`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203496Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`0.125, 0.25, 1 and 2.5 mg
`
`United Therapeutics, Inc.
`
`Division of Cardiology and Renal Products, HFD 110
`
`Shastri Bhamidipati, Ph.D.
`
`Division of New Drug Quality Assessment I
`Office of New Drug Quality Assessment
`
`Submission Date : 16—AUG-2013
`
`PDUFA Goal Date: 16-FEB-2014
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 1
`
`Reference ID: 3419754
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Table of Contents
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. Recommendations................................................................................................8
`
`A. Recommendation and Conclusion on Approvability....................................... 8
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable ............................................... 8
`
`H. Summary of Chemistry Assessments ............................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ........................... 8
`
`B. Description of How the Drug Product is Intended to be Used ..................... 10
`
`C.
`
`Basis for Approvability or Not-Approval Recommendation .................. 10
`
`III. Administrative ................................................................................................ 10
`
`A. Reviewer’s Signature ...................................................................................................... 10
`
`B. Endorsement Block ......................................................................................................... 10
`
`C. CC Block .......................................................................................................................... l0
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 2
`
`Reference ID: 3419754
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 203496
`
`2. REVIEW #:4
`
`3. REVIEW DATE: 10—DEC—20 l 3
`
`4. REVIEWER: Shastri Bhamidipati, PhD.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`NDA 203496 Original Submission
`SD#15 Quality Information
`
`SD#18 Quality Information
`
`SD# 21 Quality Information
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission; 3) Reviewed
`
`SD#33 Class 2 Resubmission
`
`SD# 36 Labeling
`SD#37 Labeling/Container—Carton Draft
`SD#38 Labeling/PPI draft
`SD# 39 Proprietary Name
`
`7. NAIvIE & ADDRESS OF APPLICANT:
`
`27—DEC-201 1
`
`lO-AUG—20 l 2
`
`24—SEPT-20 1 2
`
`1 9-OCT-2012
`
`Document Date
`
`16-AUG-2013
`
`08-OCT-201 3
`
`29—OCT-20 l 3
`
`12-NOV-2013
`
`27-NOV-201 3
`
`Name: United Therapeutics, LLC
`
`55 TW Alexander Drive
`
`Address: PO Box 14186
`
`Research Triangle Park, NC 27709
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 3
`
`Reference ID: 3419754
`
`

`

`
`
`Representative:
`
`Chemistry Review Data Sheet
`
`Dean Bunce,
`
`Executive Vice President,
`Regulatory Affairs & Compliance
`55 TW Alexander Drive
`PO Box 14186
`
`Research Triangle Park, NC 27709
`
`Telephone:
`
`919—485—8350
`
`8. DRUG PRODUCT NAME/CODE/I'YPE:
`
`a) Proprietary Name: Treprostinil Extended Release Tablets (Trade name not finalized)
`b) Non-Proprietary Name (USAN): Treprostinil Diolamine
`c) Code Name/# (ONDQA only): N/A
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50, 505(b)(1)
`
`10. PHARMACOL. CATEGORY: Cardiology, Pulmonary Arterial Hypertension
`(PAH)
`
`11. DOSAGE FORM: Extended Release Tablets
`
`12. STRENGTH/POTENCY: 0.125, 0.25, 1.0 and 2.5 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. Rx/OTC DISPENSED:
`
`X
`
`Rx
`
`OTC
`
`15. SPOTS gSPECIAL PRODUCTS ON-LINE TRACKING SYSTEM 2:
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 4
`
`Reference ID: 3419754
`
`

