CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`022387Orig1s017
`
`
`Trade Name:
`Generic or Proper
`Name:
`Sponsor:
`
`TYVASO
`treprostinil
`
`United Therapeutics Corp.
`
`Approval Date: March 31, 2021
`
`Indication:
`
`Tyvaso is a prostacyclin mimetic indicated for the treatment of:
`•
`Pulmonary arterial hypertension (PAH; WHO Group 1) to
`improve exercise ability. Studies establishing effectiveness
`predominately included patients with NYHA Functional Class
`III symptoms and etiologies of idiopathic or heritable PAH
`(56%) or PAH associated with connective tissue diseases (33%).
`
`Pulmonary hypertension associated with interstitial lung
`•
`disease (PH-ILD; WHO Group 3) to improve exercise ability.
`The study establishing effectiveness predominately included
`patients with etiologies of idiopathic interstitial pneumonia (IIP)
`(45%) inclusive of idiopathic pulmonary fibrosis (IPF),
`combined pulmonary fibrosis and emphysema (CPFE) (25%),
`and WHO Group 3 connective tissue disease (22%).
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`022387Orig1s017
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Officer/Employee List
`Multidiscipline Review(s)
`
`• Clinical
`• Statistical
`
`Product Quality Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`
`X
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
` 022387Orig1s017
`
`
`
`APPROVAL LETTER
`
`

`

`
`
` NDA 22387/S-017
`
`
`
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`United Therapeutics Corp.
`
`
`Attention: Sarah Gemberling, PhD, RAC
`
`Associate Manager, Regulatory Affairs
`
`55 TW Alexander Drive
`
`PO Box 14186
`
`Research Triangle Park, NC 27709
`
`
`
`
`Dear Dr. Gemberling:
`
`
`
`Please refer to your supplemental new drug application (sNDA) dated June 1, 2020,
`
`
`received June 1, 2020, submitted under section 505(b) of the Federal Food, Drug, and
`
`
`
`Cosmetic Act (FDCA) for Tyvaso (treprostinil) inhalation solution.
`
`
`
`
`
`This Prior Approval supplemental new drug application provides for a new indication for
`
`the treatment of pulmonary hypertension associated with interstitial lung disease (PH­
`
`ILD; WHO Group 3) to improve exercise ability.
`
`
`APPROVAL & LABELING
`
`We have completed our review of this application. It is approved, effective on the date of
`
`
`this letter, for use as recommended in the enclosed agreed-upon labeling.
`
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`
`
`
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`
`
`
`the FDA automated drug registration and listing system (eLIST), as described at
`
`
`
`
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling Prescribing
`
`Information, and Instructions for Use, with the addition of any labeling changes in
`
`
`
`
`pending “Changes Being Effected” (CBE) supplements, as well as annual reportable
`
`
`changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for
`
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`
`
`
`
`
`
`
`
` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`
`
`
` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm
`
`
`
`
`Reference ID: 4771425
`
`

`

`
`
`
`
`
` NDA 22387/S-017
`
` Page 2
`
` The SPL will be accessible from publicly available labeling repositories.
`
`
`
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`
`
`
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`
`
`
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`
`
`
`
`
` highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
`
`
`
`
` REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`
`
`
`
`new active ingredients (which includes new salts and new fixed combinations), new
`
`
`
`indications, new dosage forms, new dosing regimens, or new routes of administration
`
`
`are required to contain an assessment of the safety and effectiveness of the product for
`
`
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`
`
`or inapplicable.
`
`
`We are waiving the pediatric study requirement for this application because necessary
`
`
`
`
`
`studies are impossible or highly impracticable.
`
`
`
`PROMOTIONAL MATERIALS
`
`
`
`
`You may request advisory comments on proposed introductory advertising and
`
`promotional labeling. For information about submitting promotional materials, see the
`
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`
`
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.3
`
`You must submit final promotional materials and Prescribing Information, accompanied
`
`
`
`by a Form FDA 2253, at the time of initial dissemination or publication
`
`
`
`
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`
`
`
`
`
`
`
`
`
`Instructions for completing the form can be found at FDA.gov.5
`
`
`REPORTING REQUIREMENTS
`
` We remind you that you must comply with reporting requirements for an approved NDA
`
`
` (21 CFR 314.80 and 314.81).
`
`
`
`
`
`
`
`
`
` 3 For the most recent version of a guidance, check the FDA guidance web page at
` https://www.fda.gov/media/128163/download.
`
`
`
` 4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`
`
` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`
`
`Reference ID: 4771425
`
`

