TYVASO

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, nausea, dizziness, flushing, throat irritation, pharyngolaryngeal pain, diarrhea, and syncope. ( 6 ) 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 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 included cough and throat irritation, headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing, and syncope. Table 1 lists the adverse reactions that occurred at a rate of at least 4% and were more frequent in patients treated with Tyvaso than with placebo. Table 1: Adverse Events in ≥4% of PAH Patients Receiving Tyvaso and More Frequent More than 3% greater than placebo than Placebo in TRIUMPH I Adverse Event Treatment n (%) Tyvaso 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) The safety of Tyvaso was also studied in a long-term, open-label extension study in which 206 patients were dosed for a mean duration of 2.3 years, with a maximum exposure of 5.4 years. Eighty-nine percent (89%) of patients achieved the target dose of 9 breaths, 4 times daily. Forty-two percent (42%) achieved a dose of 12 breaths, 4 times daily. The adverse events during this chronic dosing study were qualitatively similar to those observed in the 12-week placebo-controlled trial. In a prospective, observational study comparing patients taking Tyvaso (958 patient-years of exposure) and a control group (treatment with other approved therapies for PAH; 1094 patient-years), Tyvaso was associated with a higher rate of cough (16.2 vs. 10.9 per 100 patient-years), throat irritation (4.5 vs. 1.2 per 100 pt-years), nasal discomfort (2.6 vs. 1.3 per 100 pt-years), and hemoptysis (2.5 vs. 1.3 per 100 pt-years) compared to the control group. Pulmonary Hypertension Associated with ILD In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions were similar to the experience in studies of PAH. 6.2 Post-Marketing Experience The adverse reaction of angioedema has been identified during the post-approval use of Tyvaso. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Tyvaso is a sterile formulation of treprostinil, a prostacyclin mimetic, intended for administration by oral inhalation using the Tyvaso Inhalation System. Tyvaso is supplied in 2.9 mL low density polyethylene (LDPE) ampules, containing 1.74 mg treprostinil (0.6 mg/mL). Each ampule also contains 18.9 mg sodium chloride, 18.3 mg sodium citrate dihydrate, 0.58 mg sodium hydroxide, 11.7 mg 1 N hydrochloric acid, and water for injection. Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2. 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

2 DOSAGE AND ADMINISTRATION Use only with the Tyvaso Inhalation System. ( 2.1 ) Administer undiluted, as supplied. A single breath of Tyvaso delivers approximately 6 mcg of treprostinil. ( 2.1 ) Administer in 4 separate treatment sessions each day approximately 4 hours apart, during waking hours. ( 2.1 ) Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are not tolerated, reduce to 1 or 2 breaths. ( 2.1 ) Dosage should be increased by an additional 3 breaths per treatment session at approximately 1- to 2-week intervals, if tolerated. ( 2.1 ) Titrate to target maintenance doses of 9 to 12 breaths per treatment session, 4 times daily. ( 2.1 ) 2.1 Usual Dosage in Adults Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of an ultrasonic, pulsed delivery device and its accessories. Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. Each treatment session will take 2 to 3 minutes. The treatment sessions should be approximately 4 hours apart. Initial Dosage: Therapy should begin with 3 breaths of Tyvaso (18 mcg of treprostinil) per treatment session 4 times daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated. Maintenance Dosage: Dosage should be increased by an additional 3 breaths per treatment session, 4 times daily at approximately 1- to 2-week intervals. Studies establishing effectiveness in patients with PAH and PH-ILD have used target doses of 9 to 12 breaths per treatment session, 4 times daily. If adverse effects preclude titration to target dose, Tyvaso should be continued at the highest tolerated dose. If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible at the usual dose. 2.2 Administration Tyvaso must be used only with the Tyvaso Inhalation System. Patients should follow the instructions for use for operation of the Tyvaso Inhalation System and for daily cleaning of the device components after the last treatment session of the day. To avoid potential interruptions in drug delivery because of equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device. Do not mix Tyvaso with other medications in the Tyvaso Inhalation System. Compatibility of Tyvaso with other medications has not been studied. The Tyvaso Inhalation System should be prepared for use each day according to the instructions for use. One ampule of Tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a single day. Prior to the first treatment session, the patient should twist the top off a single Tyvaso ampule and squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions, the device should be capped and stored upright with the remaining medication inside. At the end of each day, the medicine cup and any remaining medication must be discarded. The device must be cleaned each day according to the instructions for use. Avoid skin or eye contact with Tyvaso solution. Do not orally ingest the Tyvaso solution.

1 INDICATIONS AND USAGE Tyvaso is a prostacyclin mimetic indicated for the treatment of: Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies 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 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 is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies 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 controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration [see Clinical Studies (14) ] . 1.2 Pulmonary Hypertension Associated with ILD Tyvaso is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study 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) ] .

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

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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics In a clinical trial of 240 healthy volunteers, single doses of Tyvaso 54 mcg (the target maintenance dose per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 ms. The QTc effect dissipated rapidly as the concentration of treprostinil decreased. 12.3 Pharmacokinetics Pharmacokinetic information for single doses of inhaled treprostinil was obtained in healthy volunteers in 3 separate studies. Treprostinil systemic exposure (AUC and C max ) post-inhalation was shown to be proportional to the doses administered (18 mcg to 90 mcg). Absorption In a 3-period crossover study, the bioavailability of 2 single doses of Tyvaso (18 mcg and 36 mcg) was compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the absolute systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and 72% (36 mcg). Treprostinil plasma exposure data were obtained from 2 studies at the target maintenance dose, 54 mcg. The mean C max at the target dose was 0.91 and 1.32 ng/mL with corresponding mean T max of 0.25 and 0.12 hr, respectively. The mean AUC for the 54-mcg dose was 0.81 and 0.97 hr∙ng/mL, respectively. Distribution Following parenteral infusion, the apparent steady state volume of distribution (V ss ) of treprostinil is approximately 14 L/70 kg ideal body weight. In vitro treprostinil is 91% bound to human plasma proteins over the 330 to 10,000 mcg/L concentration range. Metabolism and Excretion Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%) and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each accounting for 10 to 15% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and 1 is a glucuroconjugated derivative (treprostinil glucuronide). The elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a terminal elimination half-life of approximately 4 hours using a 2-compartment model. Specific Populations Hepatic Insufficiency Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects presenting with mild-to-moderate hepatic insufficiency. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Use in Specific Populations (8.6) ] . Renal Impairment In patients with severe renal impairment requiring dialysis (n=8), administration of a single 1 mg dose of orally administered treprostinil pre- and post-dialysis resulted in AUC 0-inf that was not significantly altered compared to healthy subjects [see Use in Specific Populations (8.7) ] .

