CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`206439Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Review and Evaluation of Clinical Data
`
`
`NDA
`Sponsor:
`Drug:
`Proposed Indication:
`Material Submitted:
`Correspondence Date:
`Date Received / Agency:
`Date Review Completed:
`Reviewer:
`
`206439
`Forest
`MDX-8704
`Alzheimer’s Disease
`New Drug Application
`2/26/14
`2/26/14
`12/19/14
`Ranjit B. Mani, M.D.
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS ........................................................................................ 1
`EXECUTIVE SUMMARY ...................................................................................... 2
`1. Background.................................................................................................... 5
`2. Contents Of Submission ................................................................................ 6
`3. Contents Of Review ....................................................................................... 7
`4. History Of Development Of Proposed New Fixed-Dose Combination Drug
`Product ................................................................................................................. 7
`5. Description Of Proposed New Fixed-Dose Combination Drug Product ......... 9
`6. Clinical Data ................................................................................................. 10
`7. Summary Of Clinical Pharmacology ............................................................ 21
`8. Summary Of Biopharmaceutics ................................................................... 21
`9. Summary Of Reviews By Other Agency Disciplines .................................... 21
`10. Site Inspection Report ............................................................................... 24
`11.
`Labeling .................................................................................................... 25
`12. Financial Disclosure Certification .............................................................. 26
`13. Pediatric Waiver Request .......................................................................... 27
`14. Overall Conclusion .................................................................................... 27
`15. Recommendation ...................................................................................... 27
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 2 of 28
`12/19/14
`
`
`
`EXECUTIVE SUMMARY
`
`Recommendation
`I recommend that MDX-8704 (NAMZARIC), a fixed-dose combination drug
`product (capsule) consisting of extended-release memantine hydrochloride and
`donepezil hydrochloride, be approved for the treatment of moderate to severe
`dementia of the Alzheimer’s type.
`
`Proposed Indication
`This New Drug Application (NDA) seeks the approval of MDX-8704 (NAMZARIC)
`for the treatment of moderate to severe dementia of the Alzheimer’s type.
`
`Summary Of Clinical And Nonclinical Findings
`In this application, the sponsor seeks the approval of two strengths of MDX-8704
`(NAMZARIC), a fixed-dose combination drug, for the treatment of moderate to
`severe dementia of the Alzheimer’s type (Alzheimer’s Disease): extended-
`release memantine in a dose of 28 mg combined with donepezil in a dose of 10
`mg (also referred to as the 28 mg/10 mg strength); and extended-release
`memantine in a dose of 14 mg combined with donepezil in a dose of 10 mg (also
`referred to as the 14 mg/10 mg strength). Each of the above strengths of this
`product is intended for once daily administration.
`
`Memantine hydrochloride is currently marketed in this country under the brand
`name NAMENDA for the treatment of moderate to severe dementia of the
`Alzheimer’s type, by the sponsor of the current application. Several formulations
`of NAMENDA are approved for that indication, including an extended-release
`capsule (NAMENDA XR; 7 mg, 14 mg, 21 mg, and 28 mg strengths) which is to
`be administered once daily. Donepezil hydrochloride (ARICEPT [Eisai] and
`several generic formulations) is currently marketed in this country for the
`treatment of mild, moderate, and severe dementia of the Alzheimer’s type;
`several strengths and formulations of donepezil hydrochloride are marketed,
`including a 10 mg tablet approved for mild, moderate, and severe Alzheimer’s
`Disease.
`
`This application has been submitted under Section 505(b)(2) of the Food, Drug,
`and Cosmetic Act and relies primarily on the following to support the approval of
`the current NDA: clinical pharmacology (bioequivalence and bioavailability)
`studies of the proposed fixed-dose combination product which are described in
`full in this submission; NDA 21487 for NAMENDA and NDA 22525 for
`NAMENDA XR (by cross-reference); and the Agency’s finding of safety and
`effectiveness for ARICEPT (under NDA 20690 submitted by Eisai). The sponsor
`asserts that the safety and efficacy of the fixed-dose combination of extended-
`release memantine hydrochloride and donepezil hydrochloride is supported by
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 3 of 28
`12/19/14
`
`the Agency’s approval of both components of the fixed-dose combination and the
`additional data provided in the current application. Agreement had been reached
`between the sponsor and Agency in advance of the submission of this
`application regarding the currently proposed basis for the approval of MDX-8704
`(NAMZARIC) for the treatment of moderate to severe dementia of the
`Alzheimer’s type prior to the submission of this application.
