Mechanism Of Action
NAMZARIC capsules contain two approved medications:
memantine hydrochloride and donepezil hydrochloride. Each of those medications
is postulated to have a different mechanism in Alzheimer's disease.
Persistent activation of central nervous system 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
Current theories on the pathogenesis of the cognitive
signs and symptoms of Alzheimer's disease attribute some of them to a
deficiency of cholinergic neurotransmission. Donepezil is postulated to exert
its therapeutic effect by enhancing cholinergic function. This is accomplished
by increasing the concentration of acetylcholine in the central nervous system
through reversible inhibition of its hydrolysis by acetylcholinesterase. There
is no evidence that donepezil prevents or slows neurodegeneration in patients
with Alzheimer's disease.
NAMZARIC was bioequivalent to co-administration of
individual memantine hydrochloride extendedrelease and donepezil hydrochloride.
Exposure (AUC and Cmax) of memantine and donepezil
following NAMZARIC administration in the fed or fasted state was similar.
Further, exposure of memantine and donepezil following NAMZARIC administration
as intact capsule or capsule contents sprinkled on applesauce was similar in
Memantine is well absorbed after oral administration and
has linear pharmacokinetics over the therapeutic dose range. It is excreted
predominantly unchanged in urine and has a terminal elimination half-life of
about 60-80 hours. In a study comparing 28 mg once-daily memantine
hydrochloride extended-release to 10 mg twice-daily memantine hydrochloride, Cmax
and AUC0-24 values were 48% and 33% higher for the memantine hydrochloride
extended-release dosage regimen, respectively.
After multiple dose administration of memantine
hydrochloride extended-release, memantine peak concentrations occur around 9-12
hours postdose. There is no difference in the absorption of memantine
hydrochloride extended-release when the capsule is taken intact or when the
contents are sprinkled on applesauce.
After single-dose administration, there is no difference
in memantine exposure, based on Cmax or AUC, for memantine hydrochloride
extended-release when the 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.
The mean volume of distribution of memantine is 9-11 L/kg
and the plasma protein binding is low (45%).
Memantine undergoes partial hepatic metabolism. The
hepatic microsomal CYP450 enzyme system does not play a significant role in the
metabolism of memantine.
Memantine is excreted predominantly in the urine,
unchanged, and has a terminal elimination half-life of about 60-80 hours. About
48% of administered drug is excreted unchanged in urine; the remainder is converted
primarily to three polar metabolites which possess minimal NMDA receptor
antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and
1-nitroso-deaminated memantine. A total of 74% of the administered dose is
excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal
clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
Pharmacokinetics In Special Populations
Memantine pharmacokinetics were evaluated following single
oral administration of 20 mg memantine hydrochloride in 8 subjects with mild
renal impairment (creatinine clearance, CLcr, > 50 - 80 mL/min), 8 subjects
with moderate renal impairment (CLcr 30 - 49 mL/min), 7 subjects with severe
renal impairment (CLcr 5 - 29 mL/min) and 8 healthy subjects (CLcr > 80
mL/min) matched as closely as possible by age, weight and gender to the
subjects with renal impairment. Mean AUC0-∞ increased by 4%, 60%, and
115% in subjects with mild, moderate, and severe renal impairment,
respectively, compared to healthy subjects. The terminal elimination half-life
increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe
renal impairment, respectively, compared to healthy subjects [see DOSAGE AND
ADMINISTRATION and Use in Specific Populations].
Memantine pharmacokinetics were evaluated following the
administration of single oral doses of 20 mg in 8 subjects with moderate
hepatic impairment (Child-Pugh Class B, score 7-9) and 8 subjects who were
age-, gender-, and weight-matched to the hepatically-impaired subjects. There
was no change in memantine exposure (based on Cmax and AUC) in subjects with
moderate hepatic impairment as compared with healthy subjects. However,
terminal elimination half-life increased by about 16% in subjects with moderate
hepatic impairment as compared with healthy subjects. The pharmacokinetics of memantine
has not been evaluated in patients with severe hepatic impairment.
Following multiple dose administration of memantine
hydrochloride 20 mg daily, females had about 45% higher exposure than males,
but there was no difference in exposure when body weight was taken into
The pharmacokinetics of memantine in young and elderly
subjects are similar.
