CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-487
`
`Clinical Pharmacology and Biopharmaceutics
`Review
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 1
`
`

`
`N 21-487
`Memantine HCI
`
`IU~I' !• t: ! r, U
`
`,~1.,1 v
`
`.... - OCT -: 2 2003 Page I of 191
`
`Clinical Pharmacology/Biopharmaceutics Review
`
`PRODUCT (Generic Name):
`
`Memantine HCl
`
`NDA:
`
`21-487
`
`PRODUCT (Brand Name):
`
`NAMENDA
`
`DOSAGE FORM:
`
`Tablets
`
`DOSAGE STRENGTHS:
`
`5, 10, 15 and 20 mg
`
`INDICATION:
`
`Moderate to severe dementia of Alzheimer's
`type
`
`NDA TYPE:
`
`IS
`
`SUBMISSION DATES:
`
`12/19/02, 4/11/03, 3/5/03, 3/24/03, 8/8/03,
`8/13/03, 8/28/03
`
`SPONSOR:
`
`REVIEWER:
`
`TEAM LEADER:
`
`OCPB DIVISION:
`
`OND DIVISION:
`
`Forest Laboratories Inc
`
`Veneeta Tandon, Ph.D.
`
`Ramana Uppoor, Ph.D.
`
`DPE I, HFD 860
`
`HFD I20
`
`1.0
`
`EXECUTIVE SUMMARY
`
`Forest Laboratories Inc. seeks approval for NDA 21-487 (memantine HCl) tablets in the
`strengths of 5, I 0, 15 and 20 mg for the treatment of moderate to severe dementia of the
`Alzheimer's type (DAT). Memantine HCl is a moderate affinity uncompetitive NMDA
`receptor antagonist unlike other drugs for the treatment of DA T that are mainly
`acetylcholine esterase inhibitors. The recommended starting_ dose of memantine is 5 mg
`once daily. The recommended target dose is 20 mg/day. The dose should be increased in
`5 mg increments to 10 mg/day (5 mg twice a day), I5 mg/day (5 mg and I 0 mg as
`separate doses), and 20 mg/day (10 mg twice a day). The minimum recommended
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 2
`
`

`
`N 21-487
`Memantine HCI
`
`Page 2 of 191
`
`interval between dose increases is one week. Memantine can be taken without regard to
`food.
`
`The sponsor has submitted 23 in vivo pharmacokinetic studies to support the
`pharmacokinetics of memantine, out of which 19 studies have been reviewed. Out of
`these studies only 5 had adequate assay validation reports as per the FDA guidelines on
`Bioanalytical Validation (these include bioequivalence evaluation, food effect, two drug(cid:173)
`drug interaction studies and general pharmacokinetics after a single dose). All other
`studies had some aspect of the assay validation that was not done as per the current
`standards. The pharmacokinetic studies conducted earlier in the drug development used
`methodology where as the more recent studies utilized
`-
`method for
`the analysis of plasma and urine samples. The sponsor states that some ofthe assay
`validation was not per the FDA guidelines on Bioanalytical Validation, but were based on
`the ICH guidelines at that time. A few studies lacked the quality control runs but had the
`calibration curves. Some ofthese studies (not considered pivotal) with less stringent
`analytical validation reports were accepted based on the following reasons: (a) no drift in
`the data from assays that had adequate quality control data and used the same
`methodology, (b) pharmacokinetic parameters across studies at the same dose level had
`similar parameter values using the same
`-
`methodology, (c) parameter values
`obtained for studies at same doses using the
`method were very similar to those
`obtained using
`.nethod.
`
`-
`
`Some review issues have been identified that impact the quality of the data submitted for
`review. Key limitations from some studies are:
`• One well conducted study and two other pilot studies suggest that the absolute
`bioavailability ofmemantine is greater than 100%. The reason for this is not clear.
`• The study conducted in the mild and moderately impaired renal patients did not have
`adequate quality control data to assess the adequacy of the study. Three out of six
`subjects in the control group had CLr values that were greater than the CLt. Subjects
`with moderate renal impairment showed a 39% increase in exposure as compared to
`the normal subjects. Due to the inadequacy of the study, the results from this study
`cannot be used to propose dosage reduction in subjects with moderate renal
`·
`-
`impairment. .