`
`The combination MDX-8704 drug product (capsule) uses the same extended-
`release memantine
` used in NAMENDA XR capsules.
`
`The new clinical data contained in this submission consist of complete reports of
`the following clinical pharmacology studies.
`
`
`• MDX-PK-104, a randomized, open-label, single-dose, two-way crossover study
`intended to evaluate the bioequivalence of the memantine extended-release and
`donepezil components of MDX-8704 (using the product containing 28 mg of
`extended-release memantine and 10 mg of donepezil) with those of co-
`administered NAMENDA XR 28 mg and donepezil 10 mg. This study was
`conducted in 38 healthy men and women, aged 18 to 45 years.
`
`• MDX-PK-105, a randomized, open-label, single-dose, three-way crossover study
`intended to evaluate the effect of food and the effect of sprinkling the capsule
`contents on applesauce on the relative bioavailability of memantine and
`donepezil after the oral administration of MDX-8704 (using the product containing
`28 mg of extended-release memantine and 10 mg of donepezil). This study was
`conducted in 36 healthy men and women, aged 18 to 45 years.
`
`• The bioequivalence of both memantine and donepezil whether administered as a
`28 mg capsule of NAMENDA XR with a 10 mg tablet of donepezil or as the
`fixed-dose combination 28 mg/10 mg capsule.
`
`
`Safety assessments in the above studies included the assessment of adverse
`events, vital signs, electrocardiograms, safety laboratory tests, and suicidality;
`and physical examinations. A detailed review of the safety data for both studies
`yielded no findings of clinical concern.
`
`The pharmacokinetic results of the above studies demonstrated the following:
`
`
`
`
`
`
`• Food had no clinically meaningful effect on the bioavailability of the MDX-8704
`28 mg/10 mg capsule. The capsule was bioequivalent whether administered as
`an intact capsule or as capsule contents sprinkled in apple sauce.
`
`
`Biopharmaceutics data in this submission included in vitro dissolution profiles for
`both strengths of MDX-8704, an in vitro alcohol dose dumping study, and in vivo
`in vitro correlation for the extend-release memantine component of MDX-8704.
`
`
`Reference ID: 3676502
`
`(b) (4)
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 4 of 28
`12/19/14
`
`Conclusions Of Other Review Disciplines
`The Pharmacology –Toxicology, Clinical Pharmacology, Chemistry, and
`Biopharmaceutics review staff each concluded that this application was
`approvable, while recommending changes to the submitted Prescribing
`Information. Several other Agency offices contributed to editing the text of the
`Prescribing Information and Patient Package Insert.
`
`Overall Conclusion
`This New Drug Application provides substantial evidence for the efficacy and
`safety of MDX-8704 (NAMZARIC), a fixed-dose combination drug product
`(capsule) consisting of extended-release memantine hydrochloride and donepezil
`hydrochloride for the treatment of moderate to severe dementia of the
`Alzheimer’s type.
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 5 of 28
`12/19/14
`
`
`1. Background
`This New Drug Application (NDA) seeks the approval of MDX-8704, a fixed-dose
`combination drug product (capsule) containing extended-release memantine
`hydrochloride and donepezil hydrochloride as components, for the treatment of
`moderate to severe dementia of the Alzheimer’s type (i.e., Alzheimer’s Disease).
`
`The sponsor seeks the approval of following two strengths of MDX-8704 for that
`indication.
`
`
`• Extended-release memantine in a dose of 28 mg combined with donepezil in a
`dose of 10 mg (also referred to in this submission as the 28/10 mg strength).
`• Extended-release memantine in a dose of 14 mg combined with donepezil in a
`dose of 10 mg (also referred to in this submission as the 14/10 mg strength).
