CENTER FOR DRUG EVALUATION AND ‘
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`21-926
`
`CHEMISTRY REVIEW} S)
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`TO:
`
`FROM:
`
`SUBJECT:
`
`June 6, 2006
`
`NDA 21-926
`
`Martha R. Heimann Ph.D.
`
`Pharmaceutical Assessment Lead, ONDQA/DPA-l/Branch 1
`
`Overall Compliance and CMC Recommendations:
`NDA 21-926, Trexima (sumatriptan succinate and naproxen
`sodium) Tablets
`
`The CDER Office of Compliance (0C) issued an overall ‘Acceptable’ recommendation for
`NDA 21-926 on June 7, 2006. A copy of the establishment evaluation report is attached. Dr.
`Chaggan Tele's review for this NDA, dated May 19, 2006, recommends approval of the
`application, pending an acceptable OC recommendation. Based on Dr. Tele’s review, and the
`Compliance recommendation, the Office of New Drug Quality Assessment recommends
`approval of NDA 21-926.
`
`Appears This Way
`On Original
`
`

`

`NDA 21 -926 Overall Compliance
`ATTACHMENT
`.
`
`07—JUN—2006
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Page 1 of 6
`
`Application:
`Stamp:
`Regulatory Due:
`Applicant:
`POZEN
`1414 RALEIGH RD STE 400
`CHAPEL HILL, NC
`27517
`
`21926/000
`NDA
`08—AUG—2005
`08—JUN—2006
`
`Priority:
`Org Code:
`
`120
`
`Action Goal:
`District Goal:
`Brand Name:
`Estab. Name:
`Generic Name:
`
`O9—APR—2006
`TREXIMA
`TABS(SUMATRIPTAN/NAPROXE
`SUMATRITAM/NAPROXEN
`
`Dosage Form:
`Strength:
`
`(TABLET)
`85 MG/SOOMG
`
`Application Comment:
`
`I AM INTERESTED IN ATTENDING PREAPPROVAL INSPECTION (PAI) OF THE
`DRUG PRODUCT MANUFACTURING FACILITY.
`(on 26—AUG-2005 by C. TELE ()
`301—796-1762)
`
`FDA Contacts:
`
`L. CHEN
`C. TELE
`M. HEIMANN
`
`(HFD—lZO)
`
`301—796—1056
`301—796—1762
`301—796—1678
`
`, Project Manager
`, Review Chemist
`, Team Leader
`
`Overall Recommendation:
`
`~
`
`ACCEPTABLE on 07—JUN—2006by J. D AMBROGIO(HFD—322)301—827—
`9049
`
`Establishment:
`
`CFN
`
`-
`
`FEI
`
`-
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`
`gull-a
`
`Profile:
`
`CSN
`
`'
`
`'
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`‘ —~
`OF THE API
`IN COMBINATION DRUG PRODUCT).
`301-796-1762)
`Date
`
`Type
`
`Insp. Date
`
`(ONE
`.
`(on 26-AUG-2005 by C. TELE ()
`
`Decision & Reason
`
`Creator
`
`TELEC
`DAMBROGIOJ
`
`SUBMITTED TO OC
`OC RECOMMENDATION
`
`26—AUG-2005
`29—AUG-2005
`
`ACCEPTABLE
`BASED ON PROFILE
`
`Establishment:
`
`CFN
`
`’
`
`FEI
`
`-
`
`DMF NO:
`
`AADA:
`
`Responsibilities:
`
`Cl-
`
`Profile:
`
`TCM
`
`OAI Status:
`
`NONE
`
`

