CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 201655
`
`OPANA® ER (oxymorphone hydrochloride)
`Extended Release Tablets
`
`
`Endo Pharmaceuticals Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment/Division III/Branch
`VIII
`
`for
`
`Division of Anesthetics and Analgesics Products
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2975104
`
`
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`1. 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
`
`II. 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.......................................................... 9
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative........................................................................................................................... 9
`
`A. Reviewer’s Signature ........................................................................................................................ 9
`
`B. Endorsement Block........................................................................................................................... 9
`
`C. CC Block.......................................................................................................................................... 9
`
`Chemistry Assessment ........................................................................................... 10
`
`Reference ID: 29751 04
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 201655
`
`2. REVIEW #:3
`
`3. REVIEW DATE: 18—JUL—201 l
`
`4. REVIEWER: Craig M- Bertha, PhD.
`
`5. PREVIOUS DOCUMENTS:
`
`Document Date‘ 5)
`
`Previous Document
`
`07-JUL-2010
`23-JUL—2010
`l4—SEP—2010
`29—SEP—2010
`01-OCT—2010
`06-0CT-2010
`
`Original Submission
`Updated labeling
`Amendment (response to filing letter)
`Amendment (response to CMC DR letter)
`Amendment (stability data DP
`Amendment (updated package insert labeling)
`
`“9‘"
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Document Dates 5!
`
`Submissions 5! Reviewed
`
`13-JUN-201 1
`
`Amendment (response to complete response action letter:
`stability update: label/labeling update)
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Endo Pharmaceuticals Inc.
`
`100 Endo Boulevard
`Add‘ess‘ Chadds Ford, PA 19317
`
`Representative: Robert A. Barto. MBA. Vice President. Reg. Affairs
`
`Reference ID: 29751 04
`
`Page 3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Telephone:
`
`484—840-4262
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`3) Proprietary Name: N/A
`b) Non-Proprietary Name (USAN): oxymorphone hydrochloride
`c) Code Name/# (0NDQA only): EN3288
`(1) Chem. Type/Submission Priority (0NDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`analgesic; oxymorphone
`10. PHARMACOL. CATEGORY:
`hydrochloride is a centrally acting opioid compound and is proposed for the relief
`of moderate to severe pain in patients requiring continuous opioid therapy for an
`extended period
`
`11. DOSAGE FORM:
`
`extended release tablets
`
`12. STRENGTH/POTENCY: 5, 7.5, 10, 15, 20, 30, 40 mg oxymorphone
`hydrochloride/tablet
`
`13. ROUTE OF ADMINISTRATION: oral
`
`14. Rx/OTC DISPENSED:
`
`_.__—
`X Rx
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM 1:
`
`SPOTS product — Form Completed
`
`X Not a SPOTS product
`
`Reference ID: 29751 04
`
`Page 4
`
`

`

`‘ .A'h
`
` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`1‘ .A'H
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`N/HCl
`
`0H
`
`HO
`
`\\\\\““
`O
`
`O
`
`oxymorphone HCl
`
`Chemical Name:
`
`Molecular formula:
`
`4,5 a—epoxy—3, l4—dihydroxy—l 7-methyhnorphinan—6—one
`hydrochloride
`C17H19NO4-HC1
`
`Molecular Weight:
`CAS:
`
`337.80 g/mol
`357-07-3
`
`l7. RELATED/SUPPORTING DOCUIVIENTS:
`
`A. Supporting DMFs:
`
`ITEM REFERENCED m STATUS2
`
`m MW —
`COMPLETED
`COMMENTS3
`
`'— ”APR—2010— —
`
`7
`
`HOLDER
`
`Reference ID: 29751 04
`
`

`

`CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`2600112010
`
`21—JUL-2010
`
`29-SEP—2010
`
`' 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 — Sufficient 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)
`3 Include reference to location in most recent CMC review
`
`B. Other Supporting Documents:
`
`DATEREVIEW
`comm
`comm
`“mm was
`_—————
`
`_—————
`
`C. Related Documents:
`
`APPLICATION
`
`m—m mmmmm
`NDA 21611
`Endo
`Opana® (oxymmphone HCl) Tablets, 5 and 10 mg
`Pharmceulicals
`Inc.
`
`— NDA 21610 W 0pana® ER (oxymorphone HCl) Extended Release
`
`Reference ID: 29751 04
`
`Page 6
`
`

