CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`206439Orig1s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`1
`BIOPHARMACEUTICS REVIEW ADDENDUM — NDA 206439
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`Office of New Dru Quali Assessment
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`206-439
`Biopharmaceutics Revie—er:
`Application No.:
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` Division:
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`DNP
`1
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`Okpo Eradiri, Ph.D.
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`Biopharmaceutics Team Leader:
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`Forest Laboratories, Inc.
`Applicant:
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`Angelica Dorantes, Ph.D
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`Acting Biopharmaceutics Supervisor:
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`Trade Name: Namzafic Capsules
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`Paul Seo, PhD.
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`Memantine HCl ER/Donepezil
`Generic Name:
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`Capsules
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`Assined:
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`Indication:
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`Formulation/strength
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`Date of
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`Addendum:
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`11/21/2014.
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`J_Treatment of moderate to
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`severe dementia of the
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`Alzheimer’s t p e.
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`FDC Tablet, Memantine HCl
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`ER/ Donepezil HCl: 14/10 mg
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`2.1m__.____ngfl
`,.2,,,,...,
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`Route of
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`Administration
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`SUBMISSIONSVIEWED IN THIS DOCUMENT '
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`1 Prirmay Rev1ew due in 1
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`2/26/2014, 6/10/2014,
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`8/7/2014, 11/21/2014
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`10/26/2014
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`12/26/2014
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`1
`NDA; 505(b)(2)
`,. 505 (b)(2) Application (Rehed upon product NDA 20 690 (Aricept approved 1
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`Nov 25, 1996))
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`Associated IND: 109-763
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`SYNOPSIS:
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`This document is an addendum to the original Biopharmaceutics review by Dr. Okpo Eradiri, 1
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`uploaded into Panorama on October 26, 2014.
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`Background: At the time of completion of the original review of NDA 20643 9, the
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`Biopharmaceutics recommendation was PENDING because the following two items were
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`outstanding:
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`1. Finalization of the dissolution acceptance criteria for both active components. In an IR
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`dated 10/31/2014,
`the Applicant was asked to update the Specification Table with the
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`FDA-recommended dissolution acceptance criteria; and
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`2. The Office of Scientific Investigations had not submitted their report for the inspection of .
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`the analytical site of BE study MDX-PK-104.
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`' Review The purpose of this Addendum to the original NDA review is to update the two items and
`i finalize the Biopharmaceutics recommendation on the approvability of this NDA.
`
`Donefiezfl:
`Q = (0% at 15 min
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`—.
`-4
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`1
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`1. Finalization of the dissolution acceptance criteria for both active components:
`The Applicant responded to the IR on 11/21/2014 (SDN 9, Sequence # 008 in DARRTS)
`accepting FDA’s recommended dissolution acceptance criteria. The Specification Tables
`for both strengths of the FDC Capsules (Memantine HCl/Donepezil HCl ER FDC
`Capsules, 14/10 mg and 28/10 mg) have been updated with the recommended dissolution
`acceptance criteria:
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`‘
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`900 ml of NaCl/HCI
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`buffer, pH 1.2 at
`37 i: 0.5 °C
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`1
`2. OSI Inspection Report on the bioanalytical Site for Study MDX-PK-104:
`The OSI report on the definitive BE study (#MDX-PK-104), uploaded into DARRTS on 1
`11/14/2014 by Dr. Gajendiran Mahadevan, concluded that “the data were found to be j
`reliable”.
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`

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`RECOMMENDATION
`‘
`ONDQA/Biopharmaceutics had reviewed NDA 206439 and its amendments submitted on‘
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`1 (basket)
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`900 ml of NaCl/HCl
`buffer, pH 1.2 at
`37 d: 0.5 °C
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`Donepezil:
`Q ="”“”/0 at 15 min
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`Office of New Drug Quality Assessment
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`Okpona n a bof afggkgcnanabofaEradlri, Ph.D.,
`o=ONDQA, ou=8iopharmaceutics,
`a Erad i riI P h. D. email=okpo.eradlri@fda.hhs.gov,c=US
`Date: 2014.1 1.21 19:59:58 -05'00'
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`Digitally signed by Okponanabofa
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`Digltally signed by Angelica Dovantes -
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`3N:c=US.o=U.S.Government,
`A n g e I i ca
`ou=HHS. ou=FDA, ou=Peop|e.
`DO ra nteS _S 40.39%:ilzil02a3arftls1213000708
`Date: 2014.] 1.21 20:04:55 0500'
`
`‘ Okpo Eradiri, Ph. D.
`‘ Biopharmaceutics Reviewer
`‘ Office of New Drug Quality Assessment
`
`Angelica Dorantes, Ph.D.
`Biopharmaceutics Team Leader
`
`