`

`O7—JUN—2006
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Page 2 of 6
`
`NDA 21-926 Overall Compliance
`A TTA CHMEN T
`
`Estab. Comment:
`
`Milestone Name
`
`#
`TELE () 301—796—1762)
`Date
`Type
`
`Insp. Date
`
`(on 26—AUG-2005 by C.
`'
`Decision & Reason
`
`Creator
`
`SUBMITTED TO OC
`
`26-AUG—2005
`
`OC RECOMMENDATION
`
`29—AUG—2005
`
`‘
`
`ACCEPTABLE
`BASED ON PROFILE
`
`TELEC
`
`DAMBROGIOJ
`
`Establishment:
`
`CFN
`
`ll.
`
`FEI
`
`II.
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`1..-
`
`Profile:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`‘
`
`_.
`.
`Date
`
`(on Zb-AUG-ZUUB by C. TELE () 301-796—1762)
`Type
`Insp. Date
`Decision & Reason
`
`SUBMITTED TO OC
`OC RECOMMENDATION
`
`26—AUG—2005
`29—AUG—2005
`
`'
`
`‘
`ACCEPTABLE
`BASED ON PROFILE
`
`I-
`
`Creator
`
`TELEC
`DAMBROGIOJ
`
`Establishment:
`
`CFN
`
`-7 ,
`
`FEI
`
`-
`
`DMF Noz'
`Responsibilities:
`
`III
`
`AADA:
`
`Profile:
`
`TCM
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`III
`TELE () 301—796—1762)
`Date
`Type
`
`SUBMITTED TO OC
`SUBMITTED TO DO
`DO RECOMMENDATION
`
`26—AUG-2005
`29—AUG-2005
`O7—SEP-2005
`
`10D
`
`GMP INSPECTION COMPLETED 7/27/05, CLASSIFIED NAI
`OC RECOMMENDATION
`O7—SEP-2005
`
`Insp. Date
`
`Decision & Reason
`
`Creator
`
`(on 26—AUG—2005 by C.
`
`ACCEPTABLE
`BASED ON FILE REVIEW
`
`TELEC
`DAMBROGIOJ
`MSPATARO
`
`DAMBROGIOJ
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`

`

`07-JUN-2006
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Page 3 of 6
`
`NDA 21-926 Overall Compliance
`ATTACHMENT
`
`Establishment:
`
`9610411
`CFN
`GLAXO OPERATIONS UK LTD
`PRIORITY STREET
`
`WARE, HERTFORDSHIRE, UK
`
`FEI
`
`1000291018
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`DRUG SUBSTANCE RELEASE TESTER
`FINISHED DOSAGE MANUFACTURER
`
`Profile:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`RELEASE TESTER OF NAPROXEN DRUG SUBSTANCE MINUS ORGANIC VOLATILE
`IMPURITIES. MANUFACTURE OF DRUG PRODUCT, TREXIMA TABLETS.
`(on 26-AUG-
`2005 by C. TELE () 301—796-1762)
`Date
`Type
`Insp. Date
`
`Decision & Reason
`
`Creator
`
`26—AUG—2005
`SUBMITTED TO GO
`29—AUG—2005
`SUBMITTED TO DO
`ASSIGNED INSPECTION T 30-AUG—2005
`INSPECTION SCHEDULED
`09—MAY—2006
`INSPECTION PERFORMED
`05—JUN—2006
`DO RECOMMENDATION
`07—JUN—2006
`
`GMP
`GMP
`
`OS—JUN—2006
`OS—JUN—2006
`.
`
`”
`
`TELEC
`DAMBROGIOJ
`ADAMSS
`ADAMSS
`ADAMSS
`ADAMSS
`
`ACCEPTABLE
`INSPECTION
`'
`BASED ON INVESTIGATOR'S RECOMMENDATION. NO 483 ISSUED. AWAITING EIR.
`OC RECOMMENDATION
`DAMBROGIOJ
`07-JUN—2006
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`Estab. Comment:
`
`Milestone Name
`
`RELEASE TESTER OF NAPROXEN SODIUM DRUG SUBSTANCE MINUS ORGANIC VOLATILE
`IMPURITIES. MANUFACTURER OF DRUG PRDUCT, TREXIMA TABLETS.
`(on 26—AUG—
`2005 by C. TELE () 301-796-1762)
`Date
`Type
`Insp. Date
`
`Decision & Reason
`
`Creator
`
`26—AUG—2005
`SUBMITTED TO OC
`29—AUG—2005
`SUBMITTED TO DO
`ASSIGNED INSPECTION T 30—AUG—2005
`INSPECTION SCHEDULED
`09—MAY—2006
`INSPECTION PERFORMED
`05—JUN-2006
`DO RECOMMENDATION
`07-JUN—2006
`
`GMP
`GMP
`
`05-JUN-2006
`O5—JUN—2006
`
`4
`
`ACCEPTABLE
`INSPECTION
`BASED ON INVESTIGATOR'S RECOMMENDATION. NO 483 ISSUED. AWAITING EIR.
`DAMBROGIOJ
`OC RECOMMENDATION
`07—JUN-2006
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`TELEC
`DAMBROGIOJ
`ADAMSS
`ADAMSS
`ADAMSS
`ADAMSS
`
`Establishment:
`
`9611205
`CFN
`GLAXO WELLCOME
`2262
`
`FEI
`
`3002807079
`
`

