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Publication Date: February 2004
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MEMANTINE (NAMENDA)
A NEW OPTION FOR
ALZHEIMER'S DISEASE

Fani Lane, Pharm.D. Candidate


Introduction
Alzheimer's Disease (AD) is a neurodegenera-
tive disorder estimated to affect 4 to 8% of the
population over age 65 and up to 20% of those over
age 85 in Europe. Its incidence is increasing sub-
stantially as the population ages and the number di-
agnosed is predicted to double for every six years
of life expectancy.1 About 4 million Americans,
90% of whom are age 65 and older, have Alz-
heimer's disease. Unless prevention or a cure is
found, the number of Americans with AD could
reach 14.3 million 50 years from now.2
The theory that AD and the resulting typical
cognitive and functional impairments are due pri-
marily to a cholinergic brain deficit is increasingly
challenged by the glutamatergic hypothesis of de-
mentia. The strength of that hypothesis is based on
the following facts: glutamate is the main fast exci-
tatory neurotransmitter in the regions associated
with cognition and memory (cerebral cortex and
hippocampus), cortical and subcortical structures
that contain glutamatergic receptors are structurally
damaged during the course of AD, glutamate acts
as an excitotoxin (causing neuronal death when ex-
cessive levels are chronically released), the neuro-
chemical changes and some of the clinical symp-
toms seen in dementia can be induced experimen-
tally with excitotoxins (quinolinic acid or N-
methyl-D-aspartate), and clinical signs of dementia


correlate with deficits of glutamatergic association
fibers.
Memantine is a blocker of glutamate gated
N-methy-D-aspartate (NMDA) receptor channels,
which allows the physiological activation of
NMDA receptors during memory formation while
blocking their pathological activation. This prop-
erty is due to the rapid, voltage-dependent nature of
the interactions of memantine with the NMDA re-
ceptor channel.3 Memantine was approved in
Europe in May of 2002. There it is marketed under
the name Ebixa by Merz Pharmaceuticals. In the
U.S., the product was approved in October of 2003
and is marketed under the name Namendaby For-
est Laboratories. This article will examine the
safety, efficacy, and tolerability of memantine.

Pharmacology and Pharmacokinetics
Glutamatergic neurons form the major exci-
tatory system in the brain and play a pivotal role in
many physiological functions. Glutamate activates
several receptors such as the a-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid (AMPA) recep-
tors and the N-methyl-D-aspartate (NMDA) recep-
tors. The later have three cardinal features: high
permeability to Ca2+ ions; voltage-dependent block
by Mg2+ ions; and slow gating kinetics. Physiologi-
cally, NMDA receptors are transiently activated by
mM concentrations of glutamate, whereas during


m
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Table 1. Results of the efficacy analysis7*
Analysis with Last Observation Analysis of Observed Cases.
Base Line Carried Forwardt
Measure Bs Ln T (Change from Base Line at Week 28)
Measure (Change from Base Line at End Point)
MNT Placebo MNT Placebo p MNT Placebo p

CIBIC-Plus NA NA 4.51.12 4.81.09 0.6 4.41.12 4.71.13 0.03
Score (N=126) (N= 126) (N= 118) (N= 118) (N=97) (N=84)
ADCS-ADLsev 26.8 27.4 -3.1+6.79 -5.26.33 0.02 -2.56.27 -5.96.78 0.003
Score (N=126) (N= 126) (N= 124) (N=123) (N=97) (N=84)
65.9 68.3 -4.011.34 -10.1+13.5 <0.001 -4.511.48 -10.212.66 0.002
SIB Score (N=126) (N=126) (N=124) (N=123) (N=96) (N=83)

MNT memantine, CIBIC-Plus Clinician's Interview-Based Impression of Change Plus Caregiver Input, NA not applicable, N number of patients, ADCS-
ADLsev Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia, SIB Severe Impairment Battery.
*Plus-minus values are means SD (standard deviation).
The analysis with the last observation carried forward was performed with the intention-to-treat population.
The observed-cases analysis was performed with 181 patients observed at week 28.
p-values are based on the Wilcoxon-Mann-Whitney test for between-treatment comparisons.


