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`Drug Name(s)
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`Original Approval or Tentative Approval Date
`Chemical Type
`Review Classification
`
`NAMENDA
`(NDA) 021487
`MEMANTINE HYDROCHLORIDE
`FOREST LABS
`October 16, 2003
`1 New molecular entity (NME)
`S Standard review drug
`
`- There are no Therapeutic Equivalents
`
`- Label Information
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`- Approval History, Letters, Reviews, and Related
`Documents
`
`Products on Application (NDA) #021487
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`NAMENDA
`NAMENDA
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`MEMANTINE HYDROCHLORIDE
`
`SMG
`10MG
`
`TABLET;ORAL
`TABLET;ORAL
`
`Marketing
`Status
`
`Prescription
`Prescription
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`RLD TE
`Code
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`AB
`No
`Yes AB
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`Petitioners‘ EX’ 10 14
`Page 1
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`IPR2015-00410
`Petitioners' Ex. 1014
`Page 1
`
`

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`Petitioners‘ EX’ 10 14
`Page 2
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`22
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 2
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`

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`Label and Approval History
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`NAMENDA
`Drug Name(s)
`(NDA) 021487
`FDA Application No.
`Active Ingredient(s) MEMANTINE HYDROCHLORIDE
`Company
`FOREST LABS
`
`Label Information
`
`Go to Approval History
`
`What information does a label inc|ude?1°
`Note: Not all labels are available in electronic format from FDA.
`
`The supplement type of the 11/14/2013 approval does not usually require new labeling.
`
`View the label approved on 10/24/2013 (PDF)11 for NAMENDA, NDA no. 021487
`- To see if other previously-approved labels are available on this site, go to the "Approval History" section of this page.
`Older labels are for historical information only and should not be used for clinical purposes.
`Approval History
`NDA 021487
`
`Note: Not all reviews are available in electronic format from FDA.
`Older labels are for historical information only, and should not be used for clinical purposes.
`Approval dates can only be verified from 1984 to the present.
`
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`Number
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`11/14/2013 018
`
`Manufacturing Change or Addition
`
`Letters,
`Reviews,
`Labels,
`Patient Package Insert
`
`Note
`
`E D°Wn'0ad data
`
`This supplement type does
`not usually require new labeling.
`
`10/24/2013 014
`
`Labeling Revision
`
`10/24/2013 012
`
`Labeling Revision
`
`10/24/2013 010
`
`Labeling Revision
`
`03/11/2013 017
`
`Manufacturing Change or Addition
`
`10/04/2006 008
`
`Labeling Revision
`
`04/19/2006 007
`
`Labeling Revision
`
`05/17/2005 006
`
`Formulation Revision
`
`05/02/2005 004
`
`Labeling Revision
`
`09/22/2004 002
`
`Control Supplement
`
`10/16/2003 000
`
`Approval
`
`Label (l;Dl:)12
`Letter (PDF)13
`Label (pDl:)14
`Letter (PDF)15
`Label (PDl:)16
`Letter (PDF)17
`
`Letter (pDl:)18
`
`Letter (l;Dl:)19
`
`Letter (pDl:)20
`
`l_ettet (pDF)21
`
`Letter (pDF)22
`
`Label (PDF)23
`Letter (PDF)24
`Review 25
`
`This supplement type does
`not usually require new labeling.
`Label is not available
`on this site.
`
`Label is not available
`on this site.
`
`Label is not available
`on this site.
`
`Label is not available
`on this site.
`
`This supplement type does
`not usually require new labeling.
