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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 22387/S-009
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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` Attention: Rex Mauthe, MBA
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` Associate Vice President, Regulatory Affairs
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` P.O. Box 14185
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` 55 T.W. Alexander Drive
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` Research Triangle Park, NC 27709
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`Dear Mr. Mauthe:
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`Please refer to your Supplemental New Drug Application (sNDA) dated November 1, 2013,
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`received November 1, 2013, submitted under section 505(b)(1) of the Federal Food, Drug, and
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`Cosmetic Act (FDCA) for Tyvaso (treprostinil) solution for inhalation.
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`We acknowledge receipt of your amendments dated May 7 and 15, 2014.
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`This “Prior Approval” supplemental new drug application proposes inclusion of the results of a
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`two-year rat carcinogenicity study in the Nonclinical Toxicology Section, addition of
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`information about long-term treatment of pulmonary arterial hypertension to the Clinical Studies
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`section and provides for edits to the Pregnancy and Nursing Mothers subsections of the Use in
`Specific Populations section and minor formatting edits. The changes to USE IN SPECIFIC
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`POPULATIONS, NONCLINICAL TOXICOLOGY AND CLINICAL STUDIES are noted
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`below (additions are marked as underlined text and deletions are marked as strikethrough text):
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`In Full Prescribing Information;
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`In USE IN SPECIFIC POPULATIONS
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`Pregnancy
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`8.1
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`Pregnancy Category B
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`There are no adequate and well controlled studies with Tyvaso in pregnant women.
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`Animal reproduction studies have not been conducted with treprostinil administered by the
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`inhalation route. However, studies in pregnant rabbits using continuous subcutaneous (sc)
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`infusions of treprostinil sodium at infusion rates higher than the recommended human sc infusion
`rate resulted in an increased incidence of fetal skeletal variations associated with maternal
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`toxicity [see Developmental Toxicity Nonclinical Toxicology (13.3)]. Animal reproduction
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`studies are not always predictive of human response; Tyvaso should be used during pregnancy
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`only if clearly needed.
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`Reference ID: 3508809
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` Page 2
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`8.3
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` Nursing Mothers
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`It is not known whether treprostinil is excreted in human milk. Because many drugs are
` excreted in human milk, caution should be exercised when treprostinil is administered to nursing
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`women.
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` In NONCLINICAL TOXICOLOGY
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`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, 10.6, and 34.1 mcg/kg/day. There was no evidence for carcinogenic potential
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`associated with treprostinil inhalation in rats at systemic exposure levels up to 35 times the
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`clinical exposure at the target maintenance dose of 54 mcg. Long term studies have not been
`performed to evaluate the carcinogenic potential of treprostinil. In vitro and in vivo genetic
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`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
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`continuous subcutaneous (sc) infusions at rates of up to 450 ng treprostinil/kg/min [about 59
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`times the recommended starting human sc infusion rate (1.25 ng/kg/min) and 8 times the average
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` rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m2 basis]. In this study, males were dosed
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` from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from
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` 2 weeks prior to mating until gestational day 6.
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`13.4
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`Inhalational Toxicity
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`Rats and dogs that received daily administrations of treprostinil by inhalation for 3
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`months developed respiratory tract lesions (respiratory epithelial degeneration, goblet cell
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`hyperplasia/hypertrophy, epithelial ulceration, squamous epithelial degeneration and necrosis,
`and lung hemorrhage). Some of the same lesions seen in animals sacrificed at the end of
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`treatment (larynx, lung and nasal cavity lesions in rats, and lesions of the larynx in dogs) were
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`also observed in animals sacrificed after a 4-week recovery period. Rats also developed cardiac
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`changes (degeneration/fibrosis). A no-effect dose level for these effects was not demonstrated in
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`rats (doses as low as 7 µg/kg/day were administered); whereas 107 µg/kg/day was a no-effect
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`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
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`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
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`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
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`rats at mid and high dose levels were about 15 and 35 times, respectively, the clinical exposure at
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`the target maintenance dose of 54 mcg.
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`Reference ID: 3508809
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` In CLINICAL STUDIES
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`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
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` pulmonary arterial hypertension (WHO Group 1), nearly all with NYHA Class III (98%)
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` symptoms who were receiving either bosentan (an endothelin receptor antagonist) or sildenafil (a
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` phosphodiesterase-5 inhibitor) for at least three months prior to study initiation. Concomitant
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` therapy also could have included anticoagulants, other vasodilators (e.g., calcium channel
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` 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
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` breaths (54 mcg) per session over the course of the 12-week study. Patients were predominantly
` female (82%), had the origin of PAH as idiopathic/heritable (56%), secondary to connective
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` tissue diseases (33%) or secondary to HIV or previous use of anorexigens (12%); bosentan was
`the concomitant oral medication in 70% of those enrolled, sildenafil in 30%.
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` The primary efficacy endpoint of the trial was the change in six-minute walk distance
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`(6MWD) relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10
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` and 60 minutes after dosing), and 3-5 hours after bosentan or 0.5-2 hours after sildenafil. Patients
`receiving Tyvaso had a placebo-corrected median change from baseline in peak 6MWD of 20
`meters at Week 12 (p<0.001). The distribution of these 6MWD changes from baseline at Week
`12 were plotted across the range of observed values (Figure 1). 6MWD measured at trough
`exposure (defined as measurement of 6MWD at least 4 hours after dosing) improved by 14
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`meters. There were no placebo-controlled 6MWD assessments made after 12 weeks.
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` NDA 22387/S-009
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` Page 3
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`Reference ID: 3508809
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` The placebo-corrected median treatment effect on 6MWD was estimated (using the
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` 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
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` background therapy (Figure 2).
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`Reference ID: 3508809
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` Page 5
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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
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`In long-term follow-up of patients who were treated with Tyvaso in the pivotal study and
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`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
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`with a control group not given Tyvaso and cannot be used to determine the long-term effect of
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`Tyvaso on mortality.
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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`text.
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`Reference ID: 3508809
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` NDA 22387/S-009
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` Page 6
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` CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert), with the
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`addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
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`well as annual reportable changes not included in the enclosed labeling.
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` Information on submitting SPL files using eList may be found in the guidance for industry titled
` “SPL Standard for Content of Labeling Technical Qs and As at
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that includes labeling changes
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`changes approved in this supplemental application, as well as annual reportable changes and
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`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`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
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`date(s).
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
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`(3) the package insert(s) to:
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`Reference ID: 3508809
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`Sincerely,
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`{See appended electronic signature page}
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`Norman Stockbridge, M.D., Ph.D.
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`Director
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`Division of Cardiovascular and Renal Products
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`Office of Drug Evaluation I
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`Center for Drug Evaluation and Research
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` Page 7
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` more information about submission of promotional materials to the Office of Prescription Drug
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` Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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` REPORTING REQUIREMENTS
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` We remind you that you must comply with reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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`If you have any questions, call Wayne Amchin, Regulatory Project Manager, at (301) 796-0421.
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`ENCLOSURE:
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`Content of Labeling
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`Reference ID: 3508809
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`NORMAN L STOCKBRIDGE
`05/20/2014
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`Reference ID: 3508809
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