`
`• Adequate characterization ofthe extent of renal elimination ofmemantine has not
`been elucidated due to conflicting results from 3 studies. A lack of study in hepatic
`·impaired subjects is not justified based on the data provided.
`• There is inadequate representaion of the elderly population in the traditional
`pharmacokinetic studies. There were only 6 subjects that were~ 65 years across all
`pharmacokinetic studies with the highest age of 71 years. The mean age of
`Alzheimer's patients is >75 years. However, there is reasonable pharmacokinetic data
`in this age group in Phase 3 clinical trials.
`• A good estimation of accumulation cannot be obtained from the multiple dose studies
`as plasma samples were not taken on Day 1 of the Study. Assuming linear
`pharmacokinetics the accumulation factor after multiple doses has been predicted. A
`multiple dose study with the proposed dosing regimen (titrated regimen with a
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 3
`
`

`
`N 21-487
`Memantine HC1
`
`Page 3 of 191
`
`starting dose of 5 mg/day and escalated on weekly basis up to 20 mg/day) has not
`been conducted. Multiple dose study has been conducted with BID dosing of I xI 0
`mg memantine for 18 days (20 mg/day)
`
`Dosing adjustments may be needed for the following populations/situations:
`(a) Subjects with renal impairment may show an increase in exposure as
`compared to the normal subjects. Dose reduction may be necessary, although
`adequate data is not available at this time
`(b) Diet, drugs or disease states (such as renal tubular acidosis or severe infection
`of the urinary tract) that alter the urine pH to make it alkaline can reduce the
`clearance of the drug. Caution should be exercized in these situations.
`
`1.1
`
`RECOMMENDATION
`
`The Office of Clinical Pharmacology and Biopharmaceutics/Division of Pharmaceutical
`Evaluation I (OCPB/DPE-1) has reviewed NDA 21-487. The submission is acceptable
`from a Clinical Pharmacology and Biopharmaceutics point of view provided that the
`sponsor addresses the comments and Phase IV recommendations and agrees with the
`Agency's label recommendations. The labeling changes have been made to reflect the
`accuracy of the results obtained or to delete information from studies that were not
`conducted adequately.
`
`The Phase IV Commitment recommendations on page 4 and labeling comments outlined
`in the Detailed Labeling Recommendation section of the review on page 46 should be
`conveyed to the sponsor.
`
`The following comments should also be conveyed to the sponsor:
`
`• For future NDA applications, the sponsor should have adequate assay validation
`reports as per the FDA guidance on Bioanalytical Method Validation submitted along
`with each study report. Any deviations from the validated method, should be clarified
`within the study report. All studies should have their own standard curves and quality
`control data for the analytical runs.
`• CYP 450 inhibition studies with memantine have been conducted with liver from
`only one donor. In future such studies should be conducted with more than one donor
`as there can be large variability in CYP enzymes in livers from different donors and
`one donor may not represent this. Further all CYP isoenzymes may not be expressed
`in one donor. No information has been provided on the induction potential of
`memantine.
`• When the dosing recommendations for the memantine tablets is to give them in
`divided doses with a maximum of 20 mg/day (as 10 mg BID), it is not clear why the
`sponsor would propose to market the 15 and 20 mg tablet strengths. Please justify the
`marketing of these two strengths.
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 4
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`

`
`N 21-487
`Memantine HCI
`
`Page 4 of 191
`
`1.2
`
`PHASE IV COMMITMENTS
`
`• The ongoing renal impairment study should be submitted within I year from the date
`of approval and the label should be modified based on the results of the study.
`• About 57-82% ofmemantine is eliminated intact in the urine. This shows that about
`I 8-43% of memantine is eliminated through the metabolic route. The extent of renal
`elimination of intact memantine is not clear at this time due to conflicting results from
`the studies, the sponsor should conduct a study in subjects with moderate hepatic
`impairment compared to normal subjects. This aspect could be addressed ifthere are
`adequate number of hepatic impaired subjects in the clinical trials.
`• The sponsor should evaluate the induction potential of memantine.
`
`Jv ~~oj
`
`Veneeta Tandon, Ph.D.
