CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 22-253 & 22-254
`
`CHEMISTRY REVIEW(S)
`
`

`

`W M
`
`EMORANDUM
`
`W T
`
`NDA 22—254
`
`O:
`
`FROM:
`
`Wendy 1. Wilson, Review Chemist
`
`SUBJECT:
`
`CMC Review of Revised Labeling
`
`DATE:
`
`10/23/2008
`
`CC:
`
`Jacqueline Ware, HFD 120 RPM; Scott Goldie, ONDQA PM; Martha Heimann, ONDQA PAL; Ramesh
`Sood, ONDQA Branch Chief; Blair Fraser, ONDQA Division Director
`
`
`Revised Labeling
`
`
`Schwarz incorporated all of the CMC recommendations concerning the carton container labels during the
`initial CMC review cycle. As part of that review, we recommended that
`the sponsor
`
`/ //
`
`Overall Recommendation
`
`We recommend that Schwarz revise the labeling M\
`
`
`21(4)
`
`13(4)
`
`WM I. WM“
`
`Wendy 1. Wilson, Ph.D.
`Review Chemist
`
`ONDQA DPA-I
`
`

`

`nun—nun...-“mum—u...-n-unnu-—--¢—-mn-u—um—m-mnfimu—nn—mm—nm-mn_
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Wendy I. Wilson
`10/23/2008 04:09:43 PM
`CHEMIST
`
`Ramesh Sood
`
`10/24/2008 09:38:16 AM
`CHEMIST
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`.FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`July 16, 2008
`
`FROM:
`
`Prafull Shiromani, Ph.D.
`
`Reviewing Chemist
`Division of Neurology Products, HFD-120
`
`TO:
`
`File NDA 22-253
`
`~=====v ‘
`
`hm
`
`SUBJECT: Approval recommendation for Vimpat® (Lacosamide) Tablets, (NDA 22-253
`
`, Schwarz Biosciences, Inc.)
`
`11(4)
`
`This memo recommends the approval of Vimpat® (Lacosamide) Tablets from '
`CMC perspective based on the overall acceptable establishment report from the Office of
`Compliance, the summary of which is attached. All other CMC related issues had been
`resolved as per earlier CMC reviews.
`
`Prafull Shiromani
`Chemist
`
`

`

`
`
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`APPEARS nus WAY
`ON ORIGINAL
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Prafull Shiromani
`
`7/16/2008 09:44:34 AM
`CHEMIST
`
`

`

`
`
`MEMORANDUM
`
`
`TO:
`
`NDA 22-254 & a.“
`
`FROM:
`Wendy L Wilson, Review Chemist
`SUBJECT: Outcomes ofMicro Consult and Facility Inspections
`DATE:
`7/16/2008
`A
`
`CC:
`
`Jacqueline Ware, HFD 120 RPM; Scott Goldie, ONDQA PM; Martha Heimann, ONDQA PAL; Ramesh
`Sood, ONDQA Branch Chief; Blair Fraser, ONDQA Division Director
`
`
`Microbiology Consults
`
`The microbiology reviewer recommended approval of lacosamide injection (NDA 22-254) /"'"_'
`«f—d on O4-JUN-2008 ______.———
`
`Facilig Inspections
`
`0C provided an overall recommendation of acceptable for all facilities listed for lacosamide injection
`(NDA 22-254) W _ on 15-IUL-2008.
`”(4)
`MM
`
`M4)
`
`l3(4)
`
`/
`
`/-
`
`Overall Recommendation
`
`Based on the outcomes of the microbiology consult and facility inspections F
`M , we recommend lacosamide injection (NDA 22-254)
`[‘2 for approval pending labeling, from a CMC perspective.
`
`WM I. WM '
`
`Wendy L Wilson, Ph.D.
`Review Chemist
`
`ONDQA DPA-I
`
`

`

`This is a representation of an electronic record that was signed electronically and
`
`
`this page is the manifestation of the electronic signature '
`mfi-M-i—iS—iim-uu—u-m-un—n—n—
`
`
`
`Wendy 1. Wilson
`7/16/2008 10:40:12 AM
`CHEMIST
`
`Ramesh Sood
`
`7/16/2008 10:42:25 AM
`CHEMIST‘
`
`