`
`
`Each of the above strengths of MDX-8704 is intended for administration once
`daily.
`
`Memantine is currently marketed in this country under the brand name Namenda®
`(Forest Laboratories). Formulations of Namenda® that are currently marketed include
`tablets (5 mg and 10 mg), an oral solution (2 mg/mL) and an extended-release capsule
`(Namenda XR®; 7 mg, 14 mg, 21 mg, and 28 mg strengths). All formulations of
`Namenda® are approved for the treatment of moderate to severe Alzheimer’s Disease.
`Namenda XR® is to be taken once daily whereas tablet and oral solution formulations of
`Namenda® are to be taken twice daily. NDA numbers for the various approved
`formulations of Namenda® are: 21487 (for the 5 mg and 10 mg tablet formulations),
`21627 (for the oral solution formulation), and 22525 (for Namenda XR®). The current
`product is to use the memantine hydrochloride extended-release
` contained in
`Namenda XR® 14 mg and 28 mg capsules as its extended-release memantine
`component.
`
`Donepezil is currently marketed in this country under the brand name Aricept® [Eisai] as
`a tablet (in 5 mg, 10 mg, and 23 mg strengths) and as an orally-disintegrating tablet (in
`5 mg and 10 mg strengths). The 5 mg and 10 mg strengths of the tablet and orally-
`disintegrating tablet formulations are currently approved for the treatment of mild to
`moderate Alzheimer’s Disease. The 10 mg strengths of the tablet and orally-
`disintegrated tablet formulations, and the 23 mg strength of the tablet formulation are
`approved for the treatment of moderate to severe Alzheimer’s Disease. An oral solution
`formulation of Aricept® is also approved in this country, but has never been marketed.
`NDA numbers for the various approved formulations of Aricept® are as follows: 20690
`(for the 5 mg and 10 mg tablet strengths); 21719 (for the oral solution formulation);
`21720 (for the 5 mg and 10 mg orally-disintegrating tablet strengths); and 22568 (for the
`23 mg tablet formulation). Generic formulations of donepezil are also marketed in this
`country. All formulations of donepezil are to be administered once daily.
`
`This application has been submitted under Section 505(b)(2) of the Food, Drug,
`and Cosmetic Act. The sponsor relies primarily on the following to support the
`approval of the current NDA.
`
`Reference ID: 3676502
`
`(b) (4)
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 6 of 28
`12/19/14
`
`
`
`
`
`
`
`• Clinical pharmacology (bioequivalence and bioavailability) studies of the
`proposed fixed-dose combination product, i.e., Studies MDX-PK-104 and MDX-
`PK-105, which are described in full in this submission.
`
`• NDA 21487 for Namenda® and NDA 22525 for Namenda XR® (by cross-
`reference).
`
`• The Agency’s finding of safety and effectiveness for Aricept® (under NDA 20690,
`submitted by Eisai).
`
`The sponsor asserts that the safety and efficacy of the fixed-dose combination of
`extended-release memantine hydrochloride and donepezil hydrochloride is
`supported by the Agency’s approval of both components of the fixed-dose
`combination and the additional data provided in the current application.
`
`The extended-release memantine and donepezil combination product for which
`the sponsor is seeking approval under the current application has been
`developed under IND 109763, originally submitted on September 13, 2010, to
`which the current application is also cross-referenced. While under development,
`this combination product has been referred to first as “ADS-8704,” and then as
`“MDX-8704.” The name “MDX-8704” is also used in this review to refer to the
`fixed-dose combination drug product consisting of extended-release memantine
`hydrochloride and donepezil hydrochloride.
`
`The proprietary name “NAMZARIC” has been proposed by the sponsor for the
`proposed fixed-dose combination of extended-release memantine hydrochloride
`and donepezil hydrochloride.
`
`Note that the name “memantine,” when used at any place in this review, refers to
`memantine hydrochloride. Likewise, the name “donepezil,” when used at any
`place in this review, refers to donepezil hydrochloride.
`
`This document is intended to serve simultaneously a primary clinical
`review, a Team Leader review, and a Cross-Disciplinary Team Leader
`review.