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.

12.2 Pharmacodynamics In a clinical trial of 240 healthy volunteers, single doses of Tyvaso 54 mcg (the target maintenance dose per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 ms. The QTc effect dissipated rapidly as the concentration of treprostinil decreased.

12.3 Pharmacokinetics Pharmacokinetic information for single doses of inhaled treprostinil was obtained in healthy volunteers in 3 separate studies. Treprostinil systemic exposure (AUC and C max ) post-inhalation was shown to be proportional to the doses administered (18 mcg to 90 mcg). Absorption In a 3-period crossover study, the bioavailability of 2 single doses of Tyvaso (18 mcg and 36 mcg) was compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the absolute systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and 72% (36 mcg). Treprostinil plasma exposure data were obtained from 2 studies at the target maintenance dose, 54 mcg. The mean C max at the target dose was 0.91 and 1.32 ng/mL with corresponding mean T max of 0.25 and 0.12 hr, respectively. The mean AUC for the 54-mcg dose was 0.81 and 0.97 hr∙ng/mL, respectively. Distribution Following parenteral infusion, the apparent steady state volume of distribution (V ss ) of treprostinil is approximately 14 L/70 kg ideal body weight. In vitro treprostinil is 91% bound to human plasma proteins over the 330 to 10,000 mcg/L concentration range. Metabolism and Excretion Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%) and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each accounting for 10 to 15% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and 1 is a glucuroconjugated derivative (treprostinil glucuronide). The elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a terminal elimination half-life of approximately 4 hours using a 2-compartment model. Specific Populations Hepatic Insufficiency Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects presenting with mild-to-moderate hepatic insufficiency. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Use in Specific Populations (8.6) ] . Renal Impairment In patients with severe renal impairment requiring dialysis (n=8), administration of a single 1 mg dose of orally administered treprostinil pre- and post-dialysis resulted in AUC 0-inf that was not significantly altered compared to healthy subjects [see Use in Specific Populations (8.7) ] .

20220912

23

3 DOSAGE FORMS AND STRENGTHS Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg of treprostinil (0.6 mg per mL). Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg treprostinil (0.6 mg per mL). ( 3 )

TYVASO treprostinil treprostinil treprostinil sodium chloride trisodium citrate dihydrate sodium hydroxide hydrochloric acid water

13.2 Animal Toxicology and/or Pharmacology In a 2-year rat study with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day, there were more deaths (11) in the mid- and high-dose treprostinil groups during the first 9 weeks of the study, compared to 1 in control groups. At the high-dose level, males showed a higher incidence of inflammation in teeth and preputial gland, and females showed higher incidences of inflammation and urothelial hyperplasia in the urinary bladder. The exposures in rats at mid- and high-dose levels were about 15 and 35 times, respectively, the clinical exposure at the target maintenance dose of 54 mcg.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year rat carcinogenicity study was performed with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential associated with treprostinil inhalation in rats at systemic exposure levels up to 35 times the clinical exposure at the target maintenance dose of 54 mcg. In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not affect fertility or mating performance of male or female rats given continuous subcutaneous infusions at rates of up to 450 ng treprostinil/kg/min. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6. Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10, and 20 mg/kg/day in males and 0, 3, 7.5, and 15 mg/kg/day in females daily for 26 weeks did not significantly increase the incidence of tumors. Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an increased incidence of micronucleated polychromatic erythrocytes.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year rat carcinogenicity study was performed with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential associated with treprostinil inhalation in rats at systemic exposure levels up to 35 times the clinical exposure at the target maintenance dose of 54 mcg. In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not affect fertility or mating performance of male or female rats given continuous subcutaneous infusions at rates of up to 450 ng treprostinil/kg/min. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6. Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10, and 20 mg/kg/day in males and 0, 3, 7.5, and 15 mg/kg/day in females daily for 26 weeks did not significantly increase the incidence of tumors. Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an increased incidence of micronucleated polychromatic erythrocytes. 13.2 Animal Toxicology and/or Pharmacology In a 2-year rat study with treprostinil inhalation at target doses of 5.26, 10.6, and 34.1 mcg/kg/day, there were more deaths (11) in the mid- and high-dose treprostinil groups during the first 9 weeks of the study, compared to 1 in control groups. At the high-dose level, males showed a higher incidence of inflammation in teeth and preputial gland, and females showed higher incidences of inflammation and urothelial hyperplasia in the urinary bladder. The exposures in rats at mid- and high-dose levels were about 15 and 35 times, respectively, the clinical exposure at the target maintenance dose of 54 mcg.

NDA022387

TYVASO

treprostinil

66302-206

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 4 Ampule Pouch Carton TYVASO ® (treprostinil) INHALATION SOLUTION Treprostinil 1.74 mg / 2.9 mL (0.6 mg/mL) Four 2.9 mL ampules For oral inhalation use only See package insert and Instructions For Use manual for dosage and administration Principal Display Panel - 4 Ampule Pouch Carton

Warnings and Precautions ( 5.4 ) 05/2022

© Copyright 2022 United Therapeutics Corp. All rights reserved. Tyvaso manufactured for: United Therapeutics Corp. Research Triangle Park, NC 27709

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use). Train patients in the administration process for Tyvaso, including dosing, Tyvaso Inhalation System set up, operation, cleaning, and maintenance, according to the instructions for use [see Dosage and Administration (2.1 , 2.2) ] . To avoid potential interruptions in drug delivery because of equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device [see Dosage and Administration (2.2) ] . In the event that a scheduled treatment session is missed or interrupted, resume therapy as soon as possible [see Dosage and Administration (2.1) ] . If Tyvaso comes in contact with the skin or eyes, instruct patients to rinse immediately with water [see Dosage and Administration (2.2) ] .

