CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -8 97
`
`' CHEMISTRY REVIEW! S)
`
`

`

`
`
`NDA 21-897
`
`VivitrolTN.I (naltrexone for extended-release
`inj ectable suspension)
`
`Alkermes, Inc.
`
`Jila H. Boal, Ph. D.
`
`Division of Pre-marketing Assessment III and
`Manufacturing Science, ONDQA
`
`. Pagelofll
`
`

`

`
`
`Tableof Contents
`
`Table Of Contents2
`
`Chemistry Review DataSheet3
`
`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
`
`III. Administrative...................................................- .........................................................................9
`
`A. Reviewer’s Signature ..................................................................,............ . ......................................... 9
`
`B. Endorsement Block ...........................................................-................................................................ 9
`
`C. CC Block................. ......................................................................................................................... 9
`
`ChemistryAssessment 10
`
`Page 2 of 11
`
`

`

`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet .
`
`1. NBA # 21-897
`
`2. REVIEW #: 2
`
`3. 'REVIEW DATE: April 7, 2006
`
`4. REVIEWERziJila H. Boal, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Type C Industry Meeting Minutes
`Pre—NDA CMC Meeting Minutes
`Type C Industry Meeting Minutes
`IND 61,138, Serial No. 069
`
`Pre—NDA CMC Meeting Minutes
`IND 61,138, Serial No. 078
`INDY 61,138, Serial No. 079
`N-0000 (Original Application)
`N—000BM (Amendment 0001)
`N-OOOO (Amendment 0002)
`N-OOO-SU (Amendment 0013)
`N—OOO—BC (Amendment 0017)
`N—OOO—BC(Amendment 0029)
`N-000-BC(Amendment 0032)
`N—OOO-BC(Amendment 0033)
`N-000-BC(Amendment 0034)
`N-OOO-BC(Amendment 0035)
`N—OOO-BC(Amendment 0036)
`
`Document Date
`
`July 11, 2002'
`February 2, 2005
`July 11,2002 .
`December 10, 2004
`
`February 2, 2005
`February 22, 2005
`February 25, 2005
`3 1-March-2005
`
`11-May-2005
`3 1-March-2005
`
`29-July—2005
`16-August—2005
`04—October-2005
`14—October-2005
`27—October-2005
`
`November 3, 2005
`November4, 2005
`November 14, 2005
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissionf S) Reviewed
`
`N-OOO-BC(Amendment 0043)
`
`Document Date
`
`February 13, 2006
`
`Page3 of11
`
`

`

`
`
`Chemistry Review Data Sheet
`
`7.
`
`NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Alkermes, Inc.,
`
`Address:
`
`3
`
`Representative:
`
`Telephone:
`
`88 Sidney Street
`Cambridge, MA 02319
`Priya Jambhekar, Global Vice President,
`Regulatory and Government Affairs
`(617) 583-6547
`
`8.
`
`DRUG PRODUCT NAME/CODE/TYPE:
`
`.
`a) Proprietary Name: Vivitrol
`b) Non-Proprietary Name (USAN): Naltrexone
`0) Code Name/# (ONDC only): N/A
`d) Chem. Type/Submission Priority (ONDC only):
`0 Chem. Type: 3 (new dosage form)
`
`a Submission Priority: P
`
`9.
`
`LEGAL BASIS FOR SUBMISSION: 505 (b) (2). Reference listed drug (RLD) is Revia
`(Naltrexone HCl) Tablets, SO-mg (NDA 18-932).
`
`10. PHARMACOL. CATEGORY: Treatment of alcohol dependence
`
`11
`
`12
`
`13
`
`. DOSAGE FORM:
`
`Injectable Suspension
`
`. STRENGTH/POTENCY: 380 mg
`
`. ROUTE OF ADMINISTRATION:
`
`Intramuscular (IM)
`
`14
`
`. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15.
`
`SPOTS {S'§?l'£(fl;3.;l.... P'.l¥{.(f.)lf)'l_lC‘TS (L)N—Il'...-INE TRACKING S'YSil".lf-3,M);
`Ruminant-derived materials from bovine spongiform encephalopathy (BSE)
`
`Page 4 ofll
`
`

