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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 203496/S-001
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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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`United Therapeutics Corporation
`Attention: Rex Mauthe, MBA
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`Associate Vice President, Regulatory Affairs
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`55 T. W. Alexander Drive
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`P.O. Box 14186
`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 June 6, 2014, received
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`June 6, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
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`(FDCA) for Orenitram (Treprostinil) 0.125, 0.25, 1, and 2.5 mg Extended Release Tablets.
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`We acknowledge receipt of your amendments dated July 24, September 29, 30, and October 2,
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`2014.
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`This “Prior Approval” supplemental new drug application provides for the addition of ten-count
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`bottles of drug product, labels for the ten-count bottles and revised bottle labels for the 100-count
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`bottles to incorporate a logo for Orenitram. It also clarifies the starting dose in Highlights and in
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`Section 2.1 Recommended Dosing of the Prescribing Information, to clarify that the starting dose
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`can be either 0.25 mg two times daily or 0.125 mg three times daily. Other minor editorial
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`changes are included in the package insert.
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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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` months. This proposed
`We have not approved the shelf-life extension from 24 months to
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`shelf-life extension is not supported by the stability data you have provided.
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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
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`Reference ID: 3640130
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`(b)
`(4)
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` NDA 203496/S-001
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` Page 2
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` 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
`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
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`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
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` 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
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`should provide appropriate annotations, including supplement number(s) and annual report
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`date(s).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and immediate container labels that are identical to the carton and
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`immediate-container labels submitted on September 29, 2014, as soon as they are available, but
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`no more than 30 days after they are printed. Please submit these labels electronically according
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`to the guidance for industry Providing Regulatory Submissions in Electronic Format – Human
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`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
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`(June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually
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`mounted on heavy-weight paper or similar material. For administrative purposes, designate this
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`submission “Final Printed Carton and Container Labels for approved NDA 203496/S-001.”
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`Approval of this submission by FDA is not required before the labeling is used.
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`Marketing the productwith FPL that is not identical to the approved labeling text may render the
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`product misbranded and an unapproved new drug.
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`Reference ID: 3640130
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` NDA 203496/S-001
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` Page 3
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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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`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, please call Wayne Amchin, Regulatory Project Manager, at (301)
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`796-0421.
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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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`ENCLOSURES:
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`Content of Labeling
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`Carton and Container Labeling
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`Reference ID: 3640130
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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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`STEPHEN M GRANT
`10/06/2014
`On behalf of and at the direction of Norman Stockbridge.
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`Reference ID: 3640130
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