`Pharmacokineticist
`Division ofPharmaceutical Evaluation I
`,.,.\
`~\
`
`Team Leader: RamanaUppoor, Ph.D?~~ \0 I oz;L)03
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 5
`
`

`
`N 21-487
`Memantine HCJ
`
`Page 5 of 191
`
`2.0
`
`TABLE OF CONTENTS
`
`1.0
`
`EXECUTIVE SUMMARY ..................................................................................................... 1
`
`1.1
`1.2
`
`RECOMMENDATION .................................................................................................................. 3
`PHASE IV COMMITMENTS ........................................................................................................ 4
`
`2.0 TABLE OF CONTENTS ......................................................................................................... 5
`
`3.0 OVERALL SUMMARY OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
`FINDINGS ........................................................................•.............................................................. 8
`
`4.0 QUESTION BASED REVI~ .............................................................................................. 12
`
`GENERAL ATTRIBUTES .......................................................................................................... 12
`4.1
`Drug/Drug Product Information: .......................................................................................... 12
`4.1.1
`
`4.2
`
`GENERAL CLINICAL PHARMACOLOGY ............................................................................. 14
`
`INTRINSIC FACTORS ................................................................................................................ 28
`4.3
`4.3.1
`Effect of Renal Impairment: .............................................................................................. 28
`Effect of Hepatic Impairment: ........................................................................................... 29
`4.3.2
`Effect of age: ........................................................................................................................ 29
`4.3.3
`4.4.4
`Effect of Gender: ................................................................................................................. 30
`4.4.6
`Effect of AIDS: .................................................................................................................... 32
`
`4.4
`
`EXTRINSIC FACTORS ............................................................................................................... 33
`
`4.5
`
`GENERAL BIOPHARMACEUTICS ............... · ........................................................................... 36
`
`4.6
`5.0.
`
`ANALYTICAL ............................................................................................................................. 41
`DETAILED LABELING RECOMMENDATION ................................................................... 46
`
`6.0
`
`APPENDIX .......................................................................................................................... 50
`
`APPENDIX I ................................................................................................................................ 51
`6.1
`INDIVIDUAL STUDY REVIEW ...................................................................................................... 51
`
`ADME STUDIES .............................................................................................................................................. 52
`
`SINGLE DOSE STUDIES ................................................................................................................... 52
`
`Study: HUK-61014: Memantine pharmacokinetics, dose-relationships and absolute
`bioavailability for single oral doses of 10, 20 and 40 mg in comparison with single IV solution . ................ 52
`
`Study: 1 E 1801 /Sun Y70 17: Safety and Pharmacokinetic Study of a single oral dose of
`SUN Y7017 in Healthy Adult Males .............................................................................................................. 59
`
`Study: MEM-PK-04: An Open Label. Randomized, Three -Way Crossover,Bioavailability Study
`Comparing Memantine Modified Release to Immediate Release Tablets in Human Subjects ....................... 62
`
`Study: MRZ 90001-9506: Comparative Bioavailability of Two Galenical
`Formulations of Memantine in Elderly Subjects ........................................................................................... 64
`
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`

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`N 21-487
`Memantine HCI
`
`Page 6 of 191
`
`Study: MRZ 90001-9604: Pharmacokinetic and Relative Bioavailability of
`Memantine Tablets and Memantine Slow-Release Tablet in a Cross-Over Design in Healthy Subjects ....... 66
`
`Study: MRZ 9000I-820I: Human Pharmacokinetic Studies with Memantine ............................................... 68
`
`Study: PAZ I983: Orienting Pharmacokinetic Studies on 14C-Memantine in Healthy Subjects ................... 7I
`
`Study: MRZ 9000I-920I: Pharmacokinetics and Relative Bioavailability of Three Galenic Formulations of
`Memantine (Tab'tet, Slow Release Tablet and Solution) in a 3-Way Crossover Trial.. .................................. 74
`
`Study: HUK-6I0/5: Memantine: Safety, Tolerance and Pharmacokinetics
`after Single Intravenous Infusions of 30 and 40 mg Given at a Rate of!Omglh to Healthy Male Volunteers 75
`
`MULTIPLE DOSE STUDY ...................................................................................................................... 76
