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 only
`
`
`Initial U.S. Approval: 2002
`
`
`--------------------------- INDICATIONS AND USAGE ----------------------------
`
`Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary
`
`
`arterial hypertension (PAH) (WHO Group 1) to improve exercise ability.
`Studies establishing effectiveness included predominately patients with
`
`NYHA Functional Class III symptoms and etiologies of idiopathic or
`heritable PAH (56%) or PAH associated with connective tissue diseases
`(33%). (1)
`
`
`
`
` ----------------------- 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 four
`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 at approximately
`
`1-2 week intervals, if tolerated. (2.1)
`
`Titrate to target maintenance dosage of 9 breaths or 54 mcg per
`
`treatment session as tolerated. (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 -----------------------
`
`
`
`Efficacy has not been established in patients with significant underlying
`
`lung disease (such as asthma or chronic obstructive pulmonary disease).
`(5.1)
`In patients with low systemic arterial pressure, Tyvaso may cause
`symptomatic hypotension. (5.2)
`
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding,
`particularly in patients receiving anticoagulants. (5.4, 7.2)
`Tyvaso dosage adjustments may be necessary if inhibitors or inducers of
`CYP2C8 are added or withdrawn. (5.5, 7.5)
`
`
` Hepatic or renal insufficiency may increase exposure and decrease
`
`
`tolerability. (2.2, 2.3, 5.3)
`
`
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`Most common adverse reactions (≥ 10%) are cough, headache, nausea,
`
`dizziness, flushing, throat irritation, pharyngolaryngeal pain and diarrhea. (6)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`
`
`Therapeutics Corp. at 1-877-UNITHER (1-877-864-8437) or FDA at 1­
`800-FDA-1088 or www.fda.gov/medwatch.
`
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`
`
`Concomitant diuretics, antihypertensives or other vasodilators may
`
`
`
`increase the risk of systemic hypotension. (7.1)
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`
`
`Pregnancy: No experience. (8.1)
`
`
`
` Nursing women: No experience. (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`Revised: 06/2016
`
`______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
` 
` 
` 
` 
`USE IN SPECIFIC POPULATIONS
`INDICATIONS AND USAGE
`1
` 
` 
` 
` 
`8.1
`Pregnancy
`DOSAGE AND ADMINISTRATION
`2
`
` 
` 
` 
` 
`8.2
`Labor and Delivery
`2.1 Usual Dosage in Adults
` 
` 
` 
` 
`8.3 Nursing Mothers
`Patients with Hepatic Insufficiency
`2.2
` 
` 
` 
` 
`8.4
`Pediatric Use
`2.3
`Patients with Renal Insufficiency
` 
` 
` 
` 
`8.5 Geriatric Use
`2.4 Administration
` 
` 
` 
`8.6
`Patients with Hepatic Insufficiency
`DOSAGE FORMS AND STRENGTHS
` 
` 
` 
`8.7
`Patients with Renal Insufficiency
`CONTRAINDICATIONS
` 
` 
`OVERDOSAGE
`WARNINGS AND PRECAUTIONS
` 
` 
` 
`DESCRIPTION
`Patients with Pulmonary Disease or Pulmonary Infections
`5.1
`
` 
` 
` 
`CLINICAL PHARMACOLOGY
`5.2 Risk of Symptomatic Hypotension
` 
` 
` 
` 
`12.1 Mechanism of Action
`5.3
`Patients with Hepatic or Renal Insufficiency
` 
` 
` 
` 
`12.2 Pharmacodynamics
`5.4 Risk of Bleeding
` 
` 
` 
` 
`12.3 Pharmacokinetics
`5.5
`Effect of Other Drugs on Treprostinil
` 
` 
`NONCLINICAL TOXICOLOGY
`ADVERSE REACTIONS
` 
` 
` 
` 
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`6.1 Adverse Reactions Identified in Clinical Trials
` 
` 
` 
` 
`13.3 Developmental Toxicity
`6.2 Adverse Reactions Identified in Post-Marketing Experience
` 
` 
` 
`13.4
`Inhalational Toxicity
`DRUG INTERACTIONS
` 
` 
` 
`CLINICAL STUDIES
`7.1 Antihypertensive Agents or Other Vasodilators
`
` 
` 
` 
`14.1 Pulmonary Arterial Hypertension (WHO Group I)
`7.2 Anticoagulants
` 
` 
` 
` 
`14.2 Long-term Treatment of PAH
`
`7.3 Bosentan
` 
` 
` 
`HOW SUPPLIED/STORAGE AND HANDLING
`7.4
`Sildenafil
` 
` 
` 
`PATIENT COUNSELING INFORMATION
`7.5
`Effect of Cytochrome P450 Inhibitors and Inducers
` 
`7.6
`Effect of Other Drugs on Treprostinil
`
`8
`
` 
`
` 
`10
` 
`11
` 
`12
`
` 
`13
`
` 
`14
`
`3
`4
`5
`
` 
` 
` 
`
`6
`
` 
`
` 
`7
`
`
`
`
`
`
`Reference ID: 3940956
`
` 
`16
` 
`17
`
`
`
` * Sections or subsections omitted from the full prescribing information are
`not listed.
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`Tyvaso® (treprostinil) inhalation solution
`
`For Oral Inhalation Only
`
`1
`
`INDICATIONS AND USAGE
`
`
`Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to
`
`improve exercise ability. Studies establishing effectiveness included predominately 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)].
`
`
`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. 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 at approximately 1-2 week intervals, if
`
`tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached 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.
`
`The maximum recommended dosage is 9 breaths per treatment session, 4 times daily.
`
`
`
`
`
`
`2
`
`Reference ID: 3940956
`
`

