CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER:
`22511Orig1s000
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`CHEMISTRY REVIEW(S)
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`CMC REVIEW
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`NDA 22-511
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`Vimovo
`(naproxen and esomeprazole magnesium) delayed release tablets
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`375 mg/20 mg* and 500 mg/20 mg*
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` *Each tablet contains 22.3 mg esomeprazole
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`magnesium, equivalent to 20 mg esomeprazole.
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`Pozen Inc.
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`
`Rajiv Agarwal
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`Review Chemist
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`
`Office of New Drug Quality Assessment
`Division of Pre-Marketing Assessment II
`Branch III
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`CMC REVIEW OF NDA 22-511
`For the Division of Gastroenterology Products (HFD-180)
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`CMC REVIEW OF NDA 22-511
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`Table of Contents
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`Table of Contents .....................................................................................................2
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`CMC Review Data Sheet.........................................................................................4
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`The Executive Summary .........................................................................................9
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`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 CMC 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........................................................ 11
`C. Basis for Approvability or Not-Approval Recommendation......................................................... 11
`III. Administrative.........................................................................................................................12
`CMC Assessment................................................................................................... 13
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data.......13
`S DRUG SUBSTANCE.................................................................................................................... 13
`S.1
`General Information........................................................................................................................13
`S.2
`Manufacture ....................................................................................................................................15
`S.3
`Characterization ..............................................................................................................................16
`S.4
`Control of Drug Substance..............................................................................................................16
`S.5
`Reference Standards or Materials ...................................................................................................17
`S.6
`Container Closure System...............................................................................................................17
`S.7
`Stability...........................................................................................................................................18
`P DRUG PRODUCT ........................................................................................................................ 18
`P.1
`Description and Composition of the Drug Product .........................................................................18
`P.2
`Pharmaceutical Development..........................................................................................................23
`P.3
`Manufacture ....................................................................................................................................32
`P.4
`Control of Excipients ......................................................................................................................38
`P.5
`Control of Drug Product .................................................................................................................39
`P.6
`Reference Standards or Materials ...................................................................................................57
`P.7
`Container Closure System...............................................................................................................58
`P.8
`Stability...........................................................................................................................................60
` APPENDICES .............................................................................................................................. 67
`A.1
`Facilities and Equipment (biotech only) .........................................................................................67
`A.2
`Adventitious Agents Safety Evaluation ..........................................................................................67
`A.3
`Novel Excipients.............................................................................................................................67
`R REGIONAL INFORMATION ..................................................................................................... 68
`
`A
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`CMC REVIEW OF NDA 22-511
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`R1 Executed Batch Records ......................................................................................................................68
`R2 Comparability Protocols ......................................................................................................................68
`R3 Methods Validation Package ...............................................................................................................68
`A. Labeling & Package Insert............................................................................................................. 69
`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................. 76
`III. List Of Deficiencies:................................................................................................................76
`The following deficiencies were communicated to the applicant on 16-MAR-2010 and
`satisfactorily resolved via amendment dated 25-MAR-2010. .......................................................77
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`Page 3 of 80
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`1. NDA 22-511
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`2. REVIEW #: 1
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`3. REVIEW DATE: 07-APR-2010
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`4. REVIEWER: Rajiv Agarwal
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`5. PREVIOUS DOCUMENTS: None
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`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Document Date
`30-JUN-2009
`19-NOV-2009
`30-NOV-2009
` 04-MAR-2010
` 25-MAR-2010
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`Submission(s) Reviewed
`Original Submission
`Amendment
`Amendment
` Amendment
` Amendment
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`7. NAME & ADDRESS OF APPLICANT:
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`
`Name:
`Address:
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`CMC Review Data Sheet
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`Pozen Inc.
`1414 Raleigh Road, Suite 400
`Chapel Hill, NC 27517
`Paul A. Ossi
`919-913-1030
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`Representative:
`Telephone:
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`8. DRUG PRODUCT NAME/CODE/TYPE:
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`a) Proprietary Name:
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`b) Non-Proprietary Name (USAN):
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`c) Code Name/# (ONDQA only):
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`d) Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type:
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`• Submission Priority:
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`Vimovo
`naproxen and esomeprazole
`magnesium
`PN 400
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`4
`S
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`Page 4 of 80
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`Tablets
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`Each tablet contains naproxen
`(375 mg or 500 mg) and
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`esomeprazole magnesium
`(22.3 mg equivalent to 20 mg
`of esomeprazole)
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
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`10. PHARMACOL. CATEGORY: Treatment of the signs and symptoms of
`osteoarthritis, rheumatoid and ankylosing spondylitis in patients at risk for developing NSAID-
`associated gastric ulcers.