`
`Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and P|ayers25
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`- There are no Therapeutic Equivalents
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`1/4
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`48. http://www.fda.gov/NewsEvents/default.htm
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`49. http://www.fda.gov/CombinationProducts/default.htm
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`50. http://www.fda.gov/AdvisoryCommittees/default.htm
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`51. http://www.fda.gov/ScienceResearch/default.htm
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`52. http://www.fda.gov/Regulatorylnformation/default.htm
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`53. http://www.fda.gov/Safety/default.htm
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`54. http://www.fda.gov/ErnergencyPreparedness/default.htm
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`55. http://www.fda.gov/Internationa|Programs/default.htm
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`56. http://www.fda.gov/NewsEvents/default.htm
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`57. http://www.fda.gov/Training/default.htm
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`58. http://www.fda.gov/ICECI/default.htm
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`59. http://www.fda.gov/ForFedera|StateandLoca|Officials/default.htm
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`60. http://www.fda.gov/Forconsumers/default.htm
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`61. http://www.fda.gov/Forlndustry/default.htm
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`62. http://www.fda.gov/ForHea|thProfessiona|s/default.htm
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`63. http://www.accessdata.fda.gov/scripts/search/index.cfm?action=archive.search
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`Accessibility” Contact FDA3° Careers31 FDA Basics32 FOIA33 No Fear Act34 Site Map35 Transparency35 Website Policies37
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`http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021487s010s012s014,021627s008|b|.pdf
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`http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/0214870rig1sO10,s012,s014,0216270rig1sO08|tr.pdf
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`http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021487s010s012s014,021627s008|b|.pdf
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`http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/021487s010|tr.pdf0214870rig1s010,s012,s014,0216270rig1s008|tr.pdl
`
`http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/021487s008,021627s0O1LTR.pdf
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`19. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/0214875007, O21627s0O2LTR.pdf
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`http://www.accessdata.fda.g oviscri pts/cder/drug satfda/indexcfm?fuseaction=Search.Labe|_Approwa| History
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`20.
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`21.
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`22.
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`23.
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`24.
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`25.
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`26.
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`27.
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`28.
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`29.
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`30.
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`31.
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`32.
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`33.
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`34.
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`35.
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`36.
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`37.
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`38.
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`39.
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`40.
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`41.
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`42.
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`43.
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`44.
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`47.
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`48.
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`53.
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`54.
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`55.
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`56.
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`57.
`
`58.
`
`59.
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`60.
`
`61.
`
`62.
`
`63.
`
`64.
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`http ://www.accessdata .fda.gov/drugsatfda_docs/appletter/2005/021487s006|tr.pdf
`
`http ://www.accessdata .fda.gov/drugsatfda_docs/appletter/2005/021487s004|tr.pdf
`
`http ://www.accessdata .fda.gov/drugsatfda_docs/appletter/2004/21487s002|tr. pdf
`
`http ://www.accessdata .fda.gov/drugsatfda_docs/|a bel/2003/O21487|b|. pdf
`
`http ://www.accessdata .fda.gov/drugsatfda_docs/appletter/2003/21487|tr. pdf
`
`http ://www.accessdata .fda.gov/drugsatfda_docs/nda/2003/21-487_Narnenda .cfm
`
`http ://www.fda.gov/AboutFDA/AboutThisWebsite/WebsitePo|icies/ViewingFi|es/default.htm
`
`http ://www.fda.gov/AboutFDA/AboutThisWebsite/WebsitePo|icies/default.htm#web
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`http ://www.fda.gov/AboutFDA/AboutThisWebsite/WebsitePo|icies/ViewingFi|es/default.htm
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`
`IPR2015—OO41O
`Petitioners' Ex. 1014
`
`Page 6
`
`4/4
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 6
`
`

`
`Rx Only
`
`DESCRIPTION
`
` Approval Labeling Text
`NDA 21-487
`Page 1
`
`NAMENDA™ (memantine hydrochloride) is an orally active NMDA receptor antagonist.
`The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane
`hydrochloride with the following structural formula:
`
`NH2 . HCl
`
`CH3
`
`H3C
`
`The molecular formula is C12H21N•HCl and the molecular weight is 215.76.
`Memantine HCl occurs as a fine white to off-white powder and is soluble in water.
`NAMENDA is available for oral administration as capsule-shaped, film-coated tablets
`containing 5 mg and 10 mg of memantine hydrochloride. The tablets also contain the
`following inactive ingredients: microcrystalline cellulose, lactose monohydrate, colloidal
`silicon dioxide, talc and magnesium stearate. In addition the following inactive
`ingredients are also present as components of the film coat: hypromellose, triacetin,
`titanium dioxide, FD & C yellow #6 and FD & C blue #2 (5 mg tablets), iron oxide black
`(10 mg tablets).
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action and Pharmacodynamics
`Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors
`by the excitatory amino acid glutamate has been hypothesized to contribute to the
`symptomatology of Alzheimer’s disease. Memantine is postulated to exert its therapeutic
`effect through its action as a low to moderate affinity uncompetitive (open-channel)
`NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated
`cation channels. There is no evidence that memantine prevents or slows
`neurodegeneration in patients with Alzheimer’s Disease.
`
`Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine,
`adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+
`channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a
`potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine
`receptors with one-sixth to one-tenth the potency.