`

`
`
`
` NDA 22387/S-017
`
` Page 3
`
` Your product is a Part 3 combination product (21 CFR 3.2(e)); therefore, you must also
`
`
`
` comply with postmarketing safety reporting requirements for an approved combination
` product (21 CFR 4, Subpart B). Additional information on combination product
`
`
`
`
`
` postmarketing safety reporting is available at FDA.gov.6
`
`
`
`
`
`If you have any questions, please call Brian Cooney, Regulatory Project Manager, at
`
`(301) 796-0886.
`
`
`
`Sincerely,
`
`
`
`{See appended electronic signature page}
`
`
`
`Norman Stockbridge, MD, PhD
`
`Director
`
`
`Division of Cardiology and Nephrology
`
`Office of Cardiology, Hematology, Endocrinology,
`
`and Nephrology
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Instructions for Use
`
`
`
`
`
`
` 6 https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety­
`
`
`reporting-combination-products
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4771425
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`03/31/2021 01:37:04 PM
`
`Reference ID: 4771425
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`022387Orig1s017
`
`
`LABELING
`
`

`

`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` TYVASO safely and effectively. See full prescribing information for
` TYVASO.
`
`
` TYVASO® (treprostinil) inhalation solution, for oral inhalation use
`
`
`
` Initial U.S. Approval: 2002
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• Dosage should be increased by an additional 3 breaths per treatment
`
`
`
`
`
`
`session at approximately 1- to 2-week intervals, if tolerated. (2.1)
`
`
`
`
`
`Titrate to target maintenance doses of 9 to 12 breaths per treatment
`
`
`session, 4 times daily. (2.1)
`
`
`•
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`
`
`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg
`
`
`
`treprostinil (0.6 mg per mL). (3)
`
`
`
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------­
`
`
`None. (4)
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`Tyvaso may cause symptomatic hypotension. (5.1)
`•
`
`
`
`
`
`
`
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
`•
`
`(5.2)
`
`
`
`
`
`Tyvaso dosage adjustments may be necessary if inhibitors or inducers of
`
`
`CYP2C8 are added or withdrawn. (5 3, 7.3)
`
`
`•
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`Most common adverse reactions (≥4%) are cough, headache, nausea,
`
`
`
`dizziness, flushing, throat irritation, pharyngolaryngeal pain, diarrhea, and
`
`
`syncope. (6)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`
`
`
`
`Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`Revised: 03/2021
`
` ---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
` Indications and Usage (1.2)
` 03/2021
`
`
`
`
`
`
`
`
`
`
` --------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`
`
`
`
`
` Tyvaso is a prostacyclin mimetic indicated for the treatment of:
` Pulmonary arterial hypertension (PAH; WHO Group 1) to improve
`
`
`
`
`
`•
`
`
`
` exercise ability. Studies establishing effectiveness predominately
`
` included patients with NYHA Functional Class III symptoms and
`
`
`
`
`
`
`
`etiologies of idiopathic or heritable PAH (56%) or PAH associated with
`
`connective tissue diseases (33%). (1.1)
`
`
`Pulmonary hypertension associated with interstitial lung disease
`
`
`
`
`(PH-ILD; WHO Group 3) to improve exercise ability. The study
`
`
`
`
`establishing effectiveness predominately included patients with
`
`
`
`
`etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of
`
`
`
`idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and
`
`
`
`emphysema (CPFE) (25%), and WHO Group 3 connective tissue
`
`
`disease (22%). (1.2)
`
`
`•
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
`
`
`
`
`
`
`
`• Use only with the Tyvaso Inhalation System. (2.1)
`
`
`
`
`
`
`• Administer undiluted, as supplied. A single breath of Tyvaso delivers
`
`
`
`
