CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`206439Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Division Director Review
`
`Summary Review for Regulatory Action
`
`electronic stamp)
`illy Dunn, MD
`From
`
`Subject
`Division Director Summary Review
`NDA/BLA #
`206439
`Su lement #
`
`Applicant Name
`Forest Laboratories
`Date of Submission
`2/26/14
`
`PDUFA Goal Date
`
`12/26/14
`
`Proprietary Name/
`Name
`Established
`S .
`Dosage Forms/Strength
`
`Namzaric/extended—release memantine hydrochloride
`and donepezil hydrochloride
`Oral capsule/extended-release memantine combined
`with donepezil in once daily doses of 28 mg/ 10 mg or
`14 mg/ 10 mg
`Treatment of moderate to severe dementia of the
`Proposed Indication(s)
`
`Alzheimer’s type
`Action/Recommended Action for Approval
`NME:
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`
`Names of discipline reviewers
`Ran'it Mani, MD
`
`Xiaoyu Dong, PhD
`David Hawver, PhD
`
`0ND=Ofice ofNew Drugs
`0PDP=Ofice of Prescription Drug Promotion
`OSE=0flice of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`OSI=0mce of Scientific Investigations
`CD'IIFCross—Discipline Team Leader
`CDRH=Cemer for Devices and Radiologic Health
`
`PMHS=Pediatric and Maternal Health Staff
`DDRE=Division of Drug Risk Evaluation
`DRISK=Division ofRisk Management
`0MP=Ofice of Medical Policy
`DIVIPP=Division of Medical Policy Programs
`SEALD=Study Endpoints and Labeling Development
`CSS=Contmlled Substance Staff
`
`Page 1 of 5
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`Reference ID: 3678207
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`

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`Division Director Review
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`1. Introduction
`
`This submission is an application for the approval of a fixed-dose combination (which, for
`convenience, I will call MDX in this memo, drawn from its investigational designation of
`MDX-8704) of extended-release memantine (MEM) and donepezil (DPZ) in doses of MEM
`28 mg combined with DPZ 10 mg (28/10) and MEM 14 mg combined with DPZ 10 mg
`(14/10).
`
`Extended-release memantine is an approved drug for the treatment of moderate to severe
`dementia of the Alzheimer’s type, marketed by the sponsor of the current application as
`Namenda XR in various strengths, including 14 mg and 28 mg. Donepezil is an approved
`drug for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type,
`marketed as Aricept in various strengths, including 10 mg.
`
`This application is supported by cross-reference to the sponsor’s own approved memantine
`(Namenda) and extended-release memantine (Namenda XR) applications, reliance on our
`previous finding of safety and effectiveness for approved donepezil (Aricept), clinical
`pharmacology studies intended to evaluate bioequivalence and bioavailability of the new
`product, additional nonclinical studies, and manufacturing information.
`
`The members of the review team recommend approval and I will briefly discuss their major
`findings.
`
`2. Background
`
`This is the first application for this product. The underlying rationale for this product is that of
`a combination of convenience, as Namenda XR and donepezil are frequently taken together in
`clinical use, and such a combination should simplify administration and enhance compliance
`with prescribed therapy. During development, the sponsor discussed the rationale for the
`development of MDX with us and reached agreement with us on the proposed basis for
`approval described above over the course of several meetings, including an end of Phase 2
`meeting on October 13, 2011, a Type C meeting on June 20, 2013, and a pre-NDA meeting on
`November 19, 2013. There are no outstanding issues from those meetings.
`
`3. CMC/Device
`
`I concur with the conclusions reached by Dr. Chu, Dr. Eradiri, and Dr. Dong regarding the
`acceptability of the manufacturing of the drug product and drug substance. Manufacturing site
`inspections were acceptable. Stability testing supports an expiry of 18 months. There are no
`outstanding issues.
`
`Page 2 of 5
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`Reference ID: 3678207
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`Division Director Review
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`4. Nonclinical Pharmacology/Toxicology
`
`The sponsor submitted additional nonclinical studies of the combination of MEM and DPZ. In
`addition to evaluating toxicity and dose-ranging, the submitted studies included data the
`sponsor argues support a synergistic effect of MEM and DPZ on cognitive function and
`acetylcholine levels. Dr. Hawver reviewed these data, as did the nonclinical supervisor, Dr.