`

`l .a' h
`
`m: ‘
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`— .A. n
`
`m ‘
`
`1. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`Chemical Name(s):
`l. Acetic acid, 2—[[(lR,2R,3aS,9aS)—2,3,3a,4,9,9a—hexahydro-2—hydroxy—1-[(3S)-3-
`hydroxyoctyl]-lH-benz[f]inden—5-yl]oxy]-, compd. with 2,2'-iminobis[ethanol] (1:1)
`
`2. 2-hydroxy-N—(2—hydroxyethyl)ethanaminium 2—( {(1R,2R,3aS,9aS)—2—hydroxy—l-[(3S)—3—
`hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro— lH—cyclopenta[b]naphthalen—5—yl} oxy)acetate
`
`oAcozH
`
`\/\”/\/ CH3
`
`HO
`
`OH
`
`Molecular Formula: C23H34 Os.C4H1 1N02
`Molecular Weight: 495. 66 (salt form) 390.52 (acid form)
`CAS: [830354—48—8]
`Laboratory Code : UT-15C
`
`l7. RELATED/SUPPORTING DOCUMENTS*:
`
`* SinsorsubmittedicntDMFinformation(DMFholdersandLOA)_
`
`A. DMFs:
`
`ITEM
`
`DATE
`
`TYPE
`
`HOLDER
`
`REFERENC CODE1
`I
`
`STATUS2
`
`REVIEW
`
`COMMENTS
`
`COMPLETED
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 5
`
`Reference ID: 3419754
`
`

`

` CHEMISTRY REVIEW
`
`
`
`Chemistry Review Data Sheet
`
`
`
`' Action codes for DMF Table:
`1 — DMF Reviewed
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Suflicient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`m APPLICATION NUMBER
`_ 71537
`
`DESCRIPTION
`Tr ostinil Diethanolamine
`
`18. STATUS:
`
`ONDQA:
`CONSULTS/ CMC
`
`RELATED
`
`RECOMMENDATION
`
`DATE
`
`Not requested. The methods are
`
`0 0
`
`9-DEC-2013
`3
`-OCT-2012
`30-AUG-2012
`02—OCT—2012
`
`REVIEWS
`Biometrics —
`EES
`Acceptable
`Recommended A y roval
`Recommended approval
`
`Biopharmaeeutics/
`Clinical
`
`Pharmacolo 3
`Methods Validation
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 6
`
`Reference ID: 3419754
`
`

`

`conventional and do not qualify for
`internal validation b FDA labs
`Proposed Trade names
`(but)
`were duly
`reviewed and determined
`
`unacceptable. Newly proposed
`trade name, Orenitram, is
`acceptable.
`Cate . orical Exclusion u anted
`
`Nov-29-2013
`
`Loretta Holmes
`
`
`
`Microbiology
`
`Not Applicable
`
`19. ORDER OF REVIEW (001) Only)
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`Ifno, explain reason(s) below:
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 7
`
`Reference ID: 3419754
`
`

`

`
`
`Executive Summary Section
`
`Chemistry Review for NDA 203496
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA 203496 for Orenitram (treprostinil) Extended Release Tablets (0.125, 0.25,
`l and 2.5 mg) is approvable from CMC perspective based on evaluation of labeling,
`container/carton draft information provided in the resubmission (SD#33 16-Aug-
`2013) and subsequent amendments. DMEPA has reviewed the proposed tradename,
`“Orenitram” for the drug product and deemed acceptable.
`
`Please refer to Quality Reviews filed in DARRTS for additional information. Office
`of Compliance has provided a final overall acceptable
`recommendation for all
`manufacturing and testing facilities for this NDA (Summary report attached).
`
`Recommendation on Phase 4 (Post—Marketing) Commitments,
`B.
`Agreements, and/or Risk Management Steps, if Approvable
`None applicable .
`H. Summary of Chemistry Assessments
`
`A.
`
`Description of the Drug Product(s) and Drug Substance(s)
`The proposed drug product, Orenitram consists of the active Treprostinil , a tricyclic
`benzindene analogue of prostacyclin as a diethanolamine salt which is a new chemical
`entity (NCE) developed to treat Pulmonary Arterial Hypertension (PAH). Remodulin
`(treprostinil)
`Injection and Tyvaso (treprostinil)
`Inhalation Solution are currently
`marketed by the sponsor, United Therapeutics,
`for the same indication of PAH. This
`drug product is an alternate and new oral dosage form developed as a sustained release
`formulation designed to deliver the active over 12 hr period at zero-order kinetics
`employing , “EnSoTrol® Osmotic Technology platform”. This technology entails
`coating of drug product
`tablet cores with a semi—permeable membrane agent and a
`single aperture is laser-drilled on one side of the tablet through which the drug is
`released upon administration.
`The drug product is a round
`biconvex tablet
`consisting of 0.125, 0.25, mm 1 and 2.5 mg of active treprostinil (acid form) with
`strength identifying mo green, white, yellow and pink
`m4)
`coating respectively. The tablets are also printed on one side with, “UT” and the
`corresponding strength in black. The formulation consists of
`the pharmaceutical
`excipients, xylitol, maltodextrin, sodium lauryl sulfate, magnesium stearate, cellulose
`acetate, and triethyl citrate
`(km)
`The drug product is intended to be marketed as 100 count tablets
`packaged in 40 cc HDPE opaque white plastic bottle and a
`mo
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 8
`
`Reference ID: 3419754
`
`

