` 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
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` Initial U.S. Approval: 2002
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`• Dosage should be increased by an additional 3 breaths per treatment
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`session at approximately 1- to 2-week intervals, if tolerated. (2.1)
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`Titrate to target maintenance doses of 9 to 12 breaths per treatment
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`session, 4 times daily. (2.1)
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`•
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`--------------------- DOSAGE FORMS AND STRENGTHS---------------------
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`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg
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`
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`treprostinil (0.6 mg per mL). (3)
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`------------------------------ CONTRAINDICATIONS -----------------------------
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`
`None. (4)
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`----------------------- WARNINGS AND PRECAUTIONS ----------------------
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`Tyvaso may cause symptomatic hypotension. (5.1)
`•
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`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
`•
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`(5.2)
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`Tyvaso dosage adjustments may be necessary if inhibitors or inducers of
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`CYP2C8 are added or withdrawn. (5.3, 7.3)
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`•
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`
`
`------------------------------ ADVERSE REACTIONS -----------------------------
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`Most common adverse reactions (≥4%) are cough, headache, nausea,
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`dizziness, flushing, throat irritation, pharyngolaryngeal pain, diarrhea, and
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`syncope. (6)
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`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.
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`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
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`Revised: 03/2021
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` ---------------------------RECENT MAJOR CHANGES --------------------------
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`
` Indications and Usage (1.2)
` 03/2021
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`
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`
`
` --------------------------- INDICATIONS AND USAGE----------------------------
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`
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` 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
`
`
`
`
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`
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`etiologies of idiopathic or heritable PAH (56%) or PAH associated with
`
`connective tissue diseases (33%). (1.1)
`
`
`Pulmonary hypertension associated with interstitial lung disease
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`(PH-ILD; WHO Group 3) to improve exercise ability. The study
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`
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`establishing effectiveness predominately included patients with
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`
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`etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of
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`idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and
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`
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`emphysema (CPFE) (25%), and WHO Group 3 connective tissue
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`disease (22%). (1.2)
`
`
`•
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`-----------------------DOSAGE AND ADMINISTRATION ----------------------
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`• Use only with the Tyvaso Inhalation System. (2.1)
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`• Administer undiluted, as supplied. A single breath of Tyvaso delivers
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`approximately 6 mcg of treprostinil. (2.1)
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`• Administer in 4 separate treatment sessions each day approximately
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`4 hours apart, during waking hours. (2.1)
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`Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are
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`not tolerated, reduce to 1 or 2 breaths. (2.1)
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`•
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`______________________________________________________________________________________________________________________________________
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`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`8.2 Lactation
`
`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 Usual Dosage in Adults
`
`
`
`11 DESCRIPTION
`
`2.2 Administration
`
`12 CLINICAL PHARMACOLOGY
`
`3 DOSAGE FORMS AND STRENGTHS
`
`12.1 Mechanism of Action
`
`
`4 CONTRAINDICATIONS
`
`12.2 Pharmacodynamics
`
`5 WARNINGS AND PRECAUTIONS
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`12.3 Pharmacokinetics
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`5.1 Risk of Symptomatic Hypotension
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`13 NONCLINICAL TOXICOLOGY
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`5.2 Risk of Bleeding
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`5.3 Effect of Other Drugs on Treprostinil
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`13.2 Animal Toxicology and/or Pharmacology
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`6 ADVERSE REACTIONS
`
`14 CLINICAL STUDIES
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`6.1 Clinical Trials Experience
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`
`14.1 Pulmonary Arterial Hypertension (WHO Group 1)
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`6.2 Post-Marketing Experience
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`14.2 Long-term Treatment of PAH
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`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
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`7.4 Effect of Other Drugs on Treprostinil
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`* Sections or subsections omitted from the full prescribing information are not
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`8 USE IN SPECIFIC POPULATIONS
`listed.
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`8.1 Pregnancy
`
`
`
`
`Reference ID: 4771425
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`
`Page 1
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` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Pulmonary Arterial Hypertension
`
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`
`
`
`
` 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
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` be adjusted for planned activities.
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` 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
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` 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)].
