluent or unused reconstituted solution.Select 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 gives directions for preparing several different concentrations of FLOLAN. See storage and administration time limits for the reconstituted FLOLAN below.Table 1. Reconstitution and Dilution Instructions for FLOLAN Using pH 12 STERILE DILUENT for FLOLAN.a Higher concentrations may be prepared for patients who receive FLOLAN long-term.To make 100 mL of solution with final concentration of:Directions:3,000 ng/mLDissolve contents of one 0.5-mg vial with mL of sterile diluent. Withdraw mL and add to sufficient sterile diluent to make total of 100 mL.5,000 ng/mLDissolve contents of one 0.5-mg vial with mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make total of 100 mL.10,000 ng/mLDissolve contents of two 0.5-mg vials each with mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make total of 100 mL.15,000 ng/mLa Dissolve contents of one 1.5-mg vial with mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make total of 100 mL.Storage and Administration Limits for Reconstituted FLOLANoFreshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2C to 8C (36F to 46F) for no longer than days can be administered up to:o72 hours at up to 25C (77F).o48 hours at up to 30C (86F).o24 hours at up to 35C (95F).o12 hours at up to 40C (104F). oReconstituted solutions can be used immediately. Refrigerate at 2C to 8C (36F to 46F) if not used immediately.oProtect from light.oDo not freeze reconstituted solutions.. oFreshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2C to 8C (36F to 46F) for no longer than days can be administered up to:o72 hours at up to 25C (77F).o48 hours at up to 30C (86F).o24 hours at up to 35C (95F).o12 hours at up to 40C (104F). o72 hours at up to 25C (77F).. o48 hours at up to 30C (86F).. o24 hours at up to 35C (95F).. o12 hours at up to 40C (104F).. oReconstituted solutions can be used immediately. Refrigerate at 2C to 8C (36F to 46F) if not used immediately.. oProtect from light.. oDo not freeze reconstituted solutions.. 2.2 Dosage. Initiate intravenous infusions of FLOLAN at 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 patients 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 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 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 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 minutes at infusion rates used to deliver FLOLAN. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Use 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 backup infusion pump and intravenous infusion sets.Do not administer or dilute reconstituted solutions of FLOLAN with other parenteral solutions or medications. Consider multi-lumen catheter if other intravenous therapies are routinely administered.Select 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 drug delivery reservoir appropriate for the infusion pump with total reservoir volume of at least 100 mL, using vials of pH 12 STERILE DILUENT for FLOLAN.Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 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:. Flolan infusion rate formula.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: 0.5 mg or 1.5 mg of epoprostenol, freeze-dried powder in single-dose vial for reconstitution with the supplied diluent.. For injection: 0.5 mg or 1.5 mg of epoprostenol freeze-dried powder in single-dose vial for reconstitution with the supplied diluent. (3).

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. FLOLAN for injection is supplied as 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.FLOLAN for injection0.5-mg (500,000 ng) per vial, carton of 1NDC 0173-0517-001.5-mg (1,500,000 ng) per vial, carton of 1NDC 0173-0519-00pH 12 STERILE DILUENT for FLOLAN50 mL per vial, carton of 2NDC 0173-0857-02. 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, 15C to 25C (59F to 77F) 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, 15C to 25C (59F to 77F). DO NOT FREEZE.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. FLOLAN is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Trials establishing effectiveness included predominantly (97%) patients with New York Heart Association (NYHA) Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (49%) or PAH associated with connective tissue diseases (51%).. FLOLAN is prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly (97%) patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (49%) or PAH associated with connective tissue diseases (51%). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Advise patients:oFLOLAN must be reconstituted only with pH 12 STERILE DILUENT for FLOLAN.oReconstituted solutions prepared with pH 12 STERILE DILUENT for FLOLAN do NOT require use with cold pouch.oFLOLAN is infused continuously through permanent indwelling central venous catheter via 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. patients decision to receive FLOLAN should be based upon the understanding that there is high likelihood that therapy with FLOLAN will be needed for prolonged periods, possibly years. Consider the patients ability to accept and care for permanent intravenous catheter and infusion pump.oFLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing PET or PETG. Only use materials provided by healthcare provider or pharmacist.oTo adjust infusion rates of FLOLAN only under the direction of physician.oTo avoid interruptions in drug delivery, the patient should have access to backup infusion pump and intravenous infusion sets.oTo contact their healthcare providers if any unusual bruising or bleeding