CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022255Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`Vimpat® (lacosamide) Oral Solution
`NDA 22-255
`Branch Chief Review
`Chemistry, Manufacturing, and Controls
`
`
`Applicant: Schwarz Biosciences, Inc.
`8010 Arco Corporate Drive, Suite 100
`Raleigh, NC 27617
`
`adjunctive treatment of partial-onset seizures in patients with epilepsy, aged 17 years and
`
`
`Indication:
`older
`
`Presentation: Immediate-release oral solution containing 10 mg/mL of lacosamide and the following
`excipients: glycerin, carboxymethylcellulose sodium, sorbitol solution, polyethylene glycol, sodium
`chloride, anhydrous citric acid, acesulfame potassium, methylparaben
` strawberry flavor, masking
`flavor, and water. The drug product is packaged in
`
` polyethylene terephthalate bottles sealed with white, child-proof, tamper-evident
`
` caps.
`
`
`EER Status:
`
`Consults:
`
`
`
`Acceptable 15-JUL-2008
`
`Microbiology – Approval 30-MAR-2010
`EA – OPS No significant impact 15-MAY-2008
`Methods Validation – Revalidation by Agency not requested.
`
`16-OCT-2009
`
`
`Resubmission:
`
`Post-Approval Agreements: None
`
`Drug Substance: The applicant referenced NDA 22-253 for all information concerning the chemistry,
`manufacturing, and control of lacosamide drug substance. We approved NDA 22-253 on 28-OCT-2008.
`
`Conclusion: Drug substance is acceptable.
`
`Drug Product: This resubmission is in response to the DMEPA request for the sponsor to reformulate
`the oral solution so that standard dosing measurements and devices could be used for administration. The
`original oral solution concentration was
`. Based on DMEPA’s request, Schwarz proposed a 10
`mg/mL formulation. The 10 mg/mL formulation is similar to the original
` formulation with
`slight modifications in excipient amounts. Schwarz removed the
`
`based on comments received from the European Union. Schwarz confirms that this reformulation does
`not require any changes in the drug product manufacturers, manufacturing process, analytical methods, or
`impurity profile. All analytical methods remain appropriate for use and validated with respect to the new
`10 mg/mL formulation.
`
`
`.
`
`
`
`Each bottle of drug product contains lacosamide (10.0 mg/mL), glycerin USP
` polyethylene
`carboxymethylcellulose sodium USP
` sorbitol solution USP (
`glycol
` USP
` sodium chloride USP
` anhydrous citric acid USP
`
`, acesulfame potassium NF
` methylparaben
` USP
` strawberry
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`flavor
`
`), masking flavor
`
`), and purified water USP
`
`
`
`
`
`Specification of the drug product includes: appearance, contents, odor, color, clarity, identification by RP-
`HPLC and UV spectrophotometry, methylparaben content by RP-HPLC, pH, purity by RP-HPLC,
`impurities and related substances by RP-HPLC, assay by RP-HPLC, assay of methylparaben by RP-
`HPLC, and microbial limits. The lacosamide reference standard for drug product is the same as that for
`drug substance. All test methods are compendial or have been appropriately validated for their intended
`purpose. The drug product stability data supports the proposed 18 month expiry for drug product stored
`at controlled room temperature [25º C (77º F); excursion permitted to 15-30º C (59-86º F)], and packaged
`in the proposed commercial bottles, sealed with caps.
`
`In accordance with 21 CFR 320.22, the data provided adequately support granting the biowaiver request.
`Based on these results and the fact that the drug substance in the oral solution formulation is in the
`dissolved state, a request for waiver of an in vivo bioequivalence study for the 10 mg/mL lacosamide oral
`solution is justified. The conclusions of the ONDQA Biopharmaceutics reviewer (23-FEB-2010) indicate
`that the data provided support granting the biowaiver request. The CMC microbiology team
`recommended approval (30-MAR-2010).
`
`Conclusion: Drug product is acceptable.
`
`Additional Items:
`• The applicant agreed to conduct primary stability studies on the first three consecutive drug product
`batches, in all packaging configurations, to firmly establish the proposed drug product expiry.