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` 1.2 Pulmonary Hypertension Associated with ILD
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`Tyvaso is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease
`
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`(PH-ILD; WHO Group 3) to improve exercise ability. The study establishing effectiveness
`
`
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`predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive
`
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`
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`of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%),
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`and WHO Group 3 connective tissue disease (22%) [see Clinical Studies (14)].
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Usual Dosage in Adults
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`Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of an
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`ultrasonic, pulsed delivery device and its accessories.
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`Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. Each
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`treatment session will take 2 to 3 minutes. The treatment sessions should be approximately 4 hours apart.
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`Initial Dosage:
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`Therapy should begin with 3 breaths of Tyvaso (18 mcg of treprostinil) per treatment session 4 times
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`daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as
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`tolerated.
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`Maintenance Dosage:
`
`
`Dosage should be increased by an additional 3 breaths per treatment session, 4 times daily at
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`
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`approximately 1- to 2-week intervals. Studies establishing effectiveness in patients with PAH and
`
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`PH-ILD have used target doses of 9 to 12 breaths per treatment session, 4 times daily. If adverse effects
`
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`preclude titration to target dose, Tyvaso should be continued at the highest tolerated dose.
`
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`
`Reference ID: 4771425
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`
`Page 2
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`If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible
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`at the usual dose.
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`2.2 Administration
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`Tyvaso must be used only with the Tyvaso Inhalation System. Patients should follow the instructions for
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`use for operation of the Tyvaso Inhalation System and for daily cleaning of the device components after
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`the last treatment session of the day. To avoid potential interruptions in drug delivery because of
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`equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device.
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`Do not mix Tyvaso with other medications in the Tyvaso Inhalation System. Compatibility of Tyvaso
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`with other medications has not been studied.
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`The Tyvaso Inhalation System should be prepared for use each day according to the instructions for use.
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`One ampule of Tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a single
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`day. Prior to the first treatment session, the patient should twist the top off a single Tyvaso ampule and
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`squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions, the
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`device should be capped and stored upright with the remaining medication inside.
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`At the end of each day, the medicine cup and any remaining medication must be discarded. The device
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`must be cleaned each day according to the instructions for use.
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`Avoid skin or eye contact with Tyvaso solution. Do not orally ingest the Tyvaso solution.
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`3 DOSAGE FORMS AND STRENGTHS
`
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`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg of treprostinil (0.6 mg per mL).
`
`
`4 CONTRAINDICATIONS
`
`
`None.
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`5 WARNINGS AND PRECAUTIONS
`
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`5.1 Risk of Symptomatic Hypotension
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`Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure,
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`treatment with Tyvaso may produce symptomatic hypotension.
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`5.2 Risk of Bleeding
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`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
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`5.3 Effect of Other Drugs on Treprostinil
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`
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`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
`
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`associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical
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`effectiveness [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
`
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`Reference ID: 4771425
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`Page 3
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` 6 ADVERSE REACTIONS
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` The following potential adverse reactions are described in Warnings and Precautions (5):
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` - Decrease in systemic blood pressure [see Warnings and Precautions (5.1)].
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` - Bleeding [see Warnings and Precautions (5.2)].
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` 6.1 Clinical Trials Experience
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` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`
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` 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.
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`
` Pulmonary Arterial Hypertension
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`In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and
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`nearly all NYHA Functional Class III), the most commonly reported adverse reactions on Tyvaso
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`included cough and throat irritation, headache, gastrointestinal effects, muscle, jaw or bone pain,
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`dizziness, flushing, and syncope. Table 1 lists the adverse reactions that occurred at a rate of at least 4%
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`and were more frequent in patients treated with Tyvaso than with placebo.
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`Table 1:
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`Adverse Events in ≥4% of PAH Patients Receiving Tyvaso and More Frequenta
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`than Placebo in TRIUMPH I
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`Adverse Event
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`Treatment
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`n (%)
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` Tyvaso
`n=115
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`
` 62 (54)
`47 (41)
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`29 (25)
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`22 (19)
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` 17 (15)
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` 7 (6)
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` Placebo
`
` n=120
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` 35 (29)
`27 (23)
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`17 (14)
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`13 (11)
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` 1 (<1)
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` 1 (<1)
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` Cough
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`Headache
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`Throat Irritation / Pharyngolaryngeal Pain
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`Nausea
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` Flushing
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` Syncope
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` a More than 3% greater than placebo
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`The safety of Tyvaso was also studied in a long-term, open-label extension study in which 206 patients
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`were dosed for a mean duration of 2.3 years, with a maximum exposure of 5.4 years. Eighty-nine percent
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`(89%) of patients achieved the target dose of 9 breaths, 4 times daily. Forty-two percent (42%) achieved
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`a dose of 12 breaths, 4 times daily. The adverse events during this chronic dosing study were
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`qualitatively similar to those observed in the 12-week placebo-controlled trial.