TYVASO ® INHALATION SYSTEM Instructions for Use TYVASO ® (treprostinil) INHALATION SOLUTION Table of Contents General Instructions 2 Introduction 3 Preparing for Treatment With TYVASO 3 Preparing the Use Environment for Treatment 3 Markings, Indicators, and Symbols 4 Gathering Supplies 6 Setting Up Your TYVASO Inhalation System 8 Filling the Inhalation Device Chamber and Medicine Cup 8 Assembling the Inhalation Device 10 Turning On the Inhalation Device 13 Setting the Number of Breaths in a Treatment Session 14 Inhaling Your Medicine (TYVASO) 16 Storing the TYVASO Inhalation System Between Treatment Sessions 20 Cleaning and Maintenance of the TYVASO Inhalation System 24 End of Day Cleaning of the Accessories 24 Weekly Cleaning 27 Monthly Refill Kit 27 Device Replacement 27 Charging Your TYVASO Inhalation System 28 Rechargeable Battery 28 Troubleshooting the TYVASO Inhalation System 30 Specifications 36 Glossary 38 Warranty Information 40 General Instructions The TYVASO Inhalation System should be handled with care. Follow these important instructions to ensure proper use: Always unplug the device after each use. Do not immerse the device in water or other liquids. Do not place the device in a microwave or regular oven. Do not place the device or use the device in the presence of strong electric or magnetic fields (eg, microwave oven, magnetic imaging equipment). Do not leave the device alone with a small child. Do not use the device near flammable liquids and materials or heated surfaces. Read the instructions carefully and completely to prevent damage to your TYVASO Inhalation System and help you get the best results. This device should only be used on the order of your doctor or licensed healthcare practitioner. Ensure the breath counter is correctly programmed prior to beginning a treatment (see page 14). Do not peel or remove the labels from device. Do not drop the device. Introduction Your doctor has prescribed TYVASO ® (treprostinil) Inhalation Solution. Please see the accompanying Patient Package Insert for important safety information on TYVASO. TYVASO is breathed in (inhaled) using the TYVASO Inhalation System, which consists of the inhalation device and its accessories. These Instructions for Use (IFU) for the TYVASO Inhalation System provide important safety information. It is important that you read these instructions and the TYVASO Patient Package Insert (PPI) before setting up and using the TYVASO Inhalation System. If you have any questions, talk to your doctor or specialty pharmacy provider. Before beginning treatment with TYVASO, you will receive either a Patient Starter Kit containing a 28-day supply of TYVASO or an Institutional Starter Kit containing a 4-day supply of medication. Both kits include two (2) complete inhalation devices (all accessories and supplies included). When you refill your prescription for TYVASO each month, you will receive a Refill Kit that contains a 28-day supply of TYVASO and new accessories. You will receive a replacement device every two (2) years. Preparing for Treatment With TYVASO Preparing the Use Environment for Treatment Follow these important instructions before setting up your treatment: Use the device in a quiet, distraction-free area. Try to use the device at times when your treatment will not be interrupted. If you encounter any distractions during treatment, you can pause your treatment (see page 19). Use the device in a comfortable space where you can stand or sit in an upright position that allows you to take deep breaths. Use the device in an area that provides enough space for the TYVASO Inhalation System and its accessories. Gather all necessary supplies before starting to prepare for treatment (see pages 6 and 7). The TYVASO Inhalation System is recommended for use indoors. Be sure to use and store the inhalation device in environments that match the specified temperature and humidity ranges (see Specifications on page 36). Markings, Indicators, and Symbols Device markings The TYVASO Inhalation System complies with the requirements of Protection Class II. Class II equipment provides additional precautions, over and above basic insulation, to provide protection against electric shock. Please read the accompanying instructions and labels for important information regarding the TYVASO Inhalation System. The TYVASO Inhalation System has a Type B Applied part. Type B Applied parts comply with specific requirements to provide protection against shock and are not suitable for direct cardiac applications. The TYVASO Inhalation System should only be used on the order of your doctor or licensed healthcare provider. The TYVASO Inhalation System requires a 12V DC power supply. Gathering Supplies Gather the following supplies before starting treatment. Use only the parts and accessories that are provided with your starter kit or in the monthly refill kit. Note: supplies are not shown to scale. 1. Inhalation device 2. Water Level Cup with 45 mL of distilled water 3. Pack of TYVASO ampules Use only distilled water to fill your inhalation device once per day. Use one (1) ampule per day. 4. One of the provided power sources Note: Supplies are not shown to scale. 5. Accessories Medicine cups These accessories are replaced every month. Replacement accessories are included in the Monthly Refill Kit. Dome assembly with baffle plate inside Inhalation piece Mouthpiece Two (2) Filter shells Filter membranes (use two (2) per day) Plugs Treatment Tracker Carrying case Distilled water carrier (optional) Setting Up Your TYVASO Inhalation System Filling the Inhalation Device Chamber and Medicine Cup Before using the TYVASO Inhalation System, you should: Wash your hands Make sure the device is NOT connected to a power source Make sure the device is resting on a stable, flat surface during assembly ONLY USE DISTILLED WATER in the device. Distilled water is highly purified water that can be purchased at most grocery stores and pharmacies. It is necessary for the device to function properly. If you use another type of water (such as bottled or tap water), the device may not function properly. 1 Fill the white chamber inside the device with approximately 45 mL of distilled water (about 1.5 ounces), using the water level cup provided. Fill the cup until water level is between the two arrow markings. There is a silver sensor on the inside wall of the chamber. The water level should be above the silver sensor and below the blue ring in the device chamber. DO NOT OVERFILL the chamber, or the medicine cup will not fit correctly. Check the water level after filling the chamber. 2 Obtain one (1) medicine cup and inspect it for any damage, holes, cracks, or dents. Do not use the medicine cup if it is damaged. Insert the empty medicine cup into the chamber of the device, making sure that the cup's bottom tip is in the distilled water. The cup will sit on the blue ring. 3 Carefully cut open the top of the foil pouch, making sure not to cut the ampules. Each pouch contains four (4) ampules. Remove one (1) ampule of TYVASO. Keep unused ampules in the foil pouch because the TYVASO medicine is sensitive to light. One (1) ampule contains enough medicine for one (1) day of treatment no matter how many breaths your doctor has prescribed. 4 Gently hold the ampule in the upright (topup) position and twist off its top. 5 Point the ampule straight down toward the medicine cup's center to avoid spills. Gently squeeze the medicine out of the ampule into the medicine cup. Squeeze until it is empty. Check to see that all of the medicine is in the medicine cup. Assembling the Inhalation Device The TYVASO Inhalation System is designed so the parts only fit together properly one way. When the device is assembled correctly, the parts should fit together easily. Do not force the parts together. 1 Visually check to make sure the blue plastic baffle plate and black ring are correctly placed in the dome assembly. They should appear as they do in the images below. In the unlikely event that the baffle plate is loose or disconnected, use a new dome assembly. If you need to order a new dome assembly, contact your specialty pharmacy provider. 2 Align the raised circle on the side of the dome assembly with the circle on the side of the device. Push down and screw the dome assembly onto the device clockwise (right) until you hear a click, indicating the dome assembly is fully connected to the medicine cup. When the dome assembly is properly aligned, the filter shell port will point to the back of the device. 3 Insert the inhalation piece into the upper opening of the dome assembly and rotate toward the front of the device. Gently push down the inhalation piece to make sure it is securely inserted in the dome assembly. 4 Insert the mouthpiece into the inhalation piece. 5 Each day you will need to use a new filter membrane in each filter shell. To install a new filter membrane: Open the filter shell by unscrewing the two (2) halves. Place a new filter membrane in one (1) of the filter shell halves. Close the filter shell by screwing the two (2) halves together until you can twist no further. Note: New filter shells come with fresh filter membranes already installed. 6 Insert one (1) of the filter shells into the filter shell port on the side of the dome assembly and insert the other filter shell into the port on the bottom of the inhalation piece. The two (2) filter shells are identical and can be used in either opening. Make sure to insert the filter shells straight into their ports, rather than at an angle. If necessary, rotate the inhalation piece so you can insert the filter shell without the device getting in the way. 7 When the device is fully assembled, it should appear as it does in the photo below. For convenience, rotate the inhalation piece so you can best see the indicator lights and display screen, which provide important prompts during your treatment. Turning On the Inhalation Device 1 Connect your device to one (1) of the power source options by plugging one end of the power cord into the back of the inhalation device and the other end into the power source. If using the AC wall plug, make sure to plug the output cable into the device before plugging adapter into the power source. If using the rechargeable battery, make sure it is not also plugged into the AC wall plug. 2 To turn on the device, press and hold the ON/OFF button for approximately three (3) seconds. When you hear a short beep and the yellow status light is illuminated, release the ON/OFF button. Remember to press the center of the ON/OFF button when powering the device on or off. When the power is on, the display screen will show the last number of breaths programmed and a yellow light will appear next to the screen. Make sure the number matches the prescribed number of breaths for that treatment session. If it does not match, see the next page for instructions on setting the number of breaths in a treatment session. Setting the Number of Breaths in a Treatment Session You will inhale TYVASO during four (4) treatment sessions each day. During each treatment session, you will take a series of breaths through the mouthpiece of the TYVASO Inhalation System. Your doctor will prescribe the number of breaths you should inhale in each treatment session. You should record the number of breaths in your Treatment Tracker. 