develops.Trademark is owned by or licensed to the GSK group of companies.GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.FLL:10PI. oFLOLAN must be reconstituted only with pH 12 STERILE DILUENT for FLOLAN.. oReconstituted solutions prepared with pH 12 STERILE DILUENT for FLOLAN do NOT require use with cold pouch.. oFLOLAN is infused continuously through permanent indwelling central venous catheter via 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. patients decision to receive FLOLAN should be based upon the understanding that there is high likelihood that therapy with FLOLAN will be needed for prolonged periods, possibly years. Consider the patients ability to accept and care for permanent intravenous catheter and infusion pump.. oFLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing PET or PETG. Only use materials provided by healthcare provider or pharmacist.. oTo adjust infusion rates of FLOLAN only under the direction of physician.. oTo avoid interruptions in drug delivery, the patient should have access to backup infusion pump and intravenous infusion sets.. oTo contact their healthcare providers if any unusual bruising or bleeding develops.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals have not been performed to evaluate carcinogenic potential. 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 fertility/postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Signs and SymptomsHypoxemia, hypotension, and respiratory arrest leading to death have been reported in clinical practice following overdosage of FLOLAN.Excessive doses of FLOLAN were associated with flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea during clinical trials.One patient with PAH/SSD 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.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.TreatmentDiscontinue or reduce dose of FLOLAN.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 0173-0517-00FLOLAN(R) (epoprostenol sodium)for Injection0.5 mg/vial (500,000 ng/vial)Must be reconstituted. For intravenous infusion after dilution.Note: Use only STERILE DILUENT for FLOLAN or pH 12 STERILE DILUENT for FLOLAN for reconstitution and dilution.Rx onlySingle-Use VialEach vial contains epoprostenol sodium equivalent to 0.5 mg (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. Usual Dose: See prescribing information.Store at 15o and 25o (59o to 77oF). Do not accept if plastic overseal is missing or not securely fitted.GlaxoSmithKlineRTP, NC 27709Rev. 4/1610000000140666. Flolan 0.5 mg label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Acute Hemodynamic EffectsAcute 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 to 16 ng/kg/min. This pharmacodynamic behavior is consistent with 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 StudiesAdditional 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 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption/DistributionEpoprostenol 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 high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and 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.MetabolismTritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to primary metabolites: 6-keto-PGF1 (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1 (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 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.EliminationThe in vitro half-life of epoprostenol in human blood at 37C and pH 7.4 is approximately minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than minutes.Drug Interaction StudiesIn 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited 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 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 ConsiderationsDisease-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.DataAnimal Data: Embryo-fetal development studies have been performed in rats and rabbits during organogenesis. Epoprostenol sodium doses up to 100 mcg/kg/day, 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 postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONFLOLAN (flow-lan)(epoprostenol sodium)for injection, for intravenous useWhat is FLOLANFLOLAN is prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of the lungs. FLOLAN can improve your ability to be physically active.It is not known if FLOLAN is safe and effective in children.Do not use FLOLAN if you: ohave certain types of heart failure. Talk to your healthcare provider before using FLOLAN if you have heart failure.oare allergic to FLOLAN or any of the ingredients in FLOLAN. See the end of this leaflet for complete list of ingredients in FLOLAN.Before you use FLOLAN, tell your healthcare provider about all of your medical conditions, including if you:oare allergic to any medicine.oare pregnant or plan to become pregnant. It is not known if FLOLAN will harm your unborn baby. You and your healthcare provider should decide if you will use FLOLAN.oare breastfeeding or plan to breastfeed. It is not known if FLOLAN passes into your breast milk. You and your healthcare provider should decide if you will take FLOLAN or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Especially tell your healthcare provider if you take: oa water pill (diuretic)oa medicine for high blood pressure (hypertension)oa blood thinner medicine (antiplatelet or anticoagulant medicine)Ask your healthcare provider or pharmacist for list of these medicines, if you are not sure.Know the medicines you take. Keep list of your medicines with you to show your healthcare provider and pharmacist when you get new medicine.How should use FLOLANoFLOLAN should