`• The applicant agreed to place one batch of drug product per year for each of the largest and smallest
`packaging configuration, stored upright, on stability at 25°C/60% RH (long term conditions) with testing
`throughout the commercial life of the drug product and submission of the stability results in the annual
`report.
`• All associated Drug Master Files (DMFs) are acceptable or the pertinent information was adequately
`provided in the application.
`• The applicant submitted a methods validation package containing all relevant documentation (tests,
`methods, and acceptance criteria) for the control of the drug substance and the drug product.
`
`Overall Conclusion:
`
`From a CMC perspective, the application is recommended for Approval.
`
`Ramesh Sood, Ph.D.
`Branch Chief
`DPA I/ONDQA
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22255
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SCHWARZ
`BIOSCIENCES INC
`
`------------------------------------------
`VIMPAT
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WENDY I WILSON
`04/19/2010
`Branch Chief Memo entered on behalf of Ramesh K. Sood, Branch Chief, DPA I, ONDQA
`
`MARTHA R HEIMANN
`04/19/2010
`for Ramesh Sood
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-255
`Quality Review #2
`
`Vimpat® (lacosamide) Oral Solution
`10 mg/mL
`
`Schwarz Biosciences, Inc.
`
`
`
`
`Wendy I. Wilson-Lee, Ph. D.
`Office of New Drug Quality Assessment
`For
`Office of Neurology Drug Products
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`Table of Contents
`
`
`Table of Contents .................................................................................................................2
`
`Chemistry Review Data Sheet.............................................................................................3
`
`List of Tables.........................................................................................................................6
`
`List of Figures.......................................................................................................................7
`
`The Executive Summary......................................................................................................8
`
`I. 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
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3: ................................ 10
`S
`] ........................................................................10
` DRUG SUBSTANCE [Lacosamide,
`P
` DRUG PRODUCT [Vimpat®, Oral Solution] .............................................................................................10
`R REGIONAL INFORMATION.....................................................................................................................32
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1.................................. 32
`A. Labeling & Package Insert ............................................................................................................................33
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................................................36
`C. Establishment Inspection................................................................................................................................36
`
`III. List Of Deficiencies To Be Communicated............................................................................ 36
`
`
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`
`
`
`22-255
`
`02
`
`
`1. NDA:
`
`2. REVIEW:
`
`3. REVIEW DATE: 22-MAR-2010
`
`4. REVIEWER:
`
`5. PREVIOUS DOCUMENTS:
`
`
`Wendy I. Wilson-Lee, Ph.D.
`
`Document Date
`
`16-JUL-2008
`
`05-JUN-2008
`
`Document Date
`
`31-MAR-2010
`
`16-OCT-2009
`
`Schwarz Biosciences, Inc
`
`8010 Arco Corporate Drive
`Suite 100
`Raleigh, NC 27617
`
`Susan Tegtmeyer
`Senior Manager, Regulatory Affairs
`UCB, Inc (U S Agent)
`1950 Lake Park Drive
`Building 2100
`Smyrna, GA 30080
`
`770-970-8654
`
`Vimpat®
`Lacosamide
`
`Previous Documents
`
`Memo to File
`
`Quality Review #1
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`
`Amendment
`
`Amendment
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name:
`
`
`