`
`2. Contents Of Submission
`This NDA has been submitted in standard electronic Common Technical
`Document format. The application thus has 5 main sections, enumerated as
`listed below.
`
`
`1. Regional.
`2. Common Technical Document summaries.
`3. Quality.
`4. Nonclinical study reports.
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 7 of 28
`12/19/14
`
`5. Clinical study reports.
`
`
`Note that Section 5 of this application contains the complete study reports of the
`following 4 clinical studies.
`
`
`• MDX-PK-104.
`• MDX-PK-105.
`• MEM-PK-13.
`• MEM-PK-07.
`
`3. Contents Of Review
`The contents of this application have been reviewed using the following primary
`headings in the same consecutive order as below.
`
`
`• History of development of proposed new fixed-dose combination drug product.
`• Description of proposed new fixed-dose combination drug product.
`• Clinical data.
`• Summary of clinical pharmacology.
`• Summary of biopharmaceutics.
`• Summary of reviews by other Agency disciplines.
`• Labeling.
`• Financial disclosure certification.
`• Pediatric waiver request.
`• Overall conclusions.
`• Recommendation.
`
`
`4. History Of Development Of Proposed New Fixed-Dose
`Combination Drug Product
`4.1 Rationale For Development Of Formulation
`The rationale for the sponsor’s development of the fixed-dose combination
`product under review may briefly be summarized as follows.
`
`
` Currently, the American Association of Geriatric Psychiatrists recommends the
`treatment of mild Alzheimer’s Disease with an acetylcholinesterase inhibitor, with
`the addition of memantine when the disease worsens to the moderate phase.
`Other experts have made similar recommendations.
`
` About 70% of all memantine use is in combination with an acetylcholinesterase
`inhibitor, with donepezil accounting for a further 70% of all memantine use as
`part of such a combination.
`
` MDX-8704, administered once daily, will simplify the administration of memantine
`and donepezil in combination. The formulation also provides for the sprinkling of
`the contents of the capsule on soft foods if needed, thereby also facilitating its
`
`
`
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 8 of 28
`12/19/14
`
`administration. The expectation is that the use of MDX-8704 will lead to greater
`compliance and adherence to treatment, as well as a better therapeutic outcome.
`
`
`4.2 Interactions Between Sponsor And Agency Regarding Development Of
`Formulation
`The development of this fixed-dose combination formulation of extended-release
`memantine and donepezil has been the subject of the following interactions
`between the Agency and sponsor, all of which were subsumed under IND
`109763.
`
`
`• An End-of-Phase 2 Meeting held on October 13, 2011 (with representatives of
`Adamas Pharmaceuticals who were developing this fixed-dose combination at
`that time).
`
`• A Type C Meeting held on June 20, 2013 (with representatives of both Adamas
`Pharmaceuticals and Forest Laboratories).
`
`
`
`
`
`
`
`
`
`
`
`• Aa Pre-NDA Meeting held on November 19, 2013 (with representatives both
`Adamas Pharmaceuticals and Forest Laboratories).
`
`Please see the Minutes of each of the above meetings for full details of the
`discussion at each. However, the following agreements reached in the course of
`those meetings are especially noteworthy, from a purely clinical perspective.
`
`
`It was agreed that no additional studies of the efficacy of the fixed-dose
`combination of memantine extended-release and donepezil would be required.
`The Agency agreed that the efficacy of the co-administration of memantine and
`donepezil had already been sufficiently evaluated in two studies previously
`reviewed by the Agency: those were Study MEM-MD-02 submitted and fully
`reviewed under NDA 21487, and Study MEM-MD-50 submitted and fully
`reviewed under NDA 22525.
`
`•
`
`•
`
`It was also agreed that the conduct of two further clinical pharmacology studies,
`would be sufficient to support the approval of the proposed fixed-dose
`combination of extended-release memantine and donepezil:
`
` MDX-PK-104, a randomized, open-label, single-dose, two-way crossover study
`intended to evaluate the bioequivalence of the memantine extended-release and
`donepezil components of MDX-8704 (using the strength containing 28 mg of
`extended-release memantine and 10 mg of donepezil) with those of co-administered
`Namenda XR® 28 mg and donepezil 10 mg.