`

`10f3
`
`VimpatTM
`(lacosamide)
`Injection
`
`NDA 22-254
`
`Division Director Review
`
`Chemistry, Manufacturing, and Controls
`
`Applicant:
`
`Schwarz Biosciences, Inc.
`8010 Arco Corporate Drive, Suite 100
`Raleigh, NC 27617
`
`Indication:
`
`adjunctive treatment of partial—onset seizures in patients with epilepsy, aged 16
`years and older
`‘
`
`Presentation: Vimpat (lacosamide) Injection is supplied as a single strength, sterile. ‘s . 10
`mg/mL solution of lacosamide. Each single—use, 20 mL Vial contains 200 mg of
`lacosamide in an A saline solution in a 37* , colorless glass Vial with a
`grey rubber stopper
`: and aluminum oversea].
`
`“(43
`
`EER Status:
`
`Consults:
`
`Acceptable
`
`15—JUL-2008
`
`Microbiology -
`EA — OPS
`Methods Validation —
`
`1—JUN—2008
`Acceptable
`No significant impact 15—MAY-2008
`Revalidation by Agency not requested.
`
`Original Submission:
`
`27-SEP-2007
`
`Post-Approval Agreements:
`
`None
`
`Drug Substance:
`
`information concerning the chemistry,
`referenced NDA 22-253 for all
`The applicant
`manufacturing, and control of the lacosamide drug substance.
`
`Lacosamide is a member of a series of functionalized amino acids that were specifically
`synthesized as anticonvulsive drug candidates. The drug substance,
`lacosamide,
`is a small,
`synthetic, New Molecular Entity (NME) with an empirical formula of C13H13N203 and a
`molecular weight
`of
`250.30. Known
`chemically
`as
`(R)—2—acetamido-N-benzyl—3—
`
`methoxypropionamide,
`it is a white to light yellow powder with a melting range 0}
`Lacosamia’e is sparingly soluble in water ( f" ;) WA
`.Mand- slightly soluble in. ethanol.
`Lacosamide, a chiral drug substance,W
`
`

`

`20f3
`
`/1‘/,/
`
`I!
`
`The bulk drug substance is synthesized from
`
`Comprehensive information for all the impurities at the starting material level,
`at the intermediate level and at the final synthesis level was presented. Noteworthy were
`uh“)
`controls over I“; J starting materials and intermediates.
`
`The structure of lacosamide was elucidated using several analytical ——————-——-——-’
`
`techniques,
`
`/,
`,/ //
`
`
`
`The proposed release specification for lacosamide includes
`
`_
`
`
`1/
`f
`Theproposed regulatory methods
`
`“(4)
`
`w
`
`are either compendial or were developed and validatedfor their intended purpose. The primary
`reference standard for drug substance, manufactured by commercial process, has been
`characterized by the proposed regulatory methods as well as additional methods. The impurity
`and degradation profiles have been investigated. Reference standards for known impurities and
`in-process intermediates have been synthesized andfully characterized.
`
`
`' The stability data for three commercial batches support a
`retest period for the bulk
`drug substance stored insideW bha)
`———~————-
`{at controlled room temperature, 25 °C /60%RH, protectedfrom light.
`
`Conclusion: Drug substance is acceptable.
`
`' Drug Product:
`
`Vimpat (lacosamide) Injection is supplied as a single strength, sterile, ”~10 mg/mL
`solution of lacosamide. Each single—use, 20 mL Vial contains 200 mg of lacosamide in an
`f“ ; saline solution1n a
`:—
`colorless glass Vial with a grey rubber stopper
`\—
`and aluminum overseal.
`
`aw)
`
`, sodium chloride USP,
`Each 20 mL Vial of Vimpat contains 10 mg/mL lacosamide, ——~~«
`adjusted to pH 4.0 with hydrochloric acid USP, in Water for Injection. The manufacturing
`process is r——W h(4)W .
`
`

`

`3 of 3
`
`.
`31(4)
`
`Specification of the drug product includes:
`
`
`
`W"J ‘J
`
`_
`\ lie lacosamide reference standardffor 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 36 month expiry for drug product stored at
`controlled room temperature [25" C (77° F); excursion permitted to 15-30° C (59-860 F)],,and
`packaged in 20 mL
`—— colorless glass vials with a grey rubber stopper W
`_.w and aluminum oversea].
`
`, M4)
`
`Conclusion: Drug product is acceptable.
`
`Additional Items:
`
`
`
`
`
`(j
`o All associated Drug Master Files (DMFs) are acceptable or the pertinent information has
`been adequately provided in the application.
`
`relevant
`submitted a methods validation package containing all
`0 The applicant
`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,‘
`pending agreement on product labeling.
`'
`
`Blair A. Fraser, Ph.D.
`Director
`
`DPA I/ONDQA
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Blair Fraser
`7/16/2008 11:03:04 AM
`CHEMIST
`
`