`approximately 6 mcg of treprostinil. (2.1)
`
`
`
`
`
`
`• Administer in 4 separate treatment sessions each day approximately
`
`
`
`4 hours apart, during waking hours. (2.1)
`
`
`
`
`
`
`Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are
`
`
`
`
`not tolerated, reduce to 1 or 2 breaths. (2.1)
`
`
`•
`
`______________________________________________________________________________________________________________________________________
`
`
`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
`
`12.3 Pharmacokinetics
`
`5.1 Risk of Symptomatic Hypotension
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`5.2 Risk of Bleeding
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`5.3 Effect of Other Drugs on Treprostinil
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`6 ADVERSE REACTIONS
`
`14 CLINICAL STUDIES
`
`6.1 Clinical Trials Experience
`
`
`14.1 Pulmonary Arterial Hypertension (WHO Group 1)
`
`
`6.2 Post-Marketing Experience
`
`14.2 Long-term Treatment of PAH
`
`
`7 DRUG INTERACTIONS
`
`14.3 Pulmonary Hypertension Associated with ILD (WHO Group 3)
`
`
`7.1 Bosentan
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`7.2 Sildenafil
`
`17 PATIENT COUNSELING INFORMATION
`
`7.3 Effect of Cytochrome P450 Inhibitors and Inducers
`
`
`
`
`
`7.4 Effect of Other Drugs on Treprostinil
`
`
`* Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`listed.
`
`8.1 Pregnancy
`
`
`
`
`Reference ID: 4771425
`
`
`Page 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Pulmonary Arterial Hypertension
`
`
`
`
`
`
`
` Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to
` improve exercise ability. Studies establishing effectiveness predominately included patients with NYHA
`
`
`
`
` Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated
`
`
`
`
` with connective tissue diseases (33%).
`
`
`
` The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can
`
`
` be adjusted for planned activities.
`
`
`
`
`
`
`
`
`
`
`
` While there are long-term data on use of treprostinil by other routes of administration, nearly all
`
`
`
`
` controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an
` endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled
`
`
`
`
` clinical experience was limited to 12 weeks in duration [see Clinical Studies (14)].
`
`
`
` 1.2 Pulmonary Hypertension Associated with ILD
`
`
`
`
`
`Tyvaso is indicated for the treatment of pulmonary hypertension associated with interstitial lung disease
`
`
`(PH-ILD; WHO Group 3) to improve exercise ability. The study establishing effectiveness
`
`
`
`predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive
`
`
`
`
`
`
`
`
`
`of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%),
`
`
`
`
`and WHO Group 3 connective tissue disease (22%) [see Clinical Studies (14)].
`
`
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Usual Dosage in Adults
`
`
`
`Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of an
`
`
`
`ultrasonic, pulsed delivery device and its accessories.
`
`
`
`Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. Each
`
`
`
`
`
`
`
`treatment session will take 2 to 3 minutes. The treatment sessions should be approximately 4 hours apart.
`
`
`
`
`
`
`
`
`Initial Dosage:
`
`
`Therapy should begin with 3 breaths of Tyvaso (18 mcg of treprostinil) per treatment session 4 times
`
`
`
`
`
`
`daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as
`
`
`
`
`tolerated.
`
`
`Maintenance Dosage:
`
`
`Dosage should be increased by an additional 3 breaths per treatment session, 4 times daily at
`
`
`
`
`
`approximately 1- to 2-week intervals. Studies establishing effectiveness in patients with PAH and
`
`
`PH-ILD have used target doses of 9 to 12 breaths per treatment session, 4 times daily. If adverse effects
`
`
`preclude titration to target dose, Tyvaso should be continued at the highest tolerated dose.
`
`
`
`
`Reference ID: 4771425
`
`
`Page 2
`
`

