CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-2 72
`
`CHEMISTRY REVIEW! S!
`
`

`

`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`
`Review of Chemistry, Manufacturing, and Controls
`
` NDA #:
`
`21-272
`
`'
`
`DATE REVIEWED:
`
`05/17/02
`
`REVIEW #:
`
`03
`
`REVIEWER:
`
`JV Advani
`
`SUBMISSION TYPE DOCUMENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`11-Aug-00
`PRE-CMC submission
`18-Sep-00
`AMENDMENT (BC)
`ORIGINAL SUBMISSIONlé-Oct-OO
`
`14-Aug-00
`19-Sep-00
`18-Oct-00
`
`04-Dec-00
`AMENDMENT (BC)
`22-Dec-00
`AMENDMENT (BC)
`AMENDMENT (N-BL) 16-Aug-01 & 2 & 21-Feb-02
`Letter dated November 1, 2001 — Non-proprietary name information
`
`05-Dec-00
`29-Dec-00
`
`15-Aug-00
`20—Sep-00
`19-Oct-00
`
`12-Dec-00
`08-Jan-01
`
`NAME & ADDRESS OF APPLICANT:
`
`United Therapeutics Corporation
`P.O. Box 14186
`
`Research Triangle Park, NC 27709
`
`DRUG PRODUCT NAME
`
`Eggprietag:
`Established:
`Code Name/#:
`
`Remodulin
`Treprostinil sodium
`UT-lS, LRX-lS, 15AU81, BW AlSAU, U-62,840
`
`ChemTym/jl hengass:
`CAS Registry Number
`PHARMACOL. CATEGORY/INDICATION:
`DOSAGE FORM:
`srgugmg;
`ROQJIE OF ADMINISTRATION:
`m
`LATENT S I A I U§:
`SPECIAL PRODUCTS:
`( If yes, fill out the form for special products and
`deliver to TIA through team leader for data entry)
`STRUCT
`L FORMULA CHEMICAL NAME MOLECULAR FORMULA MOLECU AR
`
`l P
`'
`81846-19—7
`Pulmonary Arterial Hypertension
`Injection
`1.0, 2.5, 5.0, and 10.0 mg/mL
`Subcutaneous injection
`_;<__ Rx _ orc
`US. Patent pending
`__ Yes _x_ No
`
`WEIGfl !:
`h
`ic IN m s:
`
`[[( l R,2R,3 aS,9aS)-2,3,3 a,4,9,9a—hexahydro-2-hydroxy-l -[(3S)-3-hydroxyoctyl]-1H-benzminden-S-yl]oxy]acetic
`acid monosodium salt
`
`
`
`

