Veletri

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, please contact: JANSSEN at 1-800-526-7736 (1-800 JANSSEN) 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 Postmarketing 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

4 CONTRAINDICATIONS A large study evaluating the effect of epoprostenol 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 epoprostenol plus conventional therapy than in those receiving conventional therapy alone. The chronic use of VELETRI in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated. Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. VELETRI should not be used chronically in patients who develop pulmonary edema during dose initiation. VELETRI is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds. Congestive heart failure due to severe left ventricular systolic dysfunction ( 4 ) Pulmonary edema ( 4 ) Hypersensitivity to the drug or to structurally related compounds ( 4 )

11 DESCRIPTION Epoprostenol sodium is the sodium salt of epoprostenol, formulated as a sterile lyophilized powder for intravenous (IV) administration. Each vial of VELETRI contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 50 mg arginine and 100 mg sucrose. Sodium hydroxide is added to adjust pH. Epoprostenol (PGI 2 , PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation. Epoprostenol is (5 Z ,9a,11a,13 E ,15 S )-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid. Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of C 20 H 31 NaO 5 . The structural formula is: VELETRI is a white to off-white lyophilized powder material. It is reconstituted with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. The reconstituted solution of VELETRI has a pH ranging from 11 to 13 and is increasingly unstable at a lower pH. Chemical Structure