`

`Initial Quality Assessment
`Branch 1
`
`Pre-Marketing Assessment Division I
`
`0ND Division: Division of Neurology Products/Division of Anesthesia,
`Analgesia, and Rheumatology Products
`‘ NDA:
`22-253.
`-=~—~==..
`Applicant: Schwarz Biosciences
`Stamp Date:
`28—Sep-2007
`PDUFA Date: 28-Jul-2008
`Trademark: TBD.
`-
`Established Name: Lacosamide
`
`“(4)
`
`-
`
`Dosage Form: Tablets
`Route of Administration: Oral
`
`Indication: Epilepsy/Neuropathic pain
`
`PAL: Martha R. Heimann, Phi);
`
`0NDQA Fileability:
`Comments for 74-Day Letter
`
`VA
`
`[I
`El
`
`Yes No
`
`Summary and Critical Issues:
`
`Summary
`
`Lacosamide (previously known as harkoseride or erlosainide) has been developed by Schwarz
`for two indications, adjunctive treatment of partial onset seizures and management of diabetic
`neuropathic pain f" dosage forms have been developed including immediate release tablets
`
`that are the subject of NDAs 22-253 (epilepsy) and M \neuropathic pain). NDAs 22-254
`\ were submitted
`1 and provide for use of lac‘osamide injection ——-
`m for treatment of epilepsy.
`I
`
`The applicant proposes marketing of Lacosamide Tablets in 6 strengths, 50 mg 100 mg, 150 mg,
`200 mg, 250 mg and 300 mg. All tablet strengths are compositionally proportional but differ
`
`with respect to film-coat color. Recommended doses
`for management of neuropathic pain, and 200 mg to 400 mg for treatment of partial onset
`seizures. The maximum dose should not exceed \ mg/day.
`
`M4)
`
`hm
`
`Drug Substance
`
`The active ingredient, lacosamide [(R)-2-acetamido-N-benzy1—3-methoxypropionamide], is a
`well characterized small molecule with molecular formula C13H18NO3 and molecular weight
`
`250.30." The drug substance is sparingly soluble in water (~30 mg/mL at 25°C)
`
`, The
`_
`_
`,
`__
`applicant classifies lacosamide as a high solubility drug according to the Biopharmaceutics
`Classification System (BCS). The calculated dose solubility volume for the highest tablet
`
`
`
`

`

`NDA 22-253.-' #4 Initial Quality Assessment
`
`[3(4)
`
`Page 2 of 10
`
`
`
` ¢$///
`/ /
`/ /
`
`3(4)
`
`

`

`NDA 22—253 =§= Initial Quality Assessment
`
`Page 3 of 10
`
`hi4)
`
`The proposed regulatory specifications for lacosamide involve straight—forward analytical
`
`procedures. A
`HPLC method ~——\_g
`
`is used for assay and determination of
`related substances.m ‘he principal
`impurity, W 1, and the w are
`controlled with limits ofNMT “Pi and WT "70,respectively. The remaining specified
`impurities are controlled at the ICE qualification threshold, NMT .—
`
`The drug substance stability package includes between 3 and 48 months of long-term data for 4‘"
`drug substance batches that were manufactured by PM:
`.or Schwarz Pharma, County
`Clare, Ireland, and are characterized by the applicant as primary stability batches. The batches
`includeW :
`
`
`Drug Product
`
`Lacosamide 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and 300 mg film-coated tablets are
`conventional, immediate-release, oval ’— tablets. The tablet formulations are
`compositionally proportional; however, the film-coat colors are different. All tablet excipients
`are commonly used for manufacture of immediate-release solid oral dosage forms. All
`
`ingredients except #1 microcrystalline cellulose
`)and the N 'film—
`
`coat formulations are compendial.
`and the \ film-coat formulations are
`manufactured using compendial ingredients. It is noted that the proposed commercial tablet
`formulations are qualitatively and quantitatively different from the 50 mg and 100 mg tablets that
`were used for Phase 3 clinical trials. The quantitative compositions for the proposed commercial
`tablets and a comparison of the 100 mg clinical tablet formulation are presented on the following
`pages. Information on the composition of the 50 mg clinical tablet formulation was not provided
`and will berequested. These composition differences are characterized by the applicant as
`minor; and a waiver of in vivo bioequivalence studies for the commercial formulation is
`requested.
`
`Lacosamide Tablets will be manufactured by Schwarz Pharma at two sites located in Zwickau,
`Germany and Seymour, Indiana.
`[Note: Although the electronic submission is formatted with
`separate P sections for each facility, all subsections for each site except P.3.2 (Batch Formula) '
`and P3 (Description of Manufacturing Process) are linked to common PDF files] The tablets
`are manufactured from WAA
`M
`
`31(4)
`
`bid}
`
`3(4)
`
`