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`11. DOSAGE FORM:
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`12. STRENGTH/POTENCY:
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`Oral
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`13. ROUTE OF ADMINISTRATION:
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`14. Rx/OTC DISPENSED: √ Rx ___OTC
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`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
` SPOTS product – Form Completed0y
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` √ Not a SPOTS product
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
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` Naproxen:
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`Chemical name:
`Molecular formula:
`Molecular weight:
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`(S)-6-methoxy-α-methyl-2-napthaleneacetic acid
`C14H14O3
`230.26
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`Esomeprazole Magnesium:
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`Chemical name:
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`Molecular formula:
`Molecular weight:
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`RELATED/SUPPORTING DOCUMENTS:
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`C34H36N6O6S2Mg. 3H2O
`767.2 g/mol
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`A. DMFs:
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`DMF # TYPE
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`HOLDER
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`ITEM REFERENCED CO
`DE1 STATUS2
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`II
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`III
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`III
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`III
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`III
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`III
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`III
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`III
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`3 Adequate
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`3 Adequate
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`3 Adequate
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`3 Adequate
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`3 Adequate
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`3 Adequate
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`1 Adequate
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`1 Adequate
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`3 Adequate
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`1 Adequate
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`Page 6 of 80
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`bis (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-
`pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium
`trihydrate
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`COMMENTS
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`19-DEC-2000
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`DATE
`REVIEW
`COMPLETED
`20-JUN-2005 Dr. R. D. Costa for
`ANDA 77-339
`Dr. Donald Klein
`for DMF Strike
`Force
`01-AUG-2005 Dr. Craig Bertha for
`NDA
`
`13-SEP-2002 Dr. Prasad Peri for
`NDA 20-829
`13-JUN-2002 Dr. Jila Boal for
`NDA 21-400
`Dr. Ramesh Sood
`for NDA 20-334
`(S002)
`Reviewed by Rajiv
`Agarwal for NDA
`22-511.
`Reviewed by Rajiv
`Agarwal for NDA
`22-511.
`o2-AUG-2007 Dr. Craig Berths for
`NDA 22-152
`Reviewed by Rajiv
`Agarwal for NDA
`22-511.
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`20-DEC-2003
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`24-MAR-2010
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`24-MAR-2010
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`24-MAR-2010
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`III
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`III
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`III
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`III
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`III
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`1 Adequate
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`23-MAR-2010
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`3 Adequate
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`7-MAR-2008
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`1 Adequate
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`24-MAR-2010
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`3 Adequate
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`1 Adequate
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`3 Adequate
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`1 Adequate
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`24-MAR-2010
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`8-NOV-1999
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`7-APR-1997 George T. Chen for
`NDA 19-462 S-19
`Reviewed by Rajiv
`Agarwal for NDA
`22-511
`Dr. Don Klein for
`NDA 20-990
`Reviewed by Rajiv
`Agarwal for NDA
`22-511
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`24-MAR-2010
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`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
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`Page 7 of 80
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`Dr. Don Klein for
`DMF strike force on
`9-FEB-2001
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`Dr. Bogdan Kurtyka
`for NDA
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`Dr. Bogdan Kurtyka
`for NDA
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`Reviewed by Rajiv
`Agarwal for NDA
`22-511
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`Dr. Bogdan Kurtyka
`for NDA 22-262
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`Reviewed by Rajiv
`Agarwal for NDA
`22-511
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
`
`05F92577
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` 3
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`Adequate
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`9-SEP-2008
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`Adequate
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`12-MAR-2009
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`Adequate
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`12-MAR-2009
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`(b) (4)
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`6 – DMF not available
`7 – Other (explain under "Comments")
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` 2
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` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
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`B. Other Documents:
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`DOCUMENT
`IND
`NDA
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`APPLICATION NUMBER
`76,301;
`
`21-153
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` *
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` It is recommended that the dissolution testing for the naproxen component
`of the Vimovo tablets, the conventional dissolution methodology for delayed
`release product, i.e., in the acid stage (pre-exposure) followed by the buffer stage
`on the same tablet, be performed post approval (amendment dated 4-MAR-2010,
`refer to Biopharmaceutical review dated 9-MAR-2010).
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`Page 8 of 80
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`18. STATUS:
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`ONDQA:
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`CONSULTS/ CMC
`RELATED REVIEWS RECOMMENDATION
`EES
`Acceptable
`Bio-Pharmaceutics
`Adequate*
`Methods Validation
`N/A, according to the
`current ONDQA policy
`Categorical Exclusion
`granted
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`EA
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`DESCRIPTION
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`Esomeprazole magnesium (drug
`substance is also reviewed here)
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`REVIEWER
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`DATE
`24-MAR-2010 OC
`9-MAR-2010
`Tien Mien Chen
`07-APR-2010
`Rajiv Agarwal
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`22-DEC-2009
`
`Raanan Bloom, OPS
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`(b) (4)
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
`The CMC Review for NDA 22-511
`
`The Executive Summary
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` I. Recommendations
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`A. Recommendation and Conclusion on Approvability
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`This NDA has provided sufficient CMC information to assure the identity, strength,
`purity, and quality of the drug product.
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` The final “Acceptable” recommendation from the Office of Compliance is received on
`24-MAR-2010 (Attachment-1).
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`The labeling information on immediate container and carton labels is adequate.
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`Therefore, this NDA is recommended for APPROVAL form the CMC perspective.
