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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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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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`NDA 22387/S-004
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`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`EVP, Regulatory Affairs and Compliance
`55 T.W. Alexander Drive
`PO Box 14186
`Research Triangle Park, NC 27709
`
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`Dear Mr. Bunce:
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`Please refer to your supplemental New Drug Application (sNDA) dated December 16, 2010,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Tyvaso
`(treprostinil) Inhalation Solution.
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`We also acknowledge receipt of your amendment dated January 28, 2011.
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`This Prior Approval sNDA provides for the following revisions to the labeling for Tyvaso
`(treprostinil).
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`1. In INDICATIONS AND USAGE, revise the following text
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`
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`FROM
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`Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial
`hypertension (WHO Group I) in patients with NYHA Class III symptoms, to increase
`walk distance. (1)
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`TO
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`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)
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`Reference ID: 2902766
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`

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` NDA 22387/S-004
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`Page 2
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` Full Prescribing Information
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`2. In INDICATIONS AND USAGE, revise the following text
`
`
`FROM
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`Tyvaso is indicated to increase walk distance in patients with WHO Group I
`pulmonary arterial hypertension and NYHA Class III symptoms. 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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`TO
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`Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH)
`(WHO Group 1) to improve exercise ability. Studies establishing effectiveness
`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%).
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`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)].
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`Note that minor labeling revisions were made in section 14 of the labeling (CLINICAL
`STUDIES) to be consistent with the revisions made in section 1 (INDICATIONS AND
`USAGE).
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`We note that you also revised the manufacturer information from “Tyvaso manufactured
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` by Catalent Pharm Solutions” to “Tyvaso manufactured for United Therapeutics Corp.”
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`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling
`text.
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`CONTENT OF LABELING
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`Reference ID: 2902766
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`

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` NDA 22387/S-004
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`Page 3
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`As soon as possible, but no later than 14 days from the date of this letter, submit, using the FDA
`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert, Medication Guide) and include the
`labeling changes proposed in any pending “Changes Being Effected” (CBE) supplements.
`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`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 for this NDA, including
`pending “Changes Being Effected” (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 MS Word format that
`includes the changes approved in this supplemental application.
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`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
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`MedWatch Program
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`Office of Special Health Issues
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`Food and Drug Administration
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`10903 New Hampshire Ave
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`Building 32, Mail Stop 5353
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`Silver Spring, MD 20993
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, please call Dan Brum, PharmD, MBA, BCPS, RAC, Regulatory
`Project Manager, at (301)796-0578.
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`
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`Sincerely,
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`Reference ID: 2902766
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`

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` NDA 22387/S-004
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`Page 4
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`Enclosure: Package Insert
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` {See appended electronic signature page}
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`Norman Stockbridge, M.D., Ph.D.
`Director
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`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
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`Reference ID: 2902766
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`

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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
`02/08/2011
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`Reference ID: 2902766
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`