`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208082Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`‘505(b)(2) ASSESSMENT
`
`Efficacy Supplement Type SE-
`NDA Supplement #: S-
`NDA # 208082
`
`
`
`
`Proprietary Name: Austedo
`Established/Proper Name: deutetrabenazine
`Dosage Form: Oral Tablets
`Stren hs: 6 m, 9 m, and 12 m
`
`Applicant: Teva Pharmaceuticals
`
`Date of Receipt: 10/3/16
`
`Action Goal Date (if different):
`PDUFA Goal Date: 4/3/17
`
`
`RPM: Stacy Metz. PhannD
`Proposed Indication(s): Treatment of chorea associated with Huntington’s disease
`
`GENERAL INFORMATION
`
`1)
`
`Is this application for a recombinant or biologically-derived product and/or protein or peptide
`product OR is the applicant relying on a recombinant or biologically-derived product and/or
`protein or peptide product to support approval of the proposed product?
`
`YES|:| NOE
`
`If "YES “contact the (b)(2) review staflin the Immediate Oflice, Oflice ofNew Drugs.
`
`Reference ID: 4078351
`
`Page 1
`Version: Jammly 2015
`
`

`

`INFORMATION PROVIDED VIA RELIANCE
`(LISTED DRUG OR LITERATURE)
`
`2) List the information essential to the approval of the proposed drug that is provided by reliance
`on our previous finding of safety and efficacy for a listed drug by reliance on published
`literature, or by reliance on a final OTC monograph. (If not clearly identified by the
`applicant, this information can usually be derived from annotated labeling.)
`
`Source of information* (e.g.,
`published literature, name of listed
`drug(s), OTC final drug
`monograph)
`Xenazine (tetrabenazine) tablets,
`12.5 mg and 25 mg (NDA 21894)
`
`Information relied-upon (e.g., specific
`sections of the application or labeling)
`
`Clinical studies information.
`Clinical Pharmacology information.
`Non-Clinical Toxicology information.
`Post-marketing data
`
`3) The bridge in a 505(b)(2) application is information to demonstrate sufficient similarity
`between the proposed product and the listed drug(s) or to justify reliance on information
`described in published literature for approval of the 505(b)(2) product. Describe in detail how
`the applicant bridged the proposed product to the listed drug(s) and/or published literature1.
`See also Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug
`and Biological Products.
`
`The sponsor’s reliance on FDA’s finding of safety and effectiveness for Xenazine is for nonclinical
`chronic toxicity, carcinogenicity, and reproductive toxicology information, and some clinical
`pharmacology information referenced in the Xenazine label such as additional in vitro drug-drug
`interactions. The Sponsor was unable to obtain the listed drug, Xenazine, to complete BA/BE
`studies that directly compared SD-809 to Xenazine. The Sponsor’s bridging strategy compared
`human PK data from patients enrolled in clinical study SD-809-C-16. Patients entered the study
`taking a stable dose of Xenazine. PK samples were drawn at baseline while they were on a
`stable dose of Xenazine on the day before switching to SD-809, and a second set of PK samples
`were drawn after switching patients to an equivalent, stable dose of SD-809 expected to be
`similar to their prior Xenazine dose. The Cmax of the active α-HTBZ and β-HTBZ metabolites
`from SD-809 were below the Cmax of the active metabolites from Xenazine. Additionally in this
`study, efficacy was evaluated using the Unified Huntington Disease Rating Scale (UHDRS) Total
`Maximal Chorea (TMC) score. Patients who switched overnight from Xenazine to SD-809
`experienced no loss in control of chorea compared to Xenazine, as assessed by the mean UHDRS
`TMC score, through Week 1.
`
`The SD-809 NDA included additional clinical pharmacology information typically required for a
`505(b)(1) NDA including a Mass Balance Recovery Study in healthy volunteers, in vitro and in
`vivo Drug-Drug interaction studies of SD-809 and several of its’ metabolites.
`
`RELIANCE ON PUBLISHED LITERATURE
`
`1For 505(b)(2) applications that rely on a listed drug(s), bridging studies are often BA/BE studies comparing the proposed product to the listed drug(s) Other examples include: comparative
`physicochemical tests and bioassay; preclinical data (which may include bridging toxicology studies); pharmacokinetic/pharmacodynamic (PK/PD) data; and clinical data (which may
`include immunogenicity studies) A bridge may also be a scientific rationale that there is an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the listed drug(s)
`For 505(b)(2) applications that rely upon literature, the bridge is an explanation of how the literature is scientifically sound and relevant to the approval of the proposed 505(b)(2) product
`Page 2
`
`Reference ID: 4078351
`
`Version: January 2015
`
`

