HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TYVASO DPI safely and effectively. See full prescribing information for
`TYVASO DPI.
`
`TYVASO DPI™ (treprostinil) inhalation powder, for oral inhalation use
`Initial U.S. Approval: 2002
`
` --------------------------- 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)
`
`•
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`• Use only with the Tyvaso DPI Inhaler. (2.1)
`• Administer using a single inhalation per cartridge. (2.1)
`• Administer in 4 separate treatment sessions each day approximately
`4 hours apart, during waking hours. (2.1)
`Initial dosage: one 16 mcg cartridge per treatment session. (2.2)
`•
`• Dosage should be increased by an additional 16 mcg per treatment
`session at approximately 1- to 2-week intervals, if tolerated. (2.2)
`Titrate to target maintenance doses of 48 mcg to 64 mcg per treatment
`session, 4 times daily. (2.2)
`
`•
`
` --------------------- DOSAGE FORMS AND STRENGTHS----------------------
`Inhalation powder: Single-dose plastic cartridges containing 16, 32, 48, or
`64 mcg of treprostinil as a dry powder formulation. (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`None. (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS -----------------------
`Tyvaso DPI may cause symptomatic hypotension. (5.1)
`•
`•
`Tyvaso DPI inhibits platelet aggregation and increases the risk of
`bleeding. (5.2)
`Tyvaso DPI dosage adjustments may be necessary if inhibitors or
`inducers of CYP2C8 are added or withdrawn. (5.3, 7.3)
`• May cause bronchospasm: Patients with a history of hyperreactive
`airway disease may be more sensitive. (5.4)
`
`•
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`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.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`Revised: 5/2022
`
`______________________________________________________________________________________________________________________________________
`8.2 Lactation
`FULL PRESCRIBING INFORMATION: CONTENTS*
`8.4 Pediatric Use
`1 INDICATIONS AND USAGE
`8.5 Geriatric Use
`1.1 Pulmonary Arterial Hypertension
`8.6 Patients with Hepatic Insufficiency
`1.2 Pulmonary Hypertension Associated with ILD
`8.7 Patients with Renal Impairment
`2 DOSAGE AND ADMINISTRATION
`10 OVERDOSAGE
`2.1 Administration
`11 DESCRIPTION
`2.2 Usual Dosage in Adults
`11.1 Tyvaso DPI Cartridges
`3 DOSAGE FORMS AND STRENGTHS
`12 CLINICAL PHARMACOLOGY
`4 CONTRAINDICATIONS
`12.1 Mechanism of Action
`5 WARNINGS AND PRECAUTIONS
`12.2 Pharmacodynamics
`5.1 Risk of Symptomatic Hypotension
`12.3 Pharmacokinetics
`5.2 Risk of Bleeding
`13 NONCLINICAL TOXICOLOGY
`5.3 Effect of Other Drugs on Treprostinil
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.4 Bronchospasm
`13.2 Animal Toxicology and/or Pharmacology
`6 ADVERSE REACTIONS
`14 CLINICAL STUDIES
`6.1 Clinical Trials Experience
`14.1 Pulmonary Arterial Hypertension (WHO Group 1) (TRIUMPH I)
`7 DRUG INTERACTIONS
`14.2 Long-term Treatment of PAH
`7.1 Bosentan
`14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3)
`7.2 Sildenafil
`16 HOW SUPPLIED/STORAGE AND HANDLING
`7.3 Effect of Cytochrome P450 Inhibitors and Inducers
`17 PATIENT COUNSELING INFORMATION
`7.4 Effect of Other Drugs on Treprostinil
`8 USE IN SPECIFIC POPULATIONS
` Sections or subsections omitted from the full prescribing information are not
`8.1 Pregnancy
`listed.
`
` *
`
`
`
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`

`FULL PRESCRIBING INFORMATION
`
` 1
`
` INDICATIONS AND USAGE
`
`1.1 Pulmonary Arterial Hypertension
`
`Tyvaso DPI is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to
`improve exercise ability. Studies with Tyvaso establishing effectiveness predominately included patients
`with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH
`associated with connective tissue diseases (33%).
`
`The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can
`be adjusted for planned activities.
`
`While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical
`experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist
`(ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with
`Tyvaso was limited to 12 weeks in duration [see Clinical Studies (14)].
`
`1.2 Pulmonary Hypertension Associated with ILD
`
`Tyvaso DPI is indicated for the treatment of pulmonary hypertension associated with interstitial lung
`disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with Tyvaso establishing
`effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP)
`(45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema
`(CPFE) (25%), and WHO Group 3 connective tissue disease (22%) [see Clinical Studies (14.3)].