pathological activation such as that occurring in
AD, NMDA receptors are likely activated by lower
concentrations of glutamate but more or less con-
tinuously. This overactivation of glutamate recep-
tors and continuous Ca2+ influx ultimately leads to
both cognitive deficits and neuronal loss in neu-
rodegenerative dementia.4 Blockade of NMDA
receptors by memantine slows the intracellular cal-
cium accumulation and helps to prevent further
nerve damage. With a low affinity for NMDA-type
receptors, memantine may prevent excitatory amino
acid neurotoxicity without interfering with the
physiological actions of glutamate required for
memory and learning. In-vitro studies demonstrate
that memantine lacks affinity for most serotonin re-
ceptor subtypes (except 5HT3), muscarinic acetyl-
choline, ac and 3 adrenergic, dopaminergic, hista-
minic, and glycine receptors. Memantine appears to
have antagonist activity at the 5HT3 receptor and
affinity for nicotinic acetylcholine receptors, but the
clinical impact of these associations are not yet de-
fined.5
Memantine is well absorbed after oral ad-
ministration and has linear pharmacokinetics over
the therapeutic dose range. Following oral admini-
stration, memantine is highly absorbed with peak
concentrations reached in about 3-7 hours. Food
has no effect on the absorption of memantine. Its
mean volume of distribution is 9-11 L/kg and the
plasma protein binding is low (45%). 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 with minimal NMDA recep-
tor 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 se-
cretion moderated by pH dependent tubular reab-
sorption.6

Clinical Trials
The effectiveness of memantine as a treat-
ment for patients with moderate-to-severe Alz-
heimer's disease was evaluated 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 participat-
ing 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.3'78
The studies utilized different clinical scales,
such as the Clinician's Interview-Based Impression
of Change Plus Caregiver Input (CIBIC-Plus), the
Alzheimer's Disease Cooperative Study Activities
of Daily Living Inventory modified for severe de-
mentia (ADCS-ADLsev), and Severe Impairment
Battery (SIB) to evaluate the outcome measures.
Clinical global scales are interview based and in-


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Table 2. Primary endpoint CGI-C: results after 4 and 12 weeks3 *
Memantine Placebo
Follow-up Outcome
N % N %
Visit 3 Responset 48 59 34 40
(week 4) Non-response 34 41 50 60

Visit 5 Responset 60 73 38 45
(week 12) Non-response 22 27 46 55
CGI-C Clinical Global Impression of Change, N number of patients.
SIntention-to-treat analysis, N 166. Response improvement categories. INon-response no change and deterioration categories, p<0.001 stratified Wilcoxon test.


elude information obtained from either the caregiv-
ers or directly from the patient. Patients with pro-
gressive dementia invariably evolve to a stage
where they can no longer be tested by standard
neuropsychological tests. The validity and reliabil-
ity of scales such as the ADCS and SIB have been
tested in clinical trials, hence their popularity
among practitioners.9'10

Study 1 (Tiweuti--Eight-Week Study)
Patients with moderate-to-severe Alz-
heimer's disease were randomly assigned to receive
placebo or 20 mg of memantine daily for 28 weeks.
The primary efficacy variables were the CIBIC-
Plus and the ADCS-ADLsev. The secondary effi-
cacy end points included the SIB and other meas-
ures of cognition, function, and behavior. Two hun-
dred fifty-two patients (67% women; mean age, 76
years) from 32 U.S. centers were enrolled. Of these,
181 (72%) completed the study and were evaluated
at week 28. The base-line scores and the results
based on analyses with the last observation carried
forward and analyses of observed cases for the effi-
cacy variables are shown in Table 1. Patients re-
ceiving memantine had a better outcome than those
receiving placebo, according to the results of the
CIBIC-Plus (p=0.06 with the last observation car-
ried forward, p=0.03 for observed cases), the
ADCS-ADLsev (p=0.02 with the last observation
carried forward, p=0.003 for observed cases), and
the SIB (p<0.001 with the last observation carried
forward, p=0.002 for observed cases).7