`
`b) Non-Proprietary Name (USAN):
`
`
`c) Code Name/# (ONDQA only):
`
`
`
`d) Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type:
`
`3
`• Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505 (b)(1)
`
`10. PHARMACOL. CATEGORY: Anti-convulsant
`
`11. DOSAGE FORM:
`
`
`Oral Solution
`
`
`
`
`
`Page 3 of 36
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`10 mg/mL
`
`
`
`
`
`
`
`
`
`
`
`
`12. STRENGTH/POTENCY:
`
`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:
`
`Chemical Name: (R)-2-acetamide-N-benzyl-3-methoxypropionamide
`Mol. Formula: C13H18NO3
`
`Mol. Weight:
`250.30
`
`
`
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`
`DMF #
`
`TYPE
`IV
`
`III
`
`III
`III
`
`III
`III
`III
`
`III
`III
`
`III
`III
`
`III
`III
`III
`III
`III
`
`HOLDER
`
`ITEM REFERENCED
`
`CODE1
`1
`
`STATUS2
`Adequate
`
`DATE REVIEW
`COMPLETED
`17-MAR-2008
`
`4
`
`4
`4
`
`4
`4
`4
`
`4
`4
`
`4
`4
`
`4
`4
`4
`4
`4
`
`N/A
`
`04-JAN-2010
`
`N/A
`N/A
`
`N/A
`N/A
`N/A
`
`N/A
`N/A
`
`N/A
`N/A
`
`N/A
`N/A
`N/A
`N/A
`N/A
`
`04-JAN-2010
`04-JAN-2010
`
`04-JAN-2010
`04-JAN-2010
`04-JAN-2010
`
`04-JAN-2010
`04-JAN-2010
`
`04-JAN-2010
`04-JAN-2010
`
`04-JAN-2010
`04-JAN-2010
`04-JAN-2010
`04-JAN-2010
`04-JAN-2010
`
`COMMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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")
`
`
`
`Page 4 of 36
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`
`
`
`
`
`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:
`
`DOCUMENT
`NDA
`
`
`18. STATUS:
`
`
`APPLICATION NUMBER
`22-253
`
`DESCRIPTION
`Vimpat® (lacosamide) Tablets
`
`CONSULTS/ CMC RELATED REVIEWS
`Biometrics
`EES
`Pharm/Tox
`Biopharm
`LNC
`Methods Validation
`DMEPA
`EA
`Microbiology
`
`RECOMMENDATION
`N/A
`Acceptable.
`Acceptable.
`Acceptable.
`N/A
`Validation by FDA labs not needed.
`Pending.
`Finding of no significant impact.
`Acceptable.
`
`DATE
`N/A
`15-JUL-2008
`10-JUN-2008
`10-JUN-2008
`N/A
`08-JAN-2010
`
`15-MAY-2008
`30-MAR-2010
`
`REVIEWER
`N/A
`OC
`J. Fisher
`V. Tandon
`N/A
`W. Wilson-Lee
`J. Park
`R. Bloom
`V. Pawar
`
`
`
`
`
`Page 5 of 36
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`List of Tables
`
`
`
`
`
`
`Page 6 of 36
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`List of Figures
`
`
`
`Page 7 of 36
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`Chemistry Review for NDA 22-255
`
`
`The Executive Summary
`
` I. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`We recommend approval of the 10 mg/mL strength of Vimpat® (lacosamide) Oral Solution, from a CMC
`perspective, pending final labeling. Include the following three comments in the approval letter:
`
`
`1. Based on our analysis of the stability data and in accordance with ICH Q1E, we grant the
`proposed 18 month expiry for Vimpat® 10 mg/mL Oral Solution packaged in
`
` PET bottles
`,
`stored at controlled room temperature [25ºC (77ºF); excursions 15-30ºC (59-86ºF)].
`2. Based on our analysis of the in-use stability data, we grant an in-use expiry of seven (7) weeks
`after first opening of the bottle for Vimpat® (lacosamide) Oral Solution.
`3. Based on our review, we grant the request for a biowaiver for the in vivo bioequivalence study for
`Vimpat® (lacosamide) Oral Solution 10 mg/mL.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`There are no CMC Phase 4 commitments.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Lacosamide is intended for use as drug for adjunctive therapy in the treatment of partial-onset seizures in
`patients with epilepsy 17 years and older. Schwarz referenced NDA 22-253 for all information
`concerning the chemistry, manufacturing, and control of the lacosamide drug substance. Lacosamide is a
` for the (R)-enantiomer. Lacosamide is
`white to light yellow powder with a chiral purity of
`soluble in 2-propanol and sparingly soluble in water. The drug substance is not hydroscopic and does not
`form any hydrates. Lacosamide does not exhibit a pKa in the pH range of 1.5 – 12. The manufacturer
`identified four crystalline and one amorphous form of lacosamide. Form 1 and Form 2 are the most
`thermodynamically stable crystal forms. Lacosamide is a BCS Class I drug substance.