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Administration
`
`Use Tyvaso DPI only with the Tyvaso DPI Inhaler. Tyvaso DPI is administered using a single inhalation
`per cartridge. Administer Tyvaso DPI in 4 separate, equally spaced treatment sessions per day, during
`waking hours. The treatment sessions should be approximately 4 hours apart.
`
`If the prescribed dose is higher than 64 mcg per treatment session, more than 1 cartridge will be needed
`per session. Patients should follow the instructions for use for operation and care of the Tyvaso DPI
`Inhaler.
`
`Do not use the Tyvaso DPI Inhaler with other medications.
`
`Between each of the 4 daily treatment sessions, store the Tyvaso DPI Inhaler with the mouthpiece
`attached and empty. Wipe the outside of the inhaler with a clean, dry cloth only, if needed. Do not rinse
`or wash the Tyvaso DPI Inhaler; always keep the inhaler dry. After 7 days of use, throw away the used
`Tyvaso DPI Inhaler into regular household trash.
`
`2.2 Usual Dosage in Adults
`
`Initial Dosage:
`Tyvaso DPI therapy should begin with one 16 mcg cartridge per treatment session, 4 times daily.
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`Maintenance Dosage:
`Increase dosage by an additional 16 mcg per treatment session at approximately 1- to 2-week intervals.
`The target maintenance dosage is usually 48 mcg to 64 mcg per session.
`
`If adverse effects preclude titration, continue Tyvaso DPI at the highest tolerated dose.
`
`If a scheduled treatment session is missed, resume therapy as soon as possible at the usual dose.
`
`Dosage for Transition from Tyvaso® (treprostinil) Inhalation Solution:
`
`The following regimens of Tyvaso DPI and Tyvaso give similar exposure:
`
`Tyvaso DPI
`Cartridge Strength
`16 mcg
`32 mcg
`48 mcg
`64 mcg
`
`Tyvaso
`Number of Breaths
`≤5 (≤30 mcg)
`6 to 7 (36 to 42 mcg)
`8 to 10 (48 to 60 mcg)
`11 to 12 (66 to 72 mcg)
`
` DOSAGE FORMS AND STRENGTHS
`
` 3
`
`Inhalation powder: Single-dose plastic cartridges containing 16, 32, 48, or 64 mcg of treprostinil as a dry
`powder formulation.
`
`4 CONTRAINDICATIONS
`
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Symptomatic Hypotension
`
`Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure,
`treatment with Tyvaso DPI may produce symptomatic hypotension.
`
`5.2 Risk of Bleeding
`
`Tyvaso DPI inhibits platelet aggregation and increases the risk of bleeding.
`
`5.3 Effect of Other Drugs on Treprostinil
`
`Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase
`exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g.,
`rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events
`associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical
`effectiveness [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
`
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`5.4 Bronchospasm
`
`Like other inhaled prostaglandins, Tyvaso DPI may cause acute bronchospasm. Patients with asthma or
`chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk
`for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and
`during treatment with Tyvaso DPI.
`
`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)].
`
`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
`
`Cough
`Headache
`Dyspnea
`Nausea
`
`Tyvaso DPI (n=51)
`n (%)
`18 (35.3)
`8 (15.7)
`4 (7.8)
`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
`
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`

`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 Frequenta than Placebo in TRIUMPH I
`
`Adverse Event
`
`Placebo
`n=120
`
`Treatment
`n (%)
`Tyvaso Inhalation
`Solution
`n=115
`62 (54)
`47 (41)
`29 (25)
`22 (19)
`17 (15)
`7 (6)
`
`Cough
`Headache
`Throat Irritation / Pharyngolaryngeal Pain
`Nausea
`Flushing
`Syncope
`a More than 3% greater than placebo
`
`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.
`
`35 (29)
`27 (23)
`17 (14)
`13 (11)
`1 (<1)
`1 (<1)
`
`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 Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer,
`
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`

`rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the
`inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and Precautions (5.3)].
`
`7.4 Effect of Other Drugs on Treprostinil
`
`Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered
`with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in
`healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of
`treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The
`pharmacokinetics of R- and S- warfarin and the international normalized ratio (INR) in healthy subjects
`given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of
`treprostinil at an infusion rate of 10 ng/kg/min.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Risk Summary
`Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated
`risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated
`with pulmonary arterial hypertension (see Clinical Considerations). In animal studies, no adverse
`reproductive and developmental effects were seen for treprostinil at ≥8 and ≥134 times the human
`exposure when based on Cmax and AUC, respectively, following a single, inhaled 64 mcg dose of
`treprostinil inhalation powder.