`
`Study: HUK 610/I3: (14C}-Memantine: A Study of the Absorption, Metabolism and
`Excretion Following Oral Administration to Healthy Human Volunteers .................................................... 76
`
`Study: MRZ 9000 I-960 I: Pharmacokinetic Study to Investigate the Influence of
`Urinary pH and Urine Flow on Renal Clearance of Memantine .................................................................. 82
`
`Study: HUK 6/016: Memantine: Pharmacokinetic Study With Repeat Doses
`of 5, I 0, and 20 mg Every 8 h for 12 Days .................................................................................................... 89
`
`Study: MRZ 9000I-9402: Study of the Bioequivalence of the New Slow Release
`Tablet of Memantine and a Reference Tablet Formulation ........................................................................... 95
`
`BIOEQUIV ALENCE AND FOOD EFFECT STUDY ................................................................................. 98
`
`Study: MEM-PK-01: A Single-Dose Open Label, Randomized, Three-Way Crossover
`Bioequivalence and Bioavailability Study Comparing IO mg Memantine Tablets Manufactured by Forest
`Laboratories and Merz in Human Subjects ................................................................................................... 98
`
`Study: MRZ 9000I-97041MKL 2745. Study on the Influence of Food on the
`Bioavailability of Memantine from a New Memantine SR Formulation and on the Relative Bioavailability of
`This Formulation Versus an JR Formulation Following Repeated Peroral Doses.. .................................... I03
`
`ADDITIONAL PILOT STUDIES ................................................................................................................ l06
`
`Study MRZ 9000I-8609: Open Pilot Study to Assess the Penetration of Akatinol
`Me.mantine Tablets in the cerebrospinalfluid ............................................................................................. I06
`
`Study MRZ 9000I-9203: Memantine: Pilot Study of the Excretion of Memantine in Sweat ........................ I 07
`
`Study MRZ 9000I-9I 00: Determination of Memantine in Lacrimal Fluid of P(>tients Under Long-Term
`Treatment with Akatinol Memantine ........................................................................................................... I08
`
`Study MRZ 9000 I-861 0: Partial Evaluation and Tolerability of Akatinol Memantine in
`Healthy Volunteers under Mental Stress Using Pharmaco-EEG after IV administration ......................... 109
`
`IN VITRO J\fETABOLISM ..................................................................................... 98
`
`IN VITRO DRUG-DRUG INTERACTIONS ........................................................................ l02
`
`EXTRINSIC FACTORS ............................................................................................................................... ll8
`
`Study: MRZ 9000I-9702: Study of Pharmacokinetic lmeraction Between
`Memantine and Hydrochlorothiazide!Triamterene Under Steady state Conditions.. .................................. 118
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 7
`
`

`
`N 21-487
`Memantine HCI
`
`Page 7 of 191
`
`Study: MEM-PK-07: A Study ofthe Pharmacokinetic Interaction ofMemantine and Aricept in Healthy
`Young Subjects ........••••.. ; .•..................................................................................................................... I 27
`
`INTRINSIC FACTORS .................................................................•.................................•............................ 134
`
`Study: PAZ 3049. Single Oral Application (20 mg) in 12 Geriatric Volunteers with
`Reduced Renal Functions; Determination of Plasma Levels, Total Clearance and Terminal Half-Lives.
`Additionally, Comparison of Fasting and Non-fasting Pharmacokinetics at Normal Renal Function in 6
`Volunteers ...... : .................................................................................................................................... I 34
`
`Study: MEM 960I, NTIOOI 5: A Study of the Safety of single dose and Steady-
`State Pharmacokinetics of NEU 3004 in Healthy Volunteers and AIDS patients ........................................ 14 I
`
`Evaluation ofthe influence of smoking, sex and
`Study: MRZ 9000I-9702:
`Galenic formulation on A UC, t 112 and CLtol of memantine based on results derived from bioavailability
`studies(Datafrom studies MRZ 9000I-9402 and 950I were combined to do this analysis) ....................... I47
`
`BIOPHARMACEUTICS CLASSIFICATION SYSTEM .......................................................................... 148
`
`DISSOLUTION ............................................................................................................................................. 155
`
`APPENDIX II ............................................................................................................................. 158
`6.2
`SPONSOR'S PROPOSED LABEL ................................................................................................. 158
`
`6.3
`APPENDIX III ........................................................................................................................... 184
`FILING AND REVIEW FORl\1 ...................................................................................................... 184
`
`6.4
`188
`APPENDIX IV ...................................................................................... .