`

`APPENDIX
`
`INFORMATION REQUEST SENT TO APPLICANT ON 10/31/2014
`
`Your proposed dissolution acceptance criteria for Memantine HCI/Donepezil HCI Capsules are neither supported by
`the data nor adequatelyjustified; they are therefore not acceptable. In particular, the lVIVC model established for
`the single-entity memantine product, Namenda XR, in NDA 22525 does not support the dissolution acceptance
`criteria that you have proposed for the memantine component of the FDC product. We have recommended
`different dissolution acceptance criteria for memantine in the FDC product on the basis of the following:
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`i)
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`0M4) dissolution rate of the biobatch (Lot it 23559) relative to the clinical batch in NDA 22525; we
`The
`note that the change in the
`(0(4) (approved in 2010) to
`(53(4)
`(in 2013) may have contributed, at least in part, to the (5)“) dissolution rate observed in
`the FDC product; and
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`ii)
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`Batch release and long-term stability dissolution data for the biobatch and registration batches.
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`The dissolution method and FDA-recommended dissolution acceptance criteria for your proposed FDC product are
`as follows:
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`1 (basket)
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`100 rpm
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`37 i 0.5 °C
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`Donepezil:
`Q = 9' 0 at 15 min
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`900 ml of NaCi/HCI
`buffer, pH 1.2 at
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`Provide a revised Drug Product Specifications Table and amend the Drug Product Stability Protocol accordingly.
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`APPLI
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`NT’S ESPONS
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`UB ITI'ED ON 11 21 2014 SDN9IN DA RTS
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`The sponsor agrees to the FDA-recommended dissolution acceptance criteria for memantine HCl
`extended release / donepezil HCI capsules. This submission provides the revised release and stability
`drug product specifications for both dosage strengths (section 3.2.P.5.1 (14 mg/10 mg) and section
`3.2.P.5.1 (28 mg/10 mg)). The drug product stability protocol will be amended accordingly. Section
`3.2.P.8.2 is provided for reference.
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`28 mg/10 mg, 14 mg/10 mg (memantine/donepezil)
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`Moderate or severe dementia of Alzheimer’s Type
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`02/26/2014
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`Forest Research Institute, Inc.
`
`Xinning Yang, Ph.D.
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`Angela Men, M.D., Ph.D.
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`DCP I
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`Clinical Pharmacology Review
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`
`
`PRODUCT (Generic Name):
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`Memantine HCl Extended Release and Donepezil
`HCl Immediate-Release Fixed Dose Combination
`
`Namzaric
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`206,439
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`Capsule
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`PRODUCT (Brand Name):
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`NDA:
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`DOSAGE FORM:
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`DOSAGE STRENGTHS:
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`INDICATION:
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`SUBMISSION DATE:
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`APPLICANT:
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`CP REVIEWER:
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`TEAM LEADER:
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`OCP DIVISION:
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`
`NamzaricTM (MDX-8704) is a fixed-dose combination (FDC) of memantine extended-release
`(ER) and donepezil immediate-release (IR). Memantine is an N-methyl-D-aspartate (NMDA)
`receptor antagonist. It was approved for treatment of Alzheimer’s Disease (AD) under NDAs 21-
`487 (IR tablet), 21-627 (oral solution), and 22-525 (ER capsule). Donepezil is an
`acetylcholinesterase inhibitor (AChEI). It was approved for treatment of AD under NDAs 20-
`690 (IR tablet), 21-719 (oral solution), 21-720 (oral disintegrating tablet), and 22-568 (higher
`strength of tablet).
`
` and donepezil HCl
`MDX-8704 is a capsule formulation consisting of memantine HCl ER
`IR
`. MDX-8704 is available as two strengths: 28 mg memantine HCl ER/ 10 mg
`donepezil HCl and 14 mg memantine HCl/10 mg donepezil HCl. The proposed indication for
`MDX-8704 is the treatment of moderate to severe dementia of the Alzheimer’s type (AD). The
`higher strength is for use in patients currently stabilized on memantine HCl (10 mg twice daily
`IR tablet or 28 mg once daily ER capsule) and donepezil HCl 10 mg. The lower strength is only
`for use in patients with severe renal impairment currently stabilized on memantine HCl (5 mg
`twice daily IR tablet or 14 mg once daily ER capsule) and donepezil 10 mg. MDX-8704
`
`Reference ID: 3658607
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`(b) (4)
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`(b) (4)
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`