`

`
`
` 2.2 Patients with Hepatic Insufficiency
`
`
`
`Plasma clearance of treprostinil is reduced in patients with hepatic insufficiency. Patients with
`
`hepatic insufficiency may therefore be at increased risk of dose-dependent adverse reactions because of
`an increase in systemic exposure [see Warnings and Precautions (5.3), Use in Specific Populations (8.6)
`
` and Clinical Pharmacology (12.3)].
`
`
`
`
` 2.3 Patients with Renal Insufficiency
`
`
`
`Plasma clearance of treprostinil may be reduced in patients with renal insufficiency, since
`
`treprostinil and its metabolites are excreted mainly through the urinary route. Patients with renal
`
` insufficiency may therefore be at increased risk of dose-dependent adverse reactions [see Warnings and
` Precautions (5.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
`
`
`2.4 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 Patients with Pulmonary Disease or Pulmonary Infections
`
`
`The efficacy of Tyvaso has not been established in patients with significant underlying lung disease
`
`(e.g., asthma or chronic obstructive pulmonary disease). Patients with acute pulmonary infections should
`be carefully monitored to detect any worsening of lung disease and loss of drug effect.
`
`
`
`
`
`Reference ID: 3940956
`
`3
`
`

`

`5.2 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.
`
`5.3 Patients with Hepatic or Renal Insufficiency
`
`Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be
`
`
`exposed to greater systemic concentrations relative to patients with normal hepatic or renal function [see
`Dosage and Administration (2.2, 2.3), Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology
`
`(12.3)].
`
`
`5.4 Risk of Bleeding
`
`
`
`
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
`
`
`5.5 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 (7.5) and Clinical Pharmacology (12.3)].
`
`
`6 ADVERSE REACTIONS
`
`
`
`The following potential adverse reactions are described in Warnings and Precautions (5):
`Decrease in systemic blood pressure [see Warnings and Precautions (5.2)].
`-
`
`Bleeding [see Warnings and Precautions (5.4)].
`-
`
`
`
`
`Reference ID: 3940956
`
`4
`
`