`

`
`
`If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible
`
`at the usual dose.
`
`
`
`2.2 Administration
`
`
`
`Tyvaso must be used only with the Tyvaso Inhalation System. Patients should follow the instructions for
`
`
`
`
`
`use for operation of the Tyvaso Inhalation System and for daily cleaning of the device components after
`
`
`the last treatment session of the day. To avoid potential interruptions in drug delivery because of
`
`
`
`
`equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device.
`
`
`
`
`
`Do not mix Tyvaso with other medications in the Tyvaso Inhalation System. Compatibility of Tyvaso
`
`
`
`with other medications has not been studied.
`
`
`
`
`
`
`
`
`
`
`The Tyvaso Inhalation System should be prepared for use each day according to the instructions for use.
`
`
`
`
`
`
`One ampule of Tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a single
`
`
`
`
`
`
`
`
`day. Prior to the first treatment session, the patient should twist the top off a single Tyvaso ampule and
`
`
`
`
`
`
`
`
`squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions, the
`
`
`
`
`
`device should be capped and stored upright with the remaining medication inside.
`
`
`
`
`
`At the end of each day, the medicine cup and any remaining medication must be discarded. The device
`
`
`
`
`
`must be cleaned each day according to the instructions for use.
`
`
`
`
`
`
`
`
`
`Avoid skin or eye contact with Tyvaso solution. Do not orally ingest the Tyvaso solution.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
`
`Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg of treprostinil (0.6 mg per mL).
`
`
`4 CONTRAINDICATIONS
`
`
`None.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Risk of Symptomatic Hypotension
`
`
`
`
`
`
`Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure,
`
`
`treatment with Tyvaso may produce symptomatic hypotension.
`
`
`
`
`
`5.2 Risk of Bleeding
`
`
`Tyvaso inhibits platelet aggregation and increases the risk of bleeding.
`
`
`
`5.3 Effect of Other Drugs on Treprostinil
`
`
`
`
`Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase
`exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g.,
`
`rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events
`
`
`
`
`associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical
`
`
`
`
`effectiveness [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`Reference ID: 4771425
`
`
`Page 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 (5.1)].
`
`
` - Bleeding [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`
`
`
`
`
`
` the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
` may not reflect the rates observed in practice.
`
`
`
`
` Pulmonary Arterial Hypertension
`
`
`
`
`
`In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and
`
`
`
`
`
`
`
`nearly all NYHA Functional Class III), the most commonly reported adverse reactions on Tyvaso
`
`
`
`
`
`
`included cough and throat irritation, headache, gastrointestinal effects, muscle, jaw or bone pain,
`
`
`
`
`
`
`
`
`
`
`dizziness, flushing, and syncope. Table 1 lists the adverse reactions that occurred at a rate of at least 4%
`
`
`
`
`
`and were more frequent in patients treated with Tyvaso than with placebo.
`
`
`
`Table 1:
`
`
`
`Adverse Events in ≥4% of PAH Patients Receiving Tyvaso and More Frequenta
`
`
`
`than Placebo in TRIUMPH I
`
`
`Adverse Event
`
`
`Treatment
`
`n (%)
`
`
` Tyvaso
`n=115
`
`
` 62 (54)
`47 (41)
`
`29 (25)
`
`22 (19)
`
`
` 17 (15)
`
` 7 (6)
`
`
` Placebo
`
` n=120
`
` 35 (29)
`27 (23)
`
`17 (14)
`
`13 (11)
`
`
` 1 (<1)
`
` 1 (<1)
`
` Cough
`
`Headache
`
`Throat Irritation / Pharyngolaryngeal Pain
`
`
`Nausea
`
`
` Flushing
`
` Syncope
`
` a More than 3% greater than placebo
`
`
`
`
`
`The safety of Tyvaso was also studied in a long-term, open-label extension study in which 206 patients
`
`
`
`
`
`
`were dosed for a mean duration of 2.3 years, with a maximum exposure of 5.4 years. Eighty-nine percent
`
`
`
`
`
`
`
`
`(89%) of patients achieved the target dose of 9 breaths, 4 times daily. Forty-two percent (42%) achieved
`
`
`
`
`
`
`
`
`a dose of 12 breaths, 4 times daily. The adverse events during this chronic dosing study were
`
`
`
`
`qualitatively similar to those observed in the 12-week placebo-controlled trial.
`
`
`
`
`
`
`
`
`In a prospective, observational study comparing patients taking Tyvaso (958 patient-years of exposure)
`
`and a control group (treatment with other approved therapies for PAH; 1094 patient-years), Tyvaso was
`
`
`associated with a higher rate of cough (16.2 vs. 10.9 per 100 patient-years), throat irritation (4.5 vs.
`
`
`
`
`
`
`
`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.
`
`Reference ID: 4771425
`
`
`Page 4
`
`