`
`In vitro studies have shown that memantine does not affect the reversible inhibition of
`acetylcholinesterase by donepezil, galantamine, or tacrine.
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 7
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 2
`
`Pharmacokinetics
`Memantine is well absorbed after oral administration and has linear pharmacokinetics
`over the therapeutic dose range. It is excreted predominantly in the urine, unchanged, and
`has a terminal elimination half-life of about 60-80 hours.
`
`Absorption and Distribution
`Following oral administration memantine is highly absorbed with peak concentrations
`reached in about 3-7 hours. Food has no effect on the absorption of memantine. The
`mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is
`low (45%).
`
`Metabolism and Elimination
`Memantine undergoes little metabolism, with the majority (57-82%) of an administered
`dose excreted unchanged in urine; the remainder is converted primarily to three polar
`metabolites: the N-gludantan conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated
`memantine. These metabolites possess minimal NMDA receptor antagonist activity. The
`hepatic microsomal CYP450 enzyme system does not play a significant role in the
`metabolism of memantine. Memantine has a terminal elimination half-life of about 60-80
`hours. Renal clearance involves active tubular secretion moderated by pH dependent
`tubular reabsorption.
`
`Special Populations
`Renal Impairment: Adequate information on the effect of renal impairment on the
`pharmacokinetics of memantine is not available. As the major route of elimination is
`renal, however, it is very likely that subjects with moderate and severe renal impairment
`will have significantly higher exposure than normal subjects.
`
`Elderly: The pharmacokinetics of NAMENDA in young and elderly subjects are
`similar.
`
`Gender: Following multiple dose administration of NAMENDA 20 mg b.i.d, females
`had about 45 % higher exposure than males,but there was no difference in exposure when
`body weight was taken into account..
`
`Drug-Drug Interactions
`Substrates of Microsomal Enzymes: In-vitro studies have shown that memantine
`produces minimal inhibition of CYP450 enzymes CYP1A2, CYP2A6, CYP2C9,
`CYP2D6, CYP2E1, and CYP3A4. These data indicate that no pharmacokinetic
`interactions with drugs metabolized by these enzymes are expected.
`
`Inhibitors of Microsomal Enzymes: Since memantine undergoes minimal
`metabolism,with the majority of the dose excreted unchanged in urine, an interaction
`between memantine and drugs that are inhibitors of CYP 450 enzymes is unlikely.Co-
`administration of NAMENDA with the AChE inhibitor donepezil HCl does not affect
`the pharmacokinetics of either compound.
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 8
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 3
`Drugs Eliminated via Renal Mechanisms: Memantine is eliminated in part by tubular
`secretion. In-vivo studies have shown that multiple doses of the diuretic
`hydrochlorothiazide/triamterene (HCTZ/TA) did not affect the AUC of memantine at
`steady state. Memantine did not affect the bioavailability of TA, and decreased AUC and
`Cmax of HCTZ by about 20%.
`
`Drugs that make the urine alkaline: The clearance of memantine was reduced by about
`80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards
`the alkaline state may lead to an accumulation of the drug with a possible increase in
`adverse effects. Drugs that alkalinize the urine (e.g. carbonic anhydrase inhibitors,
`sodium bicarbonate) would be expected to reduce renal elimination of memantine.
`
`Drugs highly bound to plasma proteins: Because the plasma protein binding of
`memantine is low (45%), an interaction with drugs that are highly bound to plasma
`proteins, such as warfarin and digoxin, is unlikely.
`
`CLINICAL TRIALS
`
`The effectiveness of NAMENDA (memantine hydrochloride) as a treatment for patients
`with moderate to severe Alzheimer’s disease was demonstrated in 2 randomized, double-
`blind, placebo-controlled clinical studies (Studies 1 and 2) conducted in the United States
`that assessed both cognitive function and day to day function. The mean age of patients
`participating in these two trials was 76 with a range of 50-93 years. Approximately 66%
`of patients were female and 91% of patients were Caucasian.
`
`A third study (Study 3), carried out in Latvia, enrolled patients with severe dementia, but
`did not assess cognitive function as a planned endpoint.
`Study Outcome Measures: In each U.S. study, the effectiveness of NAMENDA was
`determined using both an instrument designed to evaluate overall function through
`caregiver-related assessment, and an instrument that measures cognition. Both studies
`showed that patients on NAMENDA experienced significant improvement on both
`measures compared to placebo.