`

`
`
`Chemistry Review Data Sheet '
`
`countries as defined by the U. S. Department of Agriculture (9 CFR 94.11)are not used or
`manipulatedin the manufacturing facility as noted1n the BSE statements for
`-———v-"“
`~———————~_
`11altrexone base anhydrous, 75:25
`r—'
`polymer,
`, carboxymethylcellulose and WFI.
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`Chemical Name: Morpl1inan-6-o-ne, 17--(cyclopro_pylmethyl)-4, 5--epoxy-3, l4--dihydroxy-,(SOL).
`CAS REGISTRY NUMBER:
`16590—41— 3
`MW: 341.41 Daltons
`
`Molecular Formula:
`
`C20H23NO4
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`Page5 ofll
`
`

`

`
`
`Chemistry Review Data Sheet
`
`
`
`1
`
`
`
`Reviewed by
`Jila H. Boal
`Ph.D.
`
`Alkermes
`Medisorb 7525
`
`November 2,
`
`
`
`Reviewed by
`2005
`
`~—' .polymer
`
`
`Chien-Hua Niu,
`
`
`Ph.D.
`
`1
`
`
`Naltrexone Base
`September 23,
`
`
`2005
`
` Anhydrous
`
`
`
`
`_
`
`September 23,
`
`2005
`
`August 7, 2005
`
`Reviewed by
`Jila H. Boal
`Ph.D.
`
`Reviewed by
`Jila H. Boal
`Ph.D.
`October 7,2005
`Reviewed by
`
`
`Jila H. Boal
`
`
`
`
`
`
`September 3,
`Reviewed by
`2004
`Jila H. Boal
`
`
`Ph.D.
`
`
`
`
`
`
`October 7, 2005,
`Reviewed by
`Review # 4
`Jila H. Boal
`
`
`Ph.D.
`
`
`October 9', 2005,
`Reviewed by
`
`
`
`Review # I
`Jila H. Boal
`
`
`Ph.D.
`
`
`
`December 12,
`Gurpreet Gill-
`
`
`Sangha,
`2001 and
`
`
`September 9,
`Ph.D.and
`
`
`2005 Donald Klein,
`
`
`
`Ph.D.
`
`
`
`
`
`Ph.D.
`
`
`
`N/A
`
`Sufficient
`
`information is
`
`
`
`
`provided in the
`NDA
`
`
`Alkermes, Inc.
`
`Microsphere Diluent
`
`1
`
`'
`
`I
`
`Adequate
`
`Adequate
`
`'
`
`.
`‘7
`
`1
`
`//‘3
`
`/ I
`
`I.
`
`Adequate
`
`14028
`
`II
`
`.
`
`—— III
`
`m
`
`V m
`
`—"
`
`III
`
`(5 III
`
`1 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 information in application
`5 — Authority to reference not granted
`
`Page 6 ofll
`
`

`

`
`
`Chemistry Review Data Sheet
`
`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)
`'
`
`B. Other Documents:
`
`
`
`
`Original IND
`Revia, Naltrexone
`
`Hydrochloride Tablet, 50 mg
`Syringe,
`:—~
`7
`Syrin_e, ’
`Needle. Hypodermic
`
`
`
`‘1
`
`
`,
`T
`Needle
`
`Safety
`
`Biometrics
`
`Not Consulted
`
`EES
`
`Acceptable
`
`Pharm/Tox
`
`Clinical-Pharm
`
`
`
`o Acceptable with respect to qualification
`of the drug substance and the drug
`product acceptance criteria for the level
`of impurities.
`
`April 7, 2006 Mamata De,
`Ph.D.
`
`- Acceptable with respect to toxicology
`qualification of the excipient in the drug
`
`product.
`A mutual agreement was reached between
`the CMC and clinical Pharmacology
`discipline for the following phase 4
`commitment:
`
`April 7, 2006
`
`Srikanth C.
`Nallani, Ph.D.
`
`
`
`l. The drug release specifications should be
`revised with addition of Day 14 and Day
`28 drug release information.
`
`Page 7 ofll
`
`
`
`»
`
`
`
`2005
`
`August 26,
`
`Mark E Parmon
`
`

