treprostinil

1 INDICATIONS AND USAGE Treprostinil injection is a prostacyclin mimetic indicated for: • Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%). ( 1.1 ) • Patients who require transition from epoprostenol, to reduce the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. ( 1.2 ) 1.1 Pulmonary Arterial Hypertension Treprostinil injection is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%) [see Clinical Studies ( 14.1 )] . 1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from Epoprostenol In patients with PAH requiring transition from epoprostenol, treprostinil injection is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

2 DOSAGE AND ADMINISTRATION PAH WHO Group 1 in patients with NYHA Class II-IV symptoms: • Initial dose for patients new to prostacyclin infusion therapy: 1.25 ng/kg/min; increase based on clinical response (increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment, later 2.5 ng/kg/min per week). Avoid abrupt cessation. ( 2.2 , 2.4 ) • Mild to moderate hepatic insufficiency: Decrease initial dose to 0.625 ng/kg/min. Severe hepatic insufficiency: No studies performed. ( 2.5 ) Transition from Epoprostenol: Increase the treprostinil injection dose gradually as the epoprostenol dose is decreased, based on constant observation of response. ( 2.7 ) Administration: Continuous subcutaneous infusion is the preferred mode. Use intravenous (IV) infusion if subcutaneous infusion is not tolerated. ( 2.1 , 2.6 ) 2.1 General Treprostinil injection can be administered with or without further dilution with Sterile Diluent for treprostinil or similar approved high-pH glycine diluent (e.g., Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1 below for storage and administration time limits for the different diluents. Diluted treprostinil injection has been shown to be stable at ambient temperature when stored for up to 14 days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL). Table 1: Selection of Diluent Diluent Storage Limits Administration Limits None See Section 16 16 weeks at 40°C Sterile Diluents for Treprostinil Injection, Flolan, or Epoprostenol 14 days at room temperature 48 hours at 40°C Sterile Water for Injection 0.9% Sodium Chloride for Injection 4 hours at room temperature or 24 hours refrigerated 48 hours at 40°C 2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy Treprostinil injection is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous infusion. Treprostinil injection is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated because of severe site pain or reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min. 2.4 Dosage Adjustments The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of treprostinil injection (headache, nausea, emesis, restlessness, anxiety, and infusion site pain or reaction). The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. Dosage adjustments may be undertaken more often if tolerated. Avoid abrupt cessation of infusion [see Warnings and Precautions ( 5.2 )] . Restarting a treprostinil injection infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of treprostinil injection to be re-titrated. 2.5 Patients with Hepatic Insufficiency In patients with mild or moderate hepatic insufficiency, decrease the initial dose of treprostinil injection to 0.625 ng/kg/min ideal body weight. Treprostinil injection has not been studied in patients with severe hepatic insufficiency [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . 2.6 Administration 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. Preparation Treprostinil injection is administered by subcutaneous or intravenous infusion at a calculated rate based on a patient’s dose (ng/kg/min), weight (kg), and the trep …

3 DOSAGE FORMS AND STRENGTHS 20-mL vial containing 20 mg treprostinil (1 mg per mL). 20-mL vial containing 50 mg treprostinil (2.5 mg per mL). 20-mL vial containing 100 mg treprostinil (5 mg per mL). 20-mL vial containing 200 mg treprostinil (10 mg per mL). • Treprostinil injection is supplied in 20 mL vials containing 20, 50, 100, or 200 mg of treprostinil (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL). ( 3 )

4 CONTRAINDICATIONS None None

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration [see Warnings and Precautions ( 5.1 )] . Most common adverse reactions (incidence >3%) reported in clinical studies with treprostinil injection: subcutaneous infusion site pain and reaction, headache, diarrhea, nausea, jaw pain, vasodilatation, edema, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or contact 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. Adverse Events with Subcutaneously Administered Treprostinil Injection Patients receiving treprostinil injection as a subcutaneous infusion reported a wide range of adverse events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of treprostinil injection, infusion site pain and reaction were the most common adverse events among those treated with treprostinil injection. Infusion site reaction was defined as any local adverse event other than pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration, or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of treatment. Table 3: Percentages of Subjects Reporting Subcutaneous Infusion Site Adverse Events Reaction Pain Placebo Treprostinil Injection Placebo Treprostinil Injection Severe 1 38 2 39 Requiring narcotics* NA † NA † 1 32 Leading to discontinuation 0 3 0 7 * based on prescriptions for narcotics, not actual use † medications used to treat infusion site pain were not distinguished from those used to treat site reactions Other adverse events included diarrhea, jaw pain, edema, vasodilatation, and nausea, and these are generally considered to be related to the pharmacologic effects of treprostinil injection, whether administered subcutaneously or intravenously. Adverse Reactions during Chronic Dosing Table 4 lists adverse reactions that occurred at a rate of at least 3% more frequent in patients treated with subcutaneous treprostinil injection than with placebo in controlled trials in PAH. Table 4: Adverse Reactions in Controlled 12-Week Studies of Subcutaneous Treprostinil Injection and at least 3% more frequent than on Placebo Adverse Reaction Treprostinil Injection (N=236) Percent of Patients Placebo (N=233) Percent of Patients Infusion Site Pain 85 27 Infusion Site Reaction 83 27 Headache 27 23 Diarrhea 25 16 Nausea 22 18 Rash 14 11 Jaw Pain 13 5 Vasodilatation 11 5 Edema 9 3 Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included with the exception of those too general to be informative, and those not plausibly attributable to the use of the drug, because they were associated with the condition being treated or are very common in the treated population. While hypotension occurred in both groups, the event was experienced twice as frequently in the treprostinil injection group as compared to the placebo group (4% in treprostinil injection treatment group versus 2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the administration of treprostinil injection. The safety of treprostinil injection was also studied in a long-term, open-label extension study in which 860 patients were dosed for a mean duration of 1.6 years, with a maximum exposure of 4.6 years. Twenty-nine (29%) percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min). The safety profile during this chronic dosing study was similar to that observed in the 12-week placebo-controlled study except f …