`

`O7-JUN—2006
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Page 4 of 6
`
`NDA 21-926 Overall Compliance
`ATTACHMENT
`
`JURONG,
`
`, SN
`
`DMF NO:
`
`Responsibilities:
`
`Profile:
`
`CSN
`
`AADA:
`DRUG SUBSTANCE MANUFACTURER
`DRUG SUBSTANCE RELEASE TESTER
`OAI Status:
`
`NONE
`
`MANUFACTURER AND QUALITY CONTROL OF SUMATRIPTAN SUCCINATE DRUG
`SUBSTANCE (ONE OF THE API
`IN COMBINATION DRUG PRODUCT).
`(on 26-AUG—2005
`by C. TELE () 301—796-1762)
`Date
`Type
`Insp. Date
`
`Decision & Reason
`
`Creator
`
`26—AUG—2005
`29—AUG—2005
`30-AUG—2005
`
`GMP
`
`OC RECOMMENDATION
`
`31—AUG—2005
`
`ACCEPTABLE
`BASED ON FILE REVIEW
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`TELEC
`DAMBROGIOJ
`ADAMSS
`
`ADAMSS
`
`Estab. Comment:
`
`Milestone Name
`
`SUBMITTED TO OC
`SUBMITTED TO D0
`D0 RECOMMENDATION
`
`Profile:
`
`Estab. Comment:
`
`Milestone Name
`
`SUBMITTED TO OC
`SUBMITTED TO D0
`D0 RECOMMENDATION
`
`MANUFACTURE AND QUALITY CONTROL OF SUMATRIPTAN SUCCINATE DRUG SUBSTANCE
`(API
`IN COMBINATION DRUG PRODUCT).
`(on 26-AUG—2005 by C. TELE () 301-
`796-1762)
`Date
`
`Decision & Reason
`
`Creator
`
`Type
`
`Insp. Date
`
`26—AUG—2005
`29—AUG—2005
`30—AUG—2005
`
`GMP
`
`.
`
`OC RECOMMENDATION
`
`31-AUG-2005
`
`ACCEPTABLE
`BASED ON FILE REVIEW
`ACCEPTABLE
`DISTRICT RECOMMENDATION
`
`TELEC
`DAMBROGIOJ
`ADAMSS
`.
`ADAMSS
`
`Establishment:
`
`9610421
`CFN
`GLAXO WELLCOME LTD
`DL128DT
`
`BARNARD CASTLE,
`
`, UK
`
`FEI
`
`3002807078
`
`DMF No:
`
`Responsibilities:
`
`AADA:
`FINISHED DOSAGE STABILITY TESTER
`
`Profile:
`
`CTL
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`TESTER OF THE NDA STABILITY BATCHES, STARTING AT THE 18 MONTH TIME
`POINT.
`(on 26-AUG-2005 by C. TELE () 301-796-1762)
`Date
`Type
`Insp. Date
`Decision & Reason
`
`Creator
`
`SUBMITTED TO OC
`
`26-AUG—2005
`
`TELEC
`
`