`

`
`
`Chemistry Review Data Sheet
`
`
`
`
`
`
`2. The acceptance criteria for drug release
`
`will be revisited after production of five
`
`commercial batches of the product or at
`
`the end of the first year from the date of
`
`the approval letter, whichever comes
`earlier.
`
`
`
`
`
`October 27, 2005 Dr_ Guirag
`LNC recommended the following established
`name for Vivitrol:
`Poochikian, the
`LNC chair
`
`
`
`
`
`
`“Vivitrol (naltrexone for extended-release
`inj ectable suspension)”.
`The detail of the LNC recommendation for
`the established name is captured in the
`' review of the Container and Carton Labels in
`
`DPS.
`
` Methods
`Validation
`
`
`
`
`
`Validation of dissolution, assay and
`impurities test methods will be initiated by
`this reviewer after test methods are finalized
`
`
`
`
`
`
`
`Jila H. Boal,
`Ph.D.
`
`
`
`
`
`Michelle Safarik,
`PA-C, Regulatory
`
`Review Officer
`
`Iris Masucci,
`PharmD, Labeling
`Reviewer
`
`Jila H. Boal,
`Ph.D.
`
`Stephen E.
`Langille, Ph.D.
`
`July 31, 2005
`
`As per this
`review
`
`October 24,
`2005
`
`
`
`DMETS
`
`EnSMAC
`
`information Alkermes
`
`based on the post-marketing commitment
`listed above.
`The first recommended name “Vivitrex” was not
`acceptable. The proprietary name “Vivitrol” was
`
`accepted by DMETS. With respect to package labels
`
`
`
`and drug product package inserts, while most of the
`DMETS recommendations were accepted by the
`chemistry discipline, a few comments were not
`considered in the interest of maintaining the clarity
`and prominence of the labels. For example, the
`contents of the diluents don’t need to be listed in the
`'
`.———.
`.1; instead they could be moved
`to the side panel.
`
`See DMETS review in DFS.
`
`'
`
`EA
`
`Acceptable, categorical
`exclusion granted as per
`
`Microbiology
`
`Recommended for approval
`
`_l
`
`Page 8 ofll
`
`

`

`
`
`Chemistry Assessment Section
`
`The Chemistry Review for NBA 21-897
`
`1.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`From the standpoint of Product quality CMC, NDA 21-897 is recommended for
`approval. An expiration period of 18 months may be granted based on the
`assessment of the stability data.
`
`B.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`All of the outstanding approvability issues have been resolved for the “approval”
`recommendation for this NDA. The phase four commitmentslisted below should
`be conveyed to the applicant.
`'
`
`1. Provide a commitment that the specification for the in vitro drug release testing
`will be revised to include day-14 and day-28 time points. This commitment
`starts from the production of first drug product batch.
`
`2. The acceptance criteria for in vitro drug release should be revised after
`production of five commercial batches of the drug product or after one year
`from the date of the approval letter, which ever comes first.
`
`3. Based on the above batch experience, need to establish a specification to
`control the percent cr'ystallinity in Vivitrol ,will be assessed.
`
`4. Submit the results of the above studies in a CBE-30 supplement.
`
`' III. Administrative
`
`A. Reviewer’s Signature
`
`B. Endorsement Block
`
`Jila Boal, Ph.D., CMC Reviewer, ONDQA/ April 7, 2006
`Ravi S. Harapanhalli, Ph.‘D., CMC Branch Chief, DPAMS, ONDQA/ April 7,
`
`iifa6Basham-Cruz, Project Manager, DAARP
`
`I
`
`C. CC Block,
`
`Page 9 of 11
`
`

`

`r;
`
`.
`
`e
`
`- Page(s) Withheld
`
`
`
`' /Trade Secret/Confidential
`
`E Draft Labeling .
`
`fl ‘Déliberative Process
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jila Boal
`4/7/2006 04:32:08 PM
`CHEMIST
`»
`
`Ravi Harapanhalli'
`4/7/2006 04:57:50 PM
`CHEMI ST
`
`

`

` fiEMISTRY REVIEW:
`
`NDA 21-897
`
`VivitrolTM (naltrexone for extended-release
`injectable suspension)
`
`Alkermes, Inc.
`
`Jila H. Boal, Ph. D.
`
`Division of Pre-marketing Assessment 111 and
`Manufacturing Science, ONDQA'
`
`Page 1 onI9
`
`