`

`4)
`
`(a) Regardless ofWhether the applicant has explicitly stated a reliance on published literature
`to support their application. is reliance on published literature necessary to support the
`approval of the proposed drug product (i.e., the application cannot be approved as labeled
`without the published literature)?
`
`NO X
`|:|
`YES
`If “N0, ” proceed to question #5.
`
`(b) Does any of the published literature necessary to support approval identify a specific (e. g..
`brand name) listed drug product?
`
`NO [:I
`I]
`YES
`If “N0”, proceed to question #5.
`If “YES list the listed drug(s) identified bv name and answer question #4(c).
`
`(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)?
`YES
`I]
`NO |:|
`
`'For505(b)(2)appliationsthatrdyonalisbddmfis),lnidgingsmdifimoflmBA/BEstudimoompmingtheproposedprodimtoflxlismddmgs) ounmmplesincmdezcompmatiw
`physioochcmicaltestsandbioassay, pmclinicaldm(whichmayim‘ludelnidgingt-ulogy studies);pharmacokinetidpharmzcodynamic (PK/PD) data; anddiniealdata (which may
`inchuleimnnmgmicilystmfis) Abn'dgemayalsobeasciemificntinmlethatfincismmmfmrdimwonmA‘sfimfingofsafitymdcflkfimofflnWMgfi)
`For505(b)(2)applieationsthanelqu)onlimm,mebridgcismeimlanatimofhowmelitemnrcisscimfificzllysomd andrelcvanttothcappmvalofflieprmdSOSwflwrodud
`Page 3
`
`Reference ID: 4078351
`
`Version: Jammljv 2015
`
`

`

` RELIANCE 0N LISTED DRUG(S)
`
`Reliance on published literature which identifies a specific approved (listed) drug constitutes
`reliance on that listed drug. Please answer questions #5-9 accordinglv.
`
`5) Regardless of whether the applicant has explicitly cited reliance on listed drug(s). does the
`application rely on the finding of safety and effectiveness for one or more listed drugs
`(approved drugs) to support the approval of the proposed drug product (i.e.. the application
`cannot be approved without this reliance)?
`
`NO |:|
`YES X
`If “N0, ”proceed to question #10.
`
`6) Name of listed drug(s) relied upon. and the NDA #(s). Please indicate if the applicant
`explicitly identified the product as being relied upon (see note below):
`
`Name of Listed Drug
`
`NDA #
`
`Xenazine (tetrabenazine) tablets. 12.5 mg and
`
`Did applicant
`specify reliance on
`the roduct? (Y/N)
`
`Applicants should specifv reliance on the 356h, in the cover letter, and/or with theirpatent
`certification/statement. Ifyou believe there is reliance on a listedproduct that has not been
`explicitlv identified as such by the applicant, please contact the (b)(2) review staflin the
`Immediate Ofl‘ice, Ofiice ofNew Drugs.
`
`7)
`
`If this is a (b)(2) supplement to an original (b)(2) application. does the supplement rely upon
`the same listed drug(s) as the original (b)(2) application?
`N0 D
`YES I]
`N/A X
`Ifthis application is a (b)(2) supplement to an original (b)(l) application or not a supplemental
`application, answer “N/A ”.
`If "N0 ”, please contact the (b)(2) review staflrin the Immediate Ofiice, Oflice ofNew Drugs.
`
`8) Were any of the listed drug(s) relied upon for this application:
`a) Approved in a 505(b)(2) application?
`
`NO E
`|:|
`YES
`If “YES please list which drug(s).
`Name of drug(s) approved in a 505(b)(2) application:
`
`b) Approved by the DESI process?
`
`NO [3|
`YES E]
`If "IT ”, please list which drug(s).
`Name of drug(s) approved via the DESI process:
`
`c) Described in a final OTC drug monograph?
`
`YES
`
`|:|
`
`NO E
`
`Page 4
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`
`Reference ID: 4078351
`
`