Study 2 (Tireuio--Four-Week Study)
Four hundred and four patients with moder-
ate-to-severe AD with Mini-Mental State Examina-
tion scores of 5 to 14 who had been treated with
donepezil for at least 6 months and who were still


receiving a stable dose of donepezil were random-
ized to receive memantine (starting dose 5 mg/d,
increased to 20 mg/d, n=203) plus donepezil or pla-
cebo plus donepezil (n=201) for 24 weeks. The pri-
mary outcome measure was the change from base-
line on the SIB measure of cognition and on modi-
fied 19-item AD Cooperative Study Activities of
Daily Living Inventory (ADCS-ADL19). The
change in total mean scores favored memantine/
donepezil vs. placebo/donepezil treatment for SIB
(score range 0-100, p<0.001) and for ADCS-
ADL19 (score range 0-54, p=0.03).8

Study 3 (1i ehve- Ieek Study)
Dementia was defined by Diagnostic and
Statistical Manual of Mental Disorders (DSM-III-
R) criteria and severity was assessed by the Global
Deterioration Scale (stages 5-7) and the Mini-
Mental State Examination (<10 points). Primary
endpoints were the Clinical Global Impression of
Change (CGI-C) rated by the physician, and the
Behavioral Rating Scale for Geriatric Patients
(BGP), rated by the nursing staff. Care-dependent
in-patients of both genders were considered for en-
rolment if aged between 60 and 80 years. Eighty-
two patients were randomized to memantine treat-
ment (5 mg/day during the first week and 10 mg/
day during the next 11 weeks), while 84 patients
took placebo. Results of the CGI-C are shown
in Table 2. Results of the BGP-subscore per visit
and pre-post changes (visit 5 versus visit 1) are
given in Table 3. Treatment differences between
the two groups are statistically significant in favor
of memantine (p=0.016). In summary, the results of
this trial support the hypothesis that memantine
treatment leads to functional improvement and re-
duces care dependence in severely demented pa-
tients.3


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Table 3. Primary endpoint BGP subscore: results per visit and pre-post changes3 *
Memantine Placebo
Visit
Mean SD Min/Median/Max Mean SD Min/Median/Max
1 21.37.6 6/20.5/38 21.87.7 8/21/38
2 20.87.5 6/19.5/38 21.27.6 8/20/38
3 19.37.5 3/18/38 20.57.9 7/19.5/42
4 17.48.5 1/16/37 18.98.3 2/18/37
5 15.68.8 1/13.5/37 18.19.4 3/17/38
Change visit 5 vs. 1 -3.1+12.2 -24/-5/46t -1.111.8 -17/-2/46t
BGP Behavioral Rating Scale for Geriatric Patients, SD standard deviation, Min/MaxN minimum/maximum changes.
*Intention-to-treat analysis (N=166). tWorst case replacement, p=0.016, stratified Wilcoxon test.


Dosing and Administration
Memantine is FDA-approved for the treat-
ment of symptoms of moderate-to-severe Alz-
heimer's disease or for the symptoms of dementia
associated with mild-to-moderate vascular demen-
tia. Tablets can be administered orally with or with-
out food. The initial dosage for adults and the eld-
erly is 5 mg once daily titrated slowly over 3
weeks. The dose should be increased by 5 mg/week
over a 3-week period to a target dose of 10 mg
twice daily at week 4. The maximum daily dose is
20 mg/day and it takes roughly 15 days to reach
steady state plasma concentrations.
Periodic evaluation after initiation and dur-
ing continuation of therapy may be helpful to the
clinician in deciding treatment duration (i.e., con-
tinue treatment if improvement or stability in func-
tional, cognitive or behavioral status continues).
Memantine is not indicated for adolescents and
children. Memantine elimination does not appear to
be reduced in patients with hepatic impairment; no
specific dosage adjustments are needed. Dosage ad-
justments are required in patients with severe renal
impairment. However, specific guidelines are not
available. Dosage adjustments are not required in
patients with mild-to-moderate renal impairment.
Until further data are available, avoid use in pa-
tients with renal failure.3'6'7'8