`

`In
`
`
`DATE
`COMNIENTS
`REVIEWER
`FORWARDED
`SUBJECT
`CONSULTS
`———— Seep.64ofreview#1
`IE_— 1540mm
`ACCEPTABLE
`0Crecmmnendationof15-NOV-2010
`
`_—Phatmfl‘ox N/A _—
`————
`Methods Validation
`N/A
`See evaluation ofregional infomntion
`_——_ mmmmm
`————
`_——— Sec-.73ofmicwiil
`Mncrolnology
`lack ofmicrobiological testing
`electronic mail of 19-
`Final/J. McVey,
`Acceptable, see microbiology review
`of dmg product
`AUG—2010
`PILD. and S.
`of l4—0CT—20 10
`Langille, PILD.
`
`
`
`
`
`
`
`Chemistry Review Data Sheet
`
`Inc.
`
`IND 104250
`
`Endo
`Pharmaceuticals
`
`EN3288(oxym01phone HCl)
`extended-release tablets
`
`
`
`
`
`Reference ID: 29751 04
`
`Page 7
`
`

`

`The Chemistry Review for NBA 201655
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is recommended for approval.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product, OPANA® ER(oxym01phone hydrochloride) Extended-Release
`Tablets is a solid dosage form with strengths 5, 7.5, 10, 15, 20, 30, and 40 mg (as
`the hydrochloride salt), intended for oral administration. The drug product is
`packaged in high-density polyethylene bottles that are fitted with child resistant
`closures, with each containing 60 or 100 tablets (for all strengths). The
`
`formulation for each stren
`consists of oxymorphone h drochloride
`
`polyethylene oxide
`
`
`hypromellose
`
`The formulation also contains
`
`itamm E
`
`
`
`and they are all film coated with difl'erent colorants (pink, gray, orange, white,
`green, red, yellow) to help distinguish the strengths, along with the debossing of
`the numerical strengths on one side of each tablet. For manufacturin the
`
`formulation com nents at
`
`
`
`The applicant has taken a bioequivalence approach to demonstrate a
`match to their already approved Opana® ER (oxymorphone hydrochloride)
`Extended-Release Tablets.
`
`
`The dru substance is o
`o hone h drochloride, which is a
`
`
`Reference ID: 29751 04
`
`Page 8
`
`

`

` CHEMISTRY REVIEW
`
`0 additional review
`
`of the CMC information related to production of that drug substance was needed
`to support this application.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Paraphrasing the labeling, OPANA® ER is indicated for the relief of moderate to
`severe pain in patients requiring continuous, around—the—clock opioid treatment
`for an extended period of time. The drug product is not intended for use as an as-
`needed anal esic and is not indicated for pain in the immediate post-operative
`period
`for patients not previously taking opioids,
`as there is said to be a risk of oversedation and respiratory depression requiring
`reversal with opioid antagonists. The drug product is not indicated for pain in the
`post-operative period if the pain is mild or not expected to persist for an extended
`period of time. The expiration dating period proposed of 36 months for all
`strengths of the drug product (60 and 100 count bottles), with recommended
`storage at controlled room temperature, is supported by the data provided.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`N/A
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Craig M. Bertha, Ph.D.lChemist: 18-JUL-201 l
`
`Prasad Peri, Ph.D.IBranch Chief
`
`C. CC Block
`
`DChtistodoulou/CMC Lead
`
`SPatwardhan/ONDQA PM
`LBasham/OND PM
`
`Reference ID: 29751 04
`
`Page 9
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`07/18/2011
`
`PRASAD PERI
`07/19/2011
`I concur
`
`Reference ID: 2975104
`
`

