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) ] .

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.