`

`— .a' H
`
`mm
`
`CHENIISTRY REVIEW
`
`Executive Summary Section
`
`- .A. H
`
`E m ‘
`
`closure with induction seal liner. Each bottle also contains - desiccant
`pouch and- coil.
`
`Tre-rostinil sustained release tablet formulation was develo o -
`
`
`The stability of 33 batches of
`
`
`
`
`ilot and commercial scale and
`Treprostinil sustained release tablets manufactured at
`
`acka ed in HDPE containers,mh stored at long term 25°C 60% , mterme ate 30°C 75%
`
`
`and accelerated (40°C/75%RH)
`storaie conditions were evaluated for appearance,
`
`stability per ICH guideline.
`for
`impurities, dissolution and
`assay,
`Stability data obtained were statistically assessed by pooling of batches (including
`registration batches up to 18 months) and linear regression anal
`is was em 10 ed for
`
`estimation of ex iration datin and proposed shelf-life&
`i The sponsor submitted evaluation of stability data (up
`
`to 24 months) for registration batches in terms of revised acceptance criteria for
`dissolution in response to information request (IR) letter in support of the proposed I
`shelf-life. However, based on evaluation of the stability data, a 30 month
`s e - fe is recommended for 0.25 and 2.5 mg strength tablets. The drug product is
`recommended to be stored at 25 °C (77 °F) with excursions permitted to 15-30 °C (59-
`86 °F) (USP Controlled Room Temperature).
`
`It should be noted that in res onse to labeling issues identified by DMEPA
`e sponsor
`and communicated in the CR letter,
`
`has proposed
`and change the
`color film-coat for 0.125 mg strength tablet
`
`
`to white.
`
`Drug Substance:
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 9
`
`Reference ID: 341 9754
`
`

