CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203496Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`
`
`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`Divisional Memo
`
`
`NDA:
`203496 Treprostinil extended-release tablets for
`pulmonary arterial hypertension.
`Sponsor:
`United Therapeutics
`Review date: 20 December 2013
`
`
`Reviewer:
`N. Stockbridge, M.D., Ph.D., HFD-110
`Distribution: NDA 203496
`This memo conveys the Division’s recommendation to approve treprostinil extended-
`release tablets.
`This application was originally submitted 27 December 2011 and then resubmitted 31
`January 2013 and again 16 August 2013 following Complete Response actions of 23
`October 2012 and 22 March 2013.
`The only primary review for the current submission is of CMC (Bhamidipati; 10
`December 2013), which reaffirms approvability from the product quality perspective. No
`new data were reviewed.
`The previous Complete Response was based on the finding that oral treprostinil had an
`effect on exercise capacity that was, by itself, too small to be clinically relevant when
`used alone. Orenitram had also failed to show even statistically significant effects on a
`background of another vasodilator in two studies of reasonable size.
`Those findings are, of course, still true, and labeling reflects this. Unquestionably, oral
`administration avoids adverse consequences and inconveniences of currently approved
`intravenous, subcutaneous, and inhaled routes of administration, so replacing these
`uses—for which the efficacy data are no more compelling—seems useful. Thus labeling
`suggests such substitution while denying there are study data to support it. Part of why
`I think this is reasonable is that dose is titrated to tolerability, so getting the oral dose
`right should not be particularly difficult in such a change of route of administration.
`I should also note that the sponsor and the Division have attempted to review successes
`and failures to demonstrate that one vasodilator adds to the efficacy obtained with
`another. While there are a few successes, it is not clear how well the background was
`dosed to maximum effect. There may be little reason to expect much additivity.
`
`C:\Users\STOCKBRIDGEN\Documents\NDA\N203496 Treprostinil
`oral\TreprostinilDivMemo4.doc
`
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`1
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`Last saved
`08:42 Friday, December 20, 2013
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`Reference ID: 3425858
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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.
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`/s/
`----------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`12/20/2013
`
`Reference ID: 3425858
`
`