Use with Cholinesterase Inhibitors
Coadministration of memantine with the AChE inhibitor
donepezil hydrochloride did not affect the pharmacokinetics of either compound.
Furthermore, memantine did not affect AChE inhibition by donepezil. 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
Effect of Memantine on the Metabolism of Other Drugs
In vitro studies conducted with marker substrates of
CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, - 2E1, -3A4) showed minimal
inhibition of these enzymes by memantine. In addition, in vitro studies indicate
that at concentrations exceeding those associated with efficacy, memantine does
not induce the cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No
pharmacokinetic interactions with drugs metabolized by these enzymes are
Pharmacokinetic studies evaluated the potential of
memantine for interaction with warfarin and bupropion. Memantine did not affect
the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite
hydroxybupropion. Furthermore, memantine did not affect the pharmacokinetics or
pharmacodynamics of warfarin as assessed by prothrombin INR.
Effect of Other Drugs on Memantine
Memantine is predominantly renally eliminated, and drugs
that are substrates and/or inhibitors of the CYP450 system are not expected to
alter the pharmacokinetics of memantine. A single dose of bupropion did not
affect the pharmacokinetics of memantine at steady state.
Drugs Eliminated via Renal Mechanisms
Because memantine is eliminated in part by tubular
secretion, coadministration of drugs that use the same renal cationic system,
including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine,
quinidine, and nicotine, could potentially result in altered plasma levels of
both agents. However, coadministration of memantine hydrochloride and HCTZ/TA
did not affect the bioavailability of either memantine or TA, and the
bioavailability of HCTZ decreased by 20%. In addition, coadministration of
memantine hydrochloride with the antihyperglycemic drug Glucovance® (glyburide and
metformin hydrochloride) did not affect the pharmacokinetics of memantine,
metformin, and glyburide. Furthermore, memantine did not modify the serum
glucose lowering effect of Glucovance®, indicating the absence of a
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.
Pharmacokinetics of donepezil are linear over a dose
range of 1-10 mg given once daily. The rate and extent of absorption of
donepezil hydrochloride tablets are not influenced by food.
Donepezil is absorbed with a relative oral
bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours.
The elimination half-life of donepezil is about 70 hours,
and the mean apparent plasma clearance (Cl/F) is 0.13 - 0.19 L/hr/kg. Following
multiple dose administration, donepezil accumulates in plasma by 4-7 fold, and
steady state is reached within 15 days. The steady-state volume of distribution
is 12 - 16 L/kg. Donepezil is approximately 96% bound to human plasma proteins,
mainly to albumins (about 75%) and alpha-1-acid glycoprotein (about 21%) over
the concentration range of 2-1000 ng/mL.
Donepezil is both excreted in the urine intact and
extensively metabolized to four major metabolites, two of which are known to be
active, and a number of minor metabolites, not all of which have been identified.
Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation.
Following administration of 14C-labeled donepezil, plasma
radioactivity, expressed as a percent of the administered dose, was present
primarily as intact donepezil (53%) and as 6-Odesmethyl donepezil (11%), which
has been reported to inhibit AChE to the same extent as donepezil in vitro and
was found in plasma at concentrations equal to about 20% of donepezil.
Approximately 57% and 15% of the total radioactivity was recovered in urine and
feces, respectively, over a period of 10 days, while 28% remained unrecovered,
with about 17% of the donepezil dose recovered in the urine as unchanged drug.
Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences
in clearance values among CYP2D6 genotype subgroups. When compared to the
extensive metabolizers, poor metabolizers had a 31.5% slower clearance and
ultra-rapid metabolizers had a 24% faster clearance. These results suggest
CYP2D6 has a minor role in the metabolism of donepezil.
In a study of 11 patients with moderate to severe renal
impairment (CLcr < 18 mL/min/ 1.73 m²) the clearance of donepezil
hydrochloride did not differ from 11 age- and sex-matched healthy subjects.
In a study of 10 patients with stable alcoholic cirrhosis,
the clearance of donepezil hydrochloride was decreased by 20% relative to 10
healthy age- and sex-matched subjects.