`

`
`
`Executive Summary Section
`
`Treprostinil Diethanolamine (UT-1 5C) is a white to cream-colored solid and consists of
`five chiral centers with a well-defmed single enantiomer associated with each chiral
`center. The chemical structure of Treprostinil Diethanolamine was determined to be 2-
`hydroxy-N-(Z-hydroxyethyl)
`ethanaminium 2-({(1R.2R,3aS.9aS)-2—hydroxy—l-[(3S’)-3-
`hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro—lH-cyclopenta[b]naphthalen-5-yl}oxy)acetate.
`Treprostinil diethanolamine has an aqueous solubility of 453 mg/mL in water. UT—
`15C is manufactured by United Therapeutics at Silver Spring , MD facility from
`mm the starting material and the process was qualified by way of its use
`in manufacturing of two approved drug products namely, Remodulin and Tyvaso.
`The manufacturing process for the starting material
`, acquired from two different
`vendors, was adequately described in the application and appropriately referenced to
`respective DIVIFs through Letters of authorization. The final drug substance is obtained
`in relatively more stable
`may
`The sponsor
`revised the drug substance specification to include
`diethanolamine content in UT-15C. The stability of the drug substance is adequately
`evaluated and proposed retest dating of
`mo for the drug substance lots is
`considered acceptable.
`
`Description of How the Drug Product is Intended to be Used
`The drug product is intended to be marketed as 100 count tablets packaged in 40 cc
`HDPE opaque white plastic bottle and a
`(mo closure with
`induction seal liner. Each bottle also contains
`gm desiccant pouch and mo coil.
`The recommended storage conditions for the drug product are:
`“Store at 25 °C (77 °F) with excursions permitted to 15-30 °C (59-86 °F) (USP
`Controlled Room Temperature)”
`
`Basis for Approvability or Not—Approval Recommendation
`The recommendation for approvability of this NDA 203496 for T treprostinil Extended
`Release Tablets of 0.125, 0.25, 1 and 2.5 mg strengths is based on the evaluation of
`quality information submitted in the original application and the supporting documents
`with the recommended changes to the dissolution acceptance criteria, and revised
`specification for drug substance and the drug product. A shelf-life of 36 months for 0.125
`and 1 mg strength tablets and 30 months for the remaining 0.25 and 2.5 mg strength
`tablets are recommended since the sponsor submitted no additional information.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`C. CC Block
`
`Original NDA 203496
`DNP (HFD-l 10)/NDA Division File
`DNP(HFD-1 10)/CSO/W. Amchin
`ONDQA/DNDQAI/Chemist/S. Bhamidipati
`
`NDA 203496
`
`Orenitram (treprostinil) Extended Release Tablets
`
`Page 10
`
`Reference ID: 3419754
`
`

`

`.
`
`,
`
`‘
`
`CHEMISTRY REVIEW
`
`_
`
`= =
`
`Executive Summary Section
`
`ONDQA/DNDQAI /Lead/K.Srinivasachar
`ONDQA/DNDQAI RPM/Y. Knight
`ONDQA/DNDQAI IBIanch Chief/O. Stephens
`
`NDA 203496
`
`OrenitIam (treprosfinil) Extended Release Tablets
`
`Page 1 1
`
`Reference ID: 3419754
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHASTRI P BHAMIDIPATI
`12/10/2013
`
`OLEN M STEPHENS
`12/10/2013
`
`Reference ID: 3419754
`
`