`

`Molecular Formula
`
`C23H33 Na05
`
`Molecular weight
`
`412.49
`
`SUPPORTING DOCUMENTS:
`
`Type/Number
`
`Subject
`
`,
`
`
`
`
`
`Status
`
`,
`
`Review
`Date
`
`Letter
`Date
`
`
`
`Material technical data sheets for Type I USP 20 mL Glass is provided. Refer Vol.13, pp. 854-877.
`RELATED DOCUMENTS (if applicable]:
`-—-—--_-"~
`(Submission of 5/95 for UT-15 Injection)
`QONSULTS: Microbiology: Micro deficiencies have been resolved. Micro data is acceptable.
`Microbiologist recommends approval.
`REMARKS:
`
`UT-15 Injection is a tricyclic benzindene analog ofprostacycline (PGIZ) with potent puhnonary and
`systemic vasodilatory and platelet anti-aggregatory actions in vitro and in vivo. Unlike Flolan
`(epoprostenol sodium), which must be delivered by continuous intravenous infusion, UT-15 has
`‘ sufficient chemical stability to allow for subcutaneous administration, offering patients and clinicians an
`alternate therapeutic route of administration.
`All strengths (containing 1 0 mg, 2.5 mg, 50 mL and 10.0 mg treprostinol per mL), of UT-15 Injection,
`
`is packaged1n Type I USP 20 mL
`.The 20 mL via]15 sealed with
`~ W
`
`differ1n color for product identification.
`'
`'
`—-—--. The
`An EER for establishments was requested on 08/18/00. Overall recommendation for all sites is
`ACCEPTABLE
`
`Mr. Edward Fromm (PM) sent the labeling and package information provided by firm (in vol.2.9) to
`current Labeling committee OPDRA for their review. OPDRA review and recommendations are
`received. Uniprost is not acceptable but Remodulin proprietary name is acceptable.
`Expiration date \ months is proposed when stored at 25°C for the 1.0 mg/mL, 2.5 mg/mL, and 5.0
`mg/mL, and expiration date of '--'— months for 10-mg/mL strength. Proposed expiration periods will be
`reviewed when the updated stability data is received from the applicant.
`Statistical analysis: Firm has performed the linear regression analysis at 25°C, --——'~ ' on
`potency data for lots stored in proposed commercial packaging.
`Methods validation will be requested to be performed by 2 district laboratories.
`The information submitted in this submission has been previously reviewed under M'- and its
`amendments.
`
`Firm in letter of November 1, 2001 , has indicated that USAN has adopted on July 25, 2001, treprostinil
`sodium as the non~proprietary name for Remodulin Injection.
`CONCLUSIONS & RECOMMENDATIONS: There have been no other changes in chemistry since last review dated
`03/06/01. This NDA is satisfactory as far a chemistry is concerned.
`Copy of statement on USAN adopted non proprietary name TREPROSTINIL SODIUM is attached with this review.
`
`JV Advani, Review Chemist
`
`

`

`.r
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.WW
`
`
`J. V. Advani
`
`5/17/02 04:35:47 PM
`CHEMIST
`
`Kasturi Srinivasachar
`5/17/02 05:10:55 PM
`CHEMIST
`
`

`

`NDA 21-272 #2
`
`PAGE #1
`
`DIVISION OF CARDIO-RENAL DRUG PRODUCTS
`Review of Chemistry, Manufacturing, and Controls
`
`NDA #:
`
`21—272
`
`1
`
`DATE REVIEWED:
`
`03/06/01
`
`REVIEW #:
`
`02
`
`REVIEWER:
`
`JV Advani
`
`SUBMISSION TYPE DOCUMENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`ORIGINAL SUBMISSION 16-Oct-00
`
`AMENDMENT (BC)
`AMENDMENT (BL)
`AMENDMENT (N-BC)
`AMENDMENT (N-BC)
`
`23-Feb01
`26-Feb-01
`28-Feb-01
`01-Mar-01
`
`NAME & ADDRESS OF APPLICANT:
`
`18-Oct-00
`
`26-Feb-01
`27-Feb—01
`01-Mar—01
`02-Mar-01
`
`19-Oct-00
`
`27-Feb—01
`28-Feb»01
`01-Mar-01
`02-Mar-01
`
`United Therapeutics Corporation
`PO. Box 14186
`
`Research Triangle Park, NC 27709
`
`DRUG PRODUCT NAME
`
`Proprietgy:
`Established/USAN:
`Code Name/#:
`Chem.T
`
`er.Class:
`
`Remodulin
`Treprostinol sodium
`UT-lS, LRX—lS, 15AU81, BW AlSAU, U-62,840
`1 P
`
`CAS Registry Number
`PHARMACOL. CATEGORY/INDICATION:
`DOSAGE FQRM:
`STRENGTHS:
`ROUTE OF QMINISTRATION:
`Rx/QTC:
`’
`
`PATENT STATUS'
`SPECI& PRODUCTS:
`'( If yes, fill out the form for special products and
`deliver to TIA through team leader for data entry)
`STRUC URAL FORMULA CHEMICAL NAME MOLECULAR FORMULA M LECULA
`
`WEIGHT:
`Chemical Names:
`
`81846-19-7
`Pulmonary Arterial Hypertension
`Injection
`1.0, 2.5, 5.0, and 10.0 mg/mL
`Subcutaneous injection
`A Rx __ OTC
`US. Patent pending
`_ Yes .1. No
`
`[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-l—[(3 S).3-hydroxyoctyl]-lH-benz[t]inden-5-yl]oxy]acetic
`acid (IUPAC & CAS ]
`
`
`
`