` MDX-PK-105, a randomized, open-label, single-dose, three-way crossover study
`intended to evaluate the effect of food and the effect of sprinkling the capsule
`contents on applesauce on the relative bioavailability of memantine and donepezil
`after the oral administration of MDX-8704 (using the strength containing 28 mg of
`extended-release memantine and 10 mg of donepezil).
`
`An in vitro alcohol dose dumping study of the fixed-dose combination product
`was also to be conducted.
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 9 of 28
`12/19/14
`
`
`
`•
`
`It was also agreed that the proposed strengths of the fixed-dose combination
`product (to which this application pertains) were appropriate for use in patients
`already being treated with the combination of donepezil and extended-release
`memantine administered as separate products, but at the same dosage.
`
`
`Note that in the Briefing Package for the End-of-Phase 2 Meeting held on
`October 13, 2011, and in later submissions, the sponsor had repeatedly indicated
`an intention to submit a 505(b)(2) NDA for MDX-8704: it was stated at those
`times that the proposed NDA was to reference the efficacy and safety data for
`NDA 22525 (for Namenda XR®), NDA 21487 (for Namenda® tablets and
`Namenda® oral solution), and NDA 20690 (for Aricept® tablets).
`
`5. Description Of Proposed New Fixed-Dose Combination Drug
`Product
`As stated by the sponsor in this application:
`
`
`• The combination MDX-8704 drug product uses the same extended-release
` used in Namenda XR® capsules.
`memantine
`
`• The 14 mg/10 mg MDX-8704 product is a locked, Size 2, light green opaque
`capsule with a black ‘FL 14/10’ radial imprint on the capsule.
`
`
`
`
`
`• The 28 mg/10 mg MDX-8704 product is a locked, Size 1, blue opaque capsule
`with a black ‘FL 14/10’ radial imprint on the capsule.
`
`
`The components and quantitative composition of the two strengths of MDX-8704
`proposed for marketing are summarized in the following table, which I have
`copied from the submission.
`
`
`Reference ID: 3676502
`
`(b) (4)
`
`

`

`maunmmmmmm
`NDA 206439, MDX-8704, Forest
`
`Page100f28
`12119114
`
`mm
`
`mum-mm mam-—
`
`—-:-l::_——-n-m-
`'- nu.
`1.
`i
`
`isiEii IiIl
`
`5:8iiiii;
`
`£3gé E.
`
`6. Clinical Data
`
`6.1 Introduction
`
`The efficacy of the fixed-dose combination drug product consisting of extended-
`release memantine hydrochloride and donepezil hydrochloride (MDX—8704) as a
`treatment for moderate to severe dementia of the Almeimer's type was
`established by demonstrating the bioequivalence of MDX-8704 with co-
`administered memantine hydrochloride extended-release and donepezil
`hydrochloride.
`
`Accordingly, me clinical pharmacology study mat established the bioequivalence
`noted above and other supportive clinical pharmacology studies are described in
`this section, with the focus being on safety data for the two principal clinical
`pharmacology studies unique to his application.
`
`6.2 Tabular Summary For All Clinical Studies For Which Data Has Been
`Included In This Application
`
`The reports of four clinical pharmacology studies have been included in this
`submission. Those clinical studies have been summarized in the following table,
`which has been copied from the current submission.
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
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`Page 11 of 28
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`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 12 of 28
`12/19/14
`
`
`
`
`The above table is self-explanatory.
`
`The complete reports of Studies MDX-PK-104 and MDX-PK-105 are unique to
`the current application, i.e., they have not been submitted under a New Drug
`Application previously. However, the complete reports of Studies MEM-PK-07
`and MEM-PK-13, while included in the current application, were previously
`submitted under NDA 21487 and NDA 22525, respectively, and were reviewed in
`detail together with the respective applications under which they were submitted.
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 13 of 28
`12/19/14
`
`Note that in addition to the clinical studies listed in the following table, an in vitro
`alcohol dose dumping study of the proposed fixed-dose combination product has
`been conducted.
