HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TYVASO safely and effectively. See full prescribing information for
`TYVASO.
`
`TYVASO® (treprostinil) inhalation solution, for oral inhalation use
`Initial U.S. Approval: 2002
`
` --------------------------- RECENT MAJOR CHANGES ---------------------------
`Warnings and Precautions (5.4)
`05/2022
`
` --------------------------- 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)
`
`•
`
` ----------------------- 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)
`
`•
`
` --------------------- DOSAGE FORMS AND STRENGTHS----------------------
`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg
`treprostinil (0.6 mg per mL). (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`None. (4)
`
` ----------------------- WARNINGS AND PRECAUTIONS -----------------------
`Tyvaso may cause symptomatic hypotension. (5.1)
`•
`•
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
`(5.2)
`Tyvaso 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, 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.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`Revised: 05/2022
`
`______________________________________________________________________________________________________________________________________
`8.1 Pregnancy
`FULL PRESCRIBING INFORMATION: CONTENTS*
`8.2 Lactation
`1 INDICATIONS AND USAGE
`8.4 Pediatric Use
`1.1 Pulmonary Arterial Hypertension
`8.5 Geriatric Use
`1.2 Pulmonary Hypertension Associated with ILD
`8.6 Patients with Hepatic Insufficiency
`2 DOSAGE AND ADMINISTRATION
`8.7 Patients with Renal Impairment
`2.1 Usual Dosage in Adults
`10 OVERDOSAGE
`2.2 Administration
`11 DESCRIPTION
`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)
`6.2 Post-Marketing Experience
`14.2 Long-term Treatment of PAH
`7 DRUG INTERACTIONS
`14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3)
`7.1 Bosentan
`16 HOW SUPPLIED/STORAGE AND HANDLING
`7.2 Sildenafil
`17 PATIENT COUNSELING INFORMATION
`7.3 Effect of Cytochrome P450 Inhibitors and Inducers
`7.4 Effect of Other Drugs on Treprostinil
` Sections or subsections omitted from the full prescribing information are not
`8 USE IN SPECIFIC POPULATIONS
`listed.
`
`
`
` *
`
`Reference ID: 4987170
`
`Page 1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`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)].
`
`2 DOSAGE AND ADMINISTRATION
`
`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.
`
`Page 2
`
`Reference ID: 4987170
`
`

`

`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.
`
`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).
`
`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 may produce symptomatic hypotension.
`
`5.2 Risk of Bleeding
`
`Tyvaso 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)].
`
`5.4 Bronchospasm
`
`Like other inhaled prostaglandins, Tyvaso may cause acute bronchospasm. Patients with asthma or
`chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk
`
`Page 3
`
`Reference ID: 4987170
`
`

`

`for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and
`during treatment with Tyvaso Inhalation Solution.
`
`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
`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 Frequenta
`than Placebo in TRIUMPH I
`
`Adverse Event
`
`Treatment
`n (%)
`
`Tyvaso
`n=115
`62 (54)
`47 (41)
`29 (25)
`22 (19)
`17 (15)
`7 (6)
`
`Placebo
`n=120
`35 (29)
`27 (23)
`17 (14)
`13 (11)
`1 (<1)
`1 (<1)
`
`Cough
`Headache
`Throat Irritation / Pharyngolaryngeal Pain
`Nausea
`Flushing
`Syncope
`a More than 3% greater than placebo
`
`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.
`
`Reference ID: 4987170
`
`Page 4
`
`

`

`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.
`
`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,
`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.
`
`Reference ID: 4987170
`
`Page 5
`
`

`

`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 Cmax 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
`Cmax 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 Cmax 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
`
`Reference ID: 4987170
`
`Page 6
`
`

`

`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 Tyvaso include flushing, headache, hypotension, nausea,
`vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have resolved.
`
`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 (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.
`
`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.
`
`Reference ID: 4987170
`
`Page 7
`
`

`

`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 Cmax) 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 Cmax at the target dose was 0.91 and 1.32 ng/mL with corresponding mean Tmax 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 (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.
`
`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 AUC0-inf that was not significantly
`altered compared to healthy subjects [see Use in Specific Populations (8.7)].
`
`Page 8
`
`Reference ID: 4987170
`
`

`

`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.
`
`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
`
`Page 9
`
`Reference ID: 4987170
`
`

`

`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).
`
`
`
`Reference ID: 4987170
`
`Page 10
`
`

`

`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
`
`
`
`
`
`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.
`
`Reference ID: 4987170
`
`Page 11
`
`

`

`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).
`
`
`
`Reference ID: 4987170
`
`Page 12
`
`

`

`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).
`
`
`
`
`Reference ID: 4987170
`
`Page 13
`
`

`

`Table 2:
`
`
`Clinical Worsening Events (PH-ILD)
`Tyvaso
`n=163
`n (%)
`37 (22.7%)
`
`Clinical worsening
`
`Placebo
`n=163
`n (%)
`54 (33.1%)
`
`HR (95% CI)
`
`0.61 (0.40, 0.92)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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)
`
`Lung transplantation
`
`Hospitalization due to a
`cardiopulmonary indication
`
`4 (2.5%)
`
`2 (1.2%)
`
`4 (2.5%)
`
`0
`
`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)
`
`Lung transplantation
`
`8 (4.9%)
`
`2 (1.2%)
`
`10 (6.1%)
`
`1 (0.6%)
`
`First contributing event
`
`First of each event
`
`
`Figure 5:
`
`Kaplan-Meier Plot of Time to Clinical Worsening Events (PH-ILD)
`
`
`
`Reference ID: 4987170
`
`
`
`Page 14
`
`

`

`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 po