`

`
`
`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`16-NOV-2010
`
`N201655 File
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division III, Branch VIII
`
`
`THROUGH: Prasad Peri, Ph.D.
`
`
`Acting Branch Chief
`
`
`ONDQA, Division III, Branch VIII
`
`SUBJECT: Update on Establishment Evaluation Request for N201655
`
`(oxymorphone HCl) Extended Release Tablets; CMC recommendation
`
`
`SUMMARY:
`
`The Office of Compliance issued an overall recommendation of ACCEPTABLE for the
`application on 15-NOV-2010.
`
`RECOMMENDATION: As per CMC review #2, the application was considered to be
`approvable, considering that there was no recommendation from the Office of Compliance. Now
`that the OC has put forth a recommendation of acceptable, the recommendation from the CMC
`team for the application is for approval.
`
`
`
`
`
`
`
`
`
`cc:
`OND/DAAP/LBasham
`ONDQA/DIV 3/CBertha/16-NOV-2010
`ONDQA/DIV 3/PPeri
`ONDQA/DIV3/DChristodoulou
`ONDQA/SSharp-Suarez
`OND/DAAP/EFields
`ONDQA/SPatwardhan
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________________________
`Craig M. Bertha, Ph.D.
`CMC Reviewer, ONDQA
`
`
`
`Reference ID: 2864358
`
`(b) (4)
`
`(b)
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`11/16/2010
`
`PRASAD PERI
`11/16/2010
`I concur
`
`Reference ID: 2864358
`
`

`

`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 201655
`
`(oxymorphone hydrochloride)
`Extended Release Tablets
`
`
`Endo Pharmaceuticals Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment/Division III/Branch
`VIII
`
`for
`
`Division of Anesthetics and Analgesics Products
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. Recommendations ...................................................................................................................... 8
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 8
`
`B. Reconmiendation on Phase 4 (Post—Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 8
`
`II. 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 ......................................................... 9
`
`C. Basis for Approvability or Not-Approval Recommendation ............................................................ 9
`
`III. Administrative ........................................................................................................................... 9
`
`A. Reviewer’s Signature........................................................................................................................ 9
`
`B. Endorsement Block........................................................................................................................... 9
`
`C. CC Block.......................................................................................................................................... 9
`
`Chemistry Assessment .......................................................................................... 10
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data ......................................................................................................... 10
`
`Review of 14-SEP-2010 Amendment ................................................................................................. 11
`
`
`Review of 29-SEP—2010 Amendment ................................................................................................. 11
`
`
`Review of 01-0CT-2010 Amendment ................................................................................................ 19
`Review of 06-0CT—2010 Amendment ................................................................................................ 20
`
`Page 2
`
`

`

`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 201655
`
`2. REVIEW #:2
`
`3. REVIEW DATE: 26—OCT—2010
`
`4. REVIEWER: Craig M- Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Document Date! 5!
`
`Previous Document
`
`07—JUL—2010
`23-J'UL—2010
`
`Original Submission
`Updated labeling
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Document Date! st
`
`Submission! s) Reviewed
`
`l4—SEP—2010
`29-SEP—2010
`01-ocr-2010
`06-0CT-2010
`
`Amendment (response to filing letter)
`Amendment (response to CMC DR letter)
`Amendment (stability data DP
`Amendment (updated package insert labeling)
`
`”‘9
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Endo Pharmaceuticals Inc.
`
`Address:
`
`100 Endo Boulevard
`Chadds Ford. PA 19317
`
`Representative: Robert A. Barto. MBA. Vice President, Reg. Affairs
`
`Telephone:
`
`484-840-4262
`
`8. DRUG PRODUCT NANHE/CODE/TYPE:
`
`Page 3
`
`

`

`
`
`Chemistry Review Data Sheet
`
`a) Proprietary Name: N/A
`b) Non-Proprietary Name (USAN): oxymorphone hydrochloride
`c) Code Name/# (ONDQA only): EN3288
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`analgesic; oxymorphone
`10. PHARMACOL. CATEGORY:
`hydrochloride is a centrally acting opioid compound and is proposed for the relief
`of moderate to severe pain in patients requiring continuous opioid therapy for an
`extended period
`
`11. DOSAGE FORM:
`
`extended release tablets
`
`12. STRENGTH/POTENCY: 5, 7.5, 10, 15, 20, 30, 40 mg oxymorphone
`hydrochloride/tablet
`
`13. ROUTE OF ADMINISTRATION: oral
`
`l4- Rx/OTC DISPENSED:
`
`_.___
`X Rx
`
`OTC
`
`15. SPOTS [SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM [2
`SPOTS product — Form Completed
`
`
`X Not a SPOTS product
`
`Page 4
`
`