`
`6.3 Description Of Selected Clinical Pharmacology Studies Primarily
`Supporting Current Application
`As already noted, Studies MDX-PK-104 and MDX-PK-105 are unique to the
`current application, and are therefore reviewed here in detail; as the clinical
`pharmacology data for those studies has been reviewed in detail by other
`Agency staff, this review is focused on the safety data for those studies.
`
`6.3.1 Study MDX-PK-104
`6.3.1.1 Outline Of Study Design
`This was a randomized, open-label, single-dose, two-way crossover study
`intended to evaluate the bioequivalence of the memantine extended-release and
`donepezil components of MDX-8704 (in the strength containing 28 mg of
`extended-release memantine and 10 mg of donepezil) with those of co-
`administered Namenda® XR 28 mg and Aricept® 10 mg.
`
`The study was conducted in 38 healthy men and women, aged 18 to 45 years.
`
`The following treatments were administered with a 21-day washout period
`between treatments.
`
`
`Treatment A: A single oral dose of Namenda XR® 28 mg (capsule) and
`Aricept® 10 mg (tablet) administered at the same time under fasted
`conditions.
`
`Treatment B: A single oral dose of the MDX-8704 28 mg/10 mg capsule
`administered under fasted conditions.
`
`
`6.3.1.2 Safety Results
`No deaths, serious adverse events, or severe adverse events occurred in this
`study. All treatment-emergent adverse events were mild to moderate in severity.
`
`One subject in Treatment Sequence AB who received Namenda® XR and
`Aricept® on Day 1 of Period 1 discontinued study participation after a laceration
`to, and fracture of, a finger that occurred on Day 15 of Period 1. Another subject,
`a 19-year-old man, in Treatment Sequence AB who received Namenda® XR and
`Aricept® on Day 1 of Period 1 discontinued study drug after developing pre-
`syncopal symptoms 3 hours after dosing, associated with a sitting blood pressure
`of 46/28 mmHg 3 hours after dosing.
`
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 14 of 28
`12/19/14
`
`The incidence of treatment-emergent adverse events that occurred in 3 or more
`subjects overall is in the following table, which I have copied from the
`submission.
`
`
`
`
`
`Note that study drug was administered without titration to all subjects
`participating in the study. Ordinarily (i.e., as recommended in the Prescribing
`Information), Namenda XR® would have been administered in a dose of 28 mg
`once daily only after titration over a period of 3 weeks, and donepezil would have
`been administered in a dose of 10 mg once daily only after titration over a
`minimum of 4 weeks.
`
`There were no vital sign data of concern beyond the above. Electrocardiograms,
`safety laboratory tests, physical examinations, and suicidality assessments (the
`Columbia-Suicide Severity Rating Scale) also did not yield any data of concern.
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 15 of 28
`12/19/14
`
`6.3.1.3 Pharmacokinetic Results
`The results of this study are summarized in the following tables which I have
`copied from the submission.
`
`The pharmacokinetic parameters and results of the statistical analysis for
`memantine when study drug was administered under fasted conditions are
`below.
`
`
`
`
`The pharmacokinetic parameters and results of the statistical analysis for
`donepezil when study drug was administered under fasted conditions are in the
`next table.
`
`
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 16 of 28
`12/19/14
`
`
`
`
`6.3.1.4 Sponsor’s Conclusions
`The sponsor has concluded that the results of this study demonstrated the
`bioequivalence of both memantine and donepezil whether administered as a 28
`mg capsule of Namenda® XR with a 10 mg tablet of donepezil or as the fixed-
`dose combination 28 mg/10 mg capsule.
`
`The sponsor has also concluded that the no clinically significant safety signals
`were observed during the study, and that a single oral dose of MDX-8704 (28
`mg/10 mg) was generally safe and tolerable.
`
`6.3.1.5 Reviewer’s Comment
`I concur with the sponsor’s conclusion regarding the safety and tolerability of
`MDX-8704 in this study.
`
`6.3.2 Study MDX-PK-105
`6.3.2.1 Outline Of Study Design
`This was a randomized, open-label, single-dose, three-way cross-over study
`intended to evaluate the effect of food and the effect of sprinkling the capsule
`contents on applesauce on the relative bioavailability of memantine and
`donepezil after the oral administration of MDX-8704 (using the 28 mg/10 mg
`capsule strength).