`

`NDA 203496
`
`Treprostinil Extended Release Tablets
`0.125, 0.25, “m 1 and 2.5 mg
`
`0ND Division: Division of Cardiovascular and Renal Products
`
`Applicant: United Therapeutics Corp
`Letter Date Jan 31, 2013
`
`Stamp Date Jan 31, 2013
`PDUFA Date Mar 31, 2013
`
`Established Name: Treprostinil diethanolamine
`Dosage Form: Sustained release tablets
`Route of Administration: Oral
`
`Indication: Pulmonary Arterial Hypertension
`Quality Reviewer: Shastii Bhamidipati, Ph.D.
`
`Summary:
`In response to labeling issues identified by DMEPA
`and communicated in the CR letter, the sponsor has proposed
`and change the color film-coat for 0.125 mg
`@(oto white. If this change is acceptable to the Agency, the sponsor
`strength tablet
`will place the first three commercial lots on stability and submit the data. No additional
`information was provided in the resubmission.
`
`(b) (4)
`
`At the end of 1St review cycle, we have determined that the NDA is approvable from
`CMC perspective and recommended a shelf life of 36 months for 0.125, one and 1 mg
`strengths and 30 months for 0.25 and 2.5 mg strengths based on stability data presented
`in the original NDA and the amendments.
`
`This change in strengths is considered acceptable from ONDQA perspective and
`reportable in annual reports per SUPAC guidance. If the clinical division were to approve
`this NDA afier completion of reviewing this resubmission, we will still recommend 36
`months shelf for 0.125 and 1 mg strength tablets and 30 months for the remaining 0.25
`and 2.5 mg strength tablets since the sponsor submitted no additional information.
`
`Reference ID: 3281 1 13
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHASTRI P BHAMIDIPATI
`03/22/2013
`
`RAMESH K SOOD
`03/22/2013
`
`Reference ID: 3281113
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`(”(0
`0.125, 0.25,
`1 and 2.5 mg
`
`United Therapeutics, Inc.
`
`Division of Cardiology and Renal Products, HFD 110
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`Office of New Drug Quality Assessment
`
`Submission Date : 27-DEC-2011
`
`PDUFA Goal Date: 27-OCT-2012
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 1
`
`Reference ID: 3205838
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Table of Contents
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. Recommendations................................................................................................8
`
`A. Recommendation and Conclusion on Approvability....................................... 8
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements,
`
`and/or Risk Management Steps, if Approvable ............................................... 8
`
`H. Summary of Chemistry Assessments ............................................................... 8
`
`A. Description of the Drug Product(s) and Drug Substance(s) ........................... 8
`
`B. Description of How the Drug Product is Intended to be Used ..................... 10
`
`C.
`
`Basis for Approvability or Not-Approval Recommendation .................. 10
`
`III. Administrative ................................................................................................ 10
`
`A. Reviewer’s Signature ...................................................................................................... 10
`
`B. Endorsement Block ......................................................................................................... 10
`
`C. CC Block .......................................................................................................................... l0
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 2
`
`Reference ID: 3205838
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 203496
`
`2. REVIEW #: 2
`
`3. REVIEW DATE:
`
`l9-OCT-2012
`
`4. REVIEWER: Shastri Bhamidipati, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`NDA 203496 Original Submission
`SD#lS Quality Information
`
`27—DEC-201 1
`
`lO-AUG—20 l 2
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 3 1 Reviewed
`
`SD#18 Quality Information
`
`SD# 21 Quality Information
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Document Date
`
`24-SEPT-2012
`
`19-OCT-2012
`
`Name:
`
`United Therapeutics, LLC
`
`55 TW Alexander Drive
`
`Address:
`
`PO Box 14186
`
`Representative:
`
`Research Triangle Park, NC 27709
`Dean Bunce,
`Executive Vice President,
`
`Regulatory Affairs & Compliance
`55 TW Alexander Drive
`
`PO Box 14186
`
`Research Triangle Park, NC 27709
`
`Telephone:
`
`919-485-8350
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 3
`
`Reference ID: 3205838
`
`

`

`
`
`Chemistry Review Data Sheet
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Treprostinil Extended Release Tablets (Trade name not finalized)
`b) Non-Proprietary Name (USAN): Treprostinil Diolamine
`c) Code Name/# (ONDQA only): N/A
`(1) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 21 CFR 314.50, 505(b)(l)
`
`10. PHARMACOL. CATEGORY: Cardiology, Pulmonary Arterial Hypertension
`(PAH)
`
`11. DOSAGE FORM: Extended Release Tablets
`
`12. STRENGTH/POTENCY: 0.125, 0-25, cm 1.0 and 2.5 mg
`
`13. ROUTE OF ADMINISTRATION: Oral
`
`14. RX/OTC DISPENSED:
`
`
`X
`
`Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON—LINE TRACKING SYSTEM):
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 4
`
`Reference ID: 3205838
`
`