`

`1— .m-n
`
`‘ .A'n
`
` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`oxymorphone HCI
`
`Chemical Name:
`
`Molecular formula:
`Molecular Weight:
`CAS:
`
`4,5 a—epoxy—3,14-dihydroxy—l7-methylmorphinan—6—one
`hydrochloride
`C17H19NO4-HC1
`337.80 g/mol
`357-07-3
`
`l7. RELATED/SUPPORTING DOCUNIENTS:
`
`A. Supporting DNIFs:
`
`2
`mm mm mm was
`v
`u,
`
`DATE REVIEW
`comm
`09—APR—2010
`
`--_
`
`'-
`
`te
`
`l9-JUL-2010
`
`“——
`
`I.-
`l.- ”I
`
`Adequate
`
`Page 5
`
`

`

`
` m.) CHEMISTRY REVIEW
`
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`‘ Action codes for ow 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")
`
`2 Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`3 Include reference to location in most recent CMC review
`
`B. Other Supporting Documents:
`
`DATE REVIEW
`“WWW comm,
`
`_—————
`
`cams
`
`C. Related Documents:
`
`APPLICATION
`
`m“ mmmm
`NDA 21611
`Endo
`Opana® (oxymorphone HCl) Tablets, 5 and 10 mg
`Pharnnceuticals
`Inc.
`
`— NDA mm m_ opene® ER (exymoephene H01) Extended Release
`
`Page 6
`
`

`

`
`
`Chemistry Review Data Sheet
`
`
`
`Inc.
`
`Endo
`Pharmaceuticals
`Inc.
`
`IND 104250
`
`EN3288(oxym01phone HCl)
`extended-release tablets
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`STATUS
`DATE
`COMNIENTS
`REVIEWER
`FORWARDED
`SUBJECT
`CONSULTS
`———— Sup—Mofmvicwitl
`m— 15-JUIr2010
`_—
`————
`Methods Validation
`N/A
`See evaluation ofregional information
`_——_ “gamma
`—————
`_———_
`Micmbiology
`lack ofnimbiological testing
`electronic mail of 19-
`Final/J. Mchy,
`Acceptable, see microbiology Ieview
`of dung product
`AUG—2010
`PhD. and S.
`of I4—0CT—2010
`
`Iang'lle, “1.1).
`
`Page 7
`
`

`

`The Chemistry Review for NBA 200533
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is considered approvable. The facility inspections are
`outstanding and the above CMC recommendation does not incorporate any
`potential facility inspection issues.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product, -TM (oxymorphone hydrochloride) Extended-Release
`Tablets is a solid dosage form with strengths 5, 7.5, 10, 15, 20, 30, and 40 mg (as
`the hydrochloride salt), intended for oral administration. The drug product is
`packaged in high-density polyethylene bottles that are fitted with child resistant
`closures, with each containing 60 or 100 tablets (for all strengths). The
`
`
`
`formulation for each stren
`consists of oxymorphone h drochloride
`
`
`in a
`ofpolyethylene oxide
`
`
`yprome 0s
`The formulation also contains
`
`a—toco hero]
`
`
`
`and citric acid
`
`
`
`
`for pH adjustment. All of the strengths have the same tablet weight (221.5 mg)
`and they are all film coated with difi'erent colorants (pink, gray, orange, white,
`green, red, yellow) to help distinguish the strength, along with the debossing of
`the numerical strength on one side of each tablet. For manufacturin the
`formulation components are
`
`
`
`match to their already approved Opana® ER (oxymorphone hydrochloride)
`Extended-Release Tablets.
`
`Page 8
`
`

`

`
`
`The dru substance is o
`
`o hone h drochloride
`
`
`
`ubstance was needed
`
`to support this application.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Paraphrasing the labeling, -TM is indicated for the relief ofmoderate to
`severe pain in patients requiring continuous, around—the—clock opioid treatment
`for an extended period of time. The drug product is not intended for use as an as-
`needed anal esic and is not indicated for pain in the immediate post-operative
`
`period— for patients not previously taking opioids,
`
`as there is said to be a risk of oversedation and respiratory depression requiring
`reversal with opioid antagonists. The drug product is not indicated for pain in the
`post-operative period if the pain is mild or not expected to persist for an extended
`period of time.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`The oflice of compliance has not issued a decision with regard to the GMP status
`of the application.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Craig M. Bertha, PhD/Chemistry Reviewer: 26-OCT-2010
`
`Prasad Peri, PhD/Acting Branch Chief
`
`C. CC Block
`
`DChn'stiodoulou/CMC Lead
`
`SSuarez/Biopharm.
`LBasham/PM
`
`Page 9
`
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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/
`----------------------------------------------------
`
`CRAIG M BERTHA
`10/26/2010
`
`PRASAD PERI
`10/27/2010
`I concur
`
`Reference ID: 2854845
`
`