`
`The estimated background risk of major birth defects and miscarriage for the indicated populations is
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`U.S. general population, the estimated background risk of major birth defects and miscarriage in
`clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
`
`Clinical Considerations
`Disease-associated maternal and embryo-fetal risk
`Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality.
`
`Data
`Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous
`administration and with treprostinil diolamine administered orally. In studies with orally administered
`treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development
`(teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of
`harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose
`tested (20 mg/kg/day), which represents about 129 and 1366 times the human exposure, when based on
`Cmax and AUC, respectively, following a single, inhaled 64 mcg dose of treprostinil inhalation powder.
`In pregnant rabbits, external fetal and soft tissue malformations and fetal skeletal malformation occurred.
`The dose at which no adverse effects were seen (0.5 mg/kg/day) represents about 8 and 134 times the
`human exposure, when based on Cmax and AUC, respectively, following a single, inhaled 64 mcg dose of
`treprostinil inhalation powder. No treprostinil treatment-related effects on labor and delivery were seen
`in animal studies. Animal reproduction studies are not always predictive of human response.
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`

`8.2 Lactation
`Risk Summary
`There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the
`effects on milk production.
`
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients have not been established. Clinical studies of inhaled
`treprostinil did not include patients younger than 18 years to determine whether they respond differently
`from older patients.
`
`8.5 Geriatric Use
`
`Across clinical studies used to establish the effectiveness of Tyvaso Inhalation Solution in patients with
`PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and
`safety profile observed in geriatric patients were similar to younger patients. In general, dose selection
`for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac
`dysfunction, and of concomitant diseases or other drug therapy.
`
`8.6 Patients with Hepatic Insufficiency
`
`Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects with mild-
`to-moderate hepatic insufficiency. Uptitrate slowly when treating patients with hepatic insufficiency
`because of the risk of an increase in systemic exposure which may lead to an increase in dose-dependent
`adverse effects. Treprostinil has not been studied in patients with severe hepatic insufficiency [see
`Clinical Pharmacology (12.3)].
`
`8.7 Patients with Renal Impairment
`
`No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by
`dialysis [see Clinical Pharmacology (12.3)].
`
`10 OVERDOSAGE
`
`In general, symptoms of overdose with inhaled treprostinil include flushing, headache, hypotension,
`nausea, vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have
`resolved.
`
`11 DESCRIPTION
`
`11.1 Tyvaso DPI Cartridges
`
`Tyvaso DPI consists of single-dose plastic cartridges filled with a white powder containing 1% of
`treprostinil, a prostacyclin mimetic, which is intended for administration by oral inhalation using the
`Tyvaso DPI Inhaler only. Treprostinil is adsorbed onto carrier particles consisting of fumaryl
`diketopiperazine (FDKP). Each cartridge contains 16, 32, 48, or 64 mcg of treprostinil with approximate
`fill weights of 1.6, 3.2, 4.8, or 6.4 mg of Tyvaso DPI, respectively.
`
`Treprostinil is (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-
`benz[f]inden-5-yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.52 and a molecular
`formula of C23H34O5.
`
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`

`The structural formula of treprostinil is:
`
`OH
`
`OH
`
`H
`
`H
`
`OCH2CO2H
`
`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 Inhalation Solution 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 as the concentration of
`treprostinil decreased.
`
`12.3 Pharmacokinetics
`
`Absorption
`Treprostinil plasma exposure data were obtained from a 6-treatment, 6-period, 6-sequence, crossover
`study of Tyvaso DPI and Tyvaso Inhalation Solution in healthy volunteers. The mean Cmax for the 16,
`48, and 64 mcg doses of Tyvaso DPI were 0.39, 1.11, and 1.33 ng/mL, respectively, with corresponding
`median Tmax of 0.17 hr. The mean AUC0-5hr for the 16, 48, and 64 mcg doses of Tyvaso DPI were 0.275,
`0.774, and 0.964 hr∙ng/mL, respectively.
`
`Treprostinil systemic exposure (AUC0-5hr and Cmax) of Tyvaso DPI post-inhalation was approximately
`proportional to the doses administered (16 to 64 mcg).
`
`Distribution
`Following parenteral infusion, the steady state volume of distribution (Vss) 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.
`
`Elimination
`With a single dose of Tyvaso DPI, the mean terminal half-life of treprostinil ranged from 27 to
`50 minutes.