1 Make sure the device is powered off. To power off the device, press and hold the ON/OFF button for three (3) seconds. When you hear a short beep and the display screen turns off, release the ON/ OFF button. To set the number of breaths, press and hold both the START/STOP and ON/OFF buttons at the same time until the display flashes and the device emits three (3) short beeps. The flashing display indicates the inhalation device is in breath programming mode. You cannot begin a treatment while the display is flashing. 2 To increase the number of breaths press the + (ON/OFF) button. To decrease the number of breaths press the – (START/STOP) button. Remember to press in the center of the buttons. 3 Once you have entered your prescribed number of breaths, remove your hands from the device and wait approximately 15 seconds. After approximately 15 seconds, the display will stop flashing and the device will emit three (3) short beeps, indicating that it has saved the new number of breaths. The new number of breaths will appear on the display. Make sure the number of breaths on the display matches the number of breaths in your prescription. If the numbers do not match, repeat steps 1-3. Inhaling Your Medicine, TYVASO ® (treprostinil) Inhalation Solution You will inhale TYVASO during four (4) treatment sessions each day. During each treatment session, you will take a series of breaths through the mouthpiece of the TYVASO Inhalation System. Inhalation Tips Technique: When breathing each TYVASO treatment, be sure to keep the device level, directing the flow of medicine into the throat and not toward the roof of the mouth. Seal your lips around the mouthpiece to ensure that you can inhale the full amount of TYVASO after it is produced by the device. Inhalation: Each breath should last approximately three (3) seconds, breathing "normal full breaths." Do not hold your breath. Exhale normally and prepare for the next breath. 1 Hold the device upright as shown below. Make sure you can see the display screen and lights clearly and that your hands do not cover the display screen or lights while holding device. If the inhalation piece or mouthpiece block your view of the display screen or lights, move the inhalation piece so you can best see them. 2 Perform steps A-G to complete one (1) treatment session. Follow the instructions exactly to make sure you receive the correct medication dose. A B C D Press the START/STOP button to begin treatment. The status light turns green and the device emits two (2) short beeps. While the device emits one (1) long beep, exhale completely. After the device emits a short beep and while the inhalation indicator light is flashing green, place your lips securely around the mouthpiece and inhale slowly for the duration of the beep (at least three (3) seconds). Exhale normally, mark a circle in the Treatment Tracker and prepare for the next breath. E F G Repeat steps B through D for the number of prescribed breaths and until the display counts down to "00". After the final breath, the display screen will show "00" then "En," indicating the treatment session is complete. Check the number of breaths you inhaled on the Treatment Tracker. To turn off the device, press and hold the ON/OFF button for three (3) seconds and then release. If the device is left in "En" mode for more than 60 seconds, it will turn off automatically. 3 To pause the treatment between breaths, press the START/STOP button. The display screen will show "PA." To resume treatment, press START/ STOP again. "PA" will disappear and the display screen will show the number of breaths remaining. If the device is disconnected from its power source for any reason (for example, a power failure), reconnect the device to a power source. Follow the instructions on page 13 to turn on the device. The display will show how many breaths are left in that treatment session. Press the START/STOP button to continue your treatment session. Storing the TYVASO Inhalation System Between Treatment Sessions If you have more treatment sessions left in the day, perform the following steps. If you have completed your last treatment session of the day, skip to Cleaning and Maintenance of the TYVASO Inhalation System (see page 24). Be sure to pack all parts, including a backup power supply, in the carry case whenever transporting your device. 1 Disconnect the device from its power source. 2 Remove both filter shells. Do NOT remove the filter membranes from filter shells until after the last treatment session of the day. 3 Remove the mouthpiece. 4 Remove the inhalation piece. 5 Leave the dome assembly and medicine cup (with the medicine still in it) connected to the device. 6 Insert a plug into each of the open holes on the dome assembly to prevent the medicine from spilling out. 7 The inhalation device with the plugged dome assembly and all the accessories can be stored in the carrying case between treatment sessions. Cleaning and Maintenance of the TYVASO Inhalation System End of Day Cleaning of the Accessories 1 Disconnect the device from the power source. 2 Remove both filter shells. 3 Open the filter shells by twisting in opposite directions. Remove and discard the used filter membranes. 4 Remove the mouthpiece. 5 Remove the inhalation piece. 6 Remove the dome assembly by turning it counter-clockwise (to the left). The medicine cup should stay attached to the dome assembly. 7 Remove the medicine cup by gently squeezing on the sides where it is attached to the dome assembly. Empty the medicine cup into a sink or waste basket, then discard the medicine cup. Be careful not to spill the medicine when removing or discarding the medicine cup. 8 Empty the distilled water from the chamber and let the inhalation device air dry upside down. You can wipe the chamber with a soft cloth or paper towel to collect water. 9 Clean the accessories (pictured below) by hand in mild, soapy, warm water, then rinse them thoroughly with water. Allow accessories to air dry. 10 Once all the items are dry, the filter shells, inhalation piece, mouthpiece, dome assembly, and inhalation device can be stored in the carrying case until the next day's treatment sessions. Weekly Cleaning Once a week, use a clean cloth to wipe the interior of the inhalation device chamber, be sure to wipe the disc in the bottom of the device. You may wipe the exterior of the device with a damp cloth if the lights or buttons become difficult to see. Proper cleaning will help to avoid corrosion and leaks and keep your device working properly. Monthly Refill Kit Once a month, you will receive a refill kit that will come with a new set of accessories from your specialty pharmacy provider. Inspect the shipment to be sure all parts are included (see page 7). Once the new kit has arrived, discard the used dome assembly, inhalation piece, mouthpiece, and two (2) filter shells. Do not recycle the used accessories. Device Replacement The inhalation device should be replaced every two (2) years from your first day of use. Replacement inhalation devices will be supplied by your specialty pharmacy provider. Charging Your TYVASO Inhalation System Rechargeable Battery The rechargeable battery is supplied with its own instructions for use. Refer to these instructions for more information. Your TYVASO Inhalation System is supplied with a portable, rechargeable battery. Do NOT use other batteries. Your battery can only be charged by using one (1) of the AC wall plugs that comes with your inhalation device. To check the battery's voltage level, press and hold the blue button on the front of the battery. You can only check the battery's voltage level when the battery is not plugged into a power source. The light below the button will turn on and indicate the battery's voltage level. A red light indicates the battery needs to be charged. A green light indicates the battery is ready to operate the device. To charge the battery, connect the AC wall plug to the battery pack and plug the AC wall plug into an outlet. A yellow light on the front of the battery will turn on, indicating that the battery is charging. Your battery may take up to 40 hours to fully charge. It is not possible to use the TYVASO Inhalation System with the battery while it is recharging. A fully charged battery will typically last up to 200 inhalations. A battery charged for one (1) night (about 10 hours) will typically last up to one (1) day of therapy (about 40 inhalations). You should connect the charged battery to the TYVASO Inhalation System only for your treatment. When using the battery pack to power the device, make sure the battery is not plugged into a power source. After your treatment session is complete, remove the power plug of the battery from the device. Charge the battery whenever you are not using it to power the inhalation device. Always have your AC wall plug or 12V DC adapter available for backup, in case the battery is not charged. Troubleshooting the TYVASO Inhalation System Problem Possible causes Corrective actions Low battery (LB) Low battery Unplug the battery from the device. Charge the battery by attaching it to the AC wall plug and outlet. Use an alternative power source, such as the AC wall plug or 12V DC adapter, for