`

`alum-n
`m ‘
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`cum-h
`E a: ‘
`
`1. CHEMICAL NANIE, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name(s):
`l. Acetic acid, 2-[[(lR,2R,3aS,9aS)—2,3,3a,4,9,9a-hexahydro-2—hydroxy—l-[(3.S’)—3-
`hydroxyoctyl]- lH—benz[f]inden—5-yl]oxy]—, compd. with 2,2'-iminobis[ethanol] (1:1)
`
`2. 2-hydroxy-N—(2-hydroxyethyl)ethanaminium 2-({(1R,2R,3aS,9a.S)—2—hydroxy—l-[(3S)-3-
`hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro—1H—cyclopenta[b]naphthalen—5—yl} oxy)acetate
`
`OACOZH
`
`CH3
`
`HO\/\N/\/0H
`H
`
`Molecular Formula: C23H34 05.C4H11N02
`
`Molecular Weight: 495. 66 (salt form) 390.52 (acid form)
`CAS: [830354-48—8]
`Laboratory Code : UT-lSC
`
`l7. RELATED/SUPPORTING DOCUMENTS*:
`
`* SinsorsubmittedientDMFinformationiliMFholdersandLOAi_
`
`A. DMFs:
`
`W TYPE
`
`HOLDER
`
`CODEl
`
`STATUS2
`
`ED
`
`DATEW
`
`COMMENTS
`
`COMPLETED
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 5
`
`Reference ID: 3205838
`
`

`

`
`
`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`fin,”
`E m: ‘
`
`
`
`' Action codes for DMF Table:
`l — DMF Reviewed
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type 1 DMF
`3 — Reviewed previously and no revision since last review
`4 — Suflicient information in application
`5 — Authority to reference not granted
`6 — DMF not available
`
`7 — Other (explain under "Comments")
`
`2Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents:
`
`m APPLICATION NUMBER
`_ 71537
`
`DESCRIPTION
`Tr ostinil Diethanolamine
`
`18. STATUS:
`
`0NDQA:
`CONSULTS/ CMC
`
`RELATED
`REVIEWS
`
`Biometrics
`
`RECOMMENDATION
`
`REV]EWER(S)
`
`A « uested. The methods are
`
`Acc- table
`
`16—0CT—2012
`
`Recommended A- nroval
`
`03-OCT—2012
`
`Jose uh Xavier
`
`Recommended approval.
`
`30-AUG-2012 Akahairuzzaman
`02—0CT—2012
`S.Hariharan
`
`Pharmacolo 3
`Methods Validation
`
`Not
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 6
`
`Reference ID: 3205838
`
`

`

`
`
`conventional and do not qualify for
`internal validation b FDA labs
`Proposed Trade names,
`0"“
`were duly
`reviewed and determined
`
`July—26-2012
`
`Forest Ford
`
`unacceptable. Newly proposed
`trade name, Orenitram, is under
`evaluation.
`
`Cate . orical Exclusion u anted
`
`Microbiolo 3
`
`Not A I .licable
`
`19. ORDER OF REVIEW (001) Only)
`
`The application submission(s) covered by this review was taken in the date order of
`receipt.
`Yes
`No
`If no, explain reason(s) below:
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 7
`
`Reference ID: 3205838
`
`

`

`
`
`Executive Summary Section
`
`Chemistry Review for NDA 203496
`The Executive Summafl
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`This NDA 203496 for Treprostinil Extended Release Tablets (0.125, 0.25, «no 1 and
`2.5 mg) is approvable from CMC perspective. This review includes evaluation of
`sponsor provided responses to the information request letter dated 28-August—2012,
`24-Sept—2012 and 19-Oct-2012. Please refer to Quality Review #1 filed in DARRTS
`on 28-August-2012 for additional information. Office of Compliance has provided a
`final overall acceptable recommendation for all manufacturing and testing facilities
`for this NDA.
`
`one for the
`It should be noted that proposed tradenames,
`drug product were considered not acceptable by DMEPA and most recently proposed
`tradename, “Orenitram” is under evaluation. In addition, changes to labeling are not
`completed.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments,
`Agreements, and/or Risk Management Steps, if Approvable
`None applicable .
`II. Summary of Chemistry Assessments
`
`A.
`
`Description of the Drug Product(s) and Drug Substance(s)
`The proposed drug product, Orenitram consists of the active Treprostinil , a tricyclic
`benzindene analogue of prostacyclin as a diethanolamine salt which is a new chemical
`entity (NCE) developed to treat Pulmonary Arterial Hypertension (PAH). Remodulin
`(treprostinil)
`Injection and Tyvaso (treprostinil)
`Inhalation Solution are currently
`marketed by the sponsor, United Therapeutics,
`for the same indication of PAH. This
`drug product is an alternate and new oral dosage form developed as a sustained release
`formulation designed to deliver the active over 12 hr period at zero-order kinetics
`employing , “EnSoTrol® Osmotic Technology platform”. This technology entails
`coating of drug product
`tablet cores with a semi-permeable membrane agent and a
`single aperture is laser-drilled on one side of the tablet through which the drug is
`released upon administration.
`The drug product is a round
`biconvex tablet
`consisting of 0.125, 0.25, on» 1 and 2.5 mg of active treprostinil (acid form) with
`strength identifying
`(mo green, white, yellow and pink
`(mo
`coating respectively. The tablets are also printed on one side with, “UT” and the
`corresponding strength in black. The formulation consists of
`the pharmaceutical
`excipients, xylitol, maltodextrin, sodium lauryl sulfate, magnesium stearate, cellulose
`acetate, and triethyl citrate
`m4)
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 8
`
`Reference ID: 3205838
`
`