`

`If ”YES ”, please list which drug(s).
`
`Name of drug(s) described in a final OTC drug monograph:
`
`d) Discontinued from marketing?
`
`NO E
`|:|
`YES
`If “YES”, please list which drug(s) and answer question (1) i. below.
`If "N0", proceed to question #9.
`
`Name of drug(s) discontinued from marketing:
`
`i) Were the products discontinued for reasons related to safety or effectiveness?
`YES
`I]
`NO [:|
`(Information regarding whether a drug has been discontinuedfrom marketingfor
`reasons ofsafety or eflectiveness may be available in the Orange Book. Refer to
`section 1.11 for an erplanation, and section 6.1 for the list ofdiscontinued drugs. If
`a determination ofthe reasonfor discontinuation has not been published in the
`Federal Register (and noted in the Orange Book), you will need to research the
`archivefile and/or consult with the review team. Do not rely solely on any
`statements made by the sponsor.)
`
`9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for
`example, “This application provides for a new indication, otitis media” or “This application
`provides for a change in dosage form, from capsule to solution”).
`
`Proposed product is a different active ingredient and potency.
`
`The purpose ofthefollowing two questions is to determine Ifthere is an approved drugproduct
`that is equivalent or very similar to the product proposedfor approval that should be referenced
`as a listed drug in the pending application.
`
`The assessment ofpharmaceutical equivalencefor a recombinant or biologically—derived product
`and/or protein or peptide product is complex. Ifyou answered YES to question #1, proceed to
`question #12; ifyou answered NO to question #1, proceed to question #10 below.
`
`10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)
`application that is already approved (via an NDA or ANDA)?
`
`(Pharmaceutical equivalents are drug products in identical dosageforms intendedfor the
`same route ofadministration that: (1) contain identical amounts ofthe identical active drug
`ingredient, i.e., the same salt or ester ofthe same therapeutic moiety, or, in the case of
`modified release dosageforms that require a reservoir or average or such forms as prefilled
`syringes where residual volume may vary, that deliver identical amounts ofthe active drug
`ingredient over the identical dosing period; (2) do not necessarily contain the same inactive
`ingredients; m (3) meet the identical compendial or other applicable standard ofidentity,
`strength, quality, andpurity, including potency and, where applicable, content uniformity,
`disintegration times, and/or dissolution rates. (21 CFR 320.1 (c), FDA ’s "Approved Drug
`Products with Therapeutic Equivalence Evaluations " (the Orange Book».
`
`Note thatforproposed combinations ofone or more previously approved drugs, a phatmaceutical
`equivalent must also be a combination ofthe same drugs.
`
`Reference ID: 4078351
`
`Page 5
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`
`

`

`YES
`
`[I NOE
`
`If "NO ” to (a) proceed to question #11.
`If ”YE " to (a), answer (b) and (c) then proceed to question #12.
`
`(b) Is the pharmaceutical equivalent approved for the same indication for which the
`505(b)(2) application is seeking approval?
`
`YESD N0|:|
`
`(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent?
`N/A E]
`YES |:|
`NO [:I
`
`Ifthis application relies only on non product-specific published literature, answer “N/A ”
`1f "YE ” to (c) and there are no additionalpharmaceutical equivalents listed, proceed to
`question #12.
`If “N0 ” g ifthere are additional pharmaceutical equivalents that are not referenced by the
`application, list the NDA pharmaceutical equivalent(s); you do M have to individually list all
`ofthe products approved as ANDAs, but please note below ifapproved approved generics are
`listed in the Orange Book. Please also contact the (b)(2) review staflin the Immediate Ofiice,
`Oflice ofNew Drugs.
`
`Pharmaceutical equivalent(s):
`
`11) (a) Is there a pharmaceutical altemative(s) already approved (via an NDA or ANDA)?
`
`(Pharmaceutical alternatives are drugproducts that contain the identical therapeutic moiety, or its
`precursor, but not necessarily in the same amount or dosageform or as the same salt or ester. Each
`such drugproduct individually meets either the identical or its own respective compendial or other
`applicable standard ofidentity, strength, quality, andpulity, includingpotency and, where applicable,
`content uniformitv, disintegration times and/or dissolution rates.
`(21 CFR 320.1(d)) Dilferent dosage
`forms and strengths within a product line by a single manufacturer are thus pharmaceutical
`alternatives, as are attended—release products when compared with immediate— or standard—release
`formulations ofthe saute active ingredient.)
`
`Note thatforproposed combinations ofone or more previously approved drugs, a pharmaceutical
`alternative must also be a combination of the same drugs.
`
`NO X
`YES E]
`If “N0", proceed to question #12.
`
`(b) Is the pharmaceutical alternative approved for the same indication for which the
`505(b)(2) application is seeking approval?
`
`YES
`
`|:|
`
`N0 |:|
`
`(c) Is the approved pharmaceutical altemative(s) referenced as the listed drug(s)?
`N/A [:1
`YES I]
`
`NO D
`
`Ifthis application relies only on non product-specific published literature, answer “N/A ”
`If "YE ” and there are no additional pharmaceutical alternatives listed, proceed to question
`#1 2.
`
`Reference ID: 4078351
`
`Page 6
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`
`