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`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
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`As a Phase 4 commitment, within one year post approval, submit new dissolution data
`on the testing of naproxen in Vimovo FDC tablets using the Agency’s recommended
`USP dissolution methodology for enteric coated (i.e., delayed release) drug products
`(refer to Biopharmaceutical review dated 9-MAR- 2010). The applicant has committed
`to the proposal via amendment dated 4-MAR-2010.
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`II. Summary of CMC Assessments
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`A. Description of the Drug Product(s) and Drug Substance(s)
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`(1) Drug Substance
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`Information regarding the drug substance, esomeprazole magnesium
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` was originally approved in NDA 21-153 for NEXIUM
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`, a Delayed-
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`Release Capsules. This drug substance is manufactured in France. A letter
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`authorizing access to NDA 21-153 is provided.
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`Similarly, the Chemistry, Manufacturing, and Control information on the
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` Naproxen
` drug substance is provided in the cross referenced DMF
` from
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`. A letter authorizing an access to the
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`DMF is provided in the submission.
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`CMC Review #1
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`Page 9 of 80
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`(2) Drug Product
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`PN 400 Tablets have been designed as a single combination tablet of two distinct
`formulations, an inner enteric coated (delayed release) component of naproxen
`containing either 375 mg or 500 mg of naproxen and an outer immediate release
`film coat of esomeprazole magnesium containing 20 mg of esomeprazole (present
`as 22.3 mg of esomeprazole magnesium). The tablet is designed to release the
`active ingredients in a coordinated, yet independent, fashion.
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`Naproxen is an analgesic, while esomeprazole magnesium, a proton pump
`inhibitor, is included in the formula to reduce gastric acid secretion and
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`subsequently minimize gastric irritation, which can result from naproxen
`administration.
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`Based on the qualitative and quantitative formulation, the two strengths of PN 400
`are dose proportional. The 375 mg and 500 mg naproxen core strength is based on
`a common formulation and hence is proportionally similar in
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`terms of naproxen and all inactive ingredients.
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`Page 10 of 80
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`(b) (4)
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`(b) (4)
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`
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`Esomeprazole magnesium is mixed with other ingredients to form an
`
`
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`The qualitative and quantitative composition of Phase 1, Phase 3, and primary
`stability (identical to commercial) batches are summarized in the submission. PN
`400 (375 mg/20 mg) batches were not used in any Phase 3 clinical trials.
`However, one primary stability batch of PN 400 (375 mg/20 mg) was used in a
`naproxen bioequivalence study, PN 400-105.
`
`This Delayed Release Tablet formulation utilizes conventional pharmaceutical
`ingredients and manufacturing processes that are well established for use in solid
`oral dosage forms. PN 400 tablets are packaged into 60 counts HDPE bottles with
`child resistant cap for commercial use and in 500 counts HDPE bottles and
`aluminum blisters (10 counts) for hospital use. Both 500 tablets bottles and
`blisters are not child resistant. Since these packaging configurations are for
`hospital use, and, therefore, they are exempted from 16 CFR 1700 requirements.
`Physician samples are available in 6-count HDPE bottles with child resistant cap.
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`An 24-month of expiration dating period is requested and it is granted based on
`the submitted stability data.
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`B. Description of How the Drug Product is Intended to be Used
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`
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`
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`The dosage is one tablet twice daily. The tablets should be swallowed whole with
`liquid. They should not be split, chewed or crushed. Vimovo should be taken at
`least 30 minutes before meals.
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`C. Basis for Approvability or Not-Approval Recommendation
`
`
`Satisfactory responses to the CMC information requests (claim for categorical
`exclusion dated 11-APR-2009 and labeling) were received on 19-NOV-2009 and
`25-MAR-2010, respectively.
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`CMC Review #1
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`Page 11 of 80
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`CMC REVIEW OF NDA 22-511
`Executive Summary Section
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`This NDA now is deemed to have provided adequate information on the raw
`material controls, manufacturing process, specifications for assuring consistent
`quality of the drug substance and drug product, and container/closure system. It
`also provided sufficient stability data to assure identity, strength, purity and
`quality of the drug product during the expiration dating period..
`
`
`III. Administrative
`A. Reviewer’s Signature:
`
`
`
`
`
`(See appended electronic signature page)
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`Rajiv Agarwal, Ph.D; Ph.D
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`B. Endorsement Block:
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`
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`(See appended electronic signature page)
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`Moo-Jhong Rhee, Ph.D, Branch Chief, Branch III, ONDQA
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`
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`C. CC Block: entered electronically in DARRTS
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`CMC Review #1
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`Page 12 of 80
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`68 pages withheld in full immediately after this page as (b)(4) CCI/TS.
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`

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`Application
`Type/Number
`--------------------
`NDA-22511
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`POZEN INC
`
`------------------------------------------
`PN 400
`NAPROXEN/ESOMEPRAZOLE
`MAGNESIUM
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RAJIV AGARWAL
`04/07/2010
`
`MOO JHONG RHEE
`04/07/2010
`Chief, Branch III
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`