treatment. Defective adapter (AC wall plug or 12V DC adapter) Ensure that the plug is properly connected to an outlet. AC wall plug is still plugged into battery and battery is connected to device. Turn off device (see page 14). Disconnect AC wall plug from battery. Check battery status, following instructions on page 28. If device is properly powered and still does not function, contact your specialty pharmacy provider for a replacement. Low hydrogen (LH) Device chamber is empty or distilled water level in the device chamber is too low. Unplug the device from its power source. Remove the dome assembly carefully, making sure not to spill its medicine. Empty the device chamber then refill it with distilled water (see page 8) and reconnect the dome assembly (see page 10). The distilled water you are using is too purified Empty device chamber. Add one (1) teaspoon of tap water to the water fill cup. Fill cup with distilled water up to level between the two arrow markings on cup (see page 8). Pour cup's contents into device chamber. The sensor has a thin layer of build-up Clean sensor and interior surfaces of water chamber with a clean cloth. If device is properly powered and still does not function, contact your specialty pharmacy provider for a replacement. No medicine comes out of the device during a treatment session No TYVASO ® (treprostinil) Inhalation Solution in the medicine cup Unplug the device from its power source. Fill medicine cup with one (1) ampule of TYVASO. Damaged medicine cup Unplug the device from its power source. Replace the medicine cup. Distilled water level in the device chamber is too high Unplug the device from its power source. Empty the device chamber then refill it with 45 mL of distilled water. Multiple medicine cups attached to the dome assembly Unplug the device from its power source. Remove and dispose of all medicine cups in the device. Insert a single, new medicine cup into device chamber and fill with one (1) ampule of TYVASO. Difficult to breathe in medicine through the mouthpiece Filter membrane is clogged Unplug the device from its power source. Replace filter membrane (see page 11). No "click" was heard when attaching the dome assembly No medicine cup in the chamber of the device Insert an empty medicine cup into the chamber of the device and fill it with one (1) ampule of TYVASO. Multiple medicine cups attached to the dome assembly Unplug the device from its power source. Remove and dispose of all medicine cups in the device. Insert a single, new medicine cup into device chamber and fill with one (1) ampule of TYVASO. Dome assembly is not securely in place Unplug the device from its power source. Align the circle on the side of the dome assembly with the circle on the side of the device. Push down and screw the dome assembly onto the device clockwise (right) until you hear a click, indicating the dome assembly is fully connected to the medicine cup. Loss of power during treatment Device is disconnected from its power source Reconnect the device to a power source and press the ON/OFF button to turn on the device. The display will show how many breaths are left in that treatment session. Press the START/STOP button to continue your treatment session. Power source is temporarily disrupted (for example, electricity interruption due to a storm) Reconnect the device to a power source and turn on the device (see page 13). The display will show how many breaths are left in that treatment session. Press the START/ STOP button to continue your treatment session. Specifications Inhalation Device Model TD-100/A Size 98 × 66 × 105 mm Weight, inhalation device 280 g (9.9 ounces) Types of power supply AC wall plug 12V DC adapter Rechargeable battery Power input 12V DC, 1.5A maximum Operating power consumption 18 Watt maximum Ultrasonic frequency 2.4 MHz (nominal) Nebulization rate 0.50 - 0.55 mg/min (0.9% Saline) Medicine cup capacity 6 mL, nominal Contact fluid chamber capacity 45 mL, nominal Electric protection class II Type B Storage temperature/humidity -5 to 40°C/20-80% relative humidity Operating temperature/humidity 15 to 25°C/40-75% relative humidity Packaging Dimensions (Approximate Length × Width × Height) Patient Starter Kit (PSK) 12.2" × 14.3" × 16.0" Monthly Refill Kit (MRK) 9.9" × 6.1" × 16.1" Institutional Starter Kit (ISK) 12.2" × 14.3" × 16.0" TYVASO Mass and Particle Specifications for 9 breaths Mass Median Aerosol Diameter (MMAD) n=108 data points from r=3 inhalation devices. Each data point was 9 breaths. mean = 2.0 μm SD = 0.3 Total Emitted Dose per Breath n=216 data points from r=6 inhalation devices. Each data point was 1 breath. mean = 6.0 μg SD = 0.4 Total Aerosol Mass mean = 58 μg SD = 5.9 Total Respirable Dose mean = 44.6 μg SD = 3.5 Respirable Fraction mean = 73% SD = 5% Geometric Standard Deviation (GSD) mean = 2.6 μm SD = 0.4 Accessories Note: Part number subject to change. ON-110HPA Rechargeable battery ON-100Z 12V DC adapter ON-100N-US AC wall plug ON-102/1/C Medicine cup, Quantity-16 ON-109 Filter membranes ON-120/C Plugs ON-101/C Filter shell TD-103/C Dome assembly with baffle plate ON-104/C Inhalation piece ON-105/C Mouthpiece TD-118 Water level cup TD-153 Carrying case TD-155 Distilled water carrier Glossary Accessories: Parts of the TYVASO Inhalation System. See pages 6 and 7. Ampule: A sealed, lightweight clear plastic vial containing a 1-day supply of TYVASO ® (treprostinil) Inhalation Solution. Control light for inhalation: A green LED on the top surface of the inhalation device that signals when you should inhale. Baffle plate: A blue plastic piece that is inside the dome assembly. The baffle plate helps turn TYVASO into particles that are the correct size to inhale. Black ring: A round seal that fits on the bottom of the dome assembly. The seal helps ensure that TYVASO does not mix with the distilled water in the device chamber. Display screen: A small area on the inhalation device that displays number and letter prompts to guide you through your treatment sessions. Distilled water: Water that is highly purified so that it contains only essential elements. Dome assembly: The plastic accessory that contains the baffle plate and connects the mouthpiece, inhalation piece, and filter shells to the base of the inhalation device. Filter membrane: The white pad that goes into the filter shells. Filter shells: Plastic accessories that hold the filter membranes. Inhalation piece: The plastic accessory that connects the mouthpiece with the dome assembly. Inhalation device: The base of the TYVASO Inhalation System to which the accessories connect. The inhalation device contains the display screen and lights. Inhale: How you will breathe in TYVASO with the TYVASO Inhalation System. Medicine cup: The disposable plastic cone-shaped cup into which TYVASO is poured. The medicine cup fits inside the inhalation device chamber. Mouthpiece: The plastic part that you will breathe through (using your mouth) to inhale TYVASO. ON/OFF button: A manually activated control on the front of the device that switches between fully on and fully off power states. Plugs: Plastic accessories that are inserted into the openings of the dome assembly between treatment sessions. Plugs help keep TYVASO from spilling if the inhalation device tips over. Prompts: The audio and visual signals that help guide you through the treatment sessions. Sensor: The silver object on the inside wall of the device chamber. The sensor must be covered with distilled water for the TYVASO Inhalation System to function properly. Status light: A multicolored LED on the front of the inhalation device that indicates the device's operational status. Start/Stop treatment button: A manually activated control on the front of the device that begins or pauses treatment. Specialty pharmacy provider: A pharmacy that carries only specialized medicines and medical devices. Your specialty pharmacy provider is a good source of information about TYVASO and the TYVASO Inhalation System. Treatment session: One (1) of four (4) daily sessions during which you will take TYVASO with a specific number of inhalations. TYVASO: The prescription medicine that you will use with the TYVASO Inhalation System. Water chamber: The white hollow portion in the center of the inhalation device into which distilled water and the medicine cup are placed. Warranty Information Your TYVASO Inhalation System is granted a full replacement or repair warranty good for two (2) years from your date of receipt of the TYVASO Inhalation System Starter Kit or five (5) years from the date of manufacture, whichever comes first. This warranty applies to the TYVASO Inhalation System device only. Accessory components are not covered under warranty. Circumstances that may void your warranty include: Modification or disassembly of the TYVASO Inhalation System device by anyone other than a factory-authorized technician Failure to comply with the written Instructions for Use manual when operating the TYVASO Inhalation System Unapproved use of the TYVASO Inhalation System For all inquiries relating to service or warranty for your TYVASO Inhalation System, contact your specialty pharmacy provider. You should have the following information available: Device serial number (located on bottom of TYVASO Inhalation System) Date TYVASO Inhalation System was acquired Nature of the problem and any steps taken to fix it Graphics in IFU are for representation only. Images may not be shown to scale TYVASO ® INHALATION SYSTEM Instructions for Use TYVASO Inhalation Solution is for prescription use only. TYVASO is a registered trademark of United Therapeutics Corporation. Literature Issued 2016-07-30 For further questions and information, or to report an adverse reaction, please call 1-877-UNITHER (1-877-864-8437). Emergency contact information Clinician: ___________________________________ Nurse educator: ______________________________ Specialty pharmacist: __________________________ United Therapeutics: ___________________________ Distributed by: United Therapeutics Corporation Research Triangle Park, North Carolina 27709 TYVASO ® (treprostinil) INHALATION SOLUTION © 2016, United Therapeutics Corporation. All rights reserved. RTP-1-00052 Rev. E Inhalation Device Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