`
`Day-to-day function was assessed in both studies using the modified Alzheimer’s Disease
`Cooperative Study – Activities of Daily Living inventory (ADCS-ADL). The ADCS-
`ADL consists of a comprehensive battery of ADL questions used to measure the
`functional capabilities of patients. Each ADL item is rated from the highest level of
`independent performance to complete loss. The investigator performs theinventory by
`interviewing a caregiver familiar with the behavior of the patient. A subset of 19 items,
`including ratings of the patients’ ability to eat, dress, bathe, telephone, travel, shop, and
`perform other household chores has been validated for the assessment of patients with
`moderate to severe dementia. This is the modified ADCS-ADL, which has a scoring
`range of 0 to 54, with the lower scores indicating greater functional impairment.
`
`The ability of NAMENDA to improve cognitive performance was assessed in both
`studies with the Severe Impairment Battery (SIB), a multi-item instrument that has been
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 9
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 4
`validated for the evaluation of cognitive function in patients with moderate to severe
`dementia. The SIB examines selected aspects of cognitive performance, including
`elements of attention, orientation, language, memory, visuospatial ability, construction,
`praxis, and social interaction. The SIB scoring range is from 0 to 100, with lower scores
`indicating greater cognitive impairment.
`
`Study 1 (Twenty-Eight-Week Study)
`In a study of 28 weeks duration, 252 patients with moderate to severe probable
`Alzheimer’s disease (diagnosed by DSM-IV and NINCDS-ADRDA criteria, with Mini-
`Mental State Examination scores ≥3 and ≤14 and Global Deterioration Scale Stages 5-6)
`were randomized to NAMENDA or placebo. For patients randomized to NAMENDA,
`treatment was initiated at 5 mg once daily and increased weekly by 5 mg/day in divided
`doses to a dose of 20 mg/day (10 mg twice a day).
`
`Effects on the ADCS-ADL:
`Figure 1 shows the time course for the change from baseline in the ADCS-ADL score for
`patients in the two treatment groups completing the 28 weeks of the study. At 28 weeks
`of treatment, the mean difference in the ADCS-ADL change scores for the NAMENDA -
`treated patients compared to the patients on placebo was 3.4 units. Using an analysis
`based on all patients and carrying their last study observation forward (LOCF analysis),
`NAMENDA treatment was statistically significantly superior to placebo.
`
`Clinical Improvement
`
`Placebo
`NAMENDA
`
`Clinical Decline
`
`012
`
`-1
`
`-2
`
`-3
`
`-4
`
`-5
`
`-6
`
`-7
`
`in ADCS-ADL Score
`
`Mean (± SEM) Change from Baseline
`
`0
`
`4
`
`8
`
`12
`Weeks of Treatment
`Figure 1: Time course of the change from baseline in ADCS-ADL score for patients
`completing 28 weeks of treatment.
`
`16
`
`20
`
`24
`
`28
`
`Figure 2 shows the cumulative percentages of patients from each of the treatment groups
`who had attained at least the change in the ADCS-ADL shown on the X axis.
`The curves shows that both patients assigned to NAMENDA and placebo have a wide
`range of responses and generally show deterioration (a negative change in ADCS-ADL
`compared to baseline), but that the NAMENDA group is more likely to show a smaller
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 10
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 5
`decline or an improvement. (In a cumulative distribution display, a curve for an effective
`treatment would be shifted to the left of the curve for placebo, while an ineffective or
`deleterious treatment would be superimposed upon or shifted to the right of the curve for
`placebo.)
`
`Placebo
`NAMENDA
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulative Percentage of Patients
`
`10
`
`5
`
`0
`
`-5
`
`-10
`
`-15
`
`-20
`
`-25
`
`ADCS-ADL Change from Baseline
`
`Figure 2: Cumulative percentage of patients completing 28 weeks of double-blind
`treatment with specified changes from baseline in ADCS-ADL scores.
`
`Effects on the SIB:
`Figure 3 shows the time course for the change from baseline in SIB score for the two
`treatment groups over the 28 weeks of the study At 28 weeks of treatment, the mean
`difference in the SIB change scores for the NAMENDA™-treated patients compared to
`the patients on placebo was 5.7 units. Using an LOCF analysis, NAMENDA treatment
`was statistically significantly superior to placebo.