`

`NDA 22—253/22-284 Initial Quality Assessment
`
`Page 4 of 10
`
`Composition of Proposed Commercial Lacosamide Tablets -
`
`Quantitative compositionper mandated Bible!
`50mg 100mg 150mg' 209 mg" 250‘ mg 3.00 mg
`dark
`.
`yellow
`
`Cellulosc‘
`microc smllinc
`
`Wig
`
`Crospovidone
`
`Magnesium
`steamm.
`
`
`Hydroxy-_ro, [cellulose
`
`
`
`Toml(film-
`coated tablet)
`
`
`
`V
`
`126.00
`
`252.00
`
`378.00
`
`
`
`

`

`' NDA 22—253/ 5’- lnitial Quality Assessment
`
`bKd}
`
`Pages of 10
`
`Comparison of Clinical and Commercial 100 mg Lacosamide Tablets
`
`Tablet formulations {exemplary for a 100 mg doSag'e Strength)
`
`mgmmem “
`
`Lacosamidc
`
`Act ivc Substance
`
`Clinical trial
`formulation
`
`
`
`
`
`Commercial
`formulation
`
`
`(proportional)
`
`
`
`
`
`
`
`Cellulose. nucmcrystnlline
`
`
`
`
`
`Hyprdmellose 3-H
`
`,
`
`I
`
`l
`
`
`
`Crospovidonc
`
`
`Magnesium smamtc
`
`
`
`
`
`
`
`
`
`am.
`
`The proposed regulatory specifications for Lacosamide Tablets involve straight-forward
`
`analytical procedures. A
`_ ~HPLC method is used for assay
`and determination of related substances. This method is sirnilar to the drug substance
`
`assay/related substance method;- the primary differences are
`
`,W
`
`L/\ Tablet dissolution results are quantitated by HPLC, however, the method is
`different from that used for assay and related substances. It is noted that the specification does
`
`

`

`NDA 22-253/ _—-
`
`Initial Quality Assessment
`
`M4}
`
`Page 6 of 10
`
`not include a N—Wj 7
`applicant does not include a justification for omitting of these tests.
`
`
`; bottles (60-, 180-1 ’ _F——”
`Lacosamide Tablets will be packaged in
`count) 'W CMC documentation for" packaging »
`
`configurations is provided in the submission. Draft bottle labels are provided;
`
`. The
`
`M4)
`
`The NDA stability package includes data through at least 18 months for 12 primary stability
`batches of
`‘=—-
`film—coated 50 mg, 200 mg and 300 mg Lacosamide Tablets, plus 6 batches of
`colored, film-coated 50 mg tablets. The three strengths of -—=-
`tilm-coated were chosen to»
`bracket the range of commercial strengths; the 50 mg colored tablet batches include all proposed
`commercial film—coat colors. The 50 mg colored tablet batches were added to the protocol to
`address concerns raised during End of Phase 2 discussions.
`
`“$4?
`
`Critical issues for review
`
`Drug Substance
`
`The drug substance manufacturing process involvesw
`
`51(4)
`
`Drug Product
`
`The drug product is an immediate—release tablet manufactured using conventional manufacturing
`processes. No critical issues were identified during the initial assessment; however the following
`points are noted:
`'
`
`0 A biowaiver is requested for the commercial tablet formulations.
`
`0 Although the active ingredient is the (R)-isomer, the tablet specification H kgfi
`m _
`‘:est. The application should include a justification
`for omission cf any
`-~'——
`in the product.
`
`