`

`
`
` 6.1 Adverse Reactions Identified in Clinical Trials
`
`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.
`
`
`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,
`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 than Placebo
`
`
`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
` *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 (89%) percent of patients achieved the target dose of nine breaths, four times daily. Forty-two
`(42%) percent achieved a dose of 12 breaths four 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 per 100 patient-years vs. 10.9 per 100 pt-years),
`throat irritation (4.5 per 100 pt-years vs. 1.2 per 100 pt-years), nasal discomfort (2.6 per 100 pt-years vs.
`1.3 per 100 pt-years), and haemoptysis (2.5 per 100 pt-years vs. 1.3 per 100 pt-years) compared to the
`control group.
`
`Adverse Events Associated with Route of Administration
`
`Adverse events in the treated group during the double-blind and open-label phase reflecting
`
`irritation to the respiratory tract included: cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis
`and wheezing. Serious adverse events during the open-label portion of the study included pneumonia in
`
`
`
`Reference ID: 3940956
`
`5
`
`

`

`fifteen subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label
`experience.
`
`6.2 Adverse Reactions Identified in Post-Marketing Experience
`
`
`
`The following adverse reaction has been identified during the postapproval 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:
`
`
`Angioedema.
`
`
`7 DRUG INTERACTIONS
`
`Pharmacokinetic/pharmacodynamic interaction studies have not been conducted with inhaled
`
`treprostinil (Tyvaso); however, some of such studies have been conducted with orally (treprostinil
`diolamine) and subcutaneously administered treprostinil (Remodulin®).
`
`Pharmacodynamics
`
`7.1 Antihypertensive Agents or Other Vasodilators
`
`
`Concomitant administration of Tyvaso with diuretics, antihypertensive agents or other vasodilators
`
`may increase the risk of symptomatic hypotension.
`
`
`7.2 Anticoagulants
`
`
`
`Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding,
`
`particularly among patients receiving anticoagulants.
`
`Pharmacokinetics
`
`7.3 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.
`
`
`7.4 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.
`
`7.5 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
`
`
`
`
`Reference ID: 3940956
`
`6
`
`

`

`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
`
`(5.5)].
`
`
`
`7.6 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
`
`
`Pregnancy Category B
`There are no adequate and well controlled studies with Tyvaso in pregnant women. Animal
`
`reproduction studies have not been conducted with treprostinil administered by the inhalation route.
`However, studies in pregnant rabbits using continuous subcutaneous (sc) infusions of treprostinil sodium
`
`at infusion rates higher than the recommended human sc infusion rate resulted in an increased incidence
`
`of fetal skeletal variations associated with maternal toxicity. Also, a study in pregnant rabbits
`administered oral treprostinil diolamine at exposures higher than those in humans resulted in external
`fetal and soft tissue malformations and fetal skeletal malformations [see Nonclinical Toxicology (13.3)].
`Animal reproduction studies are not always predictive of human response.
`
`8.2 Labor and Delivery
`
`
`No treprostinil treatment-related effects on labor and delivery were seen in animal studies. The
`
`effect of treprostinil on labor and delivery in humans is unknown.
`
`
`8.3 Nursing Mothers
`
`
`
`
`It is not known whether treprostinil is excreted in human milk.
`
`
`
`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
`
`Clinical studies of Tyvaso did not include sufficient numbers of patients aged 65 years and over to
`
`determine whether they respond differently from 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.
`
`
`
`
`Reference ID: 3940956
`
`7
`
`

`

`
`
` 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), Dosage and Administration (2.2) and Warnings and
`
`Precautions (5.3)].
`
`
`8.7 Patients with Renal Insufficiency
`
`
`
`No studies have been performed in patients with renal insufficiency. Since treprostinil and its
`
`metabolites are excreted mainly through the urinary route, patients with renal insufficiency may have
`decreased clearance of the drug and its metabolites and consequently, dose-related adverse outcomes
`may be more frequent [see Clinical Pharmacology (12.3), Dosage and Administration (2.3) and
`Warnings and Precautions (5.3)].
`
`
`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 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, 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 390.51 and a molecular
`formula of C23H34O5.
`
`
`
`
`The structural formula of treprostinil is:
`
`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: 3940956
`
`8
`
`

