Treprostinil

1 INDICATIONS AND USAGE Treprostinil injection is a prostacyclin vasodilator 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.

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.

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 injection 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 has been shown to be stable at ambient temperature when stored for up to14 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 Injection0.9% 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. 2.3 Initial Dose for Patients Transitioning to an Implantable Intravenous Infusion Pump The initial dose of treprostinil injection should be the same as the current dose the patient is receiving using the external infusion pump at the time of transition. 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 permi

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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 a NA b NA b 1 32 Leading to discontinuation 0 3 0 7 a based on prescriptions for narcotics, not actual use b 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 control

5 WARNINGS AND PRECAUTIONS Chronic intravenous infusions delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. ( 5.1 ) Do not abruptly lower the dose or withdraw dosing. ( 5.2 ) Treprostinil injection may cause symptomatic hypotension. ( 5.4 ) Treprostinil injection inhibits platelet aggregation and increases the risk of bleeding. ( 5.5 ) 5.1 Risk of Catheter-Related Bloodstream Infection Chronic intravenous infusions of treprostinil injection delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous infusion is the preferred mode of administration. In an open-label study of IV treprostinil (n=47) using an external infusion pump, there were seven catheter-related line infections during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined as any positive blood culture) event per 3 years of use. Administration of IV treprostinil injection with a high pH glycine diluent has been associated with a lowerincidence of BSIs when compared to neutral diluents (sterile water, 0.9% sodium chloride) whenused along with catheter care guidelines. In an open-label study of an implantable pump (n=60), there were two blood stream infections (BSIs) related to the implant procedure during approximately 265 patient years. 5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction Avoid abrupt withdrawal or sudden large reductions in dosage of treprostinil injection, which may result in worsening of PAH symptoms. 5.3 Patients with Hepatic Insufficiency Titrate treprostinil injection slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic function [see Dosage and Administration (2.5) , Use in Specific Populations (8.6 ) , and Clinical Pharmacology (12.3) ] . 5.4 Risk of Symptomatic Hypotension Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with treprostinil injection may produce symptomatic hypotension. 5.5 Risk of Bleeding Treprostinil injection inhibits platelet aggregation and increases the risk of bleeding.

4 CONTRAINDICATIONS None None

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.