`BCS CONSULATATION REVIEW ........................................................................ 189
`
`APPEARS THIS WAY
`0~· ORIGWAL
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 8
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`

`
`N 21-487
`Memantine HCI
`
`Page 8 of 191
`
`3.0 OVERALL SUMMARY OF CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS FINDINGS
`
`The sponsor has submitted 23 in vivo pharmacokinetic studies to support the
`pharmacokinetics ofmemantine, out ofwhich 19 studies have been reviewed. Out of
`these studies only 5 had adequate assay validation reports (these include bioequivalence
`evaluation, food effect, two drug-drug interaction studies and general pharmacokinetics
`after a single dose), all other studies had some aspect of the assay validation that was not
`as per the current FDA guidelines. The sponsor states that some ofthe assay validation
`was not per the FDA guidelines on Bioanalytical Validation, but were based on the ICH
`guidelines at that time. A teleconference was set up to discuss the assay validation report
`and missing information from the report from numerous studies. The sponsor was
`requested to respond to these additional requests and clarifications regarding the assays.
`The PK studies conducted in the early 1990's used -
`'as the assay validation
`method. Through out the studies numerous limits of quantitation were reported, with not
`adequate quality control data for some studies. The studies conducted in the later 1990's
`used .
`-
`as the assay methodology and were adequately validated as per the
`current FDA standards. The sponsor clarified some of the assay validation concerns in
`response to the teleconference. Some studies (that were not considered pivotal) that did
`not have quality control data but had data on standard curves that were generated each
`day of the analysis, were accepted based on (a) no drift in the data during the duration of
`the assay from studies that had quality control and used the same methodology (b)
`pharmacokinetic parameters across studies at the same dose level had similar parameter
`values, (c) pharmacokinetic parameters from the studies evaluated by the
`methodology were similar to those obtained by the
`methodology.
`
`The findings from clinical pharmacology and biopharmaceutics section is as follows:
`
`Exposure-Response for Efficacy or Safety:
`
`Efficacy: No exposure-response relationship was observed for efficacy. Relationship
`between exposure and the clinical endpoint Severe Impairment Battery (SIB) was
`evaluated in one study. Results showed that subjects with higher plasma concentrations
`infact had the most mean worsening of cognition. No clear trend was observed with the
`plasma concentrations and mean worsening of cognition.
`Safety: No relationships were observed between adverse events and exposure. Dizziness
`was the only adverse event that appeared to be dose related and was highest in the 40 mg
`dose group, which is not the proposed dose for the treatment of dementia of the
`Alzheimer's type.
`
`General Pharmacokinetics (ADME characteristics) of memantine:
`Absorption:
`• Memantine appears to be highly absorbed with absolute bioavailability greater than
`100% (from two studies). The reason for this is not clear. Various postulates have
`been highlighted in the individual study report.
`
`IPR2015-00410
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`Page 9
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`

`
`N 21-487
`Memantine HCI
`
`Page 9 of 191
`
`hours.
`• Truax ranges from -
`• There is no carrier-mediated transport for memantine.
`Distribution:
`•
`In vitro protein binding is 42-45%
`• Volume of distribution is 9-11 L/kg suggesting extensive distribution.
`Metabolism:
`• Memantine is a low extraction ratio drug.
`• The predominant route of memantine metabolism is via hydroxylation to form 1-
`amino-3- hydroxymethyl-5-methyladamantane (MRZ 2/373, 11-hydroxy memantine),
`1-amino-3,5-dimethyl-7- hydroxyadamantane (MRZ 2/544, 7 -hydroxy memantine ),
`and MRZ 2/374 (6-hydroxy memantine). Other routes of metabolism are N-oxidation
`and conjugation. Quantitative estimation of these metabolites has not been conducted
`in the PK studies. The metabolites do not have NMDA receptor antagonist activity.
`• The CYP isoenzymes do not play a role in the metabolism of memantine
`Elimination:
`• The half-life ranges from 57-95 hours across studies.
`• Memantine is eliminated by both renal and non-renal routes. The extent of renal
`elimination is not very clear because of conflicting results from various studies. From
`a radiolabeled study one subject showed that 68% of the radioactivity was due to
`intact memantine with two other components accounting for 15% and 17% of the
`radioactivity. Other two studies showed that renal clearance amounted to about 90%
`and 50% respectively, of the total clearance in the two studies.
`• The renal elimination ofmemantine is in part due to active tubular excretion.