`

`O7—JUN—2006
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Page 5 of 6
`
`NDA 21-926 Overall Compliance
`ATTACHMENT
`
`OC RECOMMENDATION
`
`29—AUG-2005
`
`ACCEPTABLE
`BASED ON PROFILE
`
`DAMBROGIOJ
`
`_________.____________...._.__._.___._____.__..____.__...____-__________________...______.__.______________._
`
`Establishment:
`
`.1033964
`CFN
`GLAXOSMITHKLINE INC
`1011 NORTH ARENDELL AVE
`ZEBULON, NC
`27597
`
`FEI
`
`1033964
`
`DMF No:
`
`Responsibilities:
`
`Profile:
`
`FINISHED DOSAGE PACKAGER
`FINISHED DOSAGE STABILITY TESTER
`.
`OAI Status:
`
`CTL
`
`NONE
`
`AADA:
`
`EMilestone Name
`
`Date
`
`Type
`
`Insp. Date
`
`Decision & Reason
`
`Creator
`
`SUBMITTED TO OC
`OC RECOMMENDATION
`
`26-AUG—2005
`29—AUG—2005
`
`ACCEPTABLE
`BASED ON PROFILE
`
`TELEC
`DAMBROGIOJ
`
`Profile
`
`TCM
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`PRIMARY AND SECONDARY PACKAGING, QUALITY CONTROL AND STABILITY OF THE
`DRUG PRODUCT POST-APPROVAL.
`(on 26—AUG-2005 by C. TELE () 301-796-1762)
`Date
`Type
`Insp. Date
`Decision & Reason
`Creator
`
`SUBMITTED TO OC
`OC RECOMMENDATION
`
`26-AUG-2005
`29—AUG—2005
`
`ACCEPTABLE
`BASED ON PROFILE
`
`TELEC
`DAMBROGIOJ
`
`Establishment:
`
`1035048
`CEN
`GLAXOSMITHKLINE INC
`5 MOORE DRIVE
`
`DURHAM, NC
`
`27709
`
`FEI
`
`1035048
`
`DMF No:
`
`AADA:
`
`Responsibilities:
`
`FINISHED DOSAGE STABILITY TESTER
`
`Profile:
`
`TCM
`
`OAI Status:
`
`NONE
`
`Estab. Comment:
`
`Milestone Name
`
`Type
`
`Insp. Date
`
`INITIAL THROUGH 12 MONTH TIME POINT ON NDA STABILITY BATCHES AND ALL
`TESTING ON MODIFIED DESICCANT BATCHES.
`(on 26—AUG-2005 by C. TELE ()
`301-796—1762)
`Date
`
`Decision & Reason
`
`Creator
`
`SUBMITTED TO OC
`
`26—AUG—2005
`
`TELEC
`
`

`

`O7—JUN—2006
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`DETAIL REPORT
`
`Page 6 of 6
`
`NDA 21 -926 Overall Compliance
`ATTACHMENT
`
`0C RECOMMENDATION
`
`29—AUG-2005
`
`ACCEPTABLE
`BASED ON PROFILE
`
`DAMBROGIOJ
`
`Appears This Way
`0n Original
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Martha Heimann
`
`6/8/2006 09:54:48 AM
`CHEMIST
`
`

`

` :VHEMISTRY REVIE
`
`NDA 21-926
`
`TreximaTM
`
`(sumatriptan succinate/naproxen sodium Tablets)
`
`Pozen® Inc.
`
`Division of Neuropharmacological Drug Products
`
`Chhagan G. Tele, Ph.D.
`Division of Pre -Marketing Assessment I
`Office of New Drug Quality Assessment
`
`Review of Chemistry, Manufacturing, and Controls
`
`