`

`If ”N0 ” o_r ifthere are additional pharmaceutical alternatives that are not referenced by the
`application, list the NDA pharmaceutical alternative(s),' vou do i_iot have to inditidually list all
`ofthe products approved as ANDAs, but please note belon ifapproved generics are listed'in
`the Orange Book. Please also contact the (b)(2) review staflrin the Immediate Ofli‘ce, Oflice of
`New Drugs.
`
`Pharmaceutical altemative(s):
`
`
`PATENT CERTIFICATION/STATEMENTS
`
`12) List the patent nmnbers of all unexpired patents listed in the Orange Book for the listed
`drug(s) for which our finding of safety and effectiveness is relied upon to support approval of
`the (b)(2) product.
`
`Listed drug/Patent number(s):
`
`No patents listed E proceed to question #14
`
`13) Did the applicant address (with an appropriate certification or statement) all of the unexpired
`patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the
`(b)(2) product?
`
`NO [:I
`YES E]
`If “N0”, list which patents (and which listed drugs) were not addressed by the applicant.
`
`Listed dIug/Patent number(s):
`
`14) Which of the following patent certifications does the application contain? (Check all that
`apply Ml identifi! the patents to which each tjpe ofcertification was made, as appropriate.)
`
`E] No patent certifications are required (e.g.. because application is based solely on
`published literature that does not cite a specific innovator product)
`
`E 21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to
`FDA. (Paragraph I certification)
`
`E]
`
`21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)
`
`Patent number(s):
`
`E]
`
`21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph
`III certification)
`
`Patent nmnber(s):
`
`Expiry date(s):
`
`E]
`
`21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid unenforceable or will not be
`infringed by the manufacture use or sale of the drug product for which the
`application15 submitted. (Paragraph IV certification). IfParagraph IV certification
`was submitted, proceed to question #15.
`
`Page 7
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`
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`
`

`

`E]
`
`21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the
`NDA holder/patent owner (must also submit certification lmder 21 CFR
`314.50(i)(l)(i)(A)(4) above). Ifthe applicant has a licensing agreement with the
`NDA holder/patent owner, proceed to question #15.
`
`[:l
`
`21 CFR 314.50(i)(l)(ii): No relevant patents.
`
`E]
`
`21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent
`and the labeling for the drug product for which the applicant is seeking approval
`does not include any indications that are covered by the use patent as described in
`the corresponding use code in the Orange Book. Applicant must provide a
`statement that the method of use patent does not claim any of the proposed
`indications. (Section viii statement)
`
`Patent number(s):
`Method(s) of Use/Code(s):
`
`15) Complete the following checklist ONLY for applications containing Paragraph IV
`certification and/or applications in which the applicant and patent holder have a licensing
`agreement:
`
`(a) Patent number(s):
`(b) Did the applicant submit a signed certification stating that the NDA holder and patent
`owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]?
`N0 D
`YES
`I]
`If “N0 ”, please contact the applicant and request the signed certification.
`
`(c) Did the applicant submit documentation showing that the NDA holder and patent
`owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the
`form of a registered mail receipt.
`
`NO [I
`|:|
`YES
`If "N0”, please contact the applicant and request the documentation.
`
`(d) What is/are the date(s) on the registered mail receipt(s) (i.e.. the date(s) the NDA holder
`and patent owner(s) received notification):
`
`Date(s):
`
`Note, the date(s) entered should be the date the notification occurred (i. e., delivery
`date(s)), not the date ofthe submission in which proofofnotification was provided
`
`(e) Has the applicant been sued for patent infiingement within 45-days of receipt of the
`notification listed above?
`
`Note that you may need to call the applicant (after 45 days ofreceipt ofthe notification)
`to verifv this information UNLESS the applicant provided a written statementfrom the
`notified patent owner(s) that it consents to an immediate eflectii'e date ofapproval.
`
`YES D NO |:| Patent owner(s) consent(s) to an immediate effective date of
`approval
`
`|:|
`
`Page 8
`Version: Janualy 2015
`
`Reference ID: 4078351
`
`