2 DOSAGE AND ADMINISTRATION Important Note: Reconstitute VELETRI only as directed with Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not dilute reconstituted solutions of VELETRI or administer it with other parenteral solutions or medications [see Dosage and Administration (2.4) ] . Dosage - Infusion of VELETRI should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established. ( 2.1 ) - If symptoms of pulmonary hypertension persist or recur after improving - the infusion should be increased 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. ( 2.2 ) Administration - VELETRI is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. ( 2.3 ) - Do not mix with any other parenteral medications or solutions prior to or during administration. ( 2.4 ) Reconstitution - Reconstituted in vial with only 5 mL of either Sterile Water for Injection or Sodium Chloride 0.9% Injection. - VELETRI solution reconstituted and immediately diluted to the final concentration in the drug delivery reservoir can be administered per the conditions of use as outlined in Table 1. ( 2.4 ) - Solution for chronic delivery should be prepared in a drug delivery reservoir appropriate for the infusion pump. ( 2.4 ) 2.1 Dosage Prepare continuous chronic infusion of VELETRI as directed, and administer through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of VELETRI at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted. If dose-limiting pharmacologic effects occur, then decrease the infusion rate until VELETRI is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, use a lower dose. 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. 2.2 Dosage Adjustments 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 events due to excessive doses of VELETRI. In general, expect increases in dose from the initial chronic dose. Consider increments in dose if symptoms of pulmonary hypertension persist or recur. Adjust 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. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated. During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve [see Adverse Reactions (6.1 and 6.2) ] . Avoid abrupt withdrawal of VELETRI or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of VELETRI should be adjusted only under the direction of a physician. In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass. 2.3 Administration VELETRI, once prepared as directed [see Dosage and Administration (2.4) ] , is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, VELETRI may be administered peripherally. Infusion sets with an in-line 0.22 micron filter should be used. The ambulatory infusion pump used to administer VELETRI 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 VELETRI. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials. To avoid potential interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered. 2.4 Reconstitution VELETRI is stable only when reconstituted as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not reconstitute or mix VELETRI with any other parenteral medications or solutions prior to or during administration. Each vial is for single-dose; discard any unused solution. Use after reconstitution and immediate dilution to final concentration. Use at room temperature (77°F/25°C) VELETRI solution reconstituted with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection , and immediately diluted to the final concentration in the drug delivery reservoir can be administered at room temperature per the conditions of use as outlined in Table 1. Table 1: Maximum Duration of Administration (hours) at Room Temperature (77°F/ 25°C) of Fully Diluted Solutions in the Drug Delivery Reservoir Short excursions at 104°F (40°C) are permitted for up to: 2 hours for concentrations below 15,000 ng/mL 4 hours for concentrations between 15,000 ng/mL and 60,000 ng/mL 8 hours for concentrations above 60,000 ng/mL Final concentration range Immediate administration If stored for up to 8 days at 36° to 46°F (2° to 8°C) 0.5 mg vial ≥3,000 ng/mL and <15,000 ng/mL 48 hours 24 hours 1.5 mg vial ≥15,000 ng/mL and <60,000 ng/mL 48 hours 48 hours ≥60,000 ng/mL 72 hours 48 hours Use at higher temperatures >77°F up to 104°F (>25° to 40°C) Temperatures greater than 77°F and up to 86°F (>25°C to 30°C): A single reservoir of fully diluted solution of 60,000 ng/mL or above of VELETRI prepared as directed can be administered (either immediately or after up to 8 days storage at 36° to 46°F (2° to 8°C)) for up to 48 hours. For diluted solutions of less than 60,000 ng/mL, pump reservoirs should be changed every 24 hours. Temperatures up to 104°F (40°C): Fully diluted solutions of 60,000 ng/mL or above of VELETRI, prepared as directed, can be immediately administered for periods up to 24 hours. Do not expose this solution to direct sunlight. A concentration for the solution of VELETRI should be selected 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. VELETRI, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump. Outlined in Table 2 are directions for preparing different concentrations of VELETRI. Each vial is for single-dose; discard any unused solution. Table 2: Reconstitution and Dilution Instructions To make 100 mL of solution with Final Concentration (ng/mL) of: Directions Using the 0.5 mg vial 3,000 ng/ml Dissolve contents of one 0.5 mg vial with 5 mL of Sterile Water for Injection, USP or Sodium Chloride 0.9% Injection, USP. Withdraw 3 mL of the vial contents and add to a sufficient volume of the identical 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 Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical 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 Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. Using the 1.5 mg vial 15,000 ng/mL Higher concentrations may be prepared for patients who receive VELETRI long-term. Dissolve contents of one 1.5 mg vial with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. 30,000 ng/mL Dissolve contents of two 1.5 mg vials each with 5 mL of Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Withdraw entire vial contents and add to a sufficient volume of the identical diluent to make a total of 100 mL. Infusion rates may be calculated using the following formula: Infusion Rate (mL/hr)= [Dose (ng/kg/min)×Weight (kg)×60 min/hr] Final Concentration (ng/mL) Tables 3 to 7 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of VELETRI to be used. These tables may be used to select the most appropriate concentration of VELETRI that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. For infusion/dose rates lower than those listed in Tables 3 to 7, it is recommended that the pump rate be set by a healthcare professional such that steady state is achieved in the patient, keeping in mind the half-life of epoprostenol is no more than six minutes. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of VELETRI. Table 3: Infusion Rates for VELETRI at a Concentration of 3,000 ng/mL Patient weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 2 3 4 5 Infusion Delivery Rate (mL/hr) 20 – 1.2 1.6 2.0 30 1.2 1.8 2.4 3.0 40 1.6 2.4 3.2 4.0 50 2.0 3.0 4.0 – 60 2.4 3.6 – – 70 2.8 – – – 80 3.2 – – – 90 3.6 – – – 100 4.0 – – – Table 4: Infusion Rates for VELETRI at a Concentration of 5,000 ng/mL Patient weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 2 4 6 8 10 12 14 Infusion Delivery Rate (mL/hr) 20 – 1.0 1.4 1.9 2.4 2.9 3.4 30 – 1.4 2.2 2.9 3.6 – – 40 1.0 1.9 2.9 3.8 – – – 50 1.2 2.4 3.6 – – – – 60 1.4 2.9 – – – – – 70 1.7 3.4 – – – – – 80 1.9 3.8 – – – – – 90 2.2 – – – – – – 100 2.4 – – – – – – Table 5: Infusion Rates for VELETRI at a Concentration of 10,000 ng/mL Patient weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 20 – – 1.0 1.2 1.4 1.7 1.9 30 – 1.1 1.4 1.8 2.2 2.5 2.9 40 1.0 1.4 1.9 2.4 2.9 3.4 3.8 50 1.2 1.8 2.4 3.0 3.6 – – 60 1.4 2.2 2.9 3.6 – – – 70 1.7 2.5 3.4 – – – – 80 1.9 2.9 3.8 – – – – 90 2.2 3.2 – – – – – 100 2.4 3.6 – – – – – Table 6: Infusion Rates for VELETRI at a Concentration of 15,000 ng/mL Patient weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 4 6 8 10 12 14 16 Infusion Delivery Rate (mL/hr) 20 – – – – 1.0 1.1 1.3 30 – – 1.0 1.2 1.4 1.7 1.9 40 – 1.0 1.3 1.6 1.9 2.2 2.6 50 – 1.2 1.6 2.0 2.4 2.8 3.2 60 1.0 1.4 1.9 2.4 2.9 3.4 3.8 70 1.1 1.7 2.2 2.8 3.4 3.9 – 80 1.3 1.9 2.6 3.2 3.8 – – 90 1.4 2.2 2.9 3.6 – – – 100 1.6 2.4 3.2 4.0 – – – Table 7: Infusion Rates for VELETRI at a Concentration of 30,000 ng/mL Patient weight (kg) Dose or Drug Delivery Rate (ng/kg/min) 6 8 10 12 14 16 30 – – – – – 1.0 40 – – – 1.0 1.1 1.3 50 – – 1.0 1.2 1.4 1.6 60 – 1.0 1.2 1.4 1.7 1.9 70 – 1.1 1.4 1.7 2.0 2.2 80 1.0 1.3 1.6 1.9 2.2 2.6 90 1.1 1.4 1.8 2.2 2.5 2.9 100 1.2 1.6 2.0 2.4 2.8 3.2