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 11
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 6
`
`Clinical Improvement
`
`Placebo
`NAMENDA
`
`Clinical Decline
`
`0
`
`4
`
`8
`
`16
`12
`Weeks of Treatment
`
`20
`
`24
`
`28
`
`024
`
`-2
`
`-4
`
`-6
`
`-8
`
`-10
`
`-12
`
`in SIB Score
`
`Mean (± SEM) Change from Baseline
`
`Figure 3: Time course of the change from baseline in SIB score for patients completing
`28 weeks of treatment.
`
`Figure 4 shows the cumulative percentages of patients from each treatment group who
`had attained at least the measure of change in SIB score shown on the X axis.
`
`The curves show that both patients assigned to NAMENDA™ and placebo have a wide
`range of responses and generally show deterioration, but that the NAMENDA group is
`more likely to show a smaller decline or an improvement.
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 12
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 7
`
`Placebo
`NAMENDA
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulative Percentage of Patients
`
`15
`
`10
`
`5
`
`0
`
`-5
`
`-10
`
`-15
`
`-20
`
`-25
`
`-30
`
`SIB Change from Baseline
`
`Figure 4: Cumulative percentage of patients completing 28 weeks of double-blind
`treatment with specified changes from baseline in SIB scores.
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 13
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 8
`
`Study 2 (Twenty-Four-Week Study)
`In a study of 24 weeks duration, 404 patients with moderate to severe probable
`Alzheimer’s disease (diagnosed by NINCDS-ADRDA criteria, with Mini-Mental State
`Examination scores ≥5 and ≤14) who had been treated with donepezil for at least 6
`months and who had been on a stable dose of donepezil for the last 3 months were
`randomized to NAMENDA™ or placebo while still receiving donepezil. For patients
`randomized to NAMENDA, treatment was initiated at 5 mg once daily and increased
`weekly by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day).
`
`Effects on the ADCS-ADL:
`Figure 5 shows the time course for the change from baseline in the ADCS-ADL score for
`the two treatment groups over the 24 weeks of the study.At 24 weeks of treatment, the
`mean difference in the ADCS-ADL change scores for the NAMENDA/donepezil treated
`patients (combination therapy) compared to the patients on
`placebo/donepezil(monotherapy) was 1.6 units. Using an LOCF analysis,
`NAMENDA/donepezil treatment was statistically significantly superior to
`placebo/donepezil.
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 14
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 9
`
`Clinical Improvement
`
`Placebo/Donepezil
`NAMENDA/Donepezil
`
`Clinical Decline
`
`1
`
`0.5
`
`0
`
`-0.5
`
`-1
`
`-1.5
`
`-2
`
`-2.5
`
`-3
`
`-3.5
`
`Mean (± SEM) Change from Baseline
`
`in ADCS-ADL Score
`
`0
`
`2
`
`4
`
`6
`
`8
`
`14
`12
`10
`Weeks of Treatment
`Figure 5: Time course of the change from baseline in ADCS-ADL score for patients
`completing 24 weeks of treatment.
`
`16
`
`18
`
`20
`
`22
`
`24
`
`Figure 6 shows the cumulative percentages of patients from each of the treatment groups
`who had attained at least the measure of improvement in the ADCS-ADL shown on the X
`axis.
`The curves show that both patients assigned to NAMENDA/donepezil and
`placebo/donepezil have a wide range of responses and generally show deterioration, but
`that the NAMENDA/donepezil group is more likely to show a smaller decline or an
`improvement
`
`IPR2015-00410
`Petitioners' Ex. 1014
`Page 15
`
`

`
` Approval Labeling Text
`NDA 21-487
`Page 10
`
`Placebo//Donepezil
`NAMENDA/Donepezil
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulative Percentage of Patients
`
`15
`
`10
`
`5
`
`0
`-5
`-10
`ADCS-ADL Change from Baseline
`Figure 6: Cumulative percentage of patients completing 24 weeks of double-blind
`treatment with specified changes from baseline in ADCS-ADL scores.
`
`-15
`
`-20
`
`-25
`
`Effects on the SIB:
`Figure 7 shows the time course for the change from baseline in SIB score for the two
`treatment groups over the 24 weeks of the study .At 24 weeks of treatment, the mean
`difference in the SIB change scores for the NAMENDA™/donepezil treated patients
`compared to the patients on placebo/donepezil was 3.3 units. Using an LOCF analysis,
`NAMENDA/donepezil treatment was statistically significantly superior to
`placebo/donepezil.
`
`IPR2015-00410
`Petitione