Yutrepia

1 INDICATIONS AND USAGE • 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 YUTREPIA 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 YUTREPIA 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 ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. Do not swallow YUTREPIA capsules. Use only with the provided inhaler ( 2 ) • YUTREPIA should be administered 3 to 5 times per day. The contents of each capsule can be inhaled in 2 breaths. ( 2.1 ) • See Dosage and Administration for full instructions on dosing of patients who are treprostinil-naïve or transitioning from treprostinil inhalation solution to YUTREPIA ( 2.1 ) 2.1 Usual Dosage In Adults YUTREPIA capsules are for oral inhalation only and should be used only with the supplied inhaler. Do not swallow YUTREPIA capsules. YUTREPIA Dosing in treprostinil-naïve patients : In patients naïve to treprostinil, therapy should begin with 26.5 mcg 3 to 5 times per day, in 2 breaths based on patient response. Dosing in patients transitioning from treprostinil inhalation solution (Tyvaso) : Patients transitioning from treprostinil inhalation solution (Tyvaso), can begin YUTREPIA therapy 3 to 5 times per day, in 2 breaths, using the doses specified below ( Table 1 ): Table 1: YUTREPIA Dosing in Patients Transitioning from Treprostinil Inhalation Solution *Each breath of Tyvaso delivers approximately 6 mcg of treprostinil. Current Tyvaso Dose* YUTREPIA Dose (Number of Breaths) mcg 5 or less breaths 26.5 mcg 6 to 8 breaths 53 mcg 9 to 11 breaths 79.5 mcg 12 to 14 breaths 106 mcg 15 to 17 breaths 132.5 mcg 18 or more breaths 159 mcg In treprostinil-naïve patients and those transitioning from treprostinil inhalation solution, dose increases of 26.5 mcg per dose each week may be implemented, as tolerated. The target maintenance dosage is 79.5 mcg to 106 mcg, 4 times daily. Doses above 848 mcg per day have not been studied in patients with PAH. If a scheduled dose is missed, resume therapy as soon as possible at the usual dose.

3 DOSAGE FORMS AND STRENGTHS YUTREPIA inhalation powder contained in capsule available in 4 strengths: • 26.5 mcg: opaque yellow cap and clear body capsule with “LIQUIDIA 26.5” in black radial imprint on capsule cap. • 53 mcg: opaque green cap and clear body capsule with “LIQUIDIA 53” in white radial imprint on capsule cap. • 79.5 mcg: opaque blue cap and clear body capsule with “LIQUIDIA 79.5” in white radial imprint on capsule cap. • 106 mcg: opaque purple cap and clear body capsule with “LIQUIDIA 106” in white radial imprint on capsule cap. YUTREPIA inhalation powder contained in capsule is available in 4 strengths: 26.5 mcg, 53 mcg, 79.5 mcg, 106 mcg ( 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 with YUTREPIA (310%) are cough, headache, throat irritation, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Liquidia Technologies, Inc. at 1-888-393-LQDA (5732) 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. The safety and tolerability of YUTREPIA was evaluated in an open label study (INSPIRE) of 121 patients with PAH (WHO Group 1 and NYHA Functional Class II [80 patients] and Class III [41 patients]) followed for up to 2 months. The most commonly reported adverse reactions included cough, headache, throat irritation, dizziness, which are known side effects of treprostinil inhalation solution. Table 2 lists the adverse reactions that occurred at a rate of at least 4% of the overall INSPIRE safety population. The adverse reactions in the INSPIRE study were consistent with those observed in previous studies of inhaled treprostinil. Table 2: Adverse Reactions Occurring in ≥ 4% of Patients in the INSPIRE Study *Transition: Patients were on stable doses of treprostinil inhalation solution for at least 3 months prior to enrollment in the study and transitioned to treatment with YUTREPIA. †Add-on: Patients were prostacyclin-naïve and were taking no more than 2 approved oral PAH therapies for at least 3 months at time of enrollment and addition of treatment with YUTREPIA. Adverse Reaction Transition* N=55 Add-On† N=66 n (%) n (%) Cough 15 (27) 36 (55) Headache 14 (25) 18 (27) Throat Irritation 5 (9) 14 (21) Dizziness 6 (11) 7 (11) Diarrhea 3 (6) 8 (12) Chest Discomfort 5 (9) 5 (8) Nausea 4 (7) 5 (8) Dyspnea 3 (6) 3 (5) Flushing 1 (2) 5 (8) Oropharyngeal Pain 1 (2) 4 (6) 6.2 Adverse Reactions Identified in Post-Marketing Experience The following adverse reaction has been identified during the post-approval use of treprostinil inhalation solution. 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: • Angioedema