`

`EMISTRY REVIEW
`
`.
`
`I
`
`Table of Contents
`
`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet. ................................................................................3
`
`The Executive Summary ......................................................................................... 9
`
`1. 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
`
`11. Summary of Chemistry Assessments ......................................................................................... 9
`
`A. Description ofthe Drug Product(s) and Drug Substance(s) ........................................................... 10
`
`B. Description of How the Drug Product is Intended to be Used ........................................................ I
`
`C. Basis for Approvability or Not-Approval Recommendation ...................................................'....... 1
`
`1
`
`I
`
`III. Administrative ......................................................................................................................... 15
`
`A. Reviewer’s Signature ...................................................................................................................... 15
`
`B. Endorsement Block ......................................................................................................................... 15
`
`C. CC Block ........................................................................................................................................ 15
`
`Chemistry Assessment .................................................................. . ....................... 16
`
`1. Review Of Common Technical Document—Quality (Ctd-Q) Module 3.2: Body Of Data ....... 16
`
`S
`
`P
`
`DRUG SUBSTANCE [Name, Manufacturer] .............................................................................. 16
`
`DRUG PRODUCT [Name, Dosage form] .................................................................................... 28
`
`A APPENDICES ............................................................................................................................ 157
`
`R
`
`REGIONAL INFORMATION ................................................................................................... 176
`
`II. Review Of Common Technical Document—Quality (Ctd-Q) Module 1 ................................ 182
`
`A. Labeling & Package Insert .......................................................................................................... 182
`
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 196
`
`111.
`
`List Of Deficiencies To Be Communicated ..................................................................... 197
`
`Page2 of219
`
`

`

`
`MISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NBA # 21-897
`
`2. REVIEW #2 l
`
`3. REVIEW DATE: October 20, 2005
`Revised November 23, 2005
`
`4. REVIEWER: Jila H. Boal, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`Type C Industry Meeting Minutes
`Pre—NDA CMC Meeting Minutes
`
`Document Date
`
`July 1 1, 2002
`February 2, 2005
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiongs) Reviewed
`Type C Industry Meeting Minutes
`IND 61,138, Serial No. 069
`
`Pre—NDA CMC Meeting Minutes
`IND 61,138, Serial No. 078
`[ND 61,138, Serial No. 079
`
`\1—0000 (Original Application)
`\-OOOBM (Amendment 0001)
`1\—0000 (Amendment 0002)
`\l—OOO-SU (Amendment 0013)
`\—000-BC (Amendment 0017)
`1\-000-BC(Amendment 0029)
`‘\l-000-BC(Amendment 0032)
`\-000-BC(Amendment 0033)
`1\-000—BC(Amendment 0034) .
`\—OOO-BC(Amendment 0035)
`\—000-BC(Amendment 0036)
`
`
`
`
`
`Document Date
`
`July 11, 2002
`December 10, 2004
`
`February 2, 2005
`February 22, 2005
`February 25, 2.005
`31-March—2005
`
`l 1—May—2005
`31—March-2005
`
`29-July-2005
`16-August-2005
`04-October—2005
`l4-Oct0ber-2005
`27—October—2005
`
`November 3, 2005
`November 4, 2005
`November 14, 2005
`
`Page 3 of2l9
`
`

`

`
`EMISTRY REVIEW_
`
`Chemistry Review Data Sheet
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`Alkermes, Inc.,
`
`88 Sidney Street
`Cambridge, MA 02319
`Priya J ambhekar, Global Vice President,
`Regulatory and Government Affairs
`(617) 583-6547
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: Vivitrol
`b) Non—Proprietary Name (USAN): Naltrexone
`C) Code Name/# (ONDC only): N/A
`d) Chem. Type/Submission Priority (ONDC only):
`0 Chem. Type: 3 (new dosage form)
`0
`Submission Priority:
`P
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b) (2). Reference listed drug (RLD) is Revia
`(Naltrexone HCl) Tablets, 50—mg (NDA l8-932).
`
`10. PHARMACOL. CATEGORY: Treatment of alcohol dependence
`
`11. DOSAGE FORM:
`
`Injectable Suspension
`
`12. STRENGTH/POTENCY: 380 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Intramuscular (1M)
`
`14. Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`Ruminant-derived materials from bovine spongiform encephalopathy (BSE)
`
`Page4 of219
`
`

`

`
`£1 ‘fEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`countries as defined by the U S. Department of Agr1culture (9 CFR 94.1 1) are not used or
`manipulated1n the manufacturing facility as notedin the BSE statements for. m '
`'N _
`naltrexone base anhydrous, 75:25 _/ polymer,
`, carboxymethylcellulose and WP].
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`Chemical Name: Morphinan—6——,one 17——(cyclopropylmethyl)—4, 5-e—poxy--,3 l4—d—ihydroxy--.,(50.)
`CAS REGISTRY NUMBER.
`16590-41— 3
`MW: 341.41 Daltons
`
`Molecular Formula:
`
`C20H23NO4
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFS:
`
`PageS of219
`
`