`

` Pulmonary Hypertension Associated with ILD
`
`
`
`
`
`
`In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3),
`
`
`
`
`adverse reactions were similar to the experience in studies of PAH.
`
`
`
`6.2 Post-Marketing Experience
`
`
`
`
`
`
`
`
`The adverse reaction of angioedema has been identified during the post-approval use of Tyvaso. Because
`
`
`
`
`
`
`this reaction is reported voluntarily from a population of uncertain size, it is not always possible to
`
`
`
`reliably estimate the frequency or establish a causal relationship to drug exposure.
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Bosentan
`
`
`
`
`
`In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of
`
`
`
`treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and bosentan
`
`were observed.
`
`
`
`7.2 Sildenafil
`
`
`
`
`
`
`In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of
`
`
`
`treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and sildenafil
`
`were observed.
`
`
`
`
`7.3 Effect of Cytochrome P450 Inhibitors and Inducers
`
`
`
`
`
`
`
`In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450
`
`(CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
`
`
`
`
`
`CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6,
`
`
`CYP2C9, CYP2C19, and CYP3A.
`
`
`
`
`
`
`Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated
`
`
`
`
`
`
`that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases
`
`exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer,
`
`
`
`
`
`
`
`
`rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the
`
`
`
`
`
`
`
`inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and Precautions (5.3)].
`
`
`
`
`
`7.4 Effect of Other Drugs on Treprostinil
`
`
`
`
`Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered
`
`
`with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in
`
`
`
`
`
`
`
`
`healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of
`
`
`
`
`
`treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The
`
`
`
`
`
`
`pharmacokinetics of R- and S- warfarin and the international normalized ratio (INR) in healthy subjects
`
`
`
`
`
`given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of
`
`
`
`
`treprostinil at an infusion rate of 10 ng/kg/min.
`
`Reference ID: 4771425
`
`
`Page 5
`
`

`

`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
` Risk Summary
`Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated
`
`
`
`
`
`
`risk of adverse developmental outcomes. However, there are risks to the mother and the fetus associated
`
`
`
`
`
`
`with pulmonary arterial hypertension (see Clinical Considerations). In animal studies, no adverse
`
`
`reproductive and developmental effects were seen for treprostinil at ≥9 and ≥145 times the human
`
`
`
`
`
`exposure when based on Cmax and AUC, respectively, following a single treprostinil dose of 54 mcg.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated populations is
`
`
`
`
`
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`
`
`
`
`U.S. general population, the estimated background risk of major birth defects and miscarriage in
`
`
`
`clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
`
`
`Clinical Considerations
`Disease-associated maternal and embryo-fetal risk
`
`
`Pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality.
`
`
`
`
`
`Data
`
`Animal reproduction studies have been conducted with treprostinil via continuous subcutaneous
`
`
`
`
`administration and with treprostinil diolamine administered orally. In studies with orally administered
`
`
`
`
`
`treprostinil diolamine, no adverse effect doses for fetal viability/growth, fetal development
`
`(teratogenicity), and postnatal development were determined in rats. In pregnant rats, no evidence of
`
`
`
`harm to the fetus was observed following oral administration of treprostinil diolamine at the highest dose
`
`
`
`tested (20 mg/kg/day), which represents about 154 and 1479 times the human exposure, when based on
`
`
`
`
`Cmax and AUC, respectively, following a single Tyvaso dose of 54 mcg. In pregnant rabbits, external
`
`
`
`
`
`
`
`
`
`
`
`fetal and soft tissue malformations and fetal skeletal malformation occurred. The dose at which no
`
`
`
`
`adverse effects were seen (0.5 mg/kg/day) represents about 9 and 145 times the human exposure, when
`based on Cmax and AUC, respectively, following a single Tyvaso dose of 54 mcg. No treprostinil
`
`
`
`
`
`treatment-related effects on labor and delivery were seen in animal studies. Animal reproduction studies
`
`are not always predictive of human response.
`
`
`8.2 Lactation
`
`Risk Summary
`There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the
`
`
`
`
`
`effects on milk production.
`
`
`
`8.4 Pediatric Use
`
`
`Safety and effectiveness in pediatric patients have not been established. Clinical studies of Tyvaso did
`
`
`
`
`
`
`not include patients younger than 18 years to determine whether they respond differently from older
`
`
`
`
`
`
`patients.
`
`
`8.5 Geriatric Use
`
`
`Across clinical studies used to establish the effectiveness of Tyvaso in patients with PAH and PH-ILD,
`
`
`
`
`
`
`
`268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile
`
`
`
`
`
`
`observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly
`
`
`
`
`
`
`Reference ID: 4771425
`
`
`Page 6
`
`