7 DRUG INTERACTIONS 7.1 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 )] . 7.2 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 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 3 9 and 3 145 times the human exposure when based on C max and AUC, respectively, following a single YUTREPIA dose of 79.5 mcg [see Clinical Pharmacology ( 12.3 )] . 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 YUTREPIA dose of 79.5 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 YUTREPIA dose of 79.5 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. 8.5 Geriatric Use Placebo-controlled clinical studies of treprostinil inhalation solution did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. The open-label INSPIRE study in PAH patients included 28 patients aged 65 and over in which no age-related differences were noted. 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 Insufficiency 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 The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

11 DESCRIPTION YUTREPIA contains treprostinil sodium, a prostacyclin mimetic. The chemical name for tresprostinil sodium is 2-{[(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H,2H,3H,3aH,4H,9H,9aH-cyclopenta[b]naphthalen-5-yl]oxy}acetic acid, sodium salt with the structural formula: Treprostinil sodium has a molecular formula of C 23 H 33 O 5 Na and a molecular weight of 412.49 daltons equivalent to 390.5 daltons of Treprostinil. YUTREPIA inhalation powder contained in a capsule is intended for oral inhalation. The capsule contains white to off-white powder of treprostinil sodium and the inactive ingredients L-leucine, polysorbate 80, sodium chloride, sodium citrate, and trehalose. Each 5 mg of YUTREPIA inhalation powder contains 26.5 mcg of treprostinil, where 26.5 mcg of treprostinil is equivalent to 28 mcg of treprostinil sodium. The accompanying inhalation device for delivery of YUTREPIA inhalation powder is a disposable plastic device used to inhale the dry powder contained in the HPMC capsule. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the inhalation device, which may vary from patient to patient. Under standardized in vitro testing, the inhalation device delivers the following amounts of treprostinil for each of the YUTREPIA inhalation powder capsule strengths: YUTREPIA Inhalation Powder Delivered Dose a Amount of treprostinil delivered from the device mouthpiece under an in vitro flow rate of 99 L/min with a collection time of 1.2 seconds (2 L total volume). Capsule Strength (treprostinil) Dose Delivered a 26.5 mcg 15.1 mcg 53 mcg 36.0 mcg 79.5 mcg 56.6 mcg 106 mcg 75.7 mcg Structural Formula

10 OVERDOSAGE In general, symptoms of overdose with 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 YUTREPIA is supplied in a carton consisting of 1 capsule based, dry powder inhaler (referred to as “inhaler”), 28 capsules (7 foil blister cards of 4 capsules each), and 7 single-use cleaning brushes. The individual capsule well is connected by an air channel to a separate blister well containing a desiccant strip. Descriptions of YUTREPIA carton by capsule strength are provided in Table 4 below: Table 4: YUTREPIA Carton Contents by Capsule Strength Capsule Strength (mcg treprostinil) Capsule Description NDC Number 26.5 Opaque yellow cap, clear body, imprinted with “LIQUIDIA 26.5” in black ink radially on cap 72964-011-01 53 Opaque green cap, clear body, imprinted with “LIQUIDIA 53” in white ink radially on cap 72964-012-01 79.5 Opaque blue cap, clear body, imprinted with “LIQUIDIA 79.5” in white ink radially on cap 72964-013-01 106 Opaque purple cap, clear body, imprinted with “LIQUIDIA 106” in white ink radially on cap 72964-014-01 YUTREPIA inhalation powder capsules should only be delivered using the capsule-based inhaler. The off-white plastic inhaler consists of a blue protective cap marked with YUTREPIA and a base with a mouthpiece, capsule chamber, and two blue push buttons. Discard the inhaler device after 7 days of use or 56 actuations, whichever comes first. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Capsules should remain in the blister to protect them from moisture and light, and each capsule should be removed only when ready to administer a dose. Keep out of the reach of children.