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
`
`
`
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`
`
`------------------------------ CONTRAINDICATIONS -----------------------------­
`
`None (4)
`
`
`
`•
`
`•
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`
`
`
`
`----------------------- 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)
`
`
`
`
`Tyvaso may cause symptomatic hypotension. (5.2)
`
`
`
`
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
`
`(5.4)
`
`
`
`Tyvaso dosage adjustments may be necessary if inhibitors or inducers of
`
`
`CYP2C8 are added or withdrawn. (5.5, 7.3)
`
`
`• Hepatic or renal insufficiency may increase exposure and decrease
`
`
`
`tolerability. (2.2, 2.3, 5.3)
`
`
`•
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`
`
`
`
`------------------------------ 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 1-866-458-6479 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`Revised: 10/2017
`
`
` --------------------------- 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 ----------------------­
`
`
`
`
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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
`
`
`
`
`
`
`approximately 6 mcg of treprostinil. (2.1)
`
`
`
`
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`• Administer in 4 separate treatment sessions each day approximately four
`
`
`
`hours apart, during waking hours. (2.1)
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`
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`Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are
`
`
`
`
`not tolerated, reduce to 1 or 2 breaths. (2.1)
`
`
`
`
`
`
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`• Dosage should be increased by an additional 3 breaths per session 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)
`
`______________________________________________________________________________________________________________________________________
`
`8.1 Pregnancy
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`8.2 Lactation
`
`1 INDICATIONS AND USAGE
`
`8.4 Pediatric Use
`
`2 DOSAGE AND ADMINISTRATION
`
`8.5 Geriatric Use
`
`2.1 Usual Dosage in Adults
`
`8.6 Patients with Hepatic Insufficiency
`
`2.2 Patients with Hepatic Insufficiency
`
`
`8.7 Patients with Renal Insufficiency
`
`
`2.3 Patients with Renal Insufficiency
`
`
`10 OVERDOSAGE
`
`2.4 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 Patients with Pulmonary Disease or Pulmonary Infections
`
`
`12.3 Pharmacokinetics
`
`5.2 Risk of Symptomatic Hypotension
`
`
`13 NONCLINICAL TOXICOLOGY
`
`5.3 Patients with Hepatic or Renal Insufficiency
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`5.4 Risk of Bleeding
`
`
`13.4 Inhalational Toxicity
`
`5.5 Effect of Other Drugs on Treprostinil
`
`14 CLINICAL STUDIES
`
`6 ADVERSE REACTIONS
`
`14.1 Pulmonary Arterial Hypertension (WHO Group I)
`
`
`6.1 Adverse Reactions Identified in Clinical Trials
`
`
`
`14.2 Long-term Treatment of PAH
`
`6.2 Adverse Reactions Identified in Post-Marketing Experience
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`7 DRUG INTERACTIONS
`
`17 PATIENT COUNSELING INFORMATION
`
`7.1 Bosentan
`
`
`7.2 Sildenafil
`* Sections or subsections omitted from the full prescribing information are not
`
`
`
`7.3 Effect of Cytochrome P450 Inhibitors and Inducers
`
`listed.
`
`7.4 Effect of Other Drugs on Treprostinil
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`Reference ID: 4169842
`
`
`Page 1
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`

`

` 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.
`
`
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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
`
`
`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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`
`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
`
`
`
`
`
`daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as
`
`tolerated.
`
`
`Maintenance Dosage:
`
`
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`
`
`
`Dosage should be increased by an additional 3 breaths per treatment session at approximately 1- to 2­
`
`
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`
`
`
`week intervals, if tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached, 4 times
`
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`
`
`
`
`daily. If adverse effects preclude titration to target dose, Tyvaso should be continued at the highest
`
`tolerated dose.
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`If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible
`
`at the usual dose.
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`The maximum recommended dosage is 9 breaths per treatment session, 4 times daily.
`
`Reference ID: 4169842
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`
`Page 2
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` 2.2 Patients with Hepatic Insufficiency
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` 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)].
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`
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` 2.3 Patients with Renal Insufficiency
`
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`
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` 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)].
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` 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.
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` 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
`
`
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`
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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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`
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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
`
` Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg of treprostinil (0.6 mg per mL).
`
`
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` 4 CONTRAINDICATIONS
`
`
`
` None.
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`
`
` 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: 4169842
`
`
`Page 3
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`

`

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` 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.
`
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` 5.3 Patients with Hepatic or Renal Insufficiency
`
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` 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)].
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` 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 (7.3) 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)].
`
`
`
`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
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`
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`
`
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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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`
`
`
`Reference ID: 4169842
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`
`Page 4
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`

