CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER»:
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`22—387
`
`Trade Name:
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`TYVASO INHALATION SOLUTION
`
`Generic Name:
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`‘ Treprostinil
`
`Sponsor:
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`United Therapeutics Corporation
`
`Approval Date:
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`July 30, 2009
`
`Indications:
`
`For the treatment of pulmonary arterial. hypertension.
`(WHO Group I) in patients with NYHA Class III
`symptoms, to increase walk distance.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-387
`
`APPROVAL LETTER
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`

`

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`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
`
`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
`
`
`NDA 22-387
`
`United Therapeutics Corporation
`Attention: Mr. Dean Bunce
`P.O. Box 14186
`55 TW Alexander Drive
`Research Triangle Park, NC 27709
`
`
`Dear Mr. Bunce:
`
`Please refer to your June 27, 2008 new drug application (NDA) submitted under section
`505(b)(1) of the Federal Food, Drug, and Cosmetic Act for Tyvaso (treprostinil) Inhalation
`Solution.
`
`We acknowledge receipt of your submissions dated July 3, August 14 and 26, September 26,
`October 1, 9, 24, 29, and 31, November 12 and 13, and December 22, 2008, and January 2, 22,
`and 29, February 9, 19, and 25, March 12, April 1 (two), 3 (two), 8, 16, 17, 24, and 29, May 7,
`June 5, 17, and 25 (two), July 2, 7, 9, 22, and 28, 2009.
`
`This new drug application provides for the use of Tyvaso for the treatment of pulmonary arterial
`hypertension (WHO Group I) in patients with NYHA Class III symptoms, to increase walk
`distance.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit 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 agreed-upon labeling text. Upon receipt, we will transmit that version
`to the National Library of Medicine for public dissemination. For administrative purposes,
`please designate this submission, “SPL for approved NDA 22-387.”
`
`

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`NDA 22-387
`Page 2
`
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`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry titled
`Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (October 2005).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 22-387.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`PROPRIETARY NAME
`
`The Division of Medication Error Prevention and Analysis (DMEPA) and the Division of
`Cardiovascular and Renal Products do not object to the use of the proprietary name, Tyvaso, for
`this product.
`
`PEDIATRIC RESEARCH EQUITY ACT (PREA)
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, 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(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require
`holders of approved drug and biological product applications to conduct postmarketing studies
`and clinical trials for certain purposes, if FDA makes certain findings required by the statute
`(section 505(o)(3)(A)).
`
`We have sufficient concerns that treprostinil by the inhaled route of administration may be
`irritating to the respiratory tract. This concern is based on:
`• Adverse events observed during the clinical experience
`• Observations of oropharyngeal and other respiratory tract lesions in rats and dogs during
`the preclinical assessments of inhaled treprostinil
`• The finding that when administered by the subcutaneous route, treprostinil is extremely
`irritating at the site of administration.
`
`
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`

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`NDA 22-387
`Page 3
`
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk
`of oropharyngeal or pulmonary toxicity in patients using Tyvaso (treprostinil).
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious
`risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1. A long-term observational study in the US that will include another 1000 patient-years of
`follow-up in Tyvaso-treated patients, and 1000 patient-years of follow-up in matched
`controls receiving other treatments for pulmonary hypertension, to evaluate the potential
`association between Tyvaso (treprostinil) and oropharyngeal and pulmonary toxicity.
`
`
`The timetable you submitted on July 28, 2009 states that you will conduct this study according to
`the following timetable:
`
`
`
`
`Draft Protocol Submission:
`
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`Final Protocol Submission:
`
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`Interim Study Report #1:
`
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`Interim Study Report #2:
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`Study Completion Date:
`Final Report Submission/Supplement:
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`Submit the protocol to your IND, with a cross-reference letter to NDA 22-387. Submit all final
`report(s) to NDA 22-387. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate:
`
`
`September 15, 2009
`December 15, 2009
`December 31, 2011
`September 30, 2012
`June 30, 2013
`December 15, 2013
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`• REQUIRED POSTMARKETING PROTOCOL UNDER 505(o)
`• REQUIRED POSTMARKETING FINAL REPORT UNDER 505(o)
`• REQUIRED POSTMARKETING CORRESPONDENCE UNDER 505(o)
`
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
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`

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`NDA 22-387
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`Page 4
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`submit an annual report for studies or clinical trials required under 505(0) on the date required
`will be considered a violation of FDCA section 505(0)(3)(E)(ii) and could result in enforcement
`action.
`
`POSTMARKETING CONINIITMENTS NOT SUBJECT TO THE REPORTING
`
`REQUIRENIENTS OF 21 CFR 314.81
`
`We remind you of your postmarketing commitment in your submission dated July 28, 2009. You
`commit to:
`
`2
`
`(b) (4)
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`Submit Supplement:
`
`October 1, 2009
`February 28, 2010
`March 31, 2010
`October 31, 2010
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`POSTMARKETING CONINIITMENTS SUBJECT TO REPORTING RE UIREMENTS
`
`OF 21 CFR 314.81
`
`(b) (4) described in PMC number 2, you should perform a usability
`3. As part of the
`analysis incorporating the evaluation and prioritization of user-related risk followed by a
`human factors analysis.
`
`Final Protocol Submission:
`Study Completion Date:
`Final Report Submission:
`Submit Supplement:
`
`October 1, 2009
`February 28, 2010
`March 31, 2010
`October 31, 2010
`
`4. Conduct a study to collect pharmacokinetic data to verify expected dosing with the new
`Optineb-IR device.
`
`Final Protocol Submission:
`Final Report Submission:
`Submit Supplement:
`
`December 1, 2009
`August 30, 2010
`October 31, 2010
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under
`21 CFR 314.81(b)(2)(vii) and 3 l4.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last
`annual report, and, for clinical studies, number of patients entered into each study. All
`submissions, including supplements, relating to these postmarketing study commitments should
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`

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`NDA 22-387
`Page 5
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`be prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing
`Commitment Final Report,” or “Postmarketing Commitment Correspondence.”
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`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert(s)
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert(s), at the time of initial dissemination or publication, accompanied by a Form
`FDA 2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For
`more information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see www.fda.gov/cder/ddmac.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you 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 an electronic copy of
`the letter to both this NDA and to the following address:
`
`
`MedWatch
`Food and Drug Administration
`Suite 12B05
`5600 Fishers Lane
`Rockville, MD 20857
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`
`If you have any questions, please call Dan Brum, Pharm.D., MBA, RAC, Regulatory Project
`Manager, at (301) 796-0578.
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`NDA 22-387
`Page 6
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`Enclosure: Agreed-upon labeling
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`07/30/2009
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`