`

`NDA 22—253,
`
`-—-=‘
`
`Initial Quality Assessment
`
`-
`
`Page 7 of 10
`
`Additional issues
`
`Administrative: An environmental assessment for all proposed lacosamide dosage forms is
`included in Module 1 of the application. It is requested that the ONDQA Project Manager
`arrange for a'consult review.
`
`Establishment Evaluation: A full list of manufacturing sites and contract testing facilities is
`appended to the Form 356h. The sites that have been entered into EES for facility evaluation are
`listed in Attachment 1
`
`Labeling/Established Name: The active ingredient, lacosamide, is M.
`no issues related to consistency between the established name and labeled potency.
`
`There are
`
`13(4)
`
`Comments for 74-Day Letter
`
`The formulation of the 50 mg lacosamide clinical tablets is not provided in the original NDA.
`Provide the quantitative unit composition for all strengths of each formulation that was used in
`clinical studies to support this application.
`
`Container closure documentation for w oottles is
`provided in the application. W—
`m
`
`be;
`
`Review, Comments and Recommendation:
`
`The NDA is fileable from a CMC perspective. The drug substance is a well-characterized small
`molecule and the dosage form is relatively simple. As the applicant has submitted concurrent
`NDAs for an intravenous formulation (22-254: M it is recommended that a
`team review of the “applications be performed. At least one reviewer should have
`appropriate biopharrnaceutics experience and qualifications to review the biowaiver request for
`the commercial tablets. No novel manufacturing processes are involved and the submission does
`not appear to require a review by the Manufacturing Sciences Branch.
`
`31(4)
`
`
`Martha R. Heimann Ph.D.
`Pharmaceutical Assessment Lead
`
`
`Ramesh Sood Ph.D.
`Branch Chief
`
`Date
`
`Date
`
`

`

`M4)
`
`NDA 22-2531 =9;-
`
`lnitial Quality Assessment -
`
`ATTACHMENT 1
`
`Manufacturin 1
`
`Facility Information
`
`Sites for Lacosamide Tablets
`
`
`Function
`
`
`
`
`
`
`
`SCHWARZ PHARMA Limited
`Drug substanCe release and stability testing
`Shannon Industrial Estate
`
`Shannon; Co. Clare
`
`Ireland
`
`Registration No.: 3002808160
`Site Contact: Daniel J. Dooley
`
`Tel. No.: +353 61 714234
`
`
`US Agent: Ruth Hill
`Phone: 919 767 2634
`
`
`SCHWARZ PHARMA Produktions GmbH
`Galileistrasse 6
`
`08056 Zwickau
`
`Drug product manufacture
`
`Germany
`
`
` Drug substance release testing
`
`
`Registration No.: 3002948883
`
`Site Contact: Wilhelm Lehr
`Tel. No.: +49 375 322 300
`
`
`
`US Agent: Ruth Hill
`Phone: 919 767 2634
`
`
`
`Drug substance retest
`Drug product manufacture, packaging, release
`
`and stability testing
`
`
`
`
`
`SCHWARZ PHARMA Manufacturing
`1101 C Avenue West
`
`Seymour, IN 47274
`
`Registration No.: 1819171
`Site Contact: Chad Kurdziel
`Te1.No.: 812 523 5396
`
`

`

`NDA 22-253l’ #— . Initial Quality Assessment
`
`Wei
`
`ATTACHMENT 1
`
`Manufacturin_ Sites for Lacosamide Tablets
`
`Facility Information
`
`M4)
`
`
`
`SCHWARZ PHARMA Produktions GmbH
`Alfred-Nobel-Strafie 10
`40789 Monheim am Rhein
`
`Drug product stability testing
`
`Germany
`
`Registration No.: 3002943 189
`Site Contact: Werner Schick
`Tel. No.: +49 2173 48 1178
`
`US Agent: Ruth Hill
`Phone: 919 767 2634
`
`APPEARS THlS WAY
`
`0N ORIGENAL
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/ 5/
`
`Blair Fraser
`7/16/2008 11:07:39 AM
`CHEMIST
`
`