Toxicity and Safety
Memantine is contraindicated in patients
with known hypersensitivity to memantine hydro-
chloride (HC1) or to any excipients used in its for-
mulation. In clinical trials, seizures occurred in
0.2% of patients treated with memantine and 0.5%

rhcrmlinte


of patients treated with placebo. Co-administration
of memantine with the acetylcholinesterase (AchE)
inhibitor donepezil HC1 did not affect the pharma-
cokinetics of either compound.
Because memantine is eliminated in part by
tubular secretion, co-administration of drugs that
use the same renal cationic system, including hy-
drochlorothiazide (HCTZ), triamterene (TA), ci-
metidine, ranitidine, quinidine, and nicotine, could
potentially result in altered plasma levels of both
agents. However, co-administration of memantine
and HCTZ/TA did not affect the bioavailability of
either memantine or TA, and the bioavailability of
HCTZ decreased only by 20%. The clearance of
memantine was reduced by about 80% under alka-
line urine conditions at pH>8. Therefore, alterations
of urine pH towards the alkaline condition may lead
to an accumulation of the drug with a possible in-
crease in adverse effects. Urine pH is altered by
diet, drugs (e.g. carbonic anhydrase inhibitors, so-
dium bicarbonate) and the clinical state of the pa-
tient (e.g. renal tubular acidosis or severe infections
of the urinary tract). Memantine should be used
with caution under these conditions.6
In placebo-controlled trials in which demen-
tia patients received doses of memantine up to 20
mg/day, the likelihood of discontinuation because
of an adverse event was the same in the memantine
group as in the placebo group. Table 4 lists treat-
ment-emergent signs and symptoms that were re-
ported in at least 2% of patients in placebo-
controlled dementia trials and for which the rate of
occurrence was greater for patients treated with me-
mantine than for those treated with placebo.3'6-
8,11-12


Volume 19, Issue 5 February 2004


1


I I I I I I IP I W







Table 4. Adverse events reported in clinical trials in at least 2% of patients receiving memantine3'6-8'11-12

Placebo Memantine
Adverse Event
(N=922) (N=940)

Body as a Whole
Fatigue 1% 2%
Pain 1% 3%

Cardiovascular System
Hypertension 2% 4%

Central and Peripheral Nervous System
Dizziness 5% 7%
Headache 3% 6%

Gastrointestinal System
Constipation 3% 5%
Vomiting 2% 3%

Musculoskeletal System
Back pain 2% 3%

Psychiatric Disorders
Confusion 5% 6%
Somnolence 2% 3%
Hallucination 2% 3%

Respiratory System
Coughing 3% 4%
Dyspnea 1% 2%


Cost
The average retail price for a one-month
supply of Namenda 10 mg is $150.31 ($144.99-
$152.99).

Summary
As the elderly population in the U.S. in-
creases, there is a proportional increase in the so-
cial and economical impact of dementia, particu-
larly its most common form, Alzheimer's disease.
Dementia itself consists of a wide spectrum of dis-
eases, ranging from the mild cognitive impairment
that progresses through several clinical milestones
to advanced dementia. Drugs that are currently
available for the treatment of mild-to-moderate de-
mentia have focused on providing patients with
cholinergic substitution despite increasing amounts


of data that challenge the cholinergic brain deficit
theory. Recent clinical trials have shown the an-
tiglutamatergic drug memantine to improve cogni-
tive function in patients with vascular dementia and
reduced care dependence in those with moderately
severe to severe forms of the disease.