14 CLINICAL STUDIES 14.1 Pulmonary Arterial Hypertension (WHO Group 1) TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of patients with PAH. The study population included 235 clinically stable subjects with PAH (WHO Group 1), nearly all with NYHA Class III (98%) symptoms who were receiving either bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase-5 inhibitor) for at least 3 months prior to study initiation. Concomitant therapy also could have included anticoagulants, other vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digitalis, but not a prostacyclin. These patients were administered either placebo or Tyvaso in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Patients were predominately female (82%), had the origin of PAH as idiopathic/heritable (56%), secondary to connective tissue diseases (33%) or secondary to HIV or previous use of anorexigens (12%); bosentan was the concomitant oral medication in 70% of those enrolled, sildenafil in 30%. The primary efficacy endpoint of the trial was the change in 6-Minute Walk Distance (6MWD) relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes after dosing), and 3 to 5 hours after bosentan or 0.5 to 2 hours after sildenafil. Patients receiving Tyvaso had a placebo-corrected median change from baseline in peak 6MWD of 20 meters at Week 12 (p<0.001). The distribution of these 6MWD changes from baseline at Week 12 were plotted across the range of observed values (Figure 1). 6MWD measured at trough exposure (defined as measurement of 6MWD at least 4 hours after dosing) improved by 14 meters. There were no placebo-controlled 6MWD assessments made after 12 weeks. Figure 1: Distributions of 6MWD Changes from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges-Lehmann estimator) within various subpopulations defined by age quartile, gender, geographic region of the study site, disease etiology, baseline 6MWD quartile, and type of background therapy (Figure 2). Figure 2: Placebo-Corrected Median Treatment Effect (Hodges-Lehmann Estimate with 95% CI) on 6MWD Change from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso for Various Subgroups Figure 1 Figure 2 14.2 Long-term Treatment of PAH In long-term follow-up of patients who were treated with Tyvaso in the pivotal study and the open-label extension (N=206), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 97%, 91%, and 82%, respectively. These uncontrolled observations do not allow comparison with a control group not given Tyvaso and cannot be used to determine the long-term effect of Tyvaso on mortality. 14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3) INCREASE was a 16-week, randomized, double-blind, placebo-controlled, multicenter study that enrolled 326 patients with PH-ILD. Enrolled study patients predominately had etiologies of idiopathic interstitial pneumonia (45%) inclusive of idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema (25%), and WHO Group 3 connective tissue disease (22%). The mean baseline 6MWD was 260 meters. Patients in the INCREASE study were randomized (1:1) to either placebo or Tyvaso in 4 daily treatment sessions with a target dose of 9 breaths (54 mcg) per session and a maximum dose of 12 breaths (72 mcg) per session over the course of the 16-week study. Approximately 75% of patients randomized to Tyvaso titrated up to a dose of 9 breaths, 4 times daily or greater, with 48% of patients randomized to Tyvaso reaching a dose of 12 breaths, 4 times daily during the study. The primary efficacy endpoint was the change in 6MWD measured at peak exposure (between 10 and 60 minutes after dosing) from baseline to Week 16. Patients receiving Tyvaso had a placebo-corrected median change from baseline in peak 6MWD of 21 meters at Week 16 (p=0.004) using Hodges-Lehmann estimate (Figure 3). Figure 3: Hodges-Lehmann Estimate of Treatment Effect by Visit for 6MWD at Peak Exposure (PH-ILD) The treatment effect on 6MWD at Week 16 was consistent for various subgroups, including etiology of PH-ILD, disease severity, age, sex, baseline hemodynamics, and dose (Figure 4). Figure 4: Forest Plot on Subgroup Analyses of Peak 6MWD (Meter) at Week 16 (PH-ILD) Time to clinical worsening in the INCREASE study was defined as the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication, decrease in 6MWD >15% from baseline directly related to PH-ILD at 2 consecutive visits and at least 24 hours apart, death (all causes), or lung transplantation. Treatment with Tyvaso in patients with PH-ILD resulted in numerically fewer hospitalizations. The numbers of reported deaths were the same for both treatment groups (Table 2). Overall, treatment with Tyvaso demonstrated a statistically significant increase in the time to first clinical worsening event (log-rank test p=0.041; Figure 5), and a 39% overall reduction in the risk of a clinical worsening event (HR=0.61 [95% CI; 0.40, 0.92]; Figure 5). Table 2: Clinical Worsening Events (PH-ILD) Tyvaso n=163 n (%) Placebo n=163 n (%) HR (95% CI) Clinical worsening 37 (22.7%) 54 (33.1%) 0.61 (0.40, 0.92) First contributing event Hospitalization due to a cardiopulmonary indication 18 (11.0%) 24 (14.7%) Decrease in 6MWD >15% from baseline directly related to PH-ILD 13 (8.0%) 26 (16.0%) Death (all causes) 4 (2.5%) 4 (2.5%) Lung transplantation 2 (1.2%) 0 First of each event Hospitalization due to a cardiopulmonary indication 21 (12.9%) 30 (18.4%) Decrease in 6MWD >15% from baseline directly related to PH-ILD 16 (9.8%) 31 (19.0%) Death (all causes) 8 (4.9%) 10 (6.1%) Lung transplantation 2 (1.2%) 1 (0.6%) Figure 5: Kaplan-Meier Plot of Time to Clinical Worsening Events (PH-ILD) Figure 3 Figure 4 Figure 5