`

`
`
`
`
` COMMENTS
`
`
`
`
`
`November 2,
`Reviewed by
`2005
`Chien-Hua Niu,
`
`
`
`PhD.
`
`
`
`Reviewed by
`September 23,
`
`2005
`Jila H. Boal
`
`
`
`
`Reviewed by
`September 23,
`
`
`Jila H. Boal
` 2005
`
`Ph.D.
`
`August 7, 2005
`Reviewed by
`Jila H. Boal
`PhD.
`
`
`PhD.
`
`
`
`
`
`October 7, 2005
`Reviewed by
`
`
`
`Jila H. Boal
`
`PhD.
`
`
`
`information is
`
`provided in the
`NDA
`
`
`
`Alkermes
`
`Medisorb 7525
`../ polymer
`
`, _,._....
`
`l
`
`II
`
`.
`
`*/ II
`
`I
`
`1......
`
`Naltrexone Base
`Anhydrous
`
`9,..—
`
`__.—-,
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`’- Ill
`
`44
`
`\\\ II
`
`Ii
`
`Adequate
`
`Adequate
`
`Adequate
`
`Adequate
`
`1 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 information in application
`' 5 ~ Authority to reference not granted
`
`Page 6 0f219
`
`
`
`
`Adequate
`September 3,
`Reviewed by
`2004
`Jila H. Boal
`
`
`PhD.
`
`
`
`October 7, 2005,
`Reviewed by
`Review # 4
`Jila H. Boal
`
`PhD.
`
`
`October 9, 2005,
`
`Reviewed by
`
`
`Review # l
`Jila H. Boal
`
`
`Ph.D.
`
`
`December 12,
`Gurpreet Gill-
`
`
`Sangha,
`2001 and
`
`
`September 9,
`Ph.D.and
`
`
`'2005
`Donald Klein.
`
`
`PhD.
`
`
` Sufficient
`
`
`
`
`

`

`" fEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`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)
`
`B. Other Documents:
`
`
`
`
`Original IND
`
`Revia, Naltrexone
`
`Hydrochloride Tablet, 50 mg
`/
`Syringe, _’
`
`Syringe, __ ,__-._/
`i—
`/
`Needle. Hypodermic, "L. ‘
`
`'-
`Safety
`
`
`T
`
`I
`
`(\
`
`Needle
`
`
`
`
`18. STATUS:
`
`CONSULTS/
`' CMC
`RELATED
`REVIEWS .
`
`.
`
`_
`
`'
`REVIEWER
`
`Biometrics
`Not Consulted
`
`EES
`Acceptable
`August 26,
`Mark E Parmon
`
`2005
`
`
`
`
`
`
`
`
`Pharm/Tox
`
`Pending
`
`ClinicalPharm
`
`Acceptable provided that a mutually satisfactory
`agreement can be reached between the Agency and
`Alkermes regarding the
`a) The drug release specifications should be revised
`with addition of Day 14 and Day 28 drug release
`information.
`
`7
`
`1 1/21/2005
`.
`
`Mamata De,
`PhD.
`
`Srikanth C.
`Nallani, Ph.D.
`
`b) Conduct in vitro CYP inhibition studies using
`conventional substrates as the submitted data used
`tlorescent substrate(s) which tends to introduce
`nonspecificily in detection.
`c) Conduct in vitro studies in human hepatocytes to
`evaluate potential of naltrexone to induce CYP3A4
`
`and CYP1A2.
`
`LNC
`
`LNC recommended the following established
`name for Vivitrolf
`
`10/27/2005
`
`Dr. Guirag
`Poochikian, the
`
`Page7of219
`
`

`

`EMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`
`“Vivitrol (naltrexone for extended-release
`injectable suspension)”.
`The detail ofthe LNC recommendation for
`
`LNC chair
`
`the established name is captured in the
`review of the Container and Carton Labels in
`
`
`DFS
`
`Pending
`Validation of dissolution, assay and
`impurities test methods will be initiated by
`this reviewer after test methods are finalized.
`
`
`Jila H. Boal,
`PhD.
`
`,
`
`The first recommended name “Vivitrol” was not
`acceptable. The proprietary name “Vivitrol” was
`accepted by DMETS. With respect to package labels
`and drug product package inserts, while most ofthe
`DMETS recommendations were accepted by the
`chemistry discipline, a few comments were not
`considered in the interest of maintaining the clarity
`and prominence of the labels. For example, the
`contents ofthe diluents don’t need to be listed in the
`
`.-——-
`to the side panel.
`See DMETS review in DFS.
`
`instead they could be moved
`
`July 31, 2005
`
`PA-C, Regulatory
`Review Officer
`Iris Masucci,
`PharmD, Labeling
`Reviewer
`
`
`
`
`As per this
`Acceptable, categorical
`Jila H. Boa],
`
`PhD.
`exclusion granted as per
`review
`
`
`
`.
`information Alkerm'es
`
`
`October 24,
`Stephen E.
`2005
`Langille, PhD.
`
`
`
`Methods
`Validation
`
`
`
`DDMAC
`
`EA
`
` Michelle Safarik,
`
`
`
`
`Microbiology
`
`Recommended for approval
`
`
`
`Page 8 onI9
`
`