`
`Schwarz developed the Vimpat® 10 mg/mL oral solution as an alternative oral formulation for those
`patients who find swallowing tablets difficult. The proposed doses are 200 mg and 400 mg. There are no
`strength equivalency issues because the drug substance is a free base. The major solvent in the
`formulation is purified water. The oral solution contains sweeteners,
` and flavoring
`agents to improve the palatability of the bitter drug substance.
`
`
`
`The formulation contains a
`to ensure the drug substance remains in solution over the drug product shelf-life. With the
`exception of the flavoring agents, the excipients are compendial.
`
`The manufacturing process for Vimpat® 10 mg/mL Oral Solution is conventional
`
`
`
`. The typical Vimpat® 10 mg/mL oral solution batch sizes
`
`
`
`Page 8 of 36
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`potency,
`
`
`
`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`
`). The drug product specification ensures the identity of the drug substance
` as well as ensures the chemical purity, microbiological purity, drug substance
`, and quality of the drug product.
`
`B. Description of How the Drug Product is Intended to be Used
`
`Vimpat® Oral Solution is intended for use as an adjunctive therapy in the treatment of partial-onset
`seizures in patients 17 years or older, with epilepsy. The oral solution may be taken with or without food.
`The recommended dosing regimen includes a starting dose of 100 mg/day given twice daily with weekly
`incremental increases of 100 mg/day to reach the maintenance dose of 200 – 400 mg/day. The maximum
`dose is 400 mg/day. If necessary, the practitioner may switch the patient to intravenous administration of
`a dose equivalent to the oral dose. The Vimpat® Oral Solution will be supplied commercially with fill
`volumes of
` 465 mL in
` polyethylene terephthalate (PET) bottles
`with a child-resistant induction sealed closure
`
`
`round amber glass bottles with a child-resistant closure. The recommended Vimpat® Oral Solution
`expiry is 18 months when stored at 25oC/60% RH in the commercial container closures. Based on in-use
`stability results, the recommended in-use expiry is seven (7) weeks after first opening the bottle.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`From a CMC perspective, we recommend approval of Vimpat® Oral Solution, pending final labeling.
`Based on our analysis of the stability data and in accordance with ICH Q1E, we grant the proposed 18
`month expiry for Vimpat® 10 mg/mL Oral Solution packaged in
`
`PET bottles
`, stored at controlled room
`temperature [25ºC (77ºF); excursions 15-30ºC (59-86ºF)]. We concur with the proposed in-use expiry of
`seven (7) weeks after first opening of the bottle. Based on our review, we grant the request for a
`biowaiver for the in vivo bioequivalence study. The manufacturing process and the associated process
`controls are adequate. The CMC microbiology review recommends approval as well. The drug product
`specification ensures the identity of the drug substance
` as well as ensures the
`chemical purity, microbiological purity, drug substance potency,
` and quality of the
`drug product. The stability data supports the proposed expiry. The carton and container labels along with
`the prescribing information contain all of the required information, from a CMC perspective. The
`recommendation from the Office of Compliance was acceptable for all facilities.
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`Wendy I. Wilson-Lee, Ph.D.
`
`B. Endorsement Block
`WWilson-Lee:
`MHeimann:
`
`RSood:
`
`
`
`C. CC Block
`
`DHenry
`SDaugherty
`
`
`
`
`
`31-MAR-2010
`31-MAR-2010
`31-MAR-2010
`
`Page 9 of 36
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`27 Pages have been Withheld in Full Immediately
`Following this Page as B4 (CCI/TS)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22255
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`SCHWARZ
`BIOSCIENCES INC
`
`------------------------------------------
`VIMPAT
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WENDY I WILSON
`04/05/2010
`
`MARTHA R HEIMANN
`04/05/2010
`Signed for Ramesh Sood
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-255
`
`
`Lacosamide Oral Solution
`
`
`Schwarz Biosciences, Inc.
`
`
`
`
`Wendy I. Wilson, Ph. D.