`

`Reference ID: 4078351
`
`Page 9
`Version: January 2015
`
`APPEARS THIS 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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`STACY M METZ
`03/31/2017
`
`Reference ID: 4078351
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`March 28, 2017
`Requesting Office or Division:
`Division of Neurology Products (DNP)
`Application Type and Number: NDA 208082
`Product Name and Strength:
`Austedo (deutetrabenazine) tablets
`6 mg, 9 mg, 12 mg
`March 22, 2017
`Teva Pharmaceuticals
`2016-2844-2
`Chad Morris, PharmD, MPH
`Lolita White, PharmD
`
`Submission Date:
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA Primary Reviewer:
`DMEPA Team Leader:
`
`PURPOSE OF MEMO
`1
`The Division of Neurology Products requested that we review the container labels for Austedo
`(deutetrabenazine) tablets (Appendix A) to determine if it is acceptable from a medication error
`perspective. The request is in response to the division’s decision, since the completion of our
`previous label and labeling reviewa, to require a Medication Guide (MG).
`2
` ASSESSMENT
`On March 24, 2017, the division informed DMEPA that Austedo (deutetrabenazine) would be
`dispensed with a MG. We reviewed the container labels submitted on March 22, 2017 and
`note the container labels lack the medication guide statement required by 21 CFR 208.24(d).
`3
`CONCLUSION / RECOMMENDATIONS
`The revised container labels are unacceptable from a medication error perspective. The
`product will be dispensed with a Medication Guide (MG); therefore, each container or package
`shall instruct the authorized dispenser to provide a MG to each patient and shall state how that
`MG is provided. We provide recommendations for Teva in Section 3.1.
`
`a Morris, C. Label and Labeling Review for Austedo (deutetrabenazine) (NDA 208082). Silver Spring (MD): Food and
`Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of
`Medication Error Prevention and Analysis (US); 2017 MARCH 16. 11 p. OSE RCM No.: 2016-2844
`1
`
`Reference ID: 4075854
`
`

`

`3.1 RECOMMENDATIONS FOR TEVA
`We recommend the following be implemented prior to approval of this NDA 208082:
`1. Your product will be dispensed with a Medication Guide (MG). Each container or
`package shall therefore instruct the authorized dispenser to provide a MG to each patient
`and shall state how that MG is provided. Add a statement similar to the statements copied
`below to the principle display panel of the carton labeling in accordance with 21 CFR
`208.24(d).
`a)
`“Attention Pharmacist: Dispense the enclosed Medication Guide to each
`patient.” or
`“Attention Pharmacist: Dispense the accompanying Medication Guide to each
`patient.”
`
`b)
`
`Reference ID: 4075854
`
`2
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`APPENDIX A.
`
`CONTAINER LABELS SUBMITTED BY TEVA ON MARCH 22, 2017
`
`
`
`Reference ID: 4075854
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN C MORRIS
`03/28/2017
`
`LOLITA G WHITE
`03/28/2017
`
`Reference ID: 4075854
`
`