`

`
`
`Chemistry Assessment Section
`
`The Chemistry Review for NDA 21-897
`
`The Executive Summary
`
`1.
`
`Recommendations
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`From the standpoint of Product quality CMC, NDA 21-897 is recommended for
`approval. An expiration period of 18 months may be granted based on the
`assessment ofthe stability data.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`The data provided in the NDA clearly indicate the correlation between in vitro
`drug release at Dav 7 ant
`
`s.
`
`///
`
`U
`
`Therefore, provide an agreement that percent crystallinity and the1n vitro drug
`release will be assessed f01 the first five commercial batches of V1v1trol and the
`
`ranges for the in vitro drug release will be tightened and a specification to limit
`percent crystallinity ofnaltrexone in the microspheres ”a
`Provide this information in a “changes-being—effected in 30 days”
`supplement following the approval ofthe NDA.
`
`The commercial batches could be released ifthe drug release acceptance criteria of
`A Day 7—Day 14 = —— 15 achieved with the provision that in~vitro drug
`release test should be carried up to day 30. If the batch fails the test at that time,
`then the batch will be recalled.
`
`II.
`
`Summary of Chemistry Assessments
`
`Introduction:
`
`Page90f2l9
`
`

`

` RY REVIEW TEM
`
`Chemistry Assessment Section
`
`The NDA was reviewed under priority review time clock. The entire submission is
`electronic and is provided in eCTDQ format. Several CMC issues were resolved during
`the course of this review; therefore this review is comprehensive and includes the
`assessment of CMC information from the original submission as well as from several
`subsequent submissions. Several comments pertaining to the carton andcontainer labels
`were generated by the CMC and DMETS disciplines and were conveyed to the applicant
`and were resolved. The proposed tradename Vivitrol was accepted by the medical division
`and DMET (see DMET’s consult reviews in BPS). The established name was revised
`from “naltrexone long acting injection” to “naltrexone for extended—release injectable
`suspension” in consultation with the Labeling and Nomenclature Committee.
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Drug Product:
`
`Vivitrol (Naltrexone for Extended-release lnjectable Suspension) are
`; parenteral microspheres. The drug product is composed of naltrexone
`incorporated into a biodegradable polymer matrix, polylactide ~co-glycolide (PLG). The
`manufacturing process is the proprietary Medisorb technology developed by Alkermes.
`The Medisorb drug delivery technology is designed to enable injectable extended-
`release formulations lasting days to months to be made for products normally given
`orally or by frequent injections.
`
`Drug Substance:
`
`Naltrexoneis an opioid antagonist andis widely used for opioid detoxification It15
`available as naltrexone hydrochloride salt as well as the ‘\—¥——\
`m 7 Fhe crystalline naltrexone base is anhydrous.
`
`:e
`
`The anhydrous base18 the most suitable form for formulation of naltrexone extended
`1elease microspheres, because it is low1n water content and1°
`_r—-——’~
`
`Distinctive properties of naltrexone base anhydrous are as follows:
`
`0 Appearance: Off—white to light tan powder.
`
`0 Melting point: 168—17000
`
`0
`0
`
`ca. 1.3
`Specific Gravity:
`Ionization Constant:
`Pkg. = 8.13
`
`0 Partition Coefficient: Log P oct = 1.92
`
`
`
`/\/, //
`
`Page 100f219
`
`