8.5 Geriatric Use Across clinical studies used to establish the effectiveness of Tyvaso 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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Clinical studies of Tyvaso did not include patients younger than 18 years to determine whether they respond differently from older patients.

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 ≥9 and ≥145 times the human exposure when based on C max and AUC, respectively, following a single treprostinil dose of 54 mcg. 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 154 and 1479 times the human exposure, when based on C max and AUC, respectively, following a single Tyvaso dose of 54 mcg. 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 9 and 145 times the human exposure, when based on C max and AUC, respectively, following a single Tyvaso dose of 54 mcg. 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 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 ≥9 and ≥145 times the human exposure when based on C max and AUC, respectively, following a single treprostinil dose of 54 mcg. 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 154 and 1479 times the human exposure, when based on C max and AUC, respectively, following a single Tyvaso dose of 54 mcg. 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 9 and 145 times the human exposure, when based on C max and AUC, respectively, following a single Tyvaso dose of 54 mcg. 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 Tyvaso 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 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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Tyvaso (treprostinil) inhalation solution is supplied in 2.9 mL clear LDPE ampules packaged as 4 ampules in a foil pouch. Tyvaso is a clear colorless to slightly yellow solution containing 1.74 mg treprostinil per ampule at a concentration of 0.6 mg/mL. Ampules of Tyvaso are stable until the date indicated when stored in the unopened foil pouch at 20-25°C (68-77°F) with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Once the foil pack is opened, ampules should be used within 7 days. Because Tyvaso is light-sensitive, unopened ampules should be stored in the foil pouch. One ampule of Tyvaso should be used each day in the Tyvaso Inhalation System. After a Tyvaso ampule is opened and transferred to the medicine cup, the solution should remain in the device for no more than 1 day (24 hours). Any remaining solution should be discarded at the end of the day. Tyvaso Inhalation System Starter Kit containing a 28-ampule carton of Tyvaso (7 foil pouches each containing four 2.9 mL ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per mL]) and the Tyvaso Inhalation System. (NDC 66302-206-01) Tyvaso Inhalation System Refill Kit containing a 28-ampule carton of Tyvaso (7 foil pouches each containing four 2.9 mL ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per mL]) and accessories. (NDC 66302-206-02) Tyvaso 4 Pack Carton with 1 foil pouch containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL). (NDC 66302-206-03) Tyvaso Inhalation System Institutional Starter Kit containing a 4-ampule carton of Tyvaso (1 foil pouch containing four 2.9 mL ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per mL]) and the Tyvaso Inhalation System. (NDC 66302-206-04)