`

`NDA 21-272 #2
`
`PAGE #2
`
`Molecular Formula
`
`C23H3405
`
`(free acid)
`
`Molecular weight
`
`390.52
`
`SUPPORTING DOCUMENTS:
`
`
`
`RELATED DOCUMENTS (if applicable): . —-—-—-—-
`(Submitted on 5/95 for UT-lS Injection)
`
`CONSULTS: Microbiology. There are no pending issues regarding sterility assurance.
`
`REMARKS:
`
`UT-lS Injection is a tricyclic benzindene analog of prostacycline (PGIZ) with potent pulmonary and
`systemic vasodilatory and platelet anti-aggregatory actions in vitro and in vivo. Unlike Flolan
`(epoprostenol sodium), which must be delivered by continuous intraVenous infusion, UT—l 5 has
`sufficient chemical stability to allow for subcutaneous administration, offering patients and clinicians an
`alternate therapeutic route of administration.
`All strengths (containing 1.0 mg, 2.5 mg, 5.0 mL and 10.0 mg treprostinol per mL), of UT-] 5 Injection,
`
`is packaged in Type IUSP 20 m1.
`'
`-
`. The 20 mL vial is sealed with a
`W
`
`differin color for product identification.
`The
`The amendment of 23 Feb. 01 provides some of the responses to deficiencies notedin my
`Review #1 and discussed with the applicantin the December 7, 2000 meeting Applicant has provided
`specifications, test methods validation for one of the starting materials for use in the UT-l 5 synthesis
`process. Also firm has now provided, —-month stability data for some ofthe primary stability batches of
`all strengths.
`The amendment of 26 Feb, 01 provides the revised labeling incorporating new trade name, Remodulin
`and other changes. USAN requested that the proposed generic name be changed to treprostinol sodium
`instead of triprostinol sodium (refer original -BL- amendment of 10/16/2000).
`In an amendment of 28 Feb, 01 there is a reference to teleconference meeting on 02/28/01 for tightening
`the levels of impurities in drug substances and in the drug product and includes the commitment to
`provide the information on the levels of ___....~ impurities if present, in the drug substance. The
`amendment provides the method validation data for second starting material of the drug substance
`synthesis process.
`The amendment of OlMar, 01 provides the revised test methods for drug substance and drug product,
`with revised specifications as per commitment made on 2/28/01 in teleconference meeting and also
`provides requested specifications or certificates of analysis for drug substance raw materials.
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`The NBA may be approved from the CMC viewpoint. All pending issues identified in review #1
`have been resolved in recent amendments. The storage statement in the package insert should be
`changed to conform to the storage statement on the carton labels. The ingredient “Water for Injection”
`should be included in the list of ingredients in “Description Section” of package insert and containers.
`These revisions are reflected in the marked up draft labeling which will be sent to the Applicant.
`
`JV Advani, Review Chemist
`
`

`

`J. V. Advani
`
`3/13/01 07:01:37 AM
`CHEMIST
`
`Kasturi Srinivasachar
`3/13/01 08:53:36 AM
`CHEMIST
`
`