`

`FRY REVIEW TEMP "
`
`Chemistry Assessment Section
`
`/
`z
`/
`/
`/
`l
`/
`MN Mamifacture, characterization,
`control, reference standards, container-closure system, and stability of naltrexone base
`anhydrous drug substance, are provided via reference to ’7M
`
`DMF
`.‘he DMF was deemed adequate to support the NDA following review
`and resolution of critical CMC issues.
`
`B. Description of How the Drug Product is intended to be Used
`
`At the time of administration, Vivitrol microspheres are suspended in microsphere
`diluent to form Vivitrol suspension. The procedure for the preparation of the
`suspension is included in the “Directions for Use” section of the package insert. A
`copy ofthe direction is provided at the end ofthis review.
`
`Vivitrol suspension is stable for at least 2 hours at controlled room temperature (25
`i2°C/60% :l: 5% RH). Data from this study are summarized in section 3.2.P.8.l ofthe
`NDA submission and the submitted stability data are evaluated in the drug product
`stability section ofthis review. Note that regardless ofthe 2 hour stability data,
`“Directions for Use” in the package insert directs health practitioners to administer
`Vivitrol suspension immediately upon preparation.
`
`Proposed marketed product presentation:
`Vivitrol will be marketed as a kit containing:
`0 One 5 mL vial containing a 380 mg dose of Vivitrol microspheres packaged as a
`dry, free-flowing powder.
`
`0 One 5 mL vial containing 4 mL of sterile, aqueous diluent to prepare a suspension
`for injection.
`
`0 One 5 ml syringe
`
`0 One '/2 “ 20 gauge needle
`
`0 Two 11/2 “ 20 gauge needles with safety device
`The kit contains also a Patient Package lnsert, Physician Package lnsert and a
`“Directions for Use” leaflet.
`
`' C.- Basis for Approvability 0r Not-Approval Recommendation
`
`The main issue with the CMC assessment was the evaluation ofthe scale up of the
`manufacturing process from -- [0 - All pivotal clinical batches and primary
`stability batches were manufactured at "" scale and
`was proposed for
`commercialization. During the EOP2 and Pre—NDA meetings, the Agency commented
`on this scale up process and provided critical set of criteria to demonstrate the
`
`equivalence ofthe two processes for the NDA.
`_
`,
`,
`-_ Wm-“
`
`/
`'/
`
`\
`
`/
`/
`
`/
`/
`
`/
`/
`
`//
`
`Page ll of219
`
`

`

`
`1‘ RY REVIEW TEM \
`
`Chemistry Assessment Section
`
`//
`
`" ’
`
`'
`
`‘
`
`Evaluation ot‘the
`
`sterility and sterility test method and validation was consulted to the microbiology
`discipline. Adequacy ofthe microbial quality ofthe drug product was assessed by the
`microbiology reviewer Stephen E. Langille, Ph.D., who deemed it to be adequate for
`NDA approval (review in BPS).
`
`_ pilot scale process was
`The comparability ofthe / :ommercial process with the
`demonstrated and established based upon the assessment ofthe following data:
`
`0
`
`Same product components and composition
`
`Same manufacturing process (except for scale—related changes)
`0
`
`- Comparable in —process tests for
`~-~
`
`_
`
`I 1
`o Demonstration of comparable product quality attributes
`- Comparable dissolution curves as assessed using f2 methodology (tiered
`approach for a multi-phase release product)
`0 Comparable percent yield for microsphere formation and isolation in the”) vs
`¢—\ 3 scale v percent yield for the /— process vs
`I—‘yield for the ,_v,
`scale)
`
`4's
`‘3. __//—_~
`'
`'
`'
`'
`0 Comparable drug '
`scale (i.e
`,W l
`__—_,.__.
`
`Page 12 of219
`
`