only be given by infusion through catheter placed in vein (intravenous infusion) using an infusion pump.oYour first treatment will be given to you by your healthcare provider or nurse. This is so your healthcare provider can monitor you and find the best dose for you.oIf your healthcare provider decides that you or your caregiver can give infusions of FLOLAN at home, you or your caregiver will receive training on the right way to mix and infuse FLOLAN. Do not try to infuse FLOLAN until you have been shown the right way to infuse FLOLAN by your healthcare provider.oTreatment will be needed for long period of time, possibly years. You must be able to accept and care for catheter and infusion pump in order to be treated with FLOLAN.oUse FLOLAN exactly as your healthcare provider tells you to.oDo not change your dose or stop your infusion without talking to your healthcare provider. Stopping FLOLAN suddenly can cause serious side effects.oYou should have backup infusion pump and extra supplies needed for your infusion of FLOLAN.oFollow your healthcare providers instructions for taking blood thinner medicines, if prescribed for you.oBefore you use FLOLAN, you must mix (reconstitute) FLOLAN powder with pH 12 STERILE DILUENT for FLOLAN (comes in plastic bottle).oDo not mix FLOLAN with any other diluent. You must use pH 12 STERILE DILUENT for FLOLAN.oFLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG). Only use materials provided by healthcare provider or pharmacist. See How should store and use FLOLAN for more information about how to use and store FLOLAN the right way.oA mixed solution of FLOLAN is clear and colorless. Do not use FLOLAN if the mixed solution looks discolored or cloudy, or if the solution has flakes or particles in it.Using more than the prescribed dose of FLOLAN can lead to death. If you use more than the prescribed dose of FLOLAN, call your healthcare provider or go to the nearest emergency room right away.What are the possible side effects of FLOLANFLOLAN can cause serious side effects, including: oFluid in your lungs (pulmonary edema). If you develop pulmonary edema after starting FLOLAN, your healthcare provider will stop your treatment and you should not receive FLOLAN again.oWorsening symptoms of pulmonary arterial hypertension (PAH) with sudden decrease in the dose of FLOLAN. Do not change your dose of FLOLAN or stop your infusion without talking to your healthcare provider. If you suddenly stop or decrease your dose of FLOLAN you may develop worsening symptoms of your PAH, including shortness of breath, dizziness, weakness, or loss of strength.oWidening of your blood vessels (vasodilation). Vasodilation reactions can happen after you start FLOLAN. These reactions are common and may cause low blood pressure (hypotension), flushing, nausea, vomiting, dizziness, and headache. Your healthcare provider should check your blood pressure regularly during treatment with FLOLAN, especially when you start FLOLAN and after your dose is changed.oIncreased risk for bleeding. FLOLAN affects how well your blood clots, so your risk for bleeding is increased. This is especially true if you have other risk factors for bleeding. Tell your healthcare provider if you develop any unusual bruising or bleeding.The most common side effects of FLOLAN include:odizzinessojaw painoheadacheomuscle or bone painonausea or vomitingThese are not all the possible side effects of FLOLAN. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store and use FLOLANoStore FLOLAN powder at room temperature between 59F to 77F (15C to 25C). oProtect FLOLAN powder from light. Keep unopened vial of FLOLAN in the carton until you are ready to mix.oStore the pH 12 STERILE DILUENT for FLOLAN at room temperature, 59F to 77F (15C to 25C). Do not freeze.oVials of pH 12 STERILE DILUENT for FLOLAN are for one-time use only. Throw away any unused diluent.oThrow away any vials of FLOLAN powder and pH 12 STERILE DILUENT for FLOLAN that are out of date or that you no longer need.How to store mixed solutions of FLOLAN:oOnce FLOLAN and the diluent are mixed together, you may use right away or store in the refrigerator. Refrigerate at 36F to 46F (2C to 8C). oProtect the mixed solution of FLOLAN from light until you are ready to use it. oDo not freeze mixed solutions. Throw away any mixed solution that has been frozen.oFreshly prepared mixed solutions may be stored in the refrigerator for up to days.oMixed solutions (freshly prepared or taken out of the refrigerator) are stable for up to days at 77F (25C), up to days at 86F (30C), up to day at 95F (35C) or up to 12 hours at 104F (40C).oFLOLAN mixed with pH 12 STERILE DILUENT for FLOLAN does not require use with cold pouch.oThrow away any mixed solution if it has been refrigerated for more than days.Keep FLOLAN and all medicines out of the reach of children.General information about the safe and effective use of FLOLANMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use FLOLAN for condition for which it was not prescribed. Do not give FLOLAN to other people, even if they have the same symptoms that you have. It may harm them.This leaflet summarizes the most important information about FLOLAN. You can ask your healthcare provider or pharmacist for information about FLOLAN that is written for health professionals.What are the ingredients in FLOLANActive ingredient: epoprostenol sodium.Inactive ingredients: glycine, mannitol, sodium chloride. Sodium hydroxide may have been added.The pH 12 STERILE DILUENT for FLOLAN contains: glycine, sodium chloride, sodium hydroxide, and Water for Injection.GlaxoSmithKlineResearch Triangle Park, NC 27709Trademark is owned by or licensed to the GSK group of companies.(C)2021 GSK group of companies or its licensor.FLL:6PIL This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 8/2021. ohave certain types of heart failure. Talk to your healthcare provider before using FLOLAN if you have heart failure.. oare allergic to FLOLAN or any of the ingredients in FLOLAN. See the end of this leaflet for complete list of ingredients in FLOLAN.. oare allergic to any medicine.. oare pregnant or plan to become pregnant. It is not known if FLOLAN will harm your unborn baby. You and your healthcare provider should decide if you will use FLOLAN.. oare breastfeeding or plan to breastfeed. It is not known if FLOLAN passes into your breast milk. You and your healthcare provider should decide if you will take FLOLAN or breastfeed. You should not do both.. oa water pill (diuretic). oa medicine for high blood pressure (hypertension). oa blood thinner medicine (antiplatelet or anticoagulant medicine). oFLOLAN should only be given by infusion through catheter placed in vein (intravenous infusion) using an infusion pump.. oYour first treatment will be given to you by your healthcare provider or nurse. This is so your healthcare provider can monitor you and find the best dose for you.. oIf your healthcare provider decides that you or your caregiver can give infusions of FLOLAN at home, you or your caregiver will receive training on the right way to mix and infuse FLOLAN. Do not try to infuse FLOLAN until you have been shown the right way to infuse FLOLAN by your healthcare provider.. oTreatment will be needed for long period of time, possibly years. You must be able to accept and care for catheter and infusion pump in order to be treated with FLOLAN.. oUse FLOLAN exactly as your healthcare provider tells you to.. oDo not change your dose or stop your infusion without talking to your healthcare provider. Stopping FLOLAN suddenly can cause serious side effects.. oYou should have backup infusion pump and extra supplies needed for your infusion of FLOLAN.. oFollow your healthcare providers instructions for taking blood thinner medicines, if prescribed for you.. oBefore you use FLOLAN, you must mix (reconstitute) FLOLAN powder with pH 12 STERILE DILUENT for FLOLAN (comes in plastic bottle).oDo not mix FLOLAN with any other diluent. You must use pH 12 STERILE DILUENT for FLOLAN.oFLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG). Only use materials provided by healthcare provider or pharmacist.. oDo not mix FLOLAN with any other diluent. You must use pH 12 STERILE DILUENT for FLOLAN.. oFLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG). Only use materials provided by healthcare provider or pharmacist.. See How should store and use FLOLAN for more information about how to use and store FLOLAN the right way.. oA mixed solution of FLOLAN is clear and colorless. Do not use FLOLAN if the mixed solution looks discolored or cloudy, or if the solution has flakes or particles in it.. oFluid in your lungs (pulmonary edema). If you develop pulmonary edema after starting FLOLAN, your healthcare provider will stop your treatment and you should not receive FLOLAN again.. oWorsening symptoms of pulmonary arterial hypertension (PAH) with sudden decrease in the dose of FLOLAN. Do not change your dose of FLOLAN or stop your infusion without talking to your healthcare provider. If you suddenly stop or decrease your dose of FLOLAN you may develop worsening symptoms of your PAH, including shortness of breath, dizziness, weakness, or loss of strength.. oWidening of your blood vessels (vasodilation). Vasodilation reactions can happen after you start FLOLAN. These reactions are common and may cause low blood pressure (hypotension), flushing, nausea, vomiting, dizziness, and headache. Your healthcare provider should check your blood pressure regularly during treatment with FLOLAN, especially when you start FLOLAN and after your dose is changed.. oIncreased risk for bleeding. FLOLAN affects how well your blood clots, so your risk for bleeding is increased. This is especially true if you have other risk factors for bleeding. Tell your healthcare provider if you develop any unusual bruising or bleeding.. odizziness. ojaw pain. oheadache. omuscle or bone pain. onausea or vomiting. oStore FLOLAN powder at room temperature between 59F to 77F (15C to 25C). oProtect FLOLAN powder from light. Keep unopened vial of FLOLAN in the carton until you are ready to mix.. oStore the pH 12 STERILE DILUENT for FLOLAN at room temperature, 59F to 77F (15C to 25C). Do not freeze.. oVials of pH 12 STERILE DILUENT for FLOLAN are for one-time use only. Throw away any unused diluent.. oThrow away any vials of FLOLAN powder and pH 12 STERILE DILUENT for FLOLAN that are out of date or that you no longer need.. oOnce FLOLAN and the diluent are mixed together, you may use right away or store in the refrigerator. Refrigerate at 36F to 46F (2C to 8C). oProtect the mixed solution of FLOLAN from light until you are ready to use it. oDo not freeze mixed solutions. Throw away any mixed solution that has been frozen.. oFreshly prepared mixed solutions may be stored in the refrigerator for up to days.. oMixed solutions (freshly prepared or taken out of the refrigerator) are stable for up to days at 77F (25C), up to days at 86F (30C), up to day at 95F (35C) or up to 12 hours at 104F (40C).. oFLOLAN mixed with pH 12 STERILE DILUENT for FLOLAN does not require use with cold pouch.. oThrow away any mixed solution if it has been refrigerated for more than days.. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 8/2021.

SPL UNCLASSIFIED SECTION.

2.1 Reconstitution. Each vial is for single use only; discard any unused diluent or unused reconstituted solution.Select 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 gives directions for preparing several different concentrations of FLOLAN. See storage and administration time limits for the reconstituted FLOLAN below.Table 1. Reconstitution and Dilution Instructions for FLOLAN Using pH 12 STERILE DILUENT for FLOLAN.a Higher concentrations may be prepared for patients who receive FLOLAN long-term.To make 100 mL of solution with final concentration of:Directions:3,000 ng/mLDissolve contents of one 0.5-mg vial with mL of sterile diluent. Withdraw mL and add to sufficient sterile diluent to make total of 100 mL.5,000 ng/mLDissolve contents of one 0.5-mg vial with mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make total of 100 mL.10,000 ng/mLDissolve contents of two 0.5-mg vials each with mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make total of 100 mL.15,000 ng/mLa Dissolve contents of one 1.5-mg vial with mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make total of 100 mL.Storage and Administration Limits for Reconstituted FLOLANoFreshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2C to 8C (36F to 46F) for no longer than days can be administered up to:o72 hours at up to 25C (77F).o48 hours at up to 30C (86F).o24 hours at up to 35C (95F).o12 hours at up to 40C (104F). oReconstituted solutions can be used immediately. Refrigerate at 2C to 8C (36F to 46F) if not used immediately.oProtect from light.oDo not freeze reconstituted solutions.. oFreshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2C to 8C (36F to 46F) for no longer than days can be administered up to:o72 hours at up to 25C (77F).o48 hours at up to 30C (86F).o24 hours at up to 35C (95F).o12 hours at up to 40C (104F). o72 hours at up to 25C (77F).. o48 hours at up to 30C (86F).. o24 hours at up to 35C (95F).. o12 hours at up to 40C (104F).. oReconstituted solutions can be used immediately. Refrigerate at 2C to 8C (36F to 46F) if not used immediately.. oProtect from light.. oDo not freeze reconstituted solutions.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryLimited 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 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 ConsiderationsDisease-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.DataAnimal Data: Embryo-fetal development studies have been performed in rats and rabbits during organogenesis. Epoprostenol sodium doses up to 100 mcg/kg/day, 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 postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at 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 SummaryThere 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 mothers 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oPulmonary edema: Discontinue therapy if pulmonary edema occurs. (5.1)oRebound pulmonary hypertension: Do not abruptly discontinue or decrease the dose. (5.2)oVasodilation reactions: Monitor blood pressure and symptoms regularly during initiation and after dose change. (5.3)oIncreased risk for bleeding: Increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding. (5.4). oPulmonary edema: Discontinue therapy if pulmonary edema occurs. (5.1). oRebound pulmonary hypertension: Do not abruptly discontinue or decrease the dose. (5.2). oVasodilation reactions: Monitor blood pressure and symptoms regularly during initiation and after dose change. (5.3). oIncreased risk for bleeding: Increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding. (5.4). 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 patients death was judged attributable to the interruption of FLOLAN.. 5.3 Vasodilation. FLOLAN is 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 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)].