`

`NDA 21-272 #1
`
`’
`
`PAGE #1
`
`DIVISION OF CARDlO-RENAL DRUG PRODUCTS
`
`Review of Chemistry, Manufacturing, and Controls
`
`NDA #:
`
`21-272
`
`DATE REVIEWED:
`
`02/15/01
`
`REVIEW g:
`
`01
`
`REVIEWER:
`
`JV Advani
`
`SUBMISSIQN TYPE ' DOCUMENT DATE
`
`CDER DATE
`
`ASSIGNED DATE
`
`1 l-Aug-OO
`PRE-CMC submission
`18—Sep~00
`AMENDMENT (BC)
`ORIGINAL SUBMISSIONl6—Oct—00
`
`AMENDMENT (BC)
`AMENDMENT (BC)
`
`04-Dec-00
`22-Dec-00
`
`NAME & ADDRESS OF APPLICANT:
`
`14-Aug-00
`19-Sep-00
`18-Oct—00
`
`05-Dec-00
`29-Dec-00
`
`‘ 15-Aug-00
`20-Sep-00
`19-Oct-00
`
`12-Dec»00
`08-Jan~01
`
`United Therapeutics Corporation
`PO. Box 14186
`
`Research Triangle Park, NC 27709
`
`DRUG PRODUCT NAME
`
`Prgprietgg:
`Established:
`Code Name/#:
`Chem.Txp_e_/'I herClass:
`CAS Registry Number
`PHARMACOL. CATEGORY/INDICATION:
`DOSAGE FORM:
`STRENG] ES:
`ROUTE OF ADMINISTRATION:
`Rx/OTC:
`PATENT STATUS:
`SPECIAL PRODUCTS:
`( If yes, fill out the form for special products and ‘
`deliver to TIA through team leader for data entry)
`STRUCTURAL FO
`ULA CHEMICAL NAME MOLECULAR FORMULA MOLECULAR
`
`WEIGHT:
`.
`
`' Remodulin
`Treprostinol sodium
`UT-l 5, LRX-IS, 15AU81, BW AISAU, U-62,84O
`1 P
`81846~19~7
`Pulmonary Arterial Hypertension
`Injection
`1.0, 2.5, 5.0, and 10.0 mg/mL
`Subcutaneous injection
`_>_<__ Rx _ OTC
`US. Patent pending
`_ Yes __x_ No
`
`Chemical flames!
`[K I R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro—2—hydroxy- I -[(3 S)-3-hydroxyoctyl]- l H-benz[flinden-S-yl]oxy]acetic
`acid (IUPAC & CAS ]
`
`
`
`Molecular Formula
`
`C23H3405
`
`Molecular weight
`
`390.52
`
`f
`
`SUPPORTING DOCUMENTS:
`
`....-.-_...._.._.'._.,._.~ . ~.....,.._4..,. __
`
`,.
`
`.
`
`.. , -.-
`
`

`

`NDA 21-272 #1
`
`PAGE #2
`
`
`
`
`
`
`
`Date
`
`Date
`
`Material technical data sheets-for Type 1 USP 20 mL Glass is provided. Refer Vol.13, pp. 854-877.
`
`
`_
`,
`RELATED DOCUMENTS {if applicable): .
`(Submission of 5/95 for UT-15 Injection)
`CONSULTS: Microbiology: Micro deficiencies have been resolved. Micro data is acceptable.
`Microbiologist recommends approval.
`
`w U
`
`T-15 Injection is a tricyclic benzindene analog of prostacycline (PGIZ) with potent pulmonary and
`systemic vasodilatory and platelet anti-aggregatory actions in vitro and in vivo. Unlike Flolan
`(epoprostenol sodium), which must be delivered by continuous intravenous infusion, UT-l 5 has
`sufficient chemical stability to allow for subcutaneous administration, offering patients and clinicians an
`alternate therapeutic route of administration.
`All strengths (containing 1.0 mg, 2.5 mg, 5.0 mL and 10.0 mg treprostinol per 1111.), of UT-15 Injection,
`is packaged in Type I USP 20 mL
`_
`'
`..——————-—----- The 20 mL vial is sealed with
`‘W '
`_ The
`differ1n color for product identification.
`An EER for establishments was requested on 08/18/00. Overall recommendation for all sites is
`ACCEPTABLE
`
`Mr. Edward Fromm (PM) sent the labeling and package information provided by firm (in vol.2.9) to
`current Labeling committee OPDRA for their review. OPDRA review and recommendations are
`received. Uniprost is not acceptable but Remodulin proprietary name is acceptable.
`Expiration date “ months is proposed when stored at 25°C for the 1.0 mg/mL, 2.5 mg/mL, and 5.0
`mg/mL, and expiration date of ’ months for IO-mg/mL strength. Proposed expiration periods will be
`reviewed when the updated stability data is received from the applicant.
`Statistical analysis: Firm has performed the linear regression analysis at 25°C, —-— on
`potency data for lots stored in proposed commercial packaging.
`Methods validation will be requested to be performed by 2 district laboratories.
`l and its
`The information submitted111 this submission has been previously reviewed under ——-—---
`amendments. The firm has addressed some of our recommendations that were made during the meetings
`on 7/15/99 and at pre NDA meeting on 11/08/99. I have highlighted the firm’5 actions in these regards1n
`this review
`
`'
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`The NDA is approvable pending a satisfactory response to the deficiencies noted in the draft letter on
`page 19, which will be conveyed to the applicant.
`
`JV Advani, Review Chemist
`
`A. DRUG SUBSTANCE:
`
`