1 INDICATIONS AND USAGE VELETRI is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III–IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases. VELETRI is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III–IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases. ( 1 )

10 OVERDOSAGE Signs and symptoms of excessive doses of epoprostenol during clinical trials are the expected dose-limiting pharmacologic effects of epoprostenol, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of epoprostenol. One patient with secondary pulmonary hypertension accidentally received 50 mL of an unspecified concentration of epoprostenol. The patient vomited and became unconscious with an initially unrecordable blood pressure. Epoprostenol was discontinued and the patient regained consciousness within seconds. In clinical practice, fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of epoprostenol. Single intravenous doses of epoprostenol 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.

7 DRUG INTERACTIONS Additional reductions in blood pressure may occur when VELETRI is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for VELETRI to increase the risk of bleeding. However, patients receiving infusions of epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen. In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with epoprostenol was initiated, apparent oral clearance values for furosemide (n=23) and digoxin (n=30) were decreased by 13% and 15%, respectively, on the second day of therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be clinically significant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with epoprostenol, which may be clinically significant in patients prone to digoxin toxicity. Diuretics, antihypertensive agents, or other vasodilators : reduction in blood pressure ( 7 ) Antiplatelet agents or anticoagulants : increase the risk of bleeding ( 7 ) Patients on digoxin : elevations of digoxin concentrations clinically significant in patients prone to digoxin toxicity ( 7 )

12 CLINICAL PHARMACOLOGY 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 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. 12.3 Pharmacokinetics Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (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. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n=954) and females (n=1,024). Tritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF 1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF 1α (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.

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 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.

12.3 Pharmacokinetics Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (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. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n=954) and females (n=1,024). Tritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF 1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF 1α (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.

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3 DOSAGE FORMS AND STRENGTHS VELETRI contains epoprostenol sodium equivalent to 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol and is supplied as a sterile lyophilized material in a 10 mL vial. Injection : 10 mL single-dose vial with 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) VELETRI. ( 3 )

Veletri epoprostenol epoprostenol epoprostenol arginine sucrose sodium hydroxide Veletri epoprostenol epoprostenol epoprostenol arginine sucrose sodium hydroxide

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. Fertility was not impaired in rats given epoprostenol by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m 2 /day, IV] based on body surface area).

13 NONCLINICAL TOXICOLOGY 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. Fertility was not impaired in rats given epoprostenol by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m 2 /day, IV] based on body surface area).

NDA022260

Veletri

epoprostenol

66215-402

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 0.5 mg Vial Carton NDC 66215-403-01 Single-dose Vial Discard unused portion. VELETRI ® (epoprostenol) for Injection 0.5 mg (500,000 ng)/vial Sterile, Lyophilized Product For Intravenous Infusion Only Rx only janssen Principal Display Panel - 0.5 mg Vial Carton

Manufactured for: Actelion Pharmaceuticals US, Inc. a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2008 – 2019 Actelion Pharmaceuticals US, Inc. JN20220728

17 PATIENT COUNSELING INFORMATION Patients receiving VELETRI should receive the following information. VELETRI must be reconstituted as directed using only Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. VELETRI is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with VELETRI 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 VELETRI may result in rapid symptomatic deterioration. A patient's decision to receive VELETRI should be based upon the understanding that there is a high likelihood that therapy with VELETRI will be needed for prolonged periods, possibly years. The patient's ability to accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.