`Office of New Drug Quality Assessment
`for Division of Neurology Drug Products
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`Table of Contents
`
`
`Table of Contents .................................................................................................................2
`
`Chemistry Review Data Sheet.............................................................................................3
`
`List of Tables.........................................................................................................................6
`
`List of Figures.......................................................................................................................8
`
`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
`
`III. Administrative........................................................................................................................ 10
`A. Reviewer’s Signature .....................................................................................................................................10
`B. Endorsement Block.........................................................................................................................................10
`C. CC Block ........................................................................................................................................................10
`
`Chemistry Assessment .......................................................................................................11
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3: ................................ 11
`S
`........................................................................11
` DRUG SUBSTANCE [Lacosamide,
`P
` DRUG PRODUCT [Lacosamide Oral solution, SCHWARZ PHARMA]...................................................13
`A
` APPENDICES ..............................................................................................................................................67
`R REGIONAL INFORMATION.....................................................................................................................67
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1.................................. 68
`A. Labeling & Package Insert ............................................................................................................................68
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................................................73
`C. Establishment Inspection.................................................................................................................................73
`
`III. List of Deficiencies to be Communicated............................................................................... 74
`
`IV. Approval Letter Comments..................................................................................................... 74
`
`(b) (4)
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Chemistry Review Data Sheet
`
`
`
`22-255
`
`01
`
`
`1. NDA:
`
`2. REVIEW #:
`
`3. REVIEW DATE: 21-MAY-2008
`
`4. REVIEWER:
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Wendy I. Wilson, Ph. D.
`
`Previous Documents
`None.
`
`
`
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Original
`Amendment
`Amendment
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`Document Date
`
`N/A
`
`Document Date
`28-SEP-2007
`22-APR-2008
`14-MAY-2008
`
`Name:
`Address:
`
`Representative:
`
`Telephone:
`
`Schwarz Biosciences, Inc.
`8010 Arco Corporate Drive, Suite 100, Raleigh, NC 27617
`
`Alan L. Blumberg
`Sr. Director,
`US Regulatory Affairs
`
`919-767-2513
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN):
`
`
`c) Code Name/# (ONDQA only):
`
`
`
`d) Chem. Type/Submission Priority (ONDQA only):
`• Chem. Type:
`
`1
`• Submission Priority:
`S
`
`Lacosamide
`SPM 927
`
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`10. PHARMACOL. CATEGORY:
`
`11. DOSAGE FORM:
`
`12. STRENGTH/POTENCY:
`
`13. ROUTE OF ADMINISTRATION:
`
`14. Rx/OTC DISPENSED:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`505 (b)(1)
`
`Anticonvulsant
`
`Solution
`
`
`
`Oral
`
` _X__Rx ___OTC
`
`Page 3 of 74
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`
`
`
`
`
`
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`
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT:
`
`Chemical Name:
`Mol. Formula:
`Mol. Weight:
`
`
`(R)-2-acetamido-N-benzyl-3-methoxypropionamide
`C13H18NO3
`250.30
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`
`
`
`DMF
`
`
`
`
`
`TYPE
`
`HOLDER
`
`ITEM REFERENCED
`
`CODE1
`
`STATUS2
`
`REVIEW
`COMPLETED COMMENT
`
`IV
`
`III
`
`III
`
`III
`
`III
`
`III
`
`1
`
`4
`
`4
`
`4
`
`7
`
`4
`
`Adequate
`
`17-MAR-2008
`
`
`
`
`
`
`
`
`
`
`
`
`
`Adequate.
`
`06-FEB-2008
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`B. Other Documents:
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did not need to be reviewed)
`
`DOCUMENT
`
`IND
`IND
`IND
`IND
`
`APPLICATION NUMBER
`57,939
`
`68,407
`73,809
`
`DESCRIPTION
`ADD 234037 for Treatment of Epilepsy
`SPM 927 (formerly Harkoseride) for Treatment of Neuropathic Pain
`SPM 927 (formerly ADD 234037) for Treatment of Epilepsy
`Lacosamide (formerly SPM 927) for Treatment of Epilepsy
`
`Page 4 of 74
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`RECOMMENDATION
`
`N/A
`Pending
`Pending
`Pending
`N/A
`No validation by FDA needed.