`

`CSS Consult: Austedo'IM (deutetrabenazine) NDA 208082
`
`
`
`M E M O R A N D U M
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`March 27, 2017
`
`Billy Dunn, M.D., Director
`Division of Neurology Products
`
`From:
`
`Martin S. Rusinowitz, M.D., Senior Medical Officer
`
`Silvia Calderon, Ph.D., Senior Pharmacologist
`Controlled Substance Staff
`
`Subject:
`
`NDA 208082
`
`Name: Austedo, (deutetrabenazine, SD-809, d6-tetrabenazine)
`Indication: Chorea associated with Huntington’s disease (HD)
`Dosage: 6-mg, 9—mg, and 12-mg tablets
`Proposed dosage range is 6 mg to 48 mg per day with a starting dose of 6
`mg once daily and all doses above (mm are administered in two divided
`doses
`
`Sponsor: Auspex Pharmaceuticals (previous) / Teva Pharmaceuticals,
`Inc.(current)
`
`Materials
`
`reviewed:
`
`NDA 20802 EDR May 29, 2014
`CR letter May 27, 2016
`CSS review by A. Lerner March 8, 2016 (in DARRTS)
`Meeting Minutes Sep 20, 2016
`Sponsor resubmission EDR Oct 3, 2016
`Sponsor’s request for clarification Dec 20, 2016
`
`BACKGROUND
`
`The Sponsor is developing Austedo (SD-809SD-809, deutetrabenazine; d6-tetrabenazine) as a
`treatment for chorea associated with HD, a neurodegenerative genetic autosomal dominant
`neuropsychiatfic disorder characterized by progressive decline of motor and cognitive flmctions.
`Austedo is a vesicular monoamine transporter 2 (VMAT2) inhibitor which is structurally related
`to tetrabenazine.
`
`Reference ID: 4075739
`
`10f3
`
`

`

`CSS Consult: AustedoTM (deutetrabenazine) NDA 208082
`
`This memorandum responds to a consult request from the Division of Neurology Products
`(DNP) to reply to the Sponsor’s request for clarification (Dec 20, 2016, sequence 0030) of CSS’s
`recommendations in DNP’s CR letter (May 27, 2016) to evaluate dependence, withdrawal and
`rebound, after abrupt discontinuation of deutetrabenazine.
`
`The Sponsor received a CR letter on May 27, 2016, after submission of a 505(b) (2) New Drug
`Application for Austedo (deutetrabenazine, SD-809), with Xenazine (NDA 021894,
`tetrabenazine) as the reference listed drug. In that letter CSS requested the Sponsor evaluate
`dependence, withdrawal and rebound at the conclusion of Study ARC-HD (SD-809-C-16). This
`request was a result of sparse clinical withdrawal data along with evidence of possible rebound
`in the first week follow-up after Study SD-809-C-15 First HD ended.
`
`During a Type A meeting (Sep 20, 2016) the Sponsor had the following question for CSS:
`
`Clarification Question for CSS:
`
`Specifically, the team (at TEVA) would like further information on the statement highlighted
`in yellow below. We have investigated several of the scales listed in the CRL in First-HD and
`have not identified a rebound effect unique to SD-809. Any additional information that the
`review team could provide regarding the data assessed as suggesting a rebound effect would be
`of great assistance in assuring we can assess any effects correctly.
`
`In the Meeting Minutes (dated October 18, 2016, Sequence 0029) CSS provided the following
`response:
`
`The change in rating scales scores following withdrawal of study medication in study
`#SD-809-C-15 (First-HD) seems to indicate a possibility of the rebound, which was not
`captured in its entirety because the follow-up period after discontinuing study drug only
`lasted 1 week. It seems patients experienced rapid worsening of TMS, BARS, BBT and
`UPDRS dysarthria/speech question scores during the first week after drug discontinuation.
`This could indicate rebound and CSS recommended an extension of the follow-up period to
`clarify if the observed change in scores after discontinuation was indeed a rebound.
`
`In response, the Sponsor provided their analyses of scales TMS, BARS, BBT and UPDRS
`dysarthria/speech demonstrating, in their opinion, there was no rebound during the one follow-up
`week. Additionally they proposed the following question to CSS:
`
`Question: Does FDA agree with Teva’s definition of rebound and the resulting conclusions
`from the analysis from Study SD-809-C-15? If not, please provide further information on
`how FDA would define rebound in this data set.
`
`Reference ID: 4075739
`
`2 of 3
`
`