`
`Metabolism: 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
`
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`

`are products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative
`(treprostinil glucuronide).
`
`Excretion: Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine.
`
`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 AUC0-inf that was not significantly
`altered compared to healthy subjects [see Use in Specific Populations (8.7)].
`
`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 36 times the clinical exposure at the 64 mcg dose of
`treprostinil inhalation powder. 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 solution 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 14 and 36 times, respectively, the clinical exposure at the 64 mcg dose of
`treprostinil inhalation powder.
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`14 CLINICAL STUDIES
`
`14.1 Pulmonary Arterial Hypertension (WHO Group 1) (TRIUMPH I)
`
`TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of
`patients with PAH (NCT00147199). 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 Inhalation Solution 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 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 Inhalation Solution 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 Inhalation Solution
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`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 Inhalation Solution for Various Subgroups
`
`
`
`14.2 Long-term Treatment of PAH
`
`
`
`In long-term follow-up of patients who were treated with Tyvaso Inhalation Solution in the pivotal study
`and the open-label extension (N=206) (NCT00147199), 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 Inhalation Solution and cannot be used to determine the long-term
`effect of Tyvaso Inhalation Solution 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 (NCT02630316). Enrolled study patients predominately had
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`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 Inhalation Solution
`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 Inhalation Solution titrated up to a dose of 9 breaths, 4 times daily or greater, with
`48% of patients randomized to Tyvaso Inhalation Solution 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 Inhalation Solution 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 of Tyvaso Inhalation Solution (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).
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`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 Inhalation Solution in patients with PH-ILD
`resulted in numerically fewer hospitalizations. The numbers of reported deaths were the same for both
`treatment groups (Table 3). Overall, treatment with Tyvaso Inhalation Solution 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).
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`Table 3:
`
`
`Clinical worsening
`
`Clinical Worsening Events (PH-ILD)
`Tyvaso Inhalation
`Solution
`n=163
`n (%)
`37 (22.7%)
`
`HR (95% CI)
`
`Placebo
`n=163
`n (%)
`
`54 (33.1%)
`
`0.61 (0.40, 0.92)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`18 (11.0%)
`
`24 (14.7%)
`
`13 (8.0%)
`
`26 (16.0%)
`
`4 (2.5%)
`
`2 (1.2%)
`
`4 (2.5%)
`
`0
`
`21 (12.9%)
`
`30 (18.4%)
`
`16 (9.8%)
`
`31 (19.0%)
`
`8 (4.9%)
`
`2 (1.2%)
`
`10 (6.1%)
`
`1 (0.6%)
`
`Hospitalization due to a
`cardiopulmonary indication
`
`Decrease in 6MWD >15% from
`baseline directly related to PH-ILD
`
`Death (all causes)
`
`Lung transplantation
`
`Hospitalization due to a
`cardiopulmonary indication
`
`Decrease in 6MWD >15% from
`baseline directly related to PH-ILD
`
`Death (all causes)
`
`Lung transplantation
`
`First contributing event
`
`First of each event
`
`
`
`Figure 5:
`
`Kaplan-Meier Plot of Time to Clinical Worsening Events (PH-ILD)
`
`
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`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`Tyvaso DPI (treprostinil) inhalation powder is available as 16 mcg, 32 mcg, 48 mcg, or 64 mcg of
`treprostinil in single-dose plastic cartridges with approximate fill weights of 1.6 mg, 3.2 mg, 4.8 mg, or
`6.4 mg of Tyvaso DPI, respectively. Four cartridges are contained in a single cavity of a blister strip. A
`card contains 7 blister strips separated by perforations for a total of 28 cartridges of each labeled strength
`in Titration and Maintenance Kits. For convenience, the perforation allows users to remove a single
`blister strip containing 4 cartridges. The Institutional Kits contain 4 blister strips for a total of
`16 cartridges of each labeled strength.
`
`The cartridges are color-coded, purple for 16 mcg, dark blue for 32 mcg, light blue for 48 mcg, and light
`green for 64 mcg. Each cartridge is marked with “Tyvaso DPI” and the corresponding dosage strength of
`“16 mcg”, “32 mcg”, “48 mcg”, or “64 mcg”.
`
`The Tyvaso DPI Inhaler is individually packaged in a clear overwrap. The inhaler is fully assembled
`with a removable mouthpiece cover. The Tyvaso DPI Inhaler can be used for up to 7 days from the date
`of first use. After 7 days of use, the inhaler must be discarded and replaced with a new inhaler.
`
`Tyvaso DPI is available in the followi