`

`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 201655
`
`(oxymorphone hydrochloride)
`Extended Release Tablets
`
`
`Endo Pharmaceuticals Inc.
`
`
`
`Craig M. Bertha, Ph.D.
`Office of New Drug Quality Assessment/Division III/Branch
`VIII
`
`for
`
`Division of Anesthetics and Analgesics Products
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
`
`The Executive Summary .........................................................................................9
`
`I. Recommendations ...................................................................................................................... 9
`
`A. Recommendation and Conclusion on Approvability ....................................................................... 9
`
`B. Recommendation on Phase 4 (Post—Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 9
`
`II. Summary of Chemistry Assessments.........................................................................................9
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 9
`
`B. Description of How the Drug Product is Intended to be Used ....................................................... 10
`
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 10
`
`HI. Administrative ......................................................................................................................... 10
`
`A. Reviewer’s Signature...................................................................................................................... 10
`
`B. Endorsement Block......................................................................................................................... 10
`
`C. CC Block........................................................................................................................................ 11
`
`Chemistry Assessment .......................................................................................... 12
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data ......................................................................................................... 12
`
`s DRUG SUBSTANCE [oxymorphone HCl,
`
`m” ........................................................ 13
`
`P DRUG PRODUCT [oxymorphone HCl extended release tablets] ............................................. 16
`
`Pl Description and Composition of the Drug Product [oxymorphone HCl extended release tablets] 16
`
`P2 Pharmaceutical Development [oxymorphone HCl extended release tablets] ................................ 18
`
`P3 Manufacture [oxymorphone HCl extended release tablets] ........................................................... 29
`
`R4 Control of Excipients [oxymorphone HCl extended release tablets] ............................................. 36
`
`P5 Control of Drug Product [oxymorphone HCl extended release tablets] ........................................ 39
`
`R6 Reference Standards or Materials [oxymorphone HCl extended release tablets] .......................... 54
`
`R7 Container Closure System [oxymorphone HCl extended release tablets] ...................................... 55
`
`Page 2
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`, ”‘5"
`
`CHEMISTRY REVIEW
`
`f'F'X
`
`P.8 Stability [oxymorphone HCl extended release tablets] .................................................................. 60
`
`A APPENDICES ........................................................................................................................... 70
`
`Al Facilities and Equipment (biotech only) ........................................................................................ 70
`
`A2 Adventitious Agents Safety Evaluation ......................................................................................... 71
`
`A3 Novel Excipients ........................................................................................................................... 71
`
`R REGIONAL INFORMATION .................................................................................................. 71
`
`R1 Executed Batch Records ................................................................................................................. 71
`
`R2 Comparability Protocols ................................................................................................................. 71
`
`R3 Methods Validation Package .......................................................................................................... 71
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 .................................... 72
`
`A. Labeling & Package Insert ............................................................................................................. 72
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................... 73
`
`Page 3
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`

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`
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 201655
`
`2. REVIEW #:1
`
`3. REVIEW DATE: 02—SEP—2010
`
`4. REVIEWER: Craig M. Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Document Date
`
`N/A
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission! 5) Reviewed
`
`07-JUL—2010
`23-J'UL—2010
`
`Document Date
`
`Original
`Updated labeling
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name: Endo Pharmaceuticals Inc.
`
`100 Endo Boulevard
`Address: Chadds Ford. PA 19317
`
`Representative: Robert A. Barto. NIBA. Vice President. Reg. Affairs
`
`Telephone:
`
`484-840-4262
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: N/A
`b) Non-Proprietary Name (USAN): oxymorphone hydrochloride
`
`Page 4
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`