`

`,HEMISTRY REVIEW
`
`Table of Contents
`
`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS--------- 1
`
`Table of Contents D.I000...OOOOCOOOOOOOIOOOOOOIOO000‘...OCOIIOOOOOOCOIOOOOOOOOOOOO 00.00.000.000.0000IOOOIOOIOOIOOOOIOOOZ
`
`Chemistry Review Data Sheet..........
`
`...........
`
`.................3
`
`The Executive Summary
`
`.........
`
`........7
`
`I. Recommendations .................................................................................................................................... 7
`
`A. Recommendation and Conclusion on Approvability ......................................'.................................. 7
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable........................................................................... 7
`
`II. Summary of Chemistry Assessments ...................................................................................................... 7
`
`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 7
`B. Description of How the Drug Product is Intended to be Used.......................................................... 9
`C. Basis for Approvability or Not-Approval Recommendation .......................................................... 10
`
`III. Administrative ...................................................................................................................................... 10
`
`A. Reviewer’s Signature...................................................................................................................... 10
`B. Endorsement Block ......................................................................................................................... 10
`C. CCBlock ............... 10
`
`Chemistry Assessment.....................
`
`........
`
`...... ...11
`
`1. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data ...................... 11
`
`S DRUG SUBSTANCE ................................................................................................................... 11
`P DRUGPRODUCT ........22
`A APPENDICES ............................................................................................................................ 117
`R REGIONAL INFORMATION ................................................................................................... 117
`
`II. Review OF Common Technical Document—Quality (Ctd-Q) Module 1 .............................................. 118
`
`A. Labeling & Package Insert ........................................................................................................... 118
`B. Environmental Assessment Or Claim Of Categorical Exclusion ................................................. 123
`
`III. List Of Deficiencies To Be Communicated ....................................................................................... 123
`
`

`

`
`7 IFIEMISTRY REVIE '
`
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA 21-926
`
`2. REVIEW #: 1
`
`3. REVIEW DATE: May 19, 2006
`
`4. REVIEWER: Chhagan G. Tele, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Document Date
`
`
`
`Submission 5 Reviewed
`
`
`
`
`Original
`Amendment (N~000-BC), #006
`
`19-APR-2006
`-000-BC , #008
`
`
`05-AUG-2005
`
`
`22-FEB—2006 Amendment
`
`
`
`
`
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Representative:
`
`1414 Raleigh Road, Suite 400, Chapel Hill, NC 27517
`
`Paul Ossi, Senior Vice President, Regulatory and Project Management
`
`Pozen Inc.
`
`
`
`
`
`.
`
`3
`
`
`
`
`
`Telephone:
`
`(919) 913-1048
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: TreximaTM
`b) Non-Proprietary Name (USAN): sumatriptan succinate/naproxen sodium
`c) Code Name/# (ONDC only): MT 400
`(1) Chem. Type/Submission Priority (ONDC only):
`
`0 Chem. Type: 4
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(2); The RLD are Imitrex® (sumatriptan succinate)
`Injection, 12 mg/mL, (GSK NDA 20-080, approved 28-DEC-92 for migraine); lmitrex® Tablets 25
`
`Page 3 of 123
`
`

`

` .HEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`mg, 50 mg, and 100 mg strengths (GSK NDA 20-132, approved 01-JUN-95 for migraine); Imitrex®
`Nasal Spray 5 mg, 10 mg, and 20 mg strengths (GSK NDA 20-626, approved 26-AUG-97 for
`migraine); and Anaprox® (naproxen sodium) Tablets, 275 mg and 550 mg strengths (Roche NDA 18-
`164, approved 04-SEP-80 for arthritis).
`
`10.
`
`PHARMACOL. CATEGORY: For the acute treatment of migraine.
`
`ll.
`
`DOSAGE FORM: Tablets
`
`12.
`
`STRENGTH/POTENCY: Each Tablet contains sumatriptan succinate (85 mg as sumatriptan) and
`naproxen sodium (500 mg)
`
`13.
`
`ROUTE OF ADMINISTRATION: Oral
`
`14.
`
`Rx/OTC DISPENSED:
`
`X Rx
`
`OTC
`
`15.
`
`SPOTS [SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`SPOTS product - Form Completed
`X Not a SPOTS product
`
`16.
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR
`WEIGHT:
`
`Sumatriptan Succinate
`
`USAN Name (1989):
`
`Sumatriptan Succinate
`
`Non-Proprietary Name:
`
`3-[2-(Dimetyhlamino)ethyl]-/Vmethylindole-5-methanesulfonamide
`succinate (1 :1)
`
`N/CHs
`/
`CH3
`' ECOOH
`
`COOH
`
`\
`
`Chemical Formula:
`
`C14H21N3023 'C4H604
`
`Molecular Weight:
`
`413.49
`
`103628-48-4
`
`H I
`
`N
`H
`5
`/ \
`g
`
`C
`
`H3
`
`CAS registry #:
`
`Structure:
`
`Naproxen Sodium
`
`USAN Name (1973):
`
`Naproxen Sodium
`
`Non-Proprietary Name:
`
`(-)—Sodium (S)—6-methoxy-a-methyl-2-naphthaleneacetate
`
`Page 4 of 123
`
`