`Lois Freed, and both Dr. Hawver and Dr. Freed find that the data are insufficient to support
`such a synergistic effect due to lack of concurrent controls, small numbers of animals per
`group, and the absence of individual animal data to allow independent analyses. I concur with
`the conclusions reached by Dr. Hawver that there are no outstanding nonclinical issues that
`preclude approval.
`
`5.
`
` Clinical Pharmacology/Biopharmaceutics
`
`The sponsor submitted additional clinical pharmacology studies intended to establish the
`bioequivalence of MDX with the combination of individually administered Namenda XR and
`donepezil and assess the characteristics of the combination. Dr. Eradiri reviewed these data
`and found that high dose MDX (28/10) was bioequivalent to its co-administered individual
`components. Dr. Eradiri reviewed the request for a biowaiver for low dose MDX (14/10) and
`found it acceptable. Dr. Yang reviewed the food effect study and found no clinically
`significant effect of food on the bioavailability of MDX. I concur with the conclusions
`reached by Dr. Eradiri and Dr. Yang that there are no outstanding clinical pharmacology issues
`that preclude approval.
`
`6. Clinical Microbiology
`
`N/A
`
`7. Clinical/Statistical-Efficacy
`
`Efficacy is addressed by assessment of bioequivalence to drugs of known effectiveness. There
`are no new efficacy data. I note that each component of MDX has a different presumed
`mechanism of action in Alzheimer’s dementia. I also note that the primary study supporting
`approval of Namenda XR was of an add-on design, superimposing Namenda XR on a
`background of stable acetylcholinesterase inhibitor therapy, about 70% of which was
`donepezil.
`
`Page 3 of 5
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`Reference ID: 3678207
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`Division Director Review
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`8. Safety
`
`Safety parameters in the clinical pharmacology studies were reviewed in detail by Dr. Mani
`and are presented in his memo containing both his primary review findings and his
`recommendations as Cross-Discipline Team Leader. The safety profile of MDX, as assessed
`in the clinical pharmacology studies, is consistent with the know safety profiles of its
`individual components, and Dr. Mani finds no safety issues of concern. I concur with the
`conclusions reached by Dr. Mani that there are no outstanding safety issues that preclude
`approval.
`
`9. Advisory Committee Meeting
`
`N/A
`
`10.
`
`Pediatrics
`
`We are waiving the pediatric study requirement for this application because dementia of the
`Alzheimer’s type does not occur in children.
`
`11.
`
`Other Relevant Regulatory Issues
`
`There are no other unresolved relevant regulatory issues.
`
`12.
`
`Labeling
`
`Labeling negotiations with the sponsor have been completed and the sponsor has accepted all
`recommended changes.
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`
`I agree with the review team that this application should be approved.
`
`The sponsor has provided substantial evidence of effectiveness for MDX based on cross-
`reference to the sponsor’s own approved memantine (Namenda) and extended-release
`memantine (Namenda XR) applications, reliance on our previous finding of safety and
`effectiveness for approved donepezil (Aricept), and a demonstration of bioequivalence of
`MDX to its co-administered individual components (Namenda XR and donepezil). The
`independent contribution of each component of this fixed-dose combination has been
`established by these findings. Further, this combination should result in increased
`
`Page 4 of 5
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`Reference ID: 3678207
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`Division Director Review
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`convenience for those taking both components. There are no new safety concerns associated
`with MDX. There are no outstanding unresolved issues.
`
`There are no necessary postmarketing requirements or commitments.
`
`Specific postmarketing risk management activities are not needed.
`
`We have agreed with the sponsor on product labeling that describes the effectiveness and
`safety of extended-release memantine combined with donepezil in once daily doses of 28
`mg/10 mg or 14 mg/10 mg for the treatment of moderate to severe dementia of the
`Alzheimer’s type.
`
`For these reasons, I will issue an approval letter for this NDA, to include the agreed-upon
`product labeling.
`
`Page 5 of 5
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`Reference ID: 3678207
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM H Dunn
`12/23/2014
`
`Reference ID: 3678207
`
`