No formal pharmacokinetic study was conducted to examine
age-related differences in the pharmacokinetics of donepezil hydrochloride.
Population pharmacokinetic analysis suggested that the clearance of donepezil
in patients decreases with increasing age. When compared with 65-year old, subjects,
90-year old subjects have a 17% decrease in clearance, while 40-year old
subjects have a 33% increase in clearance. The effect of age on donepezil
clearance may not be clinically significant.
Gender and Race
No specific pharmacokinetic study was conducted to
investigate the effects of gender and race on the disposition of donepezil
hydrochloride. However, retrospective pharmacokinetic analysis and population
pharmacokinetic analysis of plasma donepezil concentrations measured in
patients with Alzheimer's disease indicate that gender and race (Japanese and
Caucasians) did not affect the clearance of donepezil hydrochloride to an
There was a relationship noted between body weight and
clearance. Over the range of body weight from 50 kg to 110 kg, clearance
increased from 7.77 L/h to 14.04 L/h, with a value of 10 L/h for 70 kg individuals.
Effect of Donepezil hydrochloride on the Metabolism of
No in vivo clinical trials have investigated the effect
of donepezil hydrochloride on the clearance of drugs metabolized by CYP3A4
(e.g., cisapride, terfenadine) or by CYP2D6 (e.g., imipramine). However, in
vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130
μM), that, given the therapeutic plasma concentrations of donepezil (164
nM), indicates little likelihood of interference. Based on in vitro studies,
donepezil shows little or no evidence of direct inhibition of CYP2B6, CYP2C8,
and CYP2C19 at clinically relevant concentrations.
Whether donepezil hydrochloride has any potential for
enzyme induction is not known. Formal pharmacokinetic studies evaluated the
potential of donepezil hydrochloride for interaction with theophylline,
cimetidine, warfarin, digoxin, and ketoconazole. No effects of donepezil
hydrochloride on the pharmacokinetics of these drugs were observed.
Effect of Other Drugs on the Metabolism of Donepezil
A small effect of CYP2D6 inhibitors was identified in a
population pharmacokinetic analysis of plasma donepezil concentrations measured
in patients with Alzheimer's disease. Donepezil clearance was reduced by
approximately 17% in patients taking 10 or 23 mg in combination with a known
CYP2D6 inhibitor. This result is consistent with the conclusion that CYP2D6 is
a minor metabolic pathway of donepezil.
Formal pharmacokinetic studies demonstrated that the
metabolism of donepezil hydrochloride is not significantly affected by
concurrent administration of digoxin or cimetidine.
An in vitro study showed that donepezil was not a
substrate of P-glycoprotein.
Drugs Highly Bound to Plasma Proteins
Drug displacement studies have been performed in vitro between
this highly bound drug (96%) and other drugs such as furosemide, digoxin, and
warfarin. Donepezil hydrochloride at concentrations of 0.3-10 micrograms/mL did
not affect the binding of furosemide (5 micrograms/mL), digoxin (2 ng/mL), and
warfarin (3 micrograms/mL) to human albumin. Similarly, the binding of
donepezil hydrochloride to human albumin was not affected by furosemide,
digoxin, and warfarin.
Animal Toxicology And/Or Pharmacology
Memantine induced neuronal lesions (vacuolation and
necrosis) in the multipolar and pyramidal cells in cortical layers III and IV
of the posterior cingulate and retrosplenial neocortices in rats, similar to
those which are known to occur in rodents administered other NMDA receptor
antagonists. Lesions were seen after a single dose of memantine. In a study in
which rats were given daily oral doses of memantine for 14 days, the no-effect
dose for neuronal necrosis was 4 times the dose of memantine at the MRHD of
NAMZARIC on a mg/m² basis.
In acute and repeat-dose neurotoxicity studies in female
rats, oral administration of memantine and donepezil in combination resulted in
increased incidence, severity, and distribution of neurodegeneration compared
with memantine alone. The no-effect levels of the combination were associated
with clinically relevant plasma memantine and donepezil exposures.
The relevance of these findings to humans is unknown.
