Tyvaso DPI

1 INDICATIONS AND USAGE Tyvaso DPI is a prostacyclin mimetic indicated for the treatment of: Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with Tyvaso establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). ( 1.1 ) Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with Tyvaso establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%). ( 1.2 ) 1.1 Pulmonary Arterial Hypertension Tyvaso DPI is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with Tyvaso establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities. While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with Tyvaso was limited to 12 weeks in duration [see Clinical Studies (14) ] . 1.2 Pulmonary Hypertension Associated with ILD Tyvaso DPI is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with Tyvaso establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%) [see Clinical Studies (14.3) ] .

2 DOSAGE AND ADMINISTRATION Use only with the Tyvaso DPI Inhaler. ( 2.1 ) Administer using a single inhalation per cartridge. ( 2.1 ) Administer in 4 separate treatment sessions each day approximately 4 hours apart, during waking hours. ( 2.1 ) Initial dosage: one 16 mcg cartridge per treatment session. ( 2.2 ) Dosage should be increased by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals, if tolerated. ( 2.2 ) Titrate to target maintenance doses of 48 mcg to 64 mcg per treatment session, 4 times daily. ( 2.2 ) 2.1 Administration Use Tyvaso DPI only with the Tyvaso DPI Inhaler. Tyvaso DPI is administered using a single inhalation per cartridge. Administer Tyvaso DPI in 4 separate, equally spaced treatment sessions per day, during waking hours. The treatment sessions should be approximately 4 hours apart. If the prescribed dose is higher than 80 mcg per treatment session, more than 1 cartridge will be needed per session. Patients should follow the instructions for use for operation and care of the Tyvaso DPI Inhaler. Do not use the Tyvaso DPI Inhaler with other medications. Between each of the 4 daily treatment sessions, store the Tyvaso DPI Inhaler with the mouthpiece attached and empty. Wipe the outside of the inhaler with a clean, dry cloth only, if needed. Do not rinse or wash the Tyvaso DPI Inhaler; always keep the inhaler dry. After 7 days of use, throw away the used Tyvaso DPI Inhaler into regular household trash. 2.2 Usual Dosage in Adults Initial Dosage: Tyvaso DPI therapy should begin with one 16 mcg cartridge per treatment session, 4 times daily. Maintenance Dosage: Increase dosage by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals. The target maintenance dosage is usually 48 mcg to 64 mcg per session. If adverse effects preclude titration, continue Tyvaso DPI at the highest tolerated dose. If a scheduled treatment session is missed, resume therapy as soon as possible at the usual dose. Dosage for Transition from Tyvaso ® (treprostinil) Inhalation Solution: The following regimens of Tyvaso DPI and Tyvaso give similar exposure: Tyvaso DPI Cartridge Strength Tyvaso Number of Breaths 16 mcg ≤5 (≤30 mcg) 32 mcg 6 to 7 (36 to 42 mcg) 48 mcg 8 to 10 (48 to 60 mcg) 64 mcg 11 to 13 (66 to 78 mcg) 80 mcg 14 to 15 (84 to 90 mcg)