`

`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 three separate studies. Treprostinil systemic exposure (AUC and Cmax) post-inhalation was
`
`shown to be proportional to the doses administered (18 mcg – 90 mcg).
`
`Absorption and Distribution
`
`
`
`In a three-period crossover study, the bioavailability of two 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 two 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.
`
`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 330-10,000 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 10-15% of the dose administered. Four of the metabolites are products of oxidation of the
`3-hydroxyloctyl side chain and one 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 two compartment model.
`
`
`Special 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 Dosage and Administration (2.2), Warnings and Precautions (5.3) and
`
`Use in Specific Populations (8.6)].
`
`
`
`
`Reference ID: 3940956
`
`9
`
`

`

`Renal Insufficiency
`
`
`
`
`No studies have been performed in patients with renal insufficiency; therefore, since treprostinil
`and its metabolites are excreted mainly through the urinary route, there is the potential for an increase in
`
`both parent drug and its metabolites and an increase in systemic exposure [see Dosage and
`Administration (2.3), Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`A two-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 (sc) infusions at rates of up to 450 ng
`treprostinil/kg/min [about 59 times the recommended starting human sc infusion rate (1.25 ng/kg/min)
`and 8 times the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m2 basis]. 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. The exposures, when based on AUC, obtained at the highest dose levels used in
`males and females are about 208- and 460-fold, respectively, the human exposure following a single
`
`
`inhaled dose of 54 mcg.
`
`Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an
`
`increased incidence of micronucleated polychromatic erythrocytes.
`
`13.3 Developmental Toxicity
`
`
`
`In pregnant rats, continuous sc infusions of treprostinil sodium during organogenesis and late
`
`gestational development, at rates as high as 900 ng treprostinil/kg/min (about 117 times the
`recommended starting human sc infusion rate and about 16 times the average rate achieved in clinical
`trials, on a ng/m2 basis), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of
`continuous sc infusions of treprostinil during organogenesis were limited to an increased incidence of
`fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar vertebra 1) associated with
`maternal toxicity (reduction in body weight and food consumption) at an infusion rate of 150 ng
`
`
`treprostinil/kg/min (about 41 times the starting human sc infusion rate and 5 times the average rate
`achieved in clinical trials, on a ng/m2 basis).
`
`
`
`Reference ID: 3940956
`
`10
`
`

`

`In studies with 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 following a single dose of 54 mcg, respectively. 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 following a single dose of 54 mcg, respectively.
`
`
`13.4 Inhalational Toxicity
`
`Rats and dogs that received daily administrations of treprostinil by inhalation for 3 months
`
`developed respiratory tract lesions (respiratory epithelial degeneration, goblet cell
` hyperplasia/hypertrophy, epithelial ulceration, squamous epithelial degeneration and necrosis, and lung
`
`hemorrhage). Some of the same lesions seen in animals sacrificed at the end of treatment (larynx, lung
`and nasal cavity lesions in rats, and lesions of the larynx in dogs) were also observed in animals
`sacrificed after a 4-week recovery period. Rats also developed cardiac changes (degeneration/fibrosis). A
`no-effect dose level for these effects was not demonstrated in rats (doses as low as 7 µg/kg/day were
`administered); whereas 107 µg/kg/day was a no-effect dose level in dogs.
`
`
`
`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 I)
`
`TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled multi-center study of
`
`patients with PAH. The study population included 235 clinically stable subjects with pulmonary arterial
`hypertension (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 three 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 four daily treatment sessions
`
`with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Patients were
`predominantly 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 six-minute walk distance (6MWD)
`
`
`relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes
`after dosing), and 3-5 hours after bosentan or 0.5-2 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.
`
`
`
`
`Reference ID: 3940956
`
`11
`
`

`

`
`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: 3940956
`
`
`12
`
`

`

`
`
`
`
` Figure 2. Placebo Corrected Median Treatment Effect (Hodges-Lehmann estimate with 95% CI) on 6MWD Change from
`
`
`Baseline at Week 12 During Peak Plasma Co