Ampules of Tyvaso are stable until the date indicated when stored in the unopened foil pouch at 20-25°C (68-77°F) with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Once the foil pack is opened, ampules should be used within 7 days. Because Tyvaso is light-sensitive, unopened ampules should be stored in the foil pouch. One ampule of Tyvaso should be used each day in the Tyvaso Inhalation System. After a Tyvaso ampule is opened and transferred to the medicine cup, the solution should remain in the device for no more than 1 day (24 hours). Any remaining solution should be discarded at the end of the day. Tyvaso Inhalation System Starter Kit containing a 28-ampule carton of Tyvaso (7 foil pouches each containing four 2.9 mL ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per mL]) and the Tyvaso Inhalation System. (NDC 66302-206-01) Tyvaso Inhalation System Refill Kit containing a 28-ampule carton of Tyvaso (7 foil pouches each containing four 2.9 mL ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per mL]) and accessories. (NDC 66302-206-02) Tyvaso 4 Pack Carton with 1 foil pouch containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL). (NDC 66302-206-03) Tyvaso Inhalation System Institutional Starter Kit containing a 4-ampule carton of Tyvaso (1 foil pouch containing four 2.9 mL ampules; each ampule contains 1.74 mg treprostinil [0.6 mg per mL]) and the Tyvaso Inhalation System. (NDC 66302-206-04)