7 DRUG INTERACTIONS • Treprostinil injection dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn. ( 7.1 ) 7.1 Effect of CYP2C8 Inhibitors and Inducers on Treprostinil Dose adjustment of treprostinil may be necessary when co-administered with CYP2C8 inducers or inhibitors. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor gemfibrozil increases exposure (both C max and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer rifampin decreases exposure to treprostinil. It has not been determined if the changes in exposure of treprostinil with inhibitors or inducers of CYP2C8 observed for the oral administration of treprostinil would be similar for treprostinil administered via the parenteral route [see Clinical Pharmacology ( 12.3 )].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug- associated risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated with pulmonary arterial hypertension (see Clinical Considerations) . In animal studies, no adverse reproductive and developmental effects were seen in rats at about 123 and 48 times the human exposure based on C max and AUC, respectively. In rabbits, external fetal and soft tissue malformations and skeletal malformations were observed at about 7 and 5 times the human exposure based on C max and AUC, respectively (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated populations 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 embryo-fetal risk Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. Data Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous administration and with treprostinil diolamine administered orally. In pregnant rats, continuous subcutaneous infusions of treprostinil during organogenesis and late gestational development, at doses as high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous infusion rate, on a ng/m2 basis and about 16 times the average rate achieved in clinical trials), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infusions of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous infusion rate, on a ng/m2 basis, and 5 times the average rate used in clinical trials). In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at doses of up to 450 ng treprostinil/kg/min, did not affect the growth and development of offspring. In studies with orally administered treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development (teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose tested (20 mg/kg/day), which represents about 123 and 48 times the human exposure, when based on Cmax and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no adverse effects were seen (0.5 mg/kg/day) represents about 7 and 5 times the human exposure, when based on C max and AUC of the average subcutaneous infusion rate achieved in clinical trials, respectively. No treprostinil treatment-related effects on labor and delivery were seen in animal studies. Animal reproduction studies are not always predictive of human response. 8.2 Lactation Risk Summary There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Clinical studies of treprostinil injection did not include sufficient numbers of patients aged ≤16 years to determine whether they respond differently from older patients. 8.5 Geriatric Use Clinical studies of treprostinil injection did not …

12.1 Mechanism of Action The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, and inhibition of platelet aggregation.

11 DESCRIPTION Treprostinil injection is a sterile solution of treprostinil, a prostacyclin mimetic, formulated for subcutaneous or intravenous administration. Treprostinil injection is supplied in 20 mL multi-dose vials in four strengths, containing 20 mg, 50 mg, 100 mg, or 200 mg (1 mg/mL, 2.5 mg/mL, 5 mg/mL or 10 mg/mL) of treprostinil. Each mL also contains 5.3 mg sodium chloride (except for the 10 mg/mL strength which contains 4.0 mg sodium chloride), 3 mg metacresol, 6.3 mg sodium citrate, and water for injection. Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2. Treprostinil is chemically stable at room temperature and neutral pH. Treprostinil is (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.52 and a molecular formula of C 23 H 34 O 5 . The structural formula of treprostinil is: Sterile Diluent for Treprostinil Injection is a high-pH (pH~10.4) glycine diluent supplied in a 50 mL single-dose vial containing 50 mL of Sterile Diluent for Treprostinil Injection. Each vial contains 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (to adjust pH), and water for injection. chemical-structure

10 OVERDOSAGE Signs and symptoms of overdose with treprostinil injection during clinical trials are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of treprostinil injection. In controlled clinical trials using an external infusion pump, seven patients received some level of overdose and in open-label follow-on treatment seven additional patients received an overdose; these occurrences resulted from accidental bolus administration of treprostinil injection, errors in pump programmed rate of administration, and prescription of an incorrect dose. In only two cases did excess delivery of treprostinil injection produce an event of substantial hemodynamic concern (hypotension, near-syncope). One pediatric patient was accidentally administered 7.5 mg of treprostinil injection via a central venous catheter. Symptoms included flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness lasting several minutes. The patient subsequently recovered.

16 HOW SUPPLIED/STORAGE AND HANDLING Treprostinil injection is supplied in 20-mL multi-dose vials as sterile solutions in water for injection, individually packaged in cartons. Unopened vials of treprostinil injection are stable until the date indicated when stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. A single vial of treprostinil injection should be used for no more than 30 days after the initial introduction into the vial. Treprostinil injection is supplied as: Treprostinil Injection Concentration Carton of 1 NDC 20 mg/20 mL 1 mg/mL NDC 0781-3420-80 50 mg/20 mL 2.5 mg/mL NDC 0781-3425-80 100 mg/20 mL 5 mg/mL NDC 0781-3427-80 200 mg/20 mL 10 mg/mL NDC 0781-3430-80 Sterile Diluent for treprostinil injection is supplied separately as: NDC 0781-6021-94 Carton of one 50 mL Single-dose vial Discard unused portion.