`

`
`
`Chemistry Review Data Sheet
`
`c) Code Name/# (ONDQA only): EN3288
`d) Chem. Type/Submission Priority (ONDQA only):
`
`0 Chem. Type: 3
`
`0 Submission Priority: P
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`analgesic; oxymorphone
`10- PHARMACOL. CATEGORY:
`hydrochloride is a centrally acting opioid compound and is proposed for the relief
`of moderate to severe pain in patients requiring continuous opioid therapy for an
`extended period
`
`11- DOSAGE FORM:
`
`extended release tablets
`
`12. STRENGTH/POTENCY: 5, 7.5, 10, 15, 20, 30, 40 mg oxymorphone
`hydrochloride/tablet
`
`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
`
`Page 5
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`1— .A.“
`
`
`CHEMISTRY REVIEW
`
`‘ .u-n
`
`t m: ‘
`
`Chemistry Review Data Sheet
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`oxymorphone HCI
`
`Chemical Name:
`
`Molecular formula:
`Molecular Weight:
`CAS:
`
`4,5 a—epoxy—3,14-dihydroxy—l7-methylmorphinan—6—one
`hydrochloride
`C17H19NO4-HC1
`337.80 g/mol
`357-07-3
`
`l7. RELATED/SUPPORTING DOCUNIENTS:
`
`A. Supporting DMFs:
`
`I:o5H
`
`5%
`
`lllllllMIMIi
`
`Page 6
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`

`

`
`
`
` m.) 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 — Sufficient informiion 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)
`3 Include reference to location in most recent CMC review
`
`B. Other Supporting Documents:
`
`DATE REVIEW
`“WWW comm
`
`cows
`
`C. Related Documents:
`
`APPLICATIONm—m mmmm
`
`NDA 21611
`
`Endo
`Pharrmceuticals
`Inc.
`
`Opana® (oxymorphone HCl) Tablets, 5 and 10 mg
`
`no hone HCl) Extended Release
`
`— NDA 21610 W o ana® ER (0
`
`Page 7
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`

`

`
`
`Chemistry Review Data Sheet
`
`— —
`
`STATUS
`DATE
`COMNIENTS
`REVIEWER
`FORWARDED
`SUBJECT
`CONSULTS
`———— Seep—64ofnvview#1
`I3_— 1541114010
`
`———— See P25 evahation
`
`————
`_——— Wm] “m
`sectionlB
`—————
`I_———_
`
`Page 8
`
`1ND 104250
`
`Inc.
`
`Endo
`Pharmaceuticals
`Inc.
`
`EN3288(oxym01phone HCl)
`extended-release tablets
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`

`

`The Chemistry Review for NBA 200533
`
`The Executive Summafl
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`The application is considered approvable. The facility inspections are
`outstanding and the above CMC recommendation does not incorporate any
`potential facility inspection issues.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None at this time.
`
`II.
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product, -TM (oxymorphone hydrochloride) Extended-Release
`Tablets is a solid dosage form with strengths 5, 7.5, 10, 15, 20, 30, and 40 mg (as
`the hydrochloride salt), intended for oral administration. The drug product is
`packaged in high-density polyethylene bottles that are fitted with child resistant
`closures, with each containing 60 or 100 tablets (for all strengths). The
`
`
`formulation for each stren
`consists of oxymorphone h drochloride
`
`
`in a
`ofpolyethylene oxide
`
`yprome ose
`
`
`a—toco hero]
`The formulation also contains
`
`and citric acid
`
`
`for pH adjustment. All of the strengths have the same tablet weight (221.5 mg)
`and they are all film coated with different colorants (pink, gray, orange, white,
`green, red, yellow) to help distinguish the strength, along with the debossing of
`the numerical strength on one side of each tablet. For manufacturin the
`formulation co
`nents are
`
` The applicant is taking a bioequivalence approach to demonstrate a
`
`match to their already approved Opana® ER (oxymorphone hydrochloride)
`Extended-Release Tablets.
`
`Page 9
`
`

`

`The drug substance is oxymorphone hydrochloride,
`
`CMC information related to production of that drug substance was needed to
`support this application.
`
`no additional review of the
`
`B. Description of How the Drug Product is Intended to be Used
`
`Paraphrasing the labeling, -TM is indicated for the relief ofmoderate to
`severe pain in patients requiring continuous, around—the—clock opioid treatment
`for an extended period of time. The drug product is not intended for use as an as-
`needed anal esic and is not indicated for pain in the immediate post-operative
`
`period— for patients not previously taking opioids,
`
`as there is said to be a risk of oversedation and respiratory depression requiring
`reversal with opioid antagonists. The drug product is not indicated for pain in the
`post-operative period if the pain is mild or not expected to persist for an extended
`period of time.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`CMC related issues that are currently unresolved are captured in the attached draft
`discipline review letter. It is expected that the applicant will be able to provide
`the requested information and data and revise the application such that it will be
`possible for