`• Memantine shows pH dependent tubular reabsorption. The renal clearance reduces by
`approximately 80-87% with alkaline urine conditions.
`
`Single dose and multiple dose pharmacokinetics:
`
`• Single doses of 1x 10 mg and 2 x 10 mg memantine have been evaluated. PK
`parameters appear to be consistent across studies.
`• No PK study has been conducted with the proposed dosing regimen. With studies
`closest to the proposed regimen, (Study 1: 1 x 10 mg QD for 4 days followed by 1 x 10
`mg BID for 18 days followed by 2x10 mg for 1 day; and Study 2: where 5 mg was
`given for 3 days, followed by 1x 10 mg QD for 4 days, followed by 2x 10 mg QD for
`12 days; Study 3: where 1x 10 mg QD was given for 5 days followed by 1x 10 mg
`BID for 20 days), accumulation cannot be determined because blood samples were
`not taken on Day 1. In another study with TID dosing, an accumulation factor of 15
`was observed. Based on linear pharmacokinetics, an accumulation factor of 10 is
`predicted upon multiple dosing.
`• Steady state is reached within 13-16 days.
`
`Dose proportionality:
`
`No robust study is available to assess dose proportionality. The crossover study designed
`to assess dose proportionality in the dose range of 10-40 mg had plasma levels that were
`close to the LLOQ at the lowest dose, although the results from a power analysis show
`
`IPR2015-00410
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`Page 10
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`

`
`N 21-487
`Memantine HCI
`
`Page 10of191
`
`that the phannacokinetic parameters are proportional in the dose range of 10-40 mg. A
`second parallel study showed that doses are approximately proportional in the range of 5-
`40mg.
`
`Pharmacokinetics in patients:
`
`No phannacokinetic studies have been conducted in patients with Alzheimer's disease.
`Comparison of steady state plasma concentration~ from clinical trial to the concentrations
`observed in healthy volunteers in the pharmacolcinetic studies show some what
`comparable concentrations, although the absolute values were higher in patients. This
`also could be because (a) no pharmacolcinetic study in the healthy volunteers was
`conducted with the proposed regimen and (b) the size ofthe population (healthy) is small.
`(c) Patients were generally older compared to healthy volunteers in phannacokinetic
`studies.
`
`Special Populations:
`
`Renal Impaiment: Study was conducted with mild and moderate renal impaired subjects,
`but assay validation was not adequate. Results showed that in the moderate impaired
`subjects there was 33% reduction in CL/F and a 39% increase in AUCO-oo.
`
`Hepatic Impairment: No study was conducted in subjects with hepatic impairment.
`
`Age: Alzheimer's disease population generally consists of patients older than 75 years.
`Appropriate representation of age has not been included in the PK studies.
`Subjects upto 71 years of age were enrolled in the PK studies. In cross study comparions
`no significant differences were seen in exposure between young (18-35 years) and older
`( 51-69 years) subjects, but t 1/2 was increased by 39% with age after a single dose of 2x
`I 0 mg. After multiple doses of 1x 10 mg BID for 18 days the subjects~ 65 years had
`30% and 27% higher Cmax and AUCO-inf, respectively. 2 PK studies had a total of six
`subjects that were ~65 years of age. Clinical relevance ofthese differences cannot be
`assertained due to the small number of subjects in the elderly group. Plasma
`concentrations ofmemantine were obtained in Phase 3 clinical trials which do not show
`major differences in elderly compared to younger healthy volunteers.
`
`Gender: No apparent gender effect was observed in the pharmacokinetics ofmemantine.
`
`Race: The effect ofrace was not evaluated. In a cross study comparison the
`pharmacokinetic parameters ofmemantine were not different between Japanese and
`Caucasians.
`
`AIDS: AIDS patients had about 35% and 24% reduction in Cmax after single and
`multiple doses ofmemantine. There was a 32% and 29% reduction in AUC after single
`and multiple doses of memantine.
`
`IPR2015-00410
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`Page 11
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`

`
`N 21-487
`Memantine HCI
`
`Page II of 191
`
`· Drug-drug Interactions:
`Memantine is neither a substrate nor an inhibitor ofCYP isoenzymes, hence drug-drug
`interaction with other CYP substrates is unlikely. Memantine is eliminated via tubular
`secretion, therefore drugs with the same mechanism of elimination were evaluated in the
`drug-drug interaction studies.
