Epoprostenol

5 WARNINGS AND PRECAUTIONS • Do not abruptly lower the dose or withdraw dosing. All dosing initiation and changes should be closely monitored. ( 5.2 , 5.3 ) 5.1 Dose Initiation Epoprostenol is a potent pulmonary and systemic vasodilator. Initiate epoprostenol in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated. 5.2 Chronic Use and Dose Adjustment During chronic use, deliver epoprostenol continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of epoprostenol and in routine catheter care. Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of epoprostenol may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with epoprostenol will likely be needed for prolonged periods, possibly years, so consider the patient’s capacity to accept and care for a permanent intravenous catheter and infusion pump. Based on clinical trials, the acute hemodynamic response (reduction in pulmonary artery resistance) to epoprostenol did not correlate well with improvement in exercise tolerance or survival during chronic use of epoprostenol. Adjust dosage of epoprostenol during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol [see Dosage and Administration (2.2) ] . Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours. 5.3 Withdrawal Effects Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III primary pulmonary hypertension patient’s death was judged attributable to the interruption of epoprostenol. Avoid abrupt withdrawal.

6 ADVERSE REACTIONS • Most common adverse reactions during: – Dose Initiation and Escalation: Nausea, vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia ( 6.1 ) – Chronic Dosing: Headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system. Adverse Events during Dose Initiation and Escalation During early clinical trials, epoprostenol was increased in 2 ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of epoprostenol. The most common dose-limiting adverse events (occurring in > 1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 8 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency. Table 8: Adverse Events during Dose Initiation and Escalation Adverse Events Occurring in > 1% of Patients Epoprostenol (n=391) Flushing 58% Headache 49% Nausea/vomiting 32% Hypotension 16% Anxiety, nervousness, agitation 11% Chest pain 11% Dizziness 8% Bradycardia 5% Abdominal pain 5% Musculoskeletal pain 3% Dyspnea 2% Back pain 2% Sweating 1% Dyspepsia 1% Hypesthesia/paresthesia 1% Tachycardia 1% Adverse Events during Chronic Administration Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of epoprostenol (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to epoprostenol. These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during epoprostenol therapy, and a role for the drug in these events cannot be excluded. Adverse Events during Chronic Administration for Idiopathic or Heritable PAH In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 9 lists adverse events that occurred at a rate at least 10% greater on epoprostenol than on conventional therapy in controlled trials for idiopathic or heritable PAH. Table 9: Adverse Events Regardless of Attribution Occurring in Patients with Idiopathic or Heritable PAH with ≥10% Difference between Epoprostenol and Conventional Therapy Alone Adverse Event Epoprostenol (n = 52) Conventional Therapy (n = 54) Occurrence More Common With Epoprostenol General Chills/fever/sepsis/flu-like symptoms 25% 11% Cardiovascular Tachycardia 35% 24% Flushing 42% 2% Gastrointestinal Diarrhea 37% 6% Nausea/vomiting 67% 48% Musculoskeletal Jaw pain 54% 0% Myalgia 44% 31% Nonspecific musculoskeletal pain 35% 15% Neurological Anxiety/nervousness/tremor 21% 9% Dizziness 83% 70% Headache 83% 33% Hypesthesia, hyperesthesia, paresthesia 12% 2% Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol. Adverse Events during Chronic Administration for PAH/SSD In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 10 lists adverse events that occurred at a rate at least 10% greater on epoprostenol in the controlled trial. Table 10: Adverse Events Regardless of Attribution Occurring in Patients with PAH/SSD With ≥10% Difference Between Epoprostenol and Conventional Therapy Alone Adverse Event Epoprostenol (n = 56) Conventional Therapy (n = 55) Cardiovascular Flushing 23% 0% Hypotension 13% 0% Gastrointestinal Anorexia 66% 47% Nausea/vomiting 41% 16% Diarrhea 50% 5% Musculoskeletal Jaw pain 75% 0% Pain/neck pain/arthralgia 84% 65% Neurological Headache 46% 5% Skin and Appendages Skin ulcer 39% 24% Eczema/rash/urticaria 25% 4% Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure. Adverse Events Attributable to the Drug Delivery System Chronic infusions of epoprostenol 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 epoprostenol. This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in epoprostenol were associated with symptoms related to excess or insufficient epoprostenol, respectively. 6.2 Post-Marketing Experience In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of epoprostenol. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to epoprostenol. Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly. Cardiac: High output cardiac failure (consider dose reduction) [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) , and Warnings and Precautions (5.3) ]. Endocrine and Metabolic: Hyperthyroidism

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from case series and case reports with epoprostenol have not established a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes when 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. 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 epoprostenol 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 studies of epoprostenol in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

8.1 Pregnancy Risk Summary Limited published data from case series and case reports with epoprostenol have not established a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes when 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.