`

`
`. HEMISTRY REVIE-
`
`Chemistry Review Data Sheet
`
`Chemical Formula:
`
`C14H13Na03
`
`Molecular Weight:
`
`252.24
`
`CAS registry #:
`
`26159-34-2
`
`Structure:
`
`(3H3
`*
`
`0O (zoom
`
`CH3O
`
`* Asymmetric carbon center
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`
`II
`
`Adequate
`16-DEC-05
`
`
`Dr. Chhaan Tele
`
`
`Adequate
`
`1 3-MAY—02
`
`
`Dr. Martha
`
`Heimann
`
`
`! y—review
`
`
`Adequate
`Dr. Alan Schroeder
`27-APR-05
`
`--review
`
`review
`
`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
`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)
`
`Page 5 of 123
`
`

`

`
`:
`‘ HEMISTRY REVIE.
`
`Chemistry Review Data Sheet
`
`LOA: Letter of Authorization
`
`B. Other Documents:
`
`
`, DOCUMENT APPLICATION NUMBER
`— 60,669
`
`68,436
`
`DESCRIPTION
`Commercial IND mi_raine In Effect 30-AUG-2000
`Commercial IND miraine In Effect 18-JAN-2004
`
`
`
`
`18. STATUS:
`
`,
`
`CONSULTS/
`
`-
`
`
`
`_REVIEWS
`1
`_—
`__—
`__ N/A _
`__——
`LNC __—
`
`DMETS
`
`to FDA labs for validation.
`
`DMETS does not recommend the use
`of the proprietary name, Trexima.
`DDMAC finds the proprietary name,
`Trexima, acceptable from a
`
`promotional perspective.
`
`04-APR-06 Laura Pincock, Pharm.D.,
`Safety Evaluator
`Division of Medication
`Errors and Technical
`
`
`
`
`Support
`
`
`
`
`
`
`; EA
`
`1
`
`Acceptable, categorical exclusion
`granted as per information from
`Pozen Inc. in this NDA
`
`As per this
`review
`
`-_—— N/A
`
`
`
`
`
`Chhagan G. Tele, Ph.D.
`(HFD-120)
`
`
`Page 6 of 123
`
`

`

`
`
`Executive Summary Section
`
`The Chemistry Review for NDA 21-926
`
`77% Exeazll've Ill/71171411
`
`I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`NDA 21-926 for TreximaTM (sumatriptan succinate/naproxen sodium) Tablets is recommended
`APPROVAL from the CMC standpoint pending on an overall acceptable recommendation from
`the Office of Compliance.
`-
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`None as per this review.
`
`11. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`TreximaTM (sumatriptan succinate/naproxen sodium) Tablets is indicated for the acute treatment of
`migraine. Trexima Tablets are - immediate release, film coated tablets and are intended for
`oral administration. Each - tablet contains 85 mg sumatriptan (as 119 mg sumatriptan
`succinate) and 500 mg naproxen sodium. This combination product is based on approved drug
`substances and on the approved single active IMITREX® (sumatriptan succinate) Tablets. A
`— , film coated, — -blue, modified capsule-shape tablet was developed to provide the
`patient with a more convenient presentation for the treatment of migraine. In addition, the
`excipients have been duplicated from the current IMITREX® Tablet formulation to maintain
`effective tablet disintegration and dispersion of the sumatriptan component, so that it is less
`dependent on gastric motility. The formulation uses conventional pharmaceutical ingredients that
`are well established for use in tablets. Trexima Tablets are a modified capsule—shape, with an
`—
`They are film coated
`—— blue and debossed with ‘ Trexima tablets are packaged into a
`7 {III—-
`"
`. compact
`with desiccant disk (hereafter referred to
`as é 7
`). The' - will contain 9 tablets
`,
`
`,. Dcsiccant disk
`
`Page 7 of 123
`
`