`

`
`
`2.1 page(s) have been
`removed because it
`
`contains trade secret
`
`-
`
`and/or confidential
`information thatIS not
`disclosable.
`
`,.
`
`

`

`/S/
`
`J.
`
`V.
`
`Advani
`
`3/1/01 05:51
`CHEMIST
`
`46 PM
`
`Kasturi Srinivasachar
`
`3/5/01 09:01:25 AM
`CHEMIST
`
`

`

`-- -.
`
`~~w
`
`1 UA Cupm 11110
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Page
`
`1. 0‘
`
`Application:
`
`NDA 212721000
`
`1
`
`Priority:
`
`IS
`
`Org Code: 1 10
`
`Stamp: 16-0CT-2000 Regulatory Due: 16-AUG-2001
`
`Action Goal:
`
`District Goal: 17-AUG-2001
`
`Applicant:
`
`UNITED THERAP
`68 TW ALEXANDER DR
`
`Brand Name:
`
`UNIPROST(TREPROSTINOL
`SODIUM)1.0/2.5/10.
`
`RESEARCH TRIANGLE PARK, NC 27 Established Name:
`Generic Name: TREPROSTINOL SODIUM
`
`Dosage Form:
`Strength:
`
`(INJECTION)
`INJ
`1.0; 2.5; 5.0;10; MG/ML
`
`FDA Contacts:
`
`E. FROMM
`
`J. ADVANI
`
`(RFD—110)
`
`(HFDJ 10)
`
`301-594-5300 , Project Manager
`
`301-594-5300 , Review Chemist
`
`K. SRINIVASACHAR (RFD-110)
`
`301-594-5376 , Team Leader
`
`Overall Recommendation:
`
`ACCEPTABLE on 26-SEP-2000bv J. D AMBROGIO(HFD-324) 301-827-0062
`
`Establishment:
`
`#
`
`DMF No:
`AADA No:
`
`OAI Status: NONE
`Profile: SVS
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 26-SEP—2000
`
`Re5ponsibilitiesz
`
`—--~
`
`Decision:
`
`Reason:
`
`Establishment:
`
`ACCEPTABLE
`
`DISTRICT RECOMMENDATION
`
`x 3
`
`AADA No:
`
`DMF No:
`
`Profile: CTL
`
`0A1 Status: NONE
`
`Re8ponsfl>ilitiesz
`
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 17-AUG-2000
`Decision:
`ACCEPTABLE
`
`Reason:
`
`BASED ON PROFILE
`
`Establishment:
`
`~
`
`DMF No:
`AADA No:
`
`—.
`
`‘
`
`0A1 Status: NONE
`Profile: CSN
`Last Milestone: 0C RECOMMENDATION
`Milestone Date: 21-SEP—2000
`
`.
`
`W
`
`Responsibilities:
`
`

`

`4.1.-.“ x; "L\IV1
`
`PUA LUEK Ebb
`
`Page
`
`101
`
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Decision:
`
`Reason:
`
`F ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`APPEEF‘J’S THFS WAY
`ON ’éinQFNAL
`
`
`
`AH‘HJFS FMS WAY
`OF:g {m‘a‘uFF‘ML
`
`_.._-—V_.—_..,_,..:-..._......E.___,,‘ _, ,,
`
`..-._ _....,,
`
`.
`
`.
`
`

`

`Environmental Assessment A
`
`*
`
`1
`
`Dr. Advani in his February 15, 2001 review states that the firm should be granted
`exclusion.
`
`