`Only two drug interaction studies with hydrochlorthiazide/triamterene and donepezil
`have been conducted so far. Ongoing drug interaction studies are with
`glyburide/metformin and gabapentin.
`
`Effect of memantine on other drugs:
`Memantine decreased the. Cmax and AUC of hydrochlorothiazide by about 20%.
`Therefore a slight reduction in diuretic effect may be observed when memantine is co-
`•
`administered with hydroclorothiazide/triamterene.
`Memantine did not have any effect on the pharmacokinetics of other drugs studied.
`
`Effect of other drugs on memantine pharmacokinetics:
`Hydroclorothiazide/triamterene or donepezil did not influence the pharmacokinetics of
`memantine. No other drug-drug interaction study was conducted.
`
`Biopharmaceutics:
`
`• BCS Class: Memantine is highly soluble, highly permeable and rapidly dissolving
`drug and can be classified as BCS Class I compound.
`• Bioeguivalence: The Merz formulation ofmemantine used in the PK and clinical
`studies is bioequivalent to the to-be-marketed Forest formulation.
`• Food Effect: Food did not affect the bioavailability ofmemantine
`• Dissolution: The dissolution methodolgy is USP I at 100 rpm with 0.1 N HCl with
`NaCl at pH 1.2. A Q of - Vo in 30 minutes was set as the quality control
`specification.
`
`APPEARS TH!S WAY
`ON ORfGIN,,L
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 12
`
`

`
`N 21-487
`Memantine HCI
`
`Page12ofl91
`
`4.0 QUESTION BASED REVIEW
`
`4.1
`
`GENERAL ATTRIBUTES
`
`4.1.1 Drug/Drug Product Information:
`
`Dosage Form/Strengths:
`
`5, 10, 15 and 20 mg Tablets
`
`Indication:
`
`Treatment of moderate to severe dementia of Alzheimer's type
`
`Dosage and administration (Sponsor's Proposed):
`The dosage ofmemantine hydrochloride shown to be effective in
`controlled clinical trials is 10-20 mg/day.
`
`The recommended starting dose of memantine is 5 mg once daily.
`The recommended target dose is 20 mg/day. The dose should be
`increased in 5 mg increments to 10 mg/day ( 5 mg twice a day), 15
`mglday (5 mg and 10 mg as separate doses), and 20 mglday (10
`mg twice a day). The minimum recommended interval between
`dose increases is one week.
`
`Memantine can be taken with or without food.
`
`Pharmacologic Class: Memantine HCl is a moderate affinity uncompetitive (open
`channel) NMDA receptor antagonist that binds preferentially to the
`NMDA receptor-operated cation channels in a use dependent and
`voltage dependent manner with rapid blocking/unblocking
`kinetics.
`
`Chemical Name:
`
`1-amino-3,5,-dimethyladamantane hydrochloride with the
`following structural formula
`
`NH2 ' HCI
`
`The molecular formula is C 12H21N.HC1 and the molecular weight is
`
`IPR2015-00410
`Petitioners' Ex. 1013
`Page 13
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`Memantine HCI
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`Page13of191
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`Physical Characteristics: Memantine HCl occurs as a fine white to off-white powder and
`is highly soluble in water, _
`
`Mechanism of action: In vitro electrophysiological studies suggest that memantine
`inhibits NMDA receptor-mediated currents in a use-dependent
`[i.e., it blocks the receptor channel in the presence of an agonist,
`e.g., glutamate] and voltage-dependent manner, with rapid
`receptor-unblocking kinetics. Because of these attributes,
`memantine can selectively antagonize pathological activation of
`NMDA receptors without affecting the physiological functioning
`of the receptor. Physiological activation ofNMDA receptors is
`known to play a critical role in synaptic plasticity processes such
`as cognition.
`
`In several in vitro and in vivo studies, memantine has been shown
`to protect neurons from cell death due to excitotoxicity. In
`addition, memantine attenuates ~-amyloid (A~)-induced
`hippocampal cell death (apoptosis) in rats in vivo, and protects
`cholinergic neurons of the rat nucleus basalis magnocellularis from
`NMDA-induced neurotoxicity.
`
`Memantine has also been shown to improve learning and memory
`in animal studies.
`
`Foreign marketing history: Memantine HCl was first approved in Germany on June 26,
`1978 as drop and table