`

`Q
`
`.
`
`CHEMISTRY REVIEW
`
`_
`
`; .
`
`Executive Summary Section
`
`The drug product is intended to be marketed as 100 count tablets
`acka ed in 40 cc HDPE opaque white plastic bottle and a
`
`*closure with induction seal liner. Each bottle also contains
`
`pouc and- coil.
`
`desiccant
`
`Trerostinil sustained release tablet formulation was develoed
`
`Treprostinil sustained release tablets manufactured at
`
`ilot and commercial scale and
`
`acka ed in HDPE containers,h stored at long term (25°C/60%RH), intermediate (30°C/75%RH)
`and accelerated (40°C/75%R.H)
`storaie conditions were evaluated for appearance,
`
`stability per ICH guideline.
`for
`impurities, dissolution and
`assay,
`Stability data obtained were statistically assessed by pooling of batches (including
`registration batches up to 18 months) and linear regression anal sis was e
`10 ed for
`e
`
`stimation of e
`
`iration datin and proposed shelf-life fl
`
`The sponsor submitted evaluation of stability data (up
`or registration batches in terms of revised acceptance criteria for
`to 24 mon
`dissolution in response to information request (1R) letter in support of the proposed
`shelf-life. However, based on evaluation of the stability data, a 30 mon
`shelf-life is recommended for 0.25 and 2.5 mg strength tablets The drug product is
`recommended to be stored at 25 °C (77 °F) with excursions permitted to 15-30 °C (59-
`86 °F) (USP Controlled Room Temperature).
`
`Drug Substance:
`
`Treprostinil Diethanolamine (UT-15C) is a white to cream-colored solid and consists of
`five chiral centers with a well-defined single enantiomer associated with each chiral
`center. The chemical structure of Treprostinjl Diethanolamine was determined to be 2-
`hydroxy-N-(Z-hydroxyethyl)ethanaminium
`2-( {(lR,2R,3aS,9aS)—2-hydroxy—l-[(3S)-3-
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 9
`
`Reference ID: 3205838
`
`