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` Table 1: Adverse Events in ≥ 4% of PAH Patients Receiving
` Tyvaso and More Frequent∗ than Placebo
`
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`
`
` 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)
`
`
`
`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 (89%) of patients achieved the target dose of nine breaths, four times daily. Forty-two percent
`
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`
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`(42%) achieved a dose of 12 breaths four times daily. The adverse events during this chronic dosing
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`
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`
`
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`study were qualitatively similar to those observed in the 12-week placebo controlled trial.
`
`
`
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`
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`
`
` Cough
`
`
` Headache
`Throat Irritation /
`
`Pharyngolaryngeal Pain
`
`
`Nausea
`Flushing
`
`Syncope
`
` *More than 3% greater than placebo
`
`
`
`
`
`
`
`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.
`
`
`
`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.
`
`
`
`Adverse Events Associated with Route of Administration
`
`
`
`
`Adverse events in the treated group during the double-blind and open-label phase reflecting irritation to
`
`
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`the respiratory tract included: cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis and
`
`
`
`
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`wheezing. Serious adverse events during the open-label portion of the study included pneumonia in
`
`
`fifteen subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label
`
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`
`
`
`
`experience.
`
`
`6.2 Adverse Reactions Identified in Post-Marketing Experience
`
`
`
`
`The following adverse reaction 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:
`
`
`Angioedema.
`
`
`
`Reference ID: 4169842
`
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`Page 5
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`
` 7 DRUG INTERACTIONS
`
`
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`
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` 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 (5.5)].
`
`
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`
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`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 INR in healthy subjects given a single 25 mg dose of
`
`
`
`
`
`warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of
`
`
`
`
`10 ng/kg/min.
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Risk Summary
`
`Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated
`
`
`
`risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated
`
`
`
`
`
`with pulmonary arterial hypertension (see Clinical Considerations). In animal studies, no adverse
`
`
`
`
`reproductive and developmental effects were seen for treprostinil at ≥9 and ≥145 times the human
`
`
`
`
`
`exposure when based on Cmax and AUC following a single treprostinil dose of 54 mcg, respectively.
`
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`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.
`
`Reference ID: 4169842
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`
`Page 6
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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.
`
`
`
`
`Data
`
`Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous
`
`
`
`administration and with treprostinil diolamine administered orally. In pregnant rats, continuous
`
`
`
`
`subcutaneous infusions of treprostinil during organogenesis and late gestational development, at doses as
`
`
`high as 900 ng treprostinil/kg/min (about 117 times the starting human subcutaneous infusion rate, on a
`
`
`ng/m2 basis and about 16 times the average rate achieved in clinical trials), resulted in no evidence of
`
`
`
`harm to the fetus. In pregnant rabbits, effects of continuous subcutaneous infusions of treprostinil during
`
`
`
`
`
`
`organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right
`
`
`
`
`rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food
`
`
`consumption) at a dose of 150 ng treprostinil/kg/min (about 41 times the starting human subcutaneous
`
`infusion rate, on a ng/m2 basis, and 5 times the average rate used in clinical trials). In rats, continuous
`
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`
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`
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`
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`
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`
`
`subcutaneous infusion of treprostinil from implantation to the end of lactation, at doses of up to 450 ng
`
`
`
`
`treprostinil/kg/min, did not affect the growth and development of offspring. 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 following a single Tyvaso 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 Tyvaso dose of 54 mcg, respectively. 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
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`
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`
`
`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
`
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`
`
`
`
`
`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.
`
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` 8.6 Patients with Hepatic Insufficiency
`
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`
`
` 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)].
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`
` 8.7 Patients with Renal Insufficiency
`
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` 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,
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`
`
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` 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 390.52 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
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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
`
` 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
`
`
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` 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).
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`Absorption and Distribution
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`In a three-period crossover study, the bioavailability of two single doses of Tyvaso (18 mcg and 36 mcg)
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`
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`was compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the
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`absolute systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and
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`72% (36 mcg).
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`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
`
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`
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`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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`Following parenteral infusion, the apparent steady state volume of distribution (Vss) of treprostinil is
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`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
`
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`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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`and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each
`
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`accounting for 10-15% of the dose administered. Four of the metabolites are products of oxidation of
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`the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative (treprostinil glucuronide).
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`The elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a
`
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`terminal elimination half-life of approximately 4 hours using a two 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 Dosage and Administration (2.2), Warnings and Precautions (5.3) and Use in
`
`Specific Populations (8.6)].
`
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`Reference ID: 4169842
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`Page 9
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` 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)].
`
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`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`
` A two-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 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,
`
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`
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`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.
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`Oral administration of treprostinil diolamine to Tg.rasH2 mice at 0, 5, 10 and 20 mg/kg/day in males and
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`0, 3, 7.5 and 15 mg/kg/day in females daily for 26 weeks did not significantly increase the incidence of
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`tumors. The exposures, when based on AUC, obtained at the highest dose levels used in males and
`
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`
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`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
`
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`
`
`
`incidence of micronucleated polychromatic erythrocytes.
`
`
`
`13.4 Inhalational Toxicity
`
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`
`
`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
`
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`
`
`
`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.
`
`
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`
`
`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.
`
`Reference ID: 4169842
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`Page 10
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` 14 CLINICAL STUDIES
`
`
`
` 14.1 Pulmonary Arterial Hypertension (WHO Group I)
`
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`
`
`
` 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
`
`
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`
`
`
`
` 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