`

`"HEMISTRY REVIE
`
`Executive Summary Section
`
`Conventional pharmaceutical excipients at typical levels are used in Trexima Tablets. The excipient
`selection was directed by the composition of IMITREX® Tablets and ANAPROX® DS (naproxen
`sodium 550 mg) Tablets manufactured by Roche Laboratories. Each tablet also contains the
`inactive ingredients croscarmellose sodium, dextrose monohydrate, dibasic calcium phosphate,
`FD&C Blue No. 2, lecithin, magnesium stearate, maltodextrin, microcrystalline cellulose,
`povidone, sodium bicarbonate, sodium carboxymethylcellulose, talc, and titanium dioxide.
`—-
`is theonly non-compendial excipient used in
`Trexima tablets formulation. The applicant included tests and specifications for
`7‘
`
`The drug product will be
`7
`V
`manufactured, packaged, and controlled by Glaxo Operations UK Limited Ware Hertfordshire. UK
`site.
`/
`
`7
`
`Stability testing (initial through 12 month time point) on NDA stability batches of Trexima Tablets
`is conducted at the SmithKline Beecham Corporation, Research Triangle Park, North Carolina. It is
`indicated by the applicant that the testing of the NDA stability batches, starting at the 18 month
`time point will be performed at Glaxo Operations UK Ltd, County Durham, UK site.
`
`The specifications for tablets included Description, Identification (HPLC and IR), Assay (HPLC),
`Drug —Related Impurities (HPLC), Dissolution (HPLC), and Content Uniformity (HPLC). Batch
`details are provided and batch analysis data are provided for three definitive NDA stability batches
`of Trexima Tablets,
`5
`”-
`Each of the batches was manufactured according to the proposed commercial
`process at the proposed commercial site of tablet manufacture and tested by the proposed
`commercial methods. Validated analytical methods were provided in the submission.
`
`Six months of primary stability data are presented for three batches of Trexima Tablets
`manufactured on a production-scale at Glaxo Operations, Ware, UK. The batches of Trexima
`Tablets are identical to those proposed for marketing and were packed in the proposed commercial
`pack; - compact . (Batches B916681A, B916682A, and B916683A) andin
`- (Batches B916681P, B916682P, and B916683P) w
`- The results of accelerated and long-term stability studies demonstrate the excellent chemical
`and physical stability of Trexima Tablets when stored for up to 6 months at 25° C/60% Relative
`Humidity (RH), and for up to 6 months at 40° C/75% RH. No significant changes were observed in
`description, sumatriptan content, naproxen sodium content, drug-related impurities content, and
`dissolution, and all results complied with specification. Cosmetic blemishes were observed on some
`of the Trexima Tablets packaged in the - compact '- 1 after storage for 3 months at
`25° C/60% RH and 40° C/75% RH and in the ~ after storage for 6 months at
`40°C/75% RH. In addition, data are presented following short-term storage of one of the three
`batches of Trexima Tablets (3916681) under the stress condition of exposure to light (ICH QlB
`option 2). No significant changes were observed in description, sumatriptan content, naproxen
`sodium content, and drug-related impurities content and all results complied with specification.
`Eighteen months of supportive stability data are presented for one batch of Trexima Tablets
`manufactured on a laboratory-scale at GlaxoSmithKline, Research Triangle Park, North Carolina.
`Tablets were manufactured according to the process described in the original IND 68,436 and were
`
`Page 8 of 123
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`~ The results show no significant changes in description, sumatriptan
`content, naproxen sodium content, drug- related impurities content, and dissolution after storage for
`18 months at 30° C/65% RH and for 6 months at 40°C/75% RH. No significant changes were
`observed in description, sumatriptan content, naproxen sodium content, or drug-related impurities