References
1. Mobius HJ. Memantine: update on the current evidence.
Int J Geriatr Psychiatry 2003; 18: S47-S54.
2. National Institute on Aging. (1999). Progress Report on
Alzheimer's Disease, 1999. National institutes of Health:
Bethesda, MD.
3. Winblad B, Poritis N. Memantine in severe dementia: re-
sults of the 9M-Best Study (Benefit and efficacy in se-
verely demented patients during treatment with meman-
tine). Int J Geriatr Psychiatry 1999; 14: 135-146.
4. Danysz W, Parsons CG. The NMDA receptor antagonist
memantine as a symptomatological and neuroprotective


PharmaNot Vlum 19 Isue5 Fbrury 00


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Volume 19, Issue 5 February 2004







treatment for Alzheimer's disease: preclinical evidence. Int


J Geriatr Psychiatry 2003; 18: S23-S32. T
5. Areosa SA, Sherriff F. Memantine for dementia. Cochrane Daptomycin (CubicinTM) is the first of a new
Database Syst Rev 2003; (3): CD003154. In: Cochrane class of antibiotics called cyclic lipopeptide
Library Issue 3, 2003. Oxford: Update Software. antibacterial agents. It works by binding to
6. Namenda [Package Insert]. St. Louis, MO; Forest Labora- bacterial membranes causing a rapid depola-
tories; 2003. rization of the membrane potential which
7. Reisberg B, Doody R, Stoffler A et al, for the Memantine
Study Group. Memantine in moderate-to-severe Alz- leads to inhibition of protein, DNA, and
heimer's disease. N Engl J Med 2003; 348: 1333-41. RNA synthesis resulting in bacterial cell
8. Tariot PN, Farlow MR et al. Memantine treatment in pa- death. It has been approved for the treatment
tients with moderate to severe Alzheimer disease already of complicated skin and skin structure
receiving donepezil: a randomized controlled trial. JAMA infections caused by susceptible strains of
2004; 291(3): 317-24.
9. Panisset M et al. Severe impairment battery. A neuropsy- Gram-positive organisms including MRSA.
chological test for severe demented patients. Arch Neurol
1994; 51(1): 41-5.
10.Schneider LS et al. Validity and reliability of the Alz-
heimer's Disease Cooperative Study Clinical Global Im-
pression of Change. The Alzheimer's Disease Cooperative
Study. Alzheimer Dis Assoc Disord 1997: 11 Suppl 2: Al n TM
S22-32. Alfuzosin (Uroxatral ) is a selective al-
11.Winblad B, Jelic V. Treating the full spectrum of dementia antagonist approved for the treatment of
with memantine. Int J Geriatr Psychiatry 2003; 18: S41- benign prostatic hyperplasia (BPH). The
S46. recommended daily dose is one 10-mg
12.Wilcock G, Mobius HJ, Stoffler A. A double-blind, pla- extended-release tablet given by mouth once
cebo-controlled multicenter study of memantine in mild to i i i
moderate vascular dementia (MMM500). Int Clin Psycho- daily. It should be used wth caution in
pharmacol 2002; 17(6): 297-305. patients taking drugs that can inhibit or
induce the cytochrome P450 3A4 isozyme
and drugs which prolong the QT interval.
Common adverse reactions include postural
hypotension, dizziness, headache, fatigue, GI
upset, and impotence.

Fosamprenavir calcium (LexivaTM) is a new
protease inhibitor approved for the treatment
of human immunodeficiency virus (HIV)
infection in adults. It is a pro-drug of The PharmaNote is Published by:
amprenavir with improved solubility over the The Department of Pharmacy Services,
parent drug providing patients the UF Family Practice Medical Group,
opportunity for a reduced pill burden. The Departments of Community Health
usual dosage in antiretroviral-naive patients and Family Medicine and Pharmacy
is 700 mg or 1400 mg taken once or twice Practice
daily, with or without ritonavir (to 'boost' University of Florida
fosamnrenavir nlasma concentrations) In


Pha rma Note Volume 19, Issue 5 February 2004


protease inhibitor-experienced patients, the
twice-daily administration regimen with
ritonavir is required to assure viral
suppression. Common side effects include:
headache, flushing, rhinitis, dyspepsia, flu
syndrome, back pain, dizziness, increased
creatine kinase, and nausea.


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.


PharmaNote


Volume 19, Issue 5 February 2004




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