`

`lof4
`
`VimpatTM
`(lacosamide)
`Tablets
`
`NDA 22-253
`
`Division Director Review
`
`Chemistry, Manufacturing, and Controls
`
`Applicant:
`
`Schwarz Biosciences, Inc.
`8010 Arco Corporate Drive, Suite 100
`Raleigh, NC 27617
`
`Indication:
`
`adjunctive treatment of partial-onset seizures in patients with epilepsy,
`aged 16 years and older
`‘
`
`
`
`, immediate release, tablets are available in
`Presentation: Film-coated, colored, oval,
`six strengths (50 mg — pinkish; 100 mg — dark yellow; 150 mg — salmon; 200 mg
`— blue; 250 mg — _-~ ,, and 300 mg — \ , debossed with V“SP” on one side
`and tablet strength on the other side.
`'
`
`Tablets of all strengths are packaged in ———’-’—'— bottles, at 60, 180,
`/—-”‘—“ count.
`
`31(4)
`
`M4}
`
`EER Status:
`
`Consults:
`
`Pending
`
`15-MAY-2008
`No significant impact
`EA — OPS
`Methods Validation — Revalidation by Agency not requested.
`
`Original Submission:
`
`27—SEP-2007
`
`Post-Approval Agreements:
`Background:
`I
`
`None
`
`This application was chosen by the Division of Neurology Products to serve as the pilot
`for the Good Review Management Principles and Practices (GRMPs) for PDUFA
`Products (April 2005).
`
`Drug Substance:
`
`Lacosamide is a member of a seriesbf fimctionaliZed amino acids that were specifically
`synthesized as anticonvulsive drug candidates. The drug substance, lacosamide, is a small,
`synthetic, New Molecular Entity (NME) with an empirical formula of C13H18N203 and a
`molecular weight of 250.30 . Known chemically as (R)—2-acetamido-N-benzy1—3-
`
`M4)
`
`

`

`20f4
`
`“4)
`
`”(4)
`
`it is a white to light yellow powder with a melting range of NA
`methoxypropionamide,
`LacosamidelS sparingly soluble1n waterM
`LiW and slightly soluble in ethanol.
`Lacosamide, a chiral drug substance, m
`
`
`‘ .
`
`_
`
`The bulk drug substance1s synthesized fi'om ———————;———_\_
`\——— .Comprehensive information for all the impurities at the starting material level,
`at the intermediate level and at the final synthesis level was presented. Noteworthy were
`controls over nae,“
`of starting materials and intermediates.
`
`’—=~=—
`The structure of lacosamide was elucidated using several analytical and
`techninnec
`
`
`/ // / //
`
`The proposed release specification for lacosamide include.c
`
`
`
`W The proposed regulatory methods are either compendial or were
`developed and validated for their intended purpose. The primary reference standard for drug
`substance, manufactured by commercial process, has beencharacterized by the proposed
`regulatory methods as well as additional methods. The impurity and degradation profiles have
`been investigated. Reference standards for known impurities and in-process intermediates have
`been synthesized and fully characterized.
`
`The stability data for three commercial batches support a / retest period for the bulk
`drug substance stored insideW [1(4}
`fl at controlled room temperature, 25°C /60%RH, protected from light.
`
`Conclusion:
`
`. Drug substance is acceptable.
`
`Drug Product:
`
`/—’ immediate release, tablets
`Vimpat (lacosamide) tablets are film-coated, colored, oval,
`available1n six strengths (50 mg— pinkish; 100 mg— dark yellow, 150 mg — salmon; 200 mg —
`blue, 250 mg ~ g and 300 mg —
`debossed with “SP” on one side and tablet
`strength on the other side. Tablets of all strengths are packaged1n ' f—A bottles,
`“N sizes, at 60, 180, ”count.
`
`”4)
`
`