`content afier short-term storage under the stress condition of exposure to light (ICH QlB option 2).
`
`The drug substance, sumatriptan succinate is currently approved for use in GlaxoSmithKline’s
`marketed products Imitrex® Injection and Imitrex® Tablets, and is provided by cross-reference to
`the parent NDA for this active pharmaceutical ingredient (Imitrex® Injection NDA 20-080, LOA
`28-APR-05). Sumatriptan succinate, is currently manufactured and supplied to the applicant by
`Glaxo Wellcome Manufacturing Pte. Ltd., Jurong, Singapore facility. Manufacture of sumatriptan
`succinate at the Jurang, Singapore facility was approved in the supplement to NDA 20—080/S-020.
`Clinical and definitive stability batches of Trexima Tablets were manufactured using sumatriptan
`succinate sourced from Jurong, Singapore. Sumatriptan succinate is a white to off-white crystalline
`powder. Naproxen sodium is a USP material and is currently approved for use in various
`proprietary (ANAPROX® Tablets, Roche NDA 18-164, 04-SEP-80) and over the counter
`medication (ALEVE). Naproxen sodium is
`‘—
`according to the details — Letter of Authorization to access this DMF was provided
`for cross-reference. The - was reviewed and found adequate by Dr. Chhagan Tele,
`HFD-l30 on 16-DEC-05 and found adequate (IR letter sent 03-JAN-06). Naproxen sodium is a
`, white to creamy white, crystalline solid with one chiral center, freely soluble in water at neutral pH.
`All the batches of Naproxen sodium drug substance presented in the original NDA were
`_ _
`_,
`.
`. Batch analysis data of three
`batches of drug substance used in manufacturing of drug product were provided. Validated
`analytical methods were provided in the DMF. A retest date of — has been established for the
`bulk Naproxen sodium by — 7
`. on the basis of . real time stability data for 3
`commercial batches.
`
`B. Description of How the Drug Product is Intended to be Used
`
`TreximaTM (sumatriptan succinate/naproxen sodium) Tablets will be marketed into
`— compact ~ with desiccant disk and —
`- ,/9 counts. The maximum recommended total daily dose is sumatriptan
`185 mg as sumatriptan-equivalent to 119 mg of sumatriptan succinate) and naproxen sodium 1500
`mg )/day. Pozen initially provided 6 months of stability data at 25° C/60% RH and 6 months
`stability data at 40° C/75% RH for registration batches of Trexima tablets. Stability data was
`updated for 18 months for long term storage in amendment #006 dated 22-FEB-06.
`
`» ._
`
`The storage conditions for the drug product were recommended as “Store at 25° C (77° F);
`excursions permitted to 15-30° C (59:86° F) [see USP Controlled Room Temperature]. Dispense in
`
`The applicant makes the usual post-approval stability commitments with regards to stability studies
`indicating that the first three production batches and each container/closure system will continue
`according to the approved stability protocols through the expiration dating period.
`
`This application qualifies for categorical exclusion from environmental assessment under the
`provisions in 21 CFR § 25.31(a).
`
`Page 9 of 123
`
`

`

` CHEMISTRY REVIEW
`
`Executive Summary Section
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`NDA 21—926 for TreximaTM tablets is recommended to be granted Approval status from CMC
`standpoint pending on overall acceptable recommendation from the Office of Compliance.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`See electronic signatures in DFS.
`
`B. Endorsement B10ck
`
`Chemist Name: Chhagan G. Tele, Ph.D.
`Branch Chief Name: Ramesh Sood, Ph.D.
`Project Manager Name: Lana Chen, Pharm.D.
`
`C. CC Block
`
`See DFS.
`
`Page 10 of123
`
`

`

`_LLLL_ Page(s) Withheld
`
`1/ Trade Secret / Confidential
`
`Draft Labeling
`
`Deliberative Process
`
`Withheld Track Number: Chemistry- :2
`
`

`

`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`
`/8/
`
`Chhagan Tele
`5/19/2006 12:45:03 PM
`CHEMIST
`
`Ramesh Sood
`5/19/2006 01:16:25 PM
`CHEMIST
`
`