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`In a prospective, observational study comparing patients taking Tyvaso (958 patient-years of exposure)
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`and a control group (treatment with other approved therapies for PAH; 1094 patient-years), Tyvaso was
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`associated with a higher rate of cough (16.2 vs. 10.9 per 100 patient-years), throat irritation (4.5 vs.
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`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
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`100 pt-years) compared to the control group.
`
`Reference ID: 4771425
`
`
`Page 4
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` Pulmonary Hypertension Associated with ILD
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`In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3),
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`adverse reactions were similar to the experience in studies of PAH.
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`6.2 Post-Marketing Experience
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`The adverse reaction of angioedema has been identified during the post-approval use of Tyvaso. Because
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`this reaction is reported voluntarily from a population of uncertain size, it is not always possible to
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`reliably estimate the frequency or establish a causal relationship to drug exposure.
`
`
`7 DRUG INTERACTIONS
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`7.1 Bosentan
`
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`In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of
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`treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and bosentan
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`were observed.
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`7.2 Sildenafil
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`In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of
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`treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and sildenafil
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`were observed.
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`7.3 Effect of Cytochrome P450 Inhibitors and Inducers
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`In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450
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`(CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
`
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`CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6,
`
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`CYP2C9, CYP2C19, and CYP3A.
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`Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated
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`that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases
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`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
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`inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and Precautions (5.3)].
`
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`7.4 Effect of Other Drugs on Treprostinil
`
`
`
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`Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered
`
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`with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in
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`healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of
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`treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The
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`pharmacokinetics of R- and S- warfarin and the international normalized ratio (INR) in healthy subjects
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`given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of
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`treprostinil at an infusion rate of 10 ng/kg/min.
`
`Reference ID: 4771425
`
`
`Page 5
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` 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
`
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`with pulmonary arterial hypertension (see Clinical Considerations). In animal studies, no adverse
`
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`reproductive and developmental effects were seen for treprostinil at ≥9 and ≥145 times the human
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`exposure when based on Cmax and AUC, respectively, following a single treprostinil dose of 54 mcg.
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`The estimated background risk of major birth defects and miscarriage for the indicated populations is
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`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
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`U.S. general population, the estimated background risk of major birth defects and miscarriage in
`
`
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`clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
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`
`Clinical Considerations
`Disease-associated maternal and embryo-fetal risk
`
`
`Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality.
`
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`
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`Data
`
`Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous
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`
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`administration and with treprostinil diolamine administered orally. In studies with orally administered
`
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`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
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`harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose
`
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`tested (20 mg/kg/day), which represents about 154 and 1479 times the human exposure, when based on
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`Cmax and AUC, respectively, following a single Tyvaso dose of 54 mcg. In pregnant rabbits, external
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`fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no
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`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
`
`
`
`
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`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
`
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`not include patients younger than 18 years to determine whether they respond differently from older
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`patients.
`
`
`8.5 Geriatric Use
`
`
`Across clinical studies used to establish the effectiveness of Tyvaso in patients with PAH and PH-ILD,
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`268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile
`
`
`
`
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`
`observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly
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`Page 6
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` patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and
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` of concomitant diseases or other drug therapy.
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`
` 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)].
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`
` 8.7 Patients with Renal Impairment
`
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`
`
` No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by
`
`
`
`
` dialysis [see Clinical Pharmacology (12.3)].
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`
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`
`
` 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.
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`
`
` 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
`
`
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`Treprostinil is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct
`
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`
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`vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.
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`12.2 Pharmacodynamics
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`
`In a clinical trial of 240 healthy volunteers, single doses of Tyvaso 54 mcg (the target maintenance dose
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`
`per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by
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`approximately 10 ms. The QTc effect dissipated rapidly as the concentration of treprostinil decreased.