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: Single-dose plastic cartridges containing 16 mcg, 32 mcg, 48 mcg, 64 mcg, or 80 mcg of treprostinil as a dry powder formulation. Inhalation powder: Single-dose plastic cartridges containing 16 mcg, 32 mcg, 48 mcg, 64 mcg, or 80 mcg of treprostinil as a dry powder formulation. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following potential adverse reactions are described in Warnings and Precautions (5): - Decrease in systemic blood pressure [see Warnings and Precautions (5.1) ] . - Bleeding [see Warnings and Precautions (5.2) ] . Most common adverse reactions (≥4%) are cough, headache, throat irritation/pharyngolaryngeal pain, nausea, flushing, dyspnea, and syncope. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 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. Pulmonary Arterial Hypertension Tyvaso DPI In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of Tyvaso Inhalation Solution who switched to a corresponding dose of Tyvaso DPI, the most commonly reported adverse events on Tyvaso DPI during the 3-week treatment phase included cough, headache, dyspnea, and nausea. Patient tolerability, as assessed by incidence of new adverse events following transition to Tyvaso DPI, was consistent with the expected known safety profile of Tyvaso Inhalation Solution. Table 1 lists the adverse events that occurred at a rate of at least 4%. Table 1: Adverse Events in ≥4% of PAH Patients Receiving Tyvaso DPI in BREEZE (Treatment Phase) Adverse Event Tyvaso DPI (n=51) n (%) Cough 18 (35.3) Headache 8 (15.7) Dyspnea 4 (7.8) Nausea 3 (5.9) The safety of Tyvaso DPI was also studied in an extension phase of the study in which 49 patients were dosed for a duration of 43 patient-years. Fifty-nine percent (59%) of patients achieved a dose of 64 mcg, 4 times daily or higher. The adverse events during this long-term, extension phase were similar to those observed in the 3-week treatment phase. Tyvaso Inhalation Solution In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most commonly reported adverse reactions on Tyvaso Inhalation Solution included cough and throat irritation, headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing, and syncope. Table 2 lists the adverse reactions that occurred at a rate of at least 4% and were more frequent in patients treated with Tyvaso Inhalation Solution than with placebo. Table 2: Adverse Events in ≥4% of PAH Patients Receiving Tyvaso Inhalation Solution and More Frequent More than 3% greater than placebo than Placebo in TRIUMPH I Adverse Event Treatment n (%) Tyvaso Inhalation Solution n=115 Placebo n=120 Cough 62 (54) 35 (29) Headache 47 (41) 27 (23) Throat Irritation / Pharyngolaryngeal Pain 29 (25) 17 (14) Nausea 22 (19) 13 (11) Flushing 17 (15) 1 (<1) Syncope 7 (6) 1 (<1) Pulmonary Hypertension Associated with ILD In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions on Tyvaso Inhalation Solution were similar to the experience in studies of PAH.

7 DRUG INTERACTIONS 7.1 Bosentan In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and bosentan were observed. 7.2 Sildenafil In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and sildenafil were observed. 7.3 Effect of Cytochrome P450 Inhibitors and Inducers In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A. 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 is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and Precautions (5.3) ] . 7.4 Effect of Other Drugs on Treprostinil Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the international normalized ratio (INR) in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.

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 for treprostinil at ≥8 and ≥134 times the human exposure when based on C max and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder. 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 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 129 and 1366 times the human exposure, when based on C max and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder. 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 8 and 134 times the human exposure, when based on C max and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder. 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 inhaled treprostinil did not include patients younger than 18 years to determine whether they respond differently from older patients. 8.5 Geriatric Use Across clinical studies used to establish the effectiveness of Tyvaso Inhalation Solution in patients with PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy. 8.6 Patients with Hepatic Insufficiency Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects with mild-to-moderate hepatic insufficiency. Uptitrate slowly when treating patients with hepatic insufficiency because of the risk of an increase in systemic exposure which may lead to an increase in dose-dependent adverse effects. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Clinical Pharmacology (12.3) ] . 8.7 Patients with Renal Impairment No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by dialysis [see Clinical Pharmacology (12.3) ] .

12.1 Mechanism of Action Treprostinil is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

11 DESCRIPTION 11.1 Tyvaso DPI Cartridges Tyvaso DPI consists of single-dose plastic cartridges filled with a white powder containing 1% of treprostinil, a prostacyclin mimetic, which is intended for administration by oral inhalation using the Tyvaso DPI Inhaler only. Treprostinil is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP). Each cartridge contains 16 mcg, 32 mcg, 48 mcg, 64 mcg, or 80 mcg of treprostinil with approximate fill weights of 1.6 mg, 3.2 mg, 4.8 mg, 6.4 mg, or 8.0 mg of Tyvaso DPI, respectively. Treprostinil is (1 R ,2 R ,3a S ,9a S )-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3 S )-3-hydroxyoctyl]-1 H -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: Chemical Structure

10 OVERDOSAGE In general, symptoms of overdose with inhaled treprostinil include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have resolved.