`

`3of4
`
`[3(4)
`
`The drug product is manufactured
`
`' _
`
`_
`
`-
`
`,
`
`W L
`
`
`, and final packaging. Adequate information on the drug
`/‘ '
`product manufacture has been provided.
`
`The composition of the 50 mg strength, oval tablet is lacosamide (50.00 mg), microcrystalline
`
`cellulose NF t
`~
`\
`
`_
`,,
`.
`V
`, crospovidone NF f ~———-4, magnesium stearate NF
`
`hypromellose USP
`<7 ' v
`o——-;. Folowing
`‘ w-s
`H—M film-coating, the total film—coated tablet weight was 126.00 mg. The higher strength
`tablets are sequential weight multiples of the lowest strength giving rise to compositionally
`proportional formulations.
`
`“(4)
`
`The sponsor has submitted adequate information to support classification of lacosamide tablets
`as a BCS class 1 drug, i.e. the drug substance is highly soluble, highly permeable. Accordingly,
`Dr. A. Selen, Associate Director, Biopharmaceutics, ONDQA, concluded in her review, dated
`04-Apr-2008, that the sponsor’s dissolution method and their biowaiver requests are acceptable.
`
`The release specification for drug product includes;A b“)
`
` ,
`
`The
`_
`_
`_
`lacosamide reference standard for drug product is the same as'that for drug substance. The
`proposed regulatory methods are either compendial or were developed and validated for their
`intended purpose.
`
`The stability data support expiration dating of 36 months for all strengths of drug product stored
`at controlled room temperature conditions [25° C (77° F); excursion permitted to 15-3 0" C (59-
`86" F)], and packaged in HDPE bottles.
`
`Conclusion: Drug product is acceptable.
`
`Additional Items:
`
`‘ / /. / /
`
`/ ll w
`
`

`

`4of4
`
`MW 31(4)
`r---v-v-v
`
`o All associated Drug Master Files (DMFs) are acceptable or the pertinent information has
`been adequately provided in the application.
`
`0 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,
`Pending a satisfactory recommendation from the Office of Compliance.
`
`Blair A. Fraser, Ph.D.
`Director
`
`DPA I/ONDQA
`
`”was nus WAY
`ma {)RlGlNAL
`
`

`

`This is a representation-of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Blair Fraser
`
`5/27/2008 01:16:22 PM
`CHEMIST
`
`

`

` . CHEMISTRY REVIEW
`
`NDA 22-254
`
`Lacosamide Injection
`
`Schwarz Biosciences, Inc.
`
`Wendy 1. Wilson, Ph; D.
`Office of New Drug Quality Assessment
`for Division of Neurology Drug Products
`
`

`

`CHEMISTRY REVIEW
`
`Table of Contents
`
`Table of Contents2
`
`Chemistry Review DataSheet3
`
`List ofTables6
`
`List of Figures8
`
`The ExecutiveSummary9
`
`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
`
`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 0r Not-Approval Recommendation .......................................................................... 10
`
`III. Administrative ........................................................................................................................ 1 1
`
`A. Reviewer’s Signature ..................................................................................................................................... 11
`
`B. Endorsement Block ......................................................................................................................................... II
`
`C. CC Block ........................................................................................................................................................ 11
`
`Chemistry Assessment
`
`12
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3: ................................ 12
`
`
`S
`
`DRUG SUBSTANCE [Lacosamidq
`
`,
`
`_
`
`....................................................................... 12
`
`31(4)
`
`........................................................... 15
`P DRUG PRODUCT [Lacosamide-Injection, 'N .7
`A APPENDICES .............................................................................................................................................. 51
`
`R REGIONAL INFORMATION ..................................................................................................................... 51
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 .................................. 53
`
`A. Labeling & Package Insert ...............
`
`........................................................ 53
`
`B. Environmental Assessment or Claim ofCategorical Excluswn ................. 55
`
`C. Establishment Inspection ................................................................................................................................. 55
`
`III. List OfDeficiencies to be Communicated ................................................ 56
`
`IV. Approval Letter Comments ..................................................................................................... 56
`
`

`

`
`CHEMISTRY REVIEW '
`Chemistry Review Data Sheet
`
`Chemistry Review Data Sheet
`
`1. NDA:
`
`22-254
`
`2. REVIEW #1
`
`01
`
`3. REVIEW DATE:
`
`l9-MAY-2008
`
`4. REVIEWER:
`
`i Wendy 1. Wilson, Ph. D.
`
`5. PREVIOUS DOCUMENTS:
`
`None
`
`N/A
`
`Previous Documents
`
`Document Date
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`Submission 3 Reviewed
`
`Document Date
`
`Original
`Amendment
`
`Amendment
`
`'
`
`'
`
`28-SEP—2007
`22-APR-2008
`
`14-MAY—2008
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`8010 Arco Corporate Drive, Suite 100, Raleigh, NC 27617
`
`Schwarz Biosciences, Inc.
`
`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):
`
`Lacosamide
`SPM 927
`
`0 Chem. Type:
`
`0 Submission Priority:
`
`1
`
`S
`
`9. LEGAL BASIS FOR SUBMISSION:
`
`505 (b)(1)
`
`10. PHARMACOL. CATEGORY:
`
`Anticonvulsant
`
`11. DOSAGE FORM:
`
`Injection, Solution
`
`12. STRENGTH/POTENCY:
`
`200 mg
`
`13. ROUTE OF ADMINISTRATION:
`
`Intravenous
`
`Page 3 of 56
`
`