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`
`12.3 Pharmacokinetics
`
`
`Pharmacokinetic information for single doses of inhaled treprostinil was obtained in healthy volunteers
`
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`in 3 separate studies. Treprostinil systemic exposure (AUC and Cmax) post-inhalation was shown to be
`
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`
`proportional to the doses administered (18 mcg to 90 mcg).
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`Absorption
`
`
`In a 3-period crossover study, the bioavailability of 2 single doses of Tyvaso (18 mcg and 36 mcg) was
`
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`
`
`compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the absolute
`
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`systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and 72%
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`
`(36 mcg).
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`
`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.
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`Distribution
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`Following parenteral infusion, the apparent steady state volume of distribution (Vss) of treprostinil is
`
`
`approximately 14 L/70 kg ideal body weight.
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`
`In vitro treprostinil is 91% bound to human plasma proteins over the 330 to 10,000 mcg/L concentration
`
`range.
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`Metabolism and Excretion
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`
`
`
`Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. Treprostinil is
`
`
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`substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%)
`
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`
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`and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each
`
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`accounting for 10 to 15% of the dose administered. Four of the metabolites are products of oxidation of
`
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`the 3-hydroxyloctyl side chain and 1 is a glucuroconjugated derivative (treprostinil glucuronide).
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`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)].
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`Renal Impairment
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`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)].
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`
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`
`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,
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`10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential associated with treprostinil
`
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`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
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`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
`
`
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`treprostinil/kg/min. In this study, males were dosed from 10 weeks prior to mating and through the
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`2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6.
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`Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10, and 20 mg/kg/day in males
`
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`
`
`and 0, 3, 7.5, and 15 mg/kg/day in females daily for 26 weeks did not significantly increase the incidence
`
`
`
`of tumors.
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`Treprostinil diolamine was tested in vivo in a rat micronucleus assay and did not induce an increased
`
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`
`
`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
`
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`
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`were more deaths (11) in the mid- and high-dose treprostinil groups during the first 9 weeks of the study,
`
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`
`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
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`
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`about 15 and 35 times, respectively, the clinical exposure at the target maintenance dose of 54 mcg.
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`
`
`14 CLINICAL STUDIES
`
`
`14.1 Pulmonary Arterial Hypertension (WHO Group 1)
`
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`
`
`TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled, multicenter study of
`
`
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`patients with PAH. The study population included 235 clinically stable subjects with PAH (WHO Group
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`
`1), nearly all with NYHA Class III (98%) symptoms who were receiving either bosentan (an endothelin
`
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`
`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%),
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`
`
`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
`
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`in 70% of those enrolled, sildenafil in 30%.
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`Page 9
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`The primary efficacy endpoint of the trial was the change in 6-Minute Walk Distance (6MWD) relative
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`to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes after
`
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`dosing), and 3 to 5 hours after bosentan or 0.5 to 2 hours after sildenafil. Patients receiving Tyvaso had a
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`placebo-corrected median change from baseline in peak 6MWD of 20 meters at Week 12 (p<0.001). The
`
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`
`distribution of these 6MWD changes from baseline at Week 12 were plotted across the range of
`
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`
`
`observed values (Figure 1). 6MWD measured at trough exposure (defined as measurement of 6MWD at
`
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`
`
`
`least 4 hours after dosing) improved by 14 meters. There were no placebo-controlled 6MWD
`
`
`
`assessments made after 12 weeks.
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`
`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).
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`Page 10
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` 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
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`
`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
`
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`
`
`Tyvaso and cannot be used to determine the long-term effect of Tyvaso on mortality.
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`
`14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3)
`
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`
`
`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
`
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`
`
`
`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.
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`Page 11
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`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
`
`
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`
`
`(72 mcg) per session over the course of the 16-week study. Approximately 75% of patients randomized
`
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`
`
`
`
`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.
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`
`
`The primary efficacy endpoint was the change in 6MWD measured at peak exposure (between 10 and
`
`
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`
`
`
`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)
`
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`
`
`
`
`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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`
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`Page 12
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` Figure 4:
`
`
`
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`
`
`
`
`
` Forest Plot on Subgroup Analyses of Peak 6MWD (Meter) at Week 16 (PH-ILD)