16 HOW SUPPLIED/STORAGE AND HANDLING Tyvaso DPI (treprostinil) inhalation powder is available as 16 mcg, 32 mcg, 48 mcg, 64 mcg, or 80 mcg of treprostinil in single-dose plastic cartridges with approximate fill weights of 1.6 mg, 3.2 mg, 4.8 mg, 6.4 mg, or 8.0 mg of Tyvaso DPI, respectively. Four cartridges are contained in a single cavity of a blister strip. A card contains 7 blister strips separated by perforations for a total of 28 cartridges of each labeled strength in Titration and Maintenance Kits. For convenience, the perforation allows users to remove a single blister strip containing 4 cartridges. The Institutional Kits contain 4 blister strips for a total of 16 cartridges of each labeled strength. The cartridges are color-coded, purple for 16 mcg, dark blue for 32 mcg, light blue for 48 mcg, light green for 64 mcg, and orange for 80 mcg. Each cartridge is marked with "Tyvaso DPI" and the corresponding dosage strength of "16 mcg", "32 mcg", "48 mcg", "64 mcg", or "80 mcg". The Tyvaso DPI Inhaler is individually packaged in a clear overwrap. The inhaler is fully assembled with a removable mouthpiece cover. The Tyvaso DPI Inhaler can be used for up to 7 days from the date of first use. After 7 days of use, the inhaler must be discarded and replaced with a new inhaler. Tyvaso DPI is available in the following configurations: Kit Contents Description NDC Number of Cartridges and Strength Number of Inhalers Tyvaso DPI (treprostinil) Inhalation Powder Titration Kit 66302-600-02 112 cartridges, each containing 16 mcg per cartridge 5 84 cartridges, each containing 32 mcg per cartridge 66302-610-02 112 cartridges, each containing 16 mcg per cartridge 5 112 cartridges, each containing 32 mcg per cartridge 28 cartridges, each containing 48 mcg per cartridge Tyvaso DPI (treprostinil) Inhalation Powder Maintenance Kit 66302-616-03 112 cartridges, each containing 16 mcg per cartridge 5 66302-632-03 112 cartridges, each containing 32 mcg per cartridge 5 66302-648-03 112 cartridges, each containing 48 mcg per cartridge 5 66302-664-03 112 cartridges, each containing 64 mcg per cartridge 5 66302-680-03 112 cartridges, each containing 80 mcg per cartridge 5 66302-620-03 112 cartridges, each containing 32 mcg per cartridge 5 112 cartridges, each containing 48 mcg per cartridge 66302-630-03 112 cartridges, each containing 32 mcg per cartridge 5 112 cartridges, each containing 64 mcg per cartridge 66302-640-03 112 cartridges, each containing 48 mcg per cartridge 5 112 cartridges, each containing 64 mcg per cartridge 66302-650-03 112 cartridges, each containing 16 mcg per cartridge 5 112 cartridges, each containing 48 mcg per cartridge 112 cartridges, each containing 64 mcg per cartridge 66302-660-03 112 cartridges, each containing 48 mcg per cartridge 5 112 cartridges, each containing 80 mcg per cartridge 66302-670-03 112 cartridges, each containing 64 mcg per cartridge 5 112 cartridges, each containing 80 mcg per cartridge Tyvaso DPI (treprostinil) Inhalation Powder Institutional Kit 66302-716-04 16 cartridges, each containing 16 mcg per cartridge 2 66302-732-04 16 cartridges, each containing 32 mcg per cartridge 2 66302-748-04 16 cartridges, each containing 48 mcg per cartridge 2 66302-764-04 16 cartridges, each containing 64 mcg per cartridge 2 66302-780-04 16 cartridges, each containing 80 mcg per cartridge 2 66302-720-04 16 cartridges, each containing 32 mcg per cartridge 2 16 cartridges, each containing 48 mcg per cartridge Blister Storage: Storage Tyvaso DPI Presentation Refrigerated storage 2°C to 8°C (36°F to 46°F) Room temperature storage 20°C to 25°C (68°F to 77°F), excursions permitted 15°C to 30°C (59°F to 86°F) Sealed (Unopened) Blister Cards or Strips May be stored until the expiration date printed on the blisters. Must be used within 8 weeks. Opened Blister Strips Do not put a blister card or strip back into the refrigerator after being opened or stored at room temperature. Must be used within 3 days. Inhaler Storage: Store …