treprostinil 0.6 MG/ML Inhalation Solution [Tyvaso]

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.

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 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 treprostinil injection concentration (mg/mL). For administration of Undiluted Treprostinil Injection the rate is calculated using the following formula: Undiluted Infusion Rate (mL/hour) = Dose (ng/kg/min) × Weight (kg) × 0.00006 Conversion factor of 0.00006 = 60 min/hour × 0.000001 mg/ng Treprostinil Injection Vial Strength (mg/mL) For administration of Diluted Treprostinil Injection the rate and concentration is calculated using the following formulas: Step 1 Diluted Treprostinil Injection Concentration (mg/mL) Dose (ng/kg/min) × Weight (kg) × 0.00006 = Infusion Rate (mL/hour) The volume of treprostinil injection needed to make the required diluted treprostinil concentration for the given reservoir size can then be calculated using the following formula: Step 2 Volume of Treprostinil Injection (mL) = Diluted Treprostinil Concentration (mg/mL) × Total Volume of Diluted Treprostinil olution in Reservoir (mL) Treprostinil Injection Vial Strength (mg/mL) The calculated volume of treprostinil injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir. Subcutaneous Infusion Treprostinil injection is administered subcutaneously by continuous infusion, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. The infusion pump should: (1) be adjustable to approximately 0.002 mL/hour, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better, (4) be positive pressure-driven, and (5) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with treprostinil injection. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets. Intravenous Infusion External Intravenous Infusion Pump:Treprostinil injection is administered intravenously by continuous infusion via a surgically placed indwelling central venous catheter using an external infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of treprostinil injection. Use of a peripheral intravenous infusion for more than a few hours increases the risk of thrombophlebitis. The infusion pump used to administer treprostinil injection should: (1) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (2) have delivery accuracy of ±6% or better, (3) be positive pressure driven, and (4) have a reservoir made of polyvinyl chloride, polypropylene or glass. Alternatively, use an infusion pump cleared for use with treprostinil injection. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. Infusion sets with an in-line 0.22- or 0.2- micron pore size filter should be used. Implantable Intravenous Infusion Pump: Use an implantable intravenous infusion pump approved for use with treprostinil injection, such as the Implantable System for treprostinil injection (ISR). Refer to the pump manufacturer's manual for specific instructions regarding preparation, programing, implantation, and refilling. 2.7 Patients Requiring Transition from Epoprostenol Transition from epoprostenol to treprostinil injection is accomplished by initiating the infusion of treprostinil injection and increasing it, while simultaneously reducing the dose of intravenous epoprostenol. The transition to treprostinil injection should take place in a hospital with constant observation of response (e.g., walk

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.

CONTRAINDICATIONS Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Severe hepatic impairment (Child Pugh Class C). ( 4 )

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