`

`
`
`Executive Summary Section
`
`hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl}oxy)acetate.
`Treprostinil diethanolamine has an aqueous solubility of 453 mg/mL in water. UT-
`15C is manufactured by United Therapeutics at Silver Spring , MD facility from
`(IN) the starting material and the process was qualified by way of its use
`in manufacturing of two approved drug products namely, Remodulin and Tyvaso.
`The manufacturing process for the starting material
`, acquired from two different
`vendors, was adequately described in the application and appropriately referenced to
`respective DMFs through Letters of authorization. The final drug substance is obtained
`in relatively more stable
`mo
`conditions. The
`sponsor
`revised the drug substance specification to include
`diethanolamine content in UT-15C. The stability of the drug substance is adequately
`evaluated and proposed retest dating of
`(mo for the drug substance lots is
`considered acceptable.
`
`B.
`
`C.
`
`Description of How the Drug Product is Intended to be Used
`The drug product is intended to be marketed as 100 count tablets packaged in 40 cc
`I-IDPE opaque white plastic bottle and a
`(mo closure with
`induction seal liner. Each bottle also contains
`mo desiccant pouch and mo coil.
`The recommended storage conditions for the drug product are:
`“Store at 25 °C (77 °F) with excursions permitted to 15-30 °C (59-86 °F) (USP
`Controlled Room Temperature)”
`
`Basis for Approvability or Not-Approval Recommendation
`The recommendation for approvability of this NDA 203496 for T treprostinil Extended
`Release Tablets of0. 125, 0.25, mm 1 and 2.5 mg strengths is based on the evaluation of
`quality information submitted in the original application and the supporting documents
`with the recommended changes to the dissolution acceptance criteria, and revised
`specification for drug substance and the drug product.
`
`1]]. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`C. CC Block
`
`Original NDA 203496
`DNP a-IFD-110)/NDA Division File
`DNP(I-IFD-1 10)/CSO/D. Brum
`ONDQA/DNDQAI/Chemist/S. Bhamidipati
`ONDQA/DNDQAI /Lead/K.Srinivasachar
`ONDQA/DNDQAI RPM/T. Bouie
`ONDQA/DNDQAI /Branch Chief/R. Sood
`
`10 Page(s) has been Withheld in Full as b4 (CCI/I‘S) immediately following this page
`
`NDA 203496
`
`Treprostinil Extended Release Tablets
`
`Page 10
`
`Reference ID: 3205838
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHASTRI P BHAMIDIPATI
`10/19/2012
`
`RAMESH K SOOD
`10/19/2012
`
`Reference ID: 3205838
`
`

`

`
`
`Chemistry Review Data Sheet
`
`NDA 203496
`
`(ll
`)(OTM
`
`(Treprostinil) Extended Release Tablets
`0') (4)
`0.125, 0.25,
`l and 2.5 mg
`
`United Therapeutics, Inc.
`
`Division of Cardiology and Renal Products, HFD 110
`
`Shastri Bhamidipati, Ph.D.
`Division of New Drug Quality Assessment I
`
`Office of New Drug Quality Assessment
`
`Submission Date : 27—DEC—2011
`
`PDUFA Goal Date: 27—OCT—2012
`
`NDA 203496
`
`(m4) (Treprostinil) Extended Release Tablets
`
`Page 1
`
`Reference ID: 3181252
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Table of Contents
`
`Chemistry Review Data Sheet.................................................................................8
`
`The Executive Summary ....................................................................................... 13
`
`I. Recommendations.............................................................................................. 13
`
`A. Recommendation and Conclusion on Approvability..................................... 13
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments, Agreements,
`
`and/or Risk Management Steps, if Approvable ............................................. 13
`
`H. Summary of Chemistry Assessments ............................................................. 13
`
`A. Description of the Drug Product(s) and Drug Substance(s) ......................... 13
`
`B. Description of How the Drug Product is Intended to be Used ..................... 15
`
`C.
`
`Basis for Approvability or Not-Approval Recommendation .................. 15
`
`III. Administrative ................................................................................................ 15
`
`A. Reviewer’s Signature.................................................................................................................... 15
`
`B. Endorsement Block....................................................................................................................... 16
`
`C. CC Block........................................................................................................................................ 16
`
`I. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`Body of Data ...................................................................................................... 17
`
`S DRUG SUBSTANCE [Treprostinil Diethanolamine, United Therapeutics] .......................... 17
`
`P DRUG PRODUCT |
`
`”(oareprostinil) ER tablets 0.125, 0.25, M" 1.0 and 2.5 mg] .......... 55
`
`R REGIONAL INFORMATION ................................................................................................ 146
`
`H. Review Of Common Technical Document—Quality (Ctd—Q) Module 1 ..... 146
`
`A. Labeling & Package Insert....................................................................................................... 146
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .............