FLOLAN

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 a 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 )

2 DOSAGE AND ADMINISTRATION • Initiate intravenous infusion through a central venous catheter at 2 ng/kg/min. ( 2.2 , 2.3 ) • Change dose in 1- to 2-ng/kg/min increments at intervals of at least 15 minutes based on clinical response. ( 2.2 ) • Avoid 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 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. 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/mL Dissolve contents of one 0.5 ‑ mg vial with 5 mL of sterile diluent. Withdraw 3 mL and add to sufficient sterile diluent to make a total of 100 mL. 5,000 ng/mL Dissolve contents of one 0.5 ‑ mg vial with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 10,000 ng/mL Dissolve contents of two 0.5 ‑ mg vials each with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 15,000 ng/mL a Dissolve contents of one 1.5 ‑ mg vial with 5 mL of sterile diluent. Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 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). o 36 hours at up to 30°C (86°F). o 24 hours at up to 35°C (95°F). o 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: Flolan infusion rate formula

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 a hypersensitivity to the drug or any of its ingredients. • Heart failure with reduced ejection fraction. ( 4 ) • Hypersensitivity to FLOLAN or any of its ingredients. ( 4 )

5 WARNINGS AND PRECAUTIONS • Pulmonary edema: Discontinue therapy if pulmonary edema occurs. ( 5.1 ) • Rebound pulmonary hypertension: Do not abruptly discontinue or decrease the dose. ( 5.2 ) • Vasodilation reactions: Monitor blood pressure and symptoms regularly during initiation and after dose change. ( 5.3 ) • Increased 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 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 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 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. 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 Therapy Adverse Reaction Idiopathic or Heritable PAH PAH/SSD FLOLAN Conventional Therapy FLOLAN Conventional Therapy (n = 52) (n = 54) (n = 56) (n = 55) Body as a whole Jaw pain 54% 0% 75% 0% Nonspecific musculoskeletal pain 35% 15% 84% 65% Headache 83% 33% 46% 5% Chills/fever/sepsis/flu-like symptoms 25% 11% 13% 11% Cardiovascular system Flushing 42% 2% 23% 0% Hypotension 27% 31% 13% 0% Tachycardia 35% 24% 43% 42% Digestive system Anorexia 25% 30% 66% 47% Nausea/Vomiting 67% 48% 41% 16% Diarrhea 37% 6% 50% 5% Skin and Appendages Skin ulcer - - 39% 24% Eczema/rash/urticaria 10% 13% 25% 4% Musculoskeletal System Myalgia 44% 31% - - Nervous system Anxiety/hyperkinesias/nervousness/tremor 21% 9% 7% 5% Hyperesthesia/hypesthesia/paresthesia 12% 2% 5% 0% Dizziness 83% 70% 59% 76% 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/m 2 /day in rats, 2.5 times the MRHD, and 1,180 mcg/m 2 /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/m 2 /day, 2.5 times the MRHD based on body surface area). There was no effect on growth and development of the offspring.