`

`patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and
`of concomitant diseases or other drug therapy.
`
`8.6 Patients with Hepatic Insufficiency
`
`Plasmaclearanceoftreprostinil, delivered subcutaneously, was reduced up to 80% in subjects with mild-
`to-moderate hepatic insufficiency. Uptitrate slowly whentreating patients with hepatic insufficiency
`becauseoftherisk of an increase in systemic exposure which maylead to an increase in dose-dependent
`adverse effects. Treprostinil has not been studied in patients with severe hepatic insufficiency /see
`Clinical Pharmacology (12.3)].
`
`8.7 Patients with Renal Impairment
`
`No dose adjustments are required in patients with renal impairment. Treprostinil is not cleared by
`dialysis [see Clinical Pharmacology(12.3)].
`
`10 OVERDOSAGE
`
`In general, symptoms of overdose with Tyvaso include flushing, headache, hypotension, nausea,
`vomiting, and diarrhea. Provide general supportive care until the symptomsof overdose have resolved.
`
`11 DESCRIPTION
`
`Tyvasois 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 mgtreprostinil (0.6 mg/mL). Each ampulealso 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 and7.2.
`
`Treprostinil is (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3.S)-3-hydroxyoctyl]-1H-
`benz[f]inden-5-yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.52 and a molecular
`formula of C23H340s.
`
`The structural formula of treprostinil is:
`
`OH
`
`
`
`
`
`witlOH
`
`CH2CO2H
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Treprostinil is a prostacyclin analogue. The major pharmacologic actions oftreprostinil are direct
`vasodilation of pulmonary and systemicarterial vascular beds andinhibition ofplatelet aggregation.
`
`Reference ID: 4771425
`
`Page 7
`
`

`

`12.2 Pharmacodynamics
`
`
`In a clinical trial of 240 healthy volunteers, single doses of Tyvaso 54 mcg (the target maintenance dose
`
`
`
`
`per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by
`
`
`
`
`
`
`
`
`
`approximately 10 ms. The QTc effect dissipated rapidly as the concentration of treprostinil decreased.
`
`
`
`
`
`
`
`
`12.3 Pharmacokinetics
`
`
`Pharmacokinetic information for single doses of inhaled treprostinil was obtained in healthy volunteers
`
`
`in 3 separate studies. Treprostinil systemic exposure (AUC and Cmax) post-inhalation was shown to be
`
`
`
`
`
`proportional to the doses administered (18 mcg to 90 mcg).
`
`
`
`
`
`Absorption
`
`
`In a 3-period crossover study, the bioavailability of 2 single doses of Tyvaso (18 mcg and 36 mcg) was
`
`
`
`
`
`
`
`compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the absolute
`
`
`
`systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and 72%
`
`
`
`
`
`(36 mcg).
`
`
`
`Treprostinil plasma exposure data were obtained from 2 studies at the target maintenance dose, 54 mcg.
`
`
`
` The mean Cmax at the target dose was 0.91 and 1.32 ng/mL with corresponding mean Tmax of 0.25 and
`
`
`
`0.12 hr, respectively. The mean AUC for the 54-mcg dose was 0.81 and 0.97 hr∙ng/mL, respectively.
`
`
`
`
`
`
`
`
`Distribution
`
`
`
`
`
`
`Following parenteral infusion, the apparent steady state volume of distribution (Vss) of treprostinil is
`
`
`approximately 14 L/70 kg ideal body weight.
`
`
`
`
`
`
`
`
`
`In vitro treprostinil is 91% bound to human plasma proteins over the 330 to 10,000 mcg/L concentration
`
`range.
`
`
`
`Metabolism and Excretion
`
`
`
`
`Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. Treprostinil is
`
`
`
`substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%)
`
`
`
`
`
`and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each
`
`
`
`
`
`
`
`accounting for 10 to 15% of the dose administered. Four of the metabolites are products of oxidation of
`
`
`
`
`
`the 3-hydroxyloctyl side chain and 1 is a glucuroconjugated derivative (treprostinil glucuronide).
`
`
`
`
`
`
`The elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a
`
`
`
`terminal elimination half-life of approximately 4 hours using a 2-compartment mode