The effectiveness of NAMZARIC as a treatment for patients
with moderate to severe Alzheimer's disease was established by demonstrating
the bioequivalence of NAMZARIC with co-administered memantine hydrochloride
extended-release and donepezil hydrochloride [see CLINICAL PHARMACOLOGY].
The effectiveness of memantine hydrochloride
extended-release as a treatment for patients with moderate to severe
Alzheimer's disease when coadministered with acetylcholinesterase inhibitors, including
donepezil hydrochloride, was based on the results of a double-blind, placebo-controlled
24-week Study Of Memantine Hydrochloride Extended-Release
This was a randomized, double-blind clinical
investigation in 677 outpatients with moderate to severe Alzheimer's disease
(diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental
State Examination [MMSE] score ≥ 3 and ≤ 14 at Screening and
Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable
dose for 3 months prior to screening. Approximately 68% of the patients
received donepezil as the AChEI. The mean age of patients participating in this
trial was 76.5 years, with a range of 49-97 years. Approximately 72% of
patients were female and 94% were Caucasian.
Study Outcome Measures
The effectiveness of memantine hydrochloride extended-release
was evaluated in this study using the co-primary efficacy parameters of Severe
Impairment Battery (SIB) and the Clinician's Interview-Based Impression of
The ability of memantine hydrochloride extended-release
to improve cognitive performance was assessed with the Severe Impairment
Battery (SIB), a multi-item instrument that has been 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.
The ability of memantine hydrochloride extended-release
to produce an overall clinical effect was assessed using a Clinician's
Interview Based Impression of Change that required the use of caregiver information,
the CIBIC-Plus. The CIBIC-Plus is not a single instrument and is not a
standardized instrument like the ADCS-ADL or SIB. Clinical trials for
investigational drugs have used a variety of CIBIC formats, each different in
terms of depth and structure. As such, results from a CIBIC-Plus reflect
clinical experience from the trial or trials in which it was used and cannot be
compared directly with the results of CIBIC-Plus evaluations from other
clinical trials. The CIBIC-Plus used in this trial was a structured instrument
based on a comprehensive evaluation at baseline and subsequent time points of
four domains: general (overall clinical status), functional (including
activities of daily living), cognitive, and behavioral. It represents the
assessment of a skilled clinician using validated scales based on his/her
observation during an interview with the patient, in combination with
information supplied by a caregiver familiar with the behavior of the patient
over the interval rated. The CIBIC-Plus is scored as a seven point categorical
rating, ranging from a score of 1, indicating “marked improvement” to a score
of 4, indicating “no change” to a score of 7, indicating “marked worsening.”
The CIBIC-Plus has not been systematically compared directly to assessments not
using information from caregivers (CIBIC) or other global methods.
In this study, 677 patients were randomized to one of the
following 2 treatments: memantine hydrochloride extended-release 28 mg/day or
placebo, while still receiving an AChEI (either donepezil, galantamine, or
Effects on Severe Impairment Battery (SIB)
Figure 1 shows the time course for the change from
baseline in SIB score for the two treatment groups completing the 24 weeks of
the study. At 24 weeks of treatment, the mean difference in the SIB change scores
for the memantine hydrochloride extended-release 28 mg/AChEI-treated
(combination therapy) patients compared to the patients on placebo/AChEI
(monotherapy) was 2.6 units. Using an LOCF analysis, memantine hydrochloride
extended-release 28 mg/AChEI treatment was statistically significantly superior
Figure 1: Time course of the change from baseline in
SIB score for patients completing 24 weeks of treatment.
Figure 2 shows the cumulative percentages of patients
from each treatment group who had attained at least the measure of improvement
in SIB score shown on the X-axis. The curves show that both patients assigned
to memantine hydrochloride extended-release 28 mg/AChEI and placebo/AChEI have
a wide range of responses, but that the memantine hydrochloride
extended-release 28 mg/AChEI group is more likely to show an improvement or a
Figure 2: Cumulative percentage of patients completing
24 weeks of double-blind treatment with specified changes from baseline in SIB
Effects on Severe Impairment Battery (SIB) in the
Subset of Patients on Concomitant Donepezil Therapy
Approximately 68% of the patients randomized to receive
either memantine hydrochloride extendedrelease 28 mg or placebo were taking
donepezil at