`Use of Vipmat as tradename is acceptable
`Recommend alternate dosing device and reformulation to allow for standard unit of measure
`Finding of no significant impact
`Pending
`
`DATE
`
`REVIEWER
`
`N/A
`
`
`
`N/A
`17-APR-2008
`
`N/A
`S. Adams
`J Edward Fisher
`V. Tandon
`N/A
`W. Wilson
`
`13-MAY-2008
`
`J. Park
`
`15-MAY-2008
`
`
`R. Bloom
`V. Pawar
`
`
`
`
`
`18. STATUS:
`
`
`CONSULTS
`
`Biometrics
`EES
`Pharm/Tox
`Biopharm
`LNC
`Methods Validation
`
`DMETS
`
`EA
`Microbiology
`
`
`
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`Page 5 of 74
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`List of Tables
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`List of Figures
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`CHEMISTRY REVIEW
`Executive Summary Section
`
`Chemistry Review for NDA 22-255
`
`
`
`The Executive Summary
`
` I. Recommendations
`
`
`A. Recommendation and Conclusion on Approvability
`
` is approvable (AE) pending labeling, completion
`From a CMC perspective, lacosamide oral solution
`of manufacturing site inspections, and completion of the microbiology review. We will add a subsequent memo to
`the file once we receive acceptable recommendations from OC and microbiology.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable
`
`There are no CMC Phase IV recommendations.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`Schwarz referenced NDA 22-253 for all information concerning the chemistry, manufacturing, and control of the
`lacosamide drug substance. Lacosamide is a white to light yellow powder with a chiral purity
` for the
`(R)-enantiomer. Lacosamide is soluble in isopropanol and sparingly soluble in water. The drug substance is not
`hydroscopic and does not form any hydrates. Lacosamide does not exhibit a pKa in the pH range of 1.5 – 12. The
`drug substance manufacturer identified four crystalline and one amorphous form of lacosamide. Form 1 and Form
`2 are the most thermodynamically stable crystal forms. Lacosamide is a BCS Class I drug substance.
`
` oral solution as an alternative oral formulation for those patients who
`Schwarz developed the lacosamide
`find swallowing tablets difficult. The proposed doses are 200 mg, 400 mg,
`. The clinical division
`recommends a maximum daily dose of 400 mg. Therefore, for our review, the maximum daily dose is 400 mg.
`
`The typical drug product use period is four weeks. There are no strength equivalency issues because the drug
`substance is a free base. The major solvent in the formulation is purified water. The formulation does not contain
`co-solvents. The oral solution contains sweeteners,
` and flavoring agents to improve the palatability
`of the bitter drug substance. The sorbitol sweetener in the formulation is
`
`of sorbitol. The formulation also
` of the drug substance through the
`oral solution to the taste buds. The oral solution also contains
`
`. The formulation contains a
`
`
` With the exception of the flavoring agents,
`the excipients are compendial. All of the excipients are commonly used in this type of drug product.
`
`The manufacturing process for lacosamide
`
` oral solution is conventional
`
`
`
` oral solution batch sizes
`The typical lacosamide
`. The proposed drug product specification ensures the identity of the drug substance
` as well as ensures the chemical purity, microbiological purity, drug substance potency,
`
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`CHEMISTRY REVIEW
`Executive Summary Section
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` and quality of the drug product. The specification establishes release and shelf-life criteria for color,
`related substances, lacosamide assay
`.
`
`
`B. Description of How the Drug Product is Intended to be Used
`
` use in the
` lacosamide,
`The sponsor applied for
`treatment of partial-onset seizures in patients,
` years or older, with epilepsy. The sponsor indicates the oral
`solution drug product as adjunctive therapy in the treatment of partial-onset seizures. The proposed drug product
`tradename is Vipmat. The oral solution may be taken with or without food. The recommended dosing regimen
`includes a starting dose of 100 mg/day given twice daily with weekly incremental increases of 100 mg/day to reach
`the maintenance dose of 200 – 400 mg/day. The maximum dose recommended by FDA is 400 mg/day. If
`necessary, the practitioner may switch the patient to intravenous administration of a dose equivalent to the oral
`dose. Based on DMET comments communicated to the sponsor, Schwarz committed to ev