`
`The study was conducted in 36 healthy men and women, aged 18 to 45 years.
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 17 of 28
`12/19/14
`
`
`Subjects were assigned to one of 6 treatment sequences, in which each subject
`received Treatments A, B, and C (with a 21-day washout period between
`treatments), as depicted in the following table.
`
`
`
`
`
`Treatments A, B, and C are explained below.
`
`
`Treatment A: A single oral dose of the MDX-8704 28 mg/10 mg capsule administered
`under fasted conditions.
`
`Treatment B: A single oral dose of the MDX-8704 28 mg/10 mg capsule administered
`after a high-fat meal.
`
`Treatment B: A single oral dose of the MDX-8704 28 mg/10 mg capsule administered as
`capsule contents sprinkled on 30 mL (2 tablespoons) of apple sauce under fasted
`conditions.
`
`
`6.3.2.2 Safety Results
`There were no deaths during the study. A single serious adverse event occurred
`in this study: a 25-year-old subject was detected to have an ectopic pregnancy
`after having a positive pregnancy test on Day 54, after completing all parts of the
`study. A 26-year old woman was discontinued from the study after ventricular
`extrasystoles were detected prior to dosing on Day 1 of Period 3; in Periods 1
`and 2, she had received Treatments A and C, respectively; she also appears to
`have received Treatment B in Period C despite the detection of ventricular
`extrasystoles.
`
`The incidence of treatment-emergent adverse events that occurred in 3 or more
`subjects overall is in the following table, which I have copied from the
`submission.
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 18 of 28
`12/19/14
`
`
`
`
`Note that study drug was administered without titration to all subjects
`participating in the study. Ordinarily (i.e., as recommended in the Prescribing
`Information), Namenda XR® would have been administered in a dose of 28 mg
`once daily only after titration over a period of 3 weeks, and donepezil would have
`been administered in a dose of 10 mg once daily only after titration over a
`minimum of 4 weeks.
`
`Vital signs, electrocardiograms, safety laboratory tests, physical examinations,
`and suicidality assessments (the Columbia-Suicide Severity Rating Scale) were
`unremarkable for any data of concern besides those already described above.
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 19 of 28
`12/19/14
`
`6.3.2.3 Pharmacokinetic Results
`The pharmacokinetic parameters and statistical analysis results for memantine
`are summarized in the following table, which I have copied from the submission.
`The table is self-explanatory.
`
`
`
`The pharmacokinetic parameters and statistical analysis results for donepezil are
`summarized in the next table, which I have also copied from the submission.
`
`
`
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 20 of 28
`12/19/14
`
`
`
`
`6.3.2.4 Sponsor’s Conclusions
`The sponsor has concluded from the results of this study that food had no
`clinically meaningful effect on the bioavailability of the MDX-8704 capsule. The
`capsule was bioequivalent whether administered as an intact capsule or as
`capsule contents sprinkled in apple sauce.
`
`The sponsor has also concluded that the incidence of treatment-emergent
`adverse events was similar for MDX-8704 (administered under fasted conditions)
`regardless of whether that formulation was administered as an intact capsule or
`as capsule contents sprinkled in apple sauce. Adverse events were generally
`lower when MDX-8704 (the 28 mg/10 mg capsule strength) was administered
`after a high-meal than in the fasted state. A single dose of MDX-8704 (28 mg/10
`mg) was generally safe and well-tolerated in this study.
`
`6.3.2.5 Reviewer’s Comment
`I concur with the sponsor’s conclusion regarding the safety and tolerability of
`MDX-8704 in this study.
`
`Reference ID: 3676502
`
`

`

`Ranjit B. Mani, MD, HFD-120 Medical Review
`NDA 206439, MDX-8704, Forest
`
`
`
`Page 21 of 28
`12/19/14
`
`
`
`7. Summary Of Clinical Pharmacology
`In Section 2.5 of the submission, the sponsor has provided the following
`summary i