14 CLINICAL STUDIES 14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH) Acute Hemodynamic Effects Acute intravenous infusions of epoprostenol for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary arterial pressure (PAPm) were variable and minor. Chronic Infusion in Idiopathic or Heritable PAH Hemodynamic Effects Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks' duration comparing epoprostenol plus conventional therapy to conventional therapy alone. Dosage of epoprostenol was determined as described in Dosage and Administration (2) and averaged 9.2 ng/kg/min at study's end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described. Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received epoprostenol chronically compared to those who did not. Table 11 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment. Table 11: Hemodynamics during Chronic Administration of Epoprostenol in Patients with Idiopathic or Heritable PAH Baseline Mean Change from Baseline at End of Treatment Period At 8 weeks: Epoprostenol N=10, conventional therapy N=11 (N is the number of patients with hemodynamic data). At 12 weeks: Epoprostenol N=38, conventional therapy N=30 (N is the number of patients with hemodynamic data). Hemodynamic Parameter Epoprostenol (N=52) Standard Therapy (N=54) Epoprostenol (N=48) Standard Therapy (N=41) CI=cardiac index, PAPm=mean pulmonary arterial pressure, PVR=pulmonary vascular resistance, SAPm=mean systemic arterial pressure, SV=stroke volume, TPR=total pulmonary resistance. CI (L/min/m 2 ) 2.0 2.0 0.3 Denotes statistically significant difference between Epoprostenol and conventional therapy groups. -0.1 PAPm (mmHg) 60 60 -5 1 PVR (Wood U) 16 17 -4 1 SAPm (mmHg) 89 91 -4 -3 SV (mL/beat) 44 43 6 -1 TPR (Wood U) 20 21 -5 1 These hemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, nonrandomized study. Clinical Effects Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous epoprostenol plus conventional therapy (N=52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N=54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index. Survival was improved in NYHA functional Class III and Class IV patients with idiopathic or heritable PAH treated with epoprostenol for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p=0.003). Chronic Infusion in PAH/Scleroderma Spectrum of Diseases (SSD) Hemodynamic Effects Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks' duration comparing epoprostenol plus conventional therapy (N=56) to conventional therapy alone (N=55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of epoprostenol was determined as described in Dosage and Administration (2 ) and averaged 11.2 ng/kg/min at study's end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not. Table 12 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment. Table 12: Hemodynamics during Chronic Administration of Epoprostenol in Patients with PAH/SSD Baseline Mean Change from Baseline at 12 Weeks Hemodynamic Parameter Epoprostenol (N=56) Conventional Therapy (N=55) Epoprostenol (N=50) Conventional Therapy (N=48) CI=cardiac index, PAPm=mean pulmonary arterial pressure, RAPm=mean right atrial pressure, PVR=pulmonary vascular resistance, SAPm=mean systemic arterial pressure. CI (L/min/m 2 ) 1.9 2.2 0.5 Denotes statistically significant difference between Epoprostenol and conventional therapy groups (N is the number of patients with hemodynamic data). -0.1 PAPm (mmHg) 51 49 -5 1 RAPm (mmHg) 13 11 -1 1 PVR (Wood U) 14 11 -5 1 SAPm (mmHg) 93 89 -8 -1 Clinical Effects Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous epoprostenol plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12 weeks were not available for 5 patients treated with epoprostenol and 7 patients treated with conventional therapy alone. No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died. No controlled clinical trials with epoprostenol have been performed in patients with pulmonary hypertension associated with other diseases.

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.

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

8.1 Pregnancy Risk Summary Limited published data from case series and case reports with VELETRI 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from case series and case reports with VELETRI 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 VELETRI 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VELETRI is supplied as a sterile lyophilized material in 10 mL vials. 10 mL vial with a white flip-off seal containing epoprostenol sodium equivalent to 0.5 mg (500,000 ng) epoprostenol, is packaged in carton of 1 vial (NDC 66215-403-01). 10 mL vial with a red flip-off seal containing epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) epoprostenol, is packaged in carton of 1 vial (NDC 66215-402-01). Store the vials of VELETRI at 68° to 77°F (20° to 25°C) [see USP Controlled Room Temperature] . 16.2 Storage and Stability Unopened vials of VELETRI are stable until the date indicated on the package when stored at 68° to 77°F (20° to 25°C). The unopened vial should be kept in the carton and not exposed to direct sunlight. Use after reconstitution and immediate dilution to final concentration can be found in Dosage and Administration (2.4) Reconstitution, Table 1: Maximum duration of administration (hours) at room temperature (77°F/25°C) of fully diluted solutions in the drug delivery reservoir. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.

16.2 Storage and Stability Unopened vials of VELETRI are stable until the date indicated on the package when stored at 68° to 77°F (20° to 25°C). The unopened vial should be kept in the carton and not exposed to direct sunlight. Use after reconstitution and immediate dilution to final concentration can be found in Dosage and Administration (2.4) Reconstitution, Table 1: Maximum duration of administration (hours) at room temperature (77°F/25°C) of fully diluted solutions in the drug delivery reservoir. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.