`

`
`
`Chemistry Assessment Section
`
`/
`/
`/
`o Comparable microsphere particle size distribution for the —- vs ' ——' oatches
`
`The drug product specifications for release and stability monitoring have been adequate
`to ensure the product quality for its intended use. They include —--ff""’_
`
`uuvuvl nu. v1 luv-.u .......
`
`As discussed during the Pre—NDA meeting, data was provided showing uniform release
`ofthe drug and its degradation products from the microspheres to support a maximum
`daily dose of approximately 26 mg of naltrexone. This resulted in a qualification
`threshold of
`“=— for the impurities and degradation products in the drug product.
`'
`Three impurities, namely r W '
`'
`m were identified in the drug substance and the drug product and they
`did not exceed the qualification threshold. An.
`_w
`W ) was identified in
`naltrexone and is currently controlled with an interim limit of not more than
`\until
`March of 2007 when its limits would be tightened to not more than
`._/ iccording
`to the agreement with the DMF holder.
`
`Drug release from the microspheres is througl M
`
`/ This occurs in a controlled fashion in three phases, initial drug washout phase,
`hydration phase, and sustained release phase. The UV based spectrophotometric method
`for the drug release was cross-validated with stability-indicating HPLC method and was
`deemed acceptable for regulatory testing. Using a release medium of phosphate buffer at
`pH 7.4 and at 37°C, the acceptance criteria for durg release were accepted on interim
`basis to include the following.
`
`Real Time In-Vitro Release
`
`Day 1
`Day 7
`A Day 7—Day 14
`
`Proposed Release
`Criteria
`/
`
`/'
`
`/
`
`.
`
`Proposed Shelf life
`Criteria
`
`The data indicated variability in the drug release on day 7 for the batches used in the
`clinical studies. The data also showed the rate and amount of drug release both increased
`with increasing temperatures (eg. ‘2 40°C). Thus, there is the potential for rapid drug
`release and increased exposure in patients with elevated temperatures, e.g. during a
`fever. The data also showed that, on average. about 30% of naltrexone is released
`
`Page l3 of2l9
`
`

`

`
`
`Chemistry Assessment Section
`
`during the first 7-10 days. This corresponds to release of approximately 1 14 mg of
`naltrexone in the initial 1-2 weeks. The Applicant proposes an upper limit drug release
`specificication of about / This means that there is the potential for release of
`approximately -J mg of naltrexone in the first 2 weeks.
`In consultation with the
`medical reviewer, Dr. Kashoki it was determined that this was acceptable from safety
`considerations since patients have previously been dosed with similar doses of oral
`naltrexone, without significant adverse effects. However, since higher doses of
`naltrexone have previously been associated with adverse events, the drug release
`specifications should remain as ‘tight’ as can be reasonably achieved. Therefore,
`applicant is being asked to revise the specifications following accrual of additional
`manufacturing experience from five consecutive commercial batches.
`
`As discussed during the Pre—NDA meeting of February 2, 2005, the applicant provided
`the in—vitro drug release data over 30-day period as well as projected cumulative drug
`release over 30-day period based on calculations from day-l4 release data. Linear
`regression analysis of cumulative release vs. time over this interval for the "_ and the
`~: batches yielded slopes ranging from
`/“ per day with model fit (R2)
`values of 0.912 to 0.999. Accordingly, the portion of the curve from Day 7 to Day 14 is
`considered indicative of the entire drug release phase from day 14 to the end i.e., day 30.
`
`The amount of drug released between Day 7 and Day 14 from the '
`GMP lots and the'
`\— Jevelopment/comparability batches ranged from ‘ to
`—’ with a mean of 18.0% i 2.4% SD.
`
`Based on the above arguments, it_will be conceivably safe to allow release ofthe
`commercial batches ifthe drug release acceptance criteria ofA Day 7—Day 14 = -/'
`"'
`is achieved with the provision that in—vitro drug release testing be continued up to
`day 30.
`
`polymer is supported by the DMF # 8481, which
`The CMC of Medisorb 75:25 —'
`was deemed adequate following the review of DMF amendment. The CMC information
`for the diluent is supported by DMF 14028, which is adequate to support the NDA.
`Adequate data is provided on container closure integrity to support the proposed
`container closure systems. The primary packaging components are supported through
`several DMFs and these DMFs were found adequate (see the section on the drug product
`container closure, in this review).
`
`Commercial drug product vials consists of5 mL, USP Type 1, colorless glass vial, 20
`mm ~—/
`gray" W”
`.‘ubber stopper, 20 mm
`aluminum
`_~%V-;eal with flip off cap. In Support ofthe proposed
`expiration dating period, applicant provided 12 months stability data for three batches of
`380 mg strength at ~— scale, 18 months stability data for three batches of 190 mg
`strength at fscale, and 3 months of stability data for three batches of380 mg strength
`at proposed
`._.. commercial scale. Applicant’s proposed expiration dating period of
`' —-'
`is not supported by these data. However, 18 months may be granted for the
`product stored as dry microspheres in the commercial vials at refrigeration (2—80C). The
`
`Page l40f219
`
`

`

`
`,
`flIRY REVIEW TE ,_
`
`Chemistry Assessment Section
`
`drug product was also shown to be stable at controlled room temperature (25 °C :l: 2°C/
`60% i 5% RH) for up to 4 weeks. However, the reconstituted microspheres in the
`diluent were shown to