`

`CSS Consult: AustedoTM (deutetrabenazine) NDA 208082
`
`Any further information FDA can provide regarding how to best define and therefore assess a
`possible rebound effect would be of great assistance. Teva would also be happy to schedule a
`brief teleconference to discuss this issue with FDA.
`
`CSS RESPONSE
`
`We understand and essentially agree with your definition of rebound and the resulting
`conclusions from the analysis from Study SD-809-C-15. Although there was re-emergence of
`many movements associated with HD, there were no other signs or symptoms reported which
`were associated with a withdrawal syndrome suggesting physical dependence. Thus, it appears
`deutetrabenazine does not produce physical dependence.
`
`Reference ID: 4075739
`
`3 of 3
`
`APPEARS THIS 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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARTIN S RUSINOWITZ
`03/27/2017
`
`SILVIA N CALDERON
`03/27/2017
`
`Reference ID: 4075739
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`March 23, 2017
`Requesting Office or Division:
`Division of Neurology Products (DNP)
`Application Type and Number: NDA 208082
`Product Name and Strength:
`Austedo (deutetrabenazine) tablets
`6 mg, 9 mg, 12 mg
`March 22, 2017
`Teva Pharmaceuticals
`2016-2844-1
`Chad Morris, PharmD, MPH
`Lolita White, PharmD
`
`Submission Date:
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA Primary Reviewer:
`DMEPA Team Leader:
`
`PURPOSE OF MEMO
`1
`This memo presents our evaluation of the revised container labels for Austedo
`(deutetrabenazine) tablets (NDA 208082) to determine if the revised container labels are
`acceptable from a medication error perspective (See Appendix A for images of the revised
`container labels). The revisions are in response to recommendations made by the Office of
`Pharmaceutical Quality (OPQ) on February 28, 2017 and DMEPA during a previous label and
`labeling reviewa OPQ requested Teva add the statement “protect from light and moisture” to
`the side panel of the container labels. DMEPA requested Teva to identify the format they
`intend to use to express the expiration date. To help minimize confusion, we recommended
`that Teva use a format similar to one of the following: MMMYYYY (for example, JAN2017) or
`MMMDDYYYY (for example, JAN012019). In an email dated March 20, 2017, Teva clarified their
`intention to use MM/YYYY as the expiration date format.
`
`a Morris, C. Label and Labeling Review for Austedo (deutetrabenazine) (NDA 208082). Silver Spring (MD): Food and
`Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of
`Medication Error Prevention and Analysis (US); 2017 MARCH 16. 11 p. OSE RCM No.: 2016-2844.
`1
`
`Reference ID: 4074002
`
`

`

` CONCLUSION
`2
`The revised container labels for Austedo (deutetrabenazine) are acceptable from a medication
`error perspective. We have no further recommendations at this time.
`
`Reference ID: 4074002
`
`2
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`APPENDIX A. REVISED CONTAINER LABELS FOR AUSTEDO SUBMITTED BY TEVA ON MARCH 22,
`2017
`
`Container labels
`
`
`
`Reference ID: 4074002
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN C MORRIS
`03/23/2017
`
`LOLITA G WHITE
`03/23/2017
`
`Reference ID: 4074002
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`March 23, 2017
`
`
`To:
`
`
`
`
`From:
`
`
`
`Billy Dunn, MD, Director
`Division of Neurology Products (DNP)
`
`Tracy Peters, PharmD, Associate Director for Labeling, DNP
`
`Stacy Metz, PharmD, Senior Regulatory Project Manager, DNP
`
`Aline Moukhtara, RN, MPH, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`
`Through: Mathilda Fienkeng, PharmD, RAC, Team Leader, OPDP
`
`Subject:
`
`NDA 208082
`OPDP labeling comments for AUSTEDO (deutetrabenazine) tablets, for
`oral use
`
`
`
`In response to DNP’s consult request dated October 31, 2016, OPDP has reviewed the
`proposed Package Insert (PI), Patient Package Insert (PPI), and carton and container
`labeling for Austedo.
`
`PI: OPDP’s comments are based on the substantially complete version of the draft PI
`received from DNP (Stacy Metz) on March 16, 2017, and are provided below.
`
`PPI: The Division of Medical Policy Programs (DMPP) and OPDP provided comments
`on the proposed PPI under a separate cover on March 23, 2017.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton
`and container labeling submitted by the Sponsor to the electronic document room on
`March 22, 2017, and we do not have any comments.
`
`If you have questions, please contact Aline Moukhtara at (301) 796-2841 or
`Aline.Moukhtara@fda.hhs.gov.
`
`
`OPDP appreciates the opportunity to provide comments.
`
`
`
`
`Reference ID: 4074265
`
`1
`
`23 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALINE M MOUKHTARA
`03/23/2017
`
`Reference ID: 4074265
`
`

`

`
`Date:
`
`To:
`
`
`Through:
`
`
`Fro