`

`
`
`
` CHEMISTRY REVIEW
`
`Chemistry Review Data Sheet
`
`14. Rx/OTC DISPENSED:
`
`l_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:
`MOI. Formula:
`M01. Weight:
`
`(R)—2-acetamido—N-benzyl-3-methoxypropionamide
`C13H18NO3
`250.30
`
`0
`
`#1,?
`\T
`i)
`
`{l
`
`,
`
`‘
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. DMFs:
`
`H
`‘N/\{/\‘\“<~1
`’\\74’;
`
`E
`
`G
`3m,
`
`
`
`
`
`DATE REVIEW
`I CODEl
`HOLDER
`ITEM REFERENCED
`
`STATUS2
`COMMENTS
`
`COMPLETED
`
`
` 26-MAR—2007
`Adequate.
`
`N/A
`
`
`16-AUG-2007
` Adequate.
`
`
`but
`
`1 Action codes for DMF Table:
`1 — DMF Reviewed.
`
`Other codes indicate why the DMF was not reviewed, as follows:
`2 —Type I 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)
`
`B. Other Documents:
`
`
`DESCRIPTION
`
`
`
`
`
`ADD 234037 for Treatment of Epilepsy
`
`
` SPM 927 (formerly Harkoseride) for Treatment of Neuropathic Pain
`
`SPM 927 (formerly ADD 234037) for Treatment ofEpilepsy
`
`
`
`Lacosamide (formerly SPM 927) for Treatment of Epilepsy
`
`
`
`
`
`Page 4 of56
`
`

`

`
`
` CHEMISTRY REVIEW.
`
`Chemistry Review Data Sheet
`
`18. STATUS:
`
`CONSULTS/ CMC RELATED
`
`REVIEWS
`RECOMMENDATION
`DATE
`REVIEWER
`N/A
`Biometrics
`
`N/A
`
`——_—
`Pending
`J Edward Fisher
`
`
`
`LNC
`
`Methods Validation
`
`Validation by FDA not needed
`
`05-MAR-2008
`
`DMETS
`
`No objection to use of Vipmat as proprietary narne
`
`13-MAY-2008
`
`Pending
`
`Microbiology
`
`Page 5 of 56
`
`

`

`
`
`Chemistry Review Data Sheet
`
`List of Tables
`
`M4)
`
`.......................................... 12
`.......................................... 14
`........................................... 15
`............................................ 16
`............................................. 17
`.................................. 18
`................................... 19
`..................................... 23
`...................................... 23
`......................................... 23
`................................... 24
`.............................. 25
`............................... 27
`................................. 28
`.................................. 28
`................................... 29
`............ 30
`............ 30
`............ 31
`............ 32
`.............. 35
`................ 36
`.................... 37
`................... 37
`................... 38
`.................... 38
`...................... 39
`........................ 39
`.................................. 4o
`.................................. 4o
`.................................. 4o
`
`................................. 42
`.......... 42
`........... 42
`........... 43
`............ 44
`........ 45
`45
`45
`45
`46
`.46
`47
`
`.49
`
`..50
`
`
`
`Page 6 0f56
`
`

`

`
`
` CHEMISTRY REVIEW
`
`
`
`Chemistry Review Data Sheet
`
`N4)
`
`/
`
`/
`
`/
`
`.5555555552
`
`APPEARS nus WAY
`0N ORIGINAL
`
`Page 7 of 56
`
`

`

`
` CHEMISTRY REVIEW V
`
`
`Chemistry Review Data Sheet
`
`List of Figures
`
`26
`
`.48
`
`M4)
`
`.y49
`53
`53
`.................................... 54
`.................................... 55
`
`EFFEARS THIS WAY
`0N GRIGINAL
`
`Page 8 0f56
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`Executive Summary Section
`
`Chemistry Review for NDA 22-254
`
`The Executive Summary
`
`1. Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`From a CMC perspective, lacosamide injection (10 mg/mL) is approvable (AE) pen