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`administered as a once-daily FDC regimen may simplify administration, increase compliance
`and adherence to treatment, and thus provide benefit for patients and their caregivers.
`
`The applicant submitted this NDA as a 505(b)(2) application which relies on previous findings of
`safety and effectiveness for the reference list drugs, Aricept (NDA 20-690) as well as Namenda
`and Namenda XR (NDAs 21-487 and 22-525). In the past, a clinical trial was conducted to
`compare efficacy/safety of Namenda XR to placebo in patients with moderate to severe AD
`already on AChEIs. That study showed Namenda XR added onto donepezil provided statistically
`significant improvement relative to donepezil alone for one of the co-primary efficacy endpoints,
`the SIB (severe impairment battery), and numerical improvement (not statistically significant) on
`the other primary endpoint, the CIBIC-plus (clinician interview-based impression of change with
`caregiver input rating score). Treatment of moderate to severe AD with concurrent memantine
`and donepezil is the current standard of care.
`
`The applicant did not conduct efficacy trials and pursued approval based on demonstration of
`bioequivalence (BE) between the 28/10 mg MDX-8704 (28 mg memantine ER and 10 mg
`donepezil IR) capsule and co-administration of the 28 mg Namenda XR® capsule (memantine
`ER) and 10 mg Aricept® tablet (Study MDX-PK-104). The applicant also conducted a PK study
`(MDX-PK-105) to evaluate the food effect on MDX-8704 and compare administration of the
`intact 28/10 mg MDX-8704 capsule and capsule contents sprinkled on applesauce. In addition,
`biowaivers for the drug product manufactured at commercial manufacturing site, and for the
`lower MDX-8704 strength (14/10 mg) were requested. This was based on comparison of
`predicted PK parameters (AUC and Cmax) derived from in vitro dissolution data and an
`established in vitro-in vivo correlation (IVIVC) model for memantine ER. Please refer to the
`review documented by Biopharmaceutical reviewer, Dr. Okpo Eradiri, for review on the BE
`study and biowaiver request.
`
`
`This review focuses on Study MDX-PK-105. The major findings are:
`• There was no significant food effect on bioavailability of (AUC and Cmax) of memantine
`and donepezil administered as MDX-8704.
`is
`• Administration of MDX-8704 as capsule contents sprinkled on applesauce
`bioequivalent to administration of intact capsule (both under fasted conditions), for
`memantine and donepezil.
`• The median Tmax was reduced to 14 hours from 24 hours for memantine when
`administered with food. Such Tmax change is similar to the food effect described in the
`labeling of Namenda XR® (updated on September 26, 2014):
`There is no difference in memantine exposure, based on Cmax or AUC, for NAMENDA XR
`whether that drug product is administered with food or on an empty stomach. However,
`peak plasma concentrations are achieved about 18 hours after administration with food
`versus approximately 25 hours after administration on an empty stomach.
`There is no difference in the absorption of NAMENDA XR when the capsule is taken
`intact or when the contents are sprinkled on applesauce.
`
`Reference ID: 3658607
`
`

`

`• The median Tmax of donepezil was prolonged to 6 hours when MDX-8704 was
`administered with high-fat meal, compared to 3 hours under fasted condition. The median
`Tmax of donepezil was reduced from 3 to 2 hours when MDX-8704 was administered as
`capsule contents sprinkled on applesauce compared to administration of intact capsule.
`Such changes are not considered clinically relevant, since MDX-8704 is used to treat a
`chronic disease.
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`Overall, no clinically significant PK difference was observed for memantine or donepezil when
`MDX-8704 was administered with food or sprinkled on applesauce.
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`In conclusion, the information submitted under NDA 206-439 has been reviewed and found to be
`acceptable from the Clinical Pharmacology’s perspective.
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`Reference ID: 3658607
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`Study Design
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`Study MDX-PK-105: A Single-Center, Randomized, Open-Label, 3-Way Crossover, Single-
`Dose Study in Healthy Adults to Evaluate the Effect of Food and the Effect of
`Administration of Capsule Contents Sprinkled on Applesauce on
`the Relative
`Bioavailability of Memantine and Donepezil After Oral Administration of MDX-8704
`(Study Period: Apr 19, 2013 – July 12, 2013)
`
`Objective
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`1. To evaluate the effect of food on the relative bioavailability of memantine and
`donepezil after oral administration of an intact MDX-8704 capsule.
`2. To evaluate the relative bioavailability of memantine and donepezil after oral
`administration of MDX-8704 as an intact capsule and capsule contents sprinkled on
`applesauce in the fasted state.
`Subjects were randomly assigned to 1 of 6 treatment sequences (ABC, ACB, BAC,
`BCA, CAB, or CBA). Each of the following treatments was administered with a 21-
`day washout period between treatments:
`Treatment A: A single oral dose of MDX-8704 (memantine HCl ER/donepezil HCl)
`28 mg/10 mg capsule administered under fasted conditions
`Treatment B: A single oral dose of MDX-8704 (memantine HCl ER/donepezil HCl)
`28 mg/10 mg capsule administered following a high-fat breakfast
`Treatment C: A single oral dose of MDX-8704 (memantine HCl ER/donepezil HCl)
`28 mg/10 mg administered as capsule contents sprinkled on 30 mL (2 tablespoons)
`of applesauce under fasted conditions
`Study Population Thirty-six subjects were enrolled in the study (25 males and 11 females). Three
`subjects prematurely discontinued, one due to an adverse event (AE), one due to a
`protocol violation, and one subject for other reasons. The mean age (± SD) and
`body mass index (± SD) were 27.3 (± 5.3) years and 25.41 (± 2.90) kg/m2,
`respectively. Twenty-five subjects were white and 10 subjects were black.
`Blood samples were collected starting on Day 1 of each period at 0 hour (predose)
`and at 1, 2, 3, 4, 6, 8, 10, 12, 14, 24, 30, 36, 48, 72, 96, 120, 168, 216, and 264
`hours after dosing.
`The PK parameters, Cmax, Tmax, AUCt, AUCinf, and T1/2, were estimated using non-
`compartmental approach.
`Descriptive statistics for all PK parameters of memantine and donepezil were
`provided for all subjects who completed the study, had no episode of emesis (within
`24 hours after administration of MDX-8704 for PK analysis of memantine and
`within 2 times the median Tmax after administration of MDX-8704 for PK analysis
`of donepezil), and had evaluable PK parameters. The Cmax, AUC0-t, and AUC0-inf of
`memantine and donepezil were compared by means of a linear mixed effects model
`with sequence, treatment, and period as fixed effects and subjects within sequence
`as a random effect. The Wilcoxon signed-rank test was performed on Tmax. A p-
`value ≤ 0.05 was considered a significant difference between treatments.
`The bioanalytical assays were validated and are acceptable.
`Analyte
`Memantine (ng/ml)
`Donepezil (ng/ml)
`Method
`LC-MS/MS
`LC-MS/MS
`2H-memantine
`2H-donepezil
`Internal Standard
`LLOQ
`0.50
`0.50
`Calibration Range
`0.5, 1, 2, 5, 10, 20, 40, 50
`0.5, 1, 2, 5, 10, 20, 40, 50
`QC
`1.5, 8, 30
`1.5, 8, 30
`Accuracy(%Bias)
`± 2%
`± 5.3%
`Precision (%CV)
`3.0%
`4.2%
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`Pharmacokinetic
`Assessments
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`Bioanalytical
`Method
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`Reference ID: 3658607
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`

`

`Safety
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`evaluations,
`laboratory
`clinical
`sign,
`vital
`(AEs),
`events
`Adverse
`electrocardiographic (ECG), physical examination, and Columbia-Suicide Severity
`Rating Scale (C-SSRS)
`
`Results
`Because of emesis, 10 subjects were excluded from the PK analysis of the Treatments A and B
`comparison, and 12 subjects were excluded from the PK analysis of the Treatments A and C
`comparison. The PK parameters and profiles of memantine and donepezil are shown as below.
`
`Table 1. Pharmacokinetic Parameters (Mean ± SD) for Memantine—Pharmacokinetic Population
`
`
`a. For AUC0-inf, n = 22 for comparison between Treatments A and B and n = 20 between Treatments A and C
`because reliable AUC0-inf value could not be calculated for Subject 001-0016.
`b. For Tmax, the median (minimum - maximum) and arithmetic mean ratios are presented for the treatment
`comparison.
`c. The Wilcoxon signed-rank test was performed to calculate the p-value for the comparison of Tmax.
`d. For T1/2, n = 22 for Treatment A because reliable value could not be calculated for Subject 001-0016.
`e. n = 21 for statistical comparisons of Treatment A versus Treatment C because Subjects 001-0010 and 001-0033
`were excluded due to vomiting after receiving Treatment C.
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`Figure 1. Mean (± SD) Plasma Concentrations of Memantine Versus Time by Treatment — PK
`Population
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`Reference ID: 3658607
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`
`
`

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`Table 2. Pharmacokinetic Parameters (Mean ± SD) for Donepezil—Pharmacokinetic Population
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`a. For Tmax, the median (minimum - maximum) and arithmetic mean ratios are presented for the treatment
`comparison.
`b. The Wilcoxon signed-rank test was performed to calculate the p-value for the comparison of Tmax.
`c. n = 21 for statistical comparisons of Treatment A versus Treatment C because Subjects 001-0010 and 001-0033
`were excluded due to vomiting after receiving Treatment C.
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`Figure 2. Mean (± SD) Plasma Concentrations of Donepezil Versus Time by Treatment — PK
`Population
`
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`Food has no significant effect on the bioavailability of the MDX-8704 capsule. The median Tmax was
`reduced to 14 hours from 24 hours for memantine, but was prolonged to 6 hours from 3 hours for
`donepezil when administered with the high-fat meal compared to under fasted conditions.
`Administration of MDX-8704 as capsule contents sprinkled on applesauce is bioequivalent to
`administration of intact capsule. The median Tmax of memantine was reduced to 14 hours from 24
`hours and the Tmax of donepezil was reduced to 2.1 hours from 3.0 hours when administered as capsule
`contents sprinkled on applesauce compared to administration of intact capsule.
`Safety
`Overall, 28 subjects (77.8%) reported treatment-emergent adverse events (TEAEs)
`considered to be related to investigational product. The most common TEAEs (> 10%
`
`
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`Reference ID: 3658607
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`

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`of all subjects) were nausea (69.4%), dizziness (50.0%), vomiting (33.3%), headache
`(27.8%), and abdominal discomfort (13.9%). The incidence of TEAEs was similar
`following administration of MDX-8704 under fasted conditions either as an intact
`capsule (62.9% of subjects) or as capsule contents sprinkled on applesauce (67.7% of
`subjects); the incidence of TEAEs was lower (44.1% of subjects) following
`administration of MDX-8704 intact capsule under fed conditions.
`The incidence of nausea and vomiting was similar following administration of MDX-
`8704 under fasted conditions either as an intact capsule (57.1% and 28.6% of subjects,
`respectively) or as capsule contents sprinkled on applesauce (55.9% and 23.5% of
`subjects, respectively) and was lower following administration of MDX-8704 intact
`capsule under fed conditions (35.3% and 5.88% of subjects, respectively).
`The majority of the TEAEs were mild to moderate in severity. All the incidences of
`vomiting were moderate in severity. The incidence of moderate nausea was similar for
`the 2 treatments administered under fasted conditions (intact capsule, 25.7%; capsule
`contents sprinkled on applesauce, 23.5%) and lower following MDX-8704 administered
`as an intact capsule under fed conditions (5.88%).
`No clinically meaningful trends were observed in clinical laboratory, vital sign, or 12-
`lead electrocardiogram results. No subject reported suicidal ideation or suicidal
`behavior.
`Conclusions No clinically significant PK difference in memantine or donepezil was observed when
`MDX-8704 was administered with food or sprinkled on applesauce.
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`Reference ID: 3658607
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`

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`LABELING RECOMMENDATIONS
`The reviewer looked through the applicant’s proposed labeling for NamzaricTM and found it
`acceptable from Clinical Pharmacology’s perspective, provided that the recommended revisions
`are made to the labeling language.
`
`Labeling recommendation to be sent to the applicant:
`The text in red color is the reviewer’s proposed addition to the labeling; the stn'kethrough text is
`recommended by the reviewer for deletion.
`(Reviewer ’s Note: It seems that the applicant’s proposed labeling was modified based on merged
`labelings of Aricepto and Namenda XRO. Only newly added language and the one subject to
`recommended changes are shown below. The language same as that in Aricept" or Namenda
`XRO labelings is not included here.)
`
`HIGHLIGHT
`
`DruiInteractions
`
`
`
`Reference ID: 3658607
`
`

`

`
`
`7 DRUG INTERACTIONS
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`
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`8.7 Hepatic Impairment
`No dosage adjustment
`is needed in
`TRADENAME
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`severe hepatic impairment [see
`(12.3)].
`
`12.3 Pharmacokinetics
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`TRADENAME
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`atients with mild or moderate hepatic impairment.
`in patients with
`Clinical Pharmacology
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`
`
`Exposure (AUC and Cm“) of memantine and donepezil following TRADENAME administration
`in the fed or fasted state was similar. Further, exposure of memantine and donepezil following
`TRADENAME administration as intact capsule or capsule contents sprinkled on applesauce was
`similar in healthy subjects.
`
`He aticIm ailment
`
`Drug-Drug Interactions
`Use with Cholinesterase Inhibitors
`
`Coadministration of memantine with the AChE inhibitor donepezil HCl did not afl'ect the
`phaimacokinetics of either compound.
`In a 24-week controlled clinical study in patients with moderate to severe
`Alzheimer’s disease,
`the adverse event profile observed with a combination of memantine
`immediate-release and donepezil was similar to that of donepezil alone.
`
`Effect of Memantine on the Metabolism of Other Drugs
`Pharmacokinetic studies evaluated the otential of memantine for interaction with
`
`and bu to ion
`
`
`pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite hydroxybupropion.
`
`
`
`Reference ID: 3658607
`
`

`

`Effect of Other Drugs on Memantine
`Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of
`the CYP450 s
`tem are not ex ected to alter the pharmacokinetics of memantine. A
`bupropion did not afi‘ect
`
`the
`
`pharmacokinetics of memantine
`
`(Reviewer ’s Note: The sentence describing the effect of buproprion on memantine does not exist
`in the current
`labeling of either Namenda or Namenda XR. However,
`in the Clinical
`Pharmacology review for Namenda XR which was documented by Dr. Huixia Zhang in
`DARRTS and also shown on Drugs@FDA, it was concluded that no effect of memantine on
`bupropion or on CYP2B6 activity (hydroxylation of bupropion) was found, nor was there an
`efl'ect of bupropion on memantine. So, it seems acceptable to add the description of buproprion’s
`eflect on memantine PK in the current labeling for NamzaricTM.)
`
`Done ezil HCI
`
`
`
`
`
`Xinning Yang, Ph.D.
`
`Division of Clinical Pharmacology I
`
`Team Leader: Angela Men, MD. Ph.D.
`
`Reference ID: 3658607
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XINNING YANG
`11/14/2014
`
`YUXIN MEN
`11/16/2014
`
`Reference ID: 3658607
`
`

`

`NDA 206439, Biopharmaceutics Assessment
`
`'
`
`BIOPHARMACEUTICS REVIEW
`
`I uali Assessment
`Office of New Dru-
`! Biopharmaceutics Reviewer:
`206-439
`Ap - Iication No.:
`w_—i 0kpo Erwin: PhD
`Applicant:
`Forest Laboratories, Inc.
`!Igrgfignggrzg? 3173;“ Leader"
`
`_radeName:
`Acting Biopharmaceutics Supervisor:
`
`IPaul Seo Ph.D.
`
`.
`
`,
`
`Indication:
`
`Formulation/strength
`
`apsules
`
`iTreatmentofmoderateto
`
`severe dementia of the
`
`IAlzheimer’s 1 ye.
`FDC Tablet, Memantine HCI
`ER/ Donepezil HCl: 14/10 mg
`I & 28/10 In.
`
`
`
`IAssi_ ned:
`
`Date of
`
`. Review:
`
`10/26/2014.
`
`_
`
`Administration
`SUBMISSIONS REVIEWED IN THIS DOCUMENT
`CDER Stamp
`IPl'imaryARRReview duein
`Date
`
`S“b"“ss'°“ ““5
`
`PDUFA
`DATE
`
`2/26/2014, 6/10/2014,
`8/7/2014
`e_fSubmission:
`
`| Type of Consult:
`i
`
`Key Review Points:
`
`12/26/2014
`
`10/26/2014
`
`2/26/2014
`NDA; 505(b)(2)
`505 (b)(2) Application (Relied upon product: NDA 20-690 (Aricept approved
`Nov 25, 1996))
`I Associated IND: 109-763
`Adequacy of the dissolution method and acceptance criteria for both
`components
`Assessment of alcohol dose dumping experimental results
`Adequacy of the design, conduct and results of definitive bioequivalence
`study on the highest strength, 28/10 mg (Memantine HCi/Donepezil)
`Validity of the IVIVC Model for the ER Component of the FDC Product
`Acceptability of the biowaiver request for the lower strength, 14/10 mg
`Acce otabili of the biowaiver re uest for the manufacturin site chan - e
`
`SUMMARY OF BIOPHARMACEUTICS FINDINGS:
`
`Submission: NDA 206439 is a 505(b)(2) submission for Memantine HCl ER @(‘icombined
`with immediate-release Donepezil HCI
`0"“) in a capsule. The proposed drug product is a FDC
`extended-release dosage form because one of the active components is an ER formulation. The
`two active drugs were previously approved: Memantine HCl (NDA’s 21487 & 22525) and
`Donepezil (NDA 20690). Both drugs have been shown to improve cognitive function in patients
`with moderate to severe Alzheimer’s disease.
`
`Page 1 of 26
`
`

`

`NDA 206439, Biopharmaceutics Assessment
`
`‘ Review: The Biopharmaceutics review is focused on the following:
`. Adequacy of the dissolution method and acceptance criteria for both components
`. Assessment of alcohol dose dumping experimental results
`. Adequacy of the design, conduct and results of the definitive bioequivalence study on the
`highest strength, 28/10 mg (Memantine HCl/Donepezil)
`. Validity of the IVIVC model for the ER memantine component of the proposed FDC
`Memantine HCl/Donepezil product
`. Acceptability of the two biowaiver requests
`
`It is noted that this NDA also included a food-effect/applesauce study and other drug-drug 2
`interaction (DDI) studies. The Office of Clinical pharmacology is reviewing these studies.
`
`. Dissolution Information
`
`.~=.l'5
`-‘ ”“1“”
`-
`Volume/'I‘emperature -'
`
`:‘TACceptsncs Criteri‘f
`"
`‘
`‘~ ~ ,
`
`1 (“5"”)
`
`100 rpm
`
`900 ml ofNaCl/HCI
`buffer pH 1 2 at
`37 ; 05 4c
`
`Domain;
`Q = 3% at 15 min
`
`Memantine:
`
`a) Dissolution Method: The Applicant proposes the same dissolution method that was
`approved for single-entity Memantine HCl ER Capsules in the quality control of
`Memantine HCl ER/ Donepezil HCl FDC Capsules. Although the method results in W"
`release of donepezil from the immediate-release
`W" it is acceptable
`because the Applicant’s data package demonstrate that donepezil drug substance is highly
`soluble and highly permeable.
`b) Dissolution Acceptance Criteria:
`The following dissolution method and acceptance criteria for Memantine HCl/Donepezil HCl ER
`FDC Capsules, 14/10 mg and 28/10 mg, are recommended:
`
`
`
`
`l 2. Alcohol Dose Dumping
`The Applicant observed alcohol dose dumping of the memantine component in 40% alcohol
`and has submitted a justification for not conducting an in-vivo study A definitive BE study
`(MDX-PK-104) comparing the proposed FDC tablet
`to the co-administered single entity
`products serves as the basis for approval of this NDA; this study has been reviewed by the
`Biopharmaceutics team. Food-effect/applesauce and DDI studies (to be reviewed by OCP)
`were also conducted.
`
`3. Bioequivalence Study for the Higher Strength
`to the co-
`A definitive BE study (MDX-PK-104) comparing the proposed FDC tablet
`administered sin 1e enti
`nroducts serves as the basis for a roval of this NDA. The
`
`Page 2 of 26
`
`

`

`NDA 206439, Biopharmaceutics Assessment
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 3 of 26
`
`
`
`
`
`
`memantine and donepezil components in the higher strength of the FDC capsules have been
`demonstrated to be bioequivalent to their respective single-entity reference products and BE
`study MDX-PK-104 is acceptable, provided the Office of Scientific Investigations does not
`identify any critical issues for this BE study.
`
`
`
`
`4. Validity of the IVIVC Model for the ER-Memantine component of the FDC product
`In order to apply the established IVIVC model (in NDA 22525) to the memantine component
`
`of the FDC capsules in this NDA (206439) to support the biowaiver requests, the predicted
`
`memantine PK parameters for the higher strength of the FDC (28/ 10 mg) were compared to
`
`those for the target (clinical batch) in NDA 22525. The IVIVC’s predicted FDC-memantine:
`Observed Namenda XR ratios for Cmax, AUC., and AUCco are 104.59, 113.85, and 112.89 %,
`
`
`respectively. The corresponding ratios for the Observed FDC: Observed Namenda XR are
`
`
`96.94, 106.79, and 107.21, respectively. Since all ratios are within 20% of the target single-
`
`
`entity product, application of the IVIVC model to this NDA is adequately supported and
`
`
`therefore this model is considered valid for the memantine component of the FDC product.
`
`
`
`5. Biowaiver Requests
`
`a) Manufacturing Site Change: The Applicant’s supporting data for the manufacturing site
`
`
`change biowaiver request are adequate. The request for a waiver of bioavailability study
`
`
`on the proposed drug product manufactured at the clinical and commercial sites is
`.
`therefore granted.
`b) Lower Strength: The Applicant’s comparative dissolution data for the low (14/28 mg) and ‘:
`
`
`high (28/ 10 mg) strengths of the FDC product have been demonstrated to be similar. The
`
`
`request for a waiver of bioavailability study on the lower strength is therefore granted.
`
`
`
` ‘ 6. Risk Assessment
`Initial Risk Assessment
`Final Risk Assessment
`
`
`
`Lifecyclc
`.
`.
`Risk
`Product
`
`
`Considerations/
`t'o
`gust:
`h Mitigation
`EiSk
`Ranking
`fatto?t:;aégx
`. attribute/
`
`
`Comments**
`va ual n
`pproac
`*
`mpac
`_ C A
`
`
`
`
`
`- Formulation
`
`No comments since
`
`- Raw materials
`The
`
`
`
`donepezil is rapidly
`. Process
`Dissolution
`
`dissolution profile of the
`
`
`
`
`dissolving, is highly
`
`
`parameters
`donepezil
`09(4)
`
`Donepezil
`
`
`soluble and highly
`
`should meet specification
`- Scale/equipment
`
`
`
`permeable.
`
`0 Site
`
`due to its high solubility
`and the
`(m4)
`
`
`
`(5) (4)
`
`
`—Adhere to SUPAC-
`
`The drug
`. Formulation
`MR guidelines for
`
`
`
`minor and major
`- Raw materials (rate
`
`
`changes.
`controlling polymers)
`
`
`
`- API sources
`: Dissolution
`
`
`0 Process
`Memantine
`-For changes in the
`
`
`
`
`container closure
`parameters
`
`
`
`- Scale/equipment
`system, adequate
`
`
`° Site
`stability/dissolution
`
`
`
`
`
`
`

`

`NDA 206439, Biopharmaceutics Assessment
`
`in HDPE bottles.
`
`(5)
`‘4’
`
`0 Formulation
`- Process
`parameters
`- Scale/equipment
`0 Site
`
`-
`
`Even though the product
`has a pronounced
`dose dumping with 40%
`alcohol. clinical trials
`indicate mild adverse
`events for doses up to
`1 00m . .
`
`Acceptable
`
`evaluated due to
`potential effect on
`release rate.
`
`Changes in
`formulation require
`evaluating potential
`alcohol dose
`dumping.
`
`Office of New Drug Quality Assessment
`
`
`Please see the CMC review for the other C 0 As.
`
`I RECOMMENDATION
`
`At this time of the review process (GRMP date), the dissolution acceptance criteria for the
`proposed drug product have not been finalized. In addition, the Office of Scientific Investigations
`has not submitted their report for the inspection of the analytical site of BB study MDX—PK-104.
`: Therefore, from the Biopharmaceutics perspective critical information needed to support the
`approval of this NDA is incomplete and the Biopharmaceutics recommendation on the
`approvability of NDA 206439 is currently PENDING.
`
`Okpo Eradiri, Ph. D.
`‘ Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`
`Angelica Dorantes, Ph.D.
`Biopharmaceutics Team Leader
`
`Page 4 of 26
`
`

`

`
`
`
`NDA 206439, Biopharmaceutics Assessment
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`
`SUMMARY OF BIOPHARMACEUTICS FINDINGS: ................................................... 1
`
`
`
`
`
`
`
`
`
`
`RECOMMENDATION ...................................................................................................... 4
`
`
`
`TABLE OF CONTENTS ................-.................................................................................... 5
`
`
`
`
`
`
`
`1
`
`
`
`2
`
`
`3
`
`
`
`
`
`INTRODUCTION ....................................................................................................... 6
`
`
`
`PROPOSED DISSOLUTION METHOD ................................................................... 7
`
`
`
`
`
`
`
`
`
`
`
`
`2.1. Reviewer’s Assessment: SATISFACTORY............................._ ........................ 10
`
`
`
`SETTING OF DISSOLUTION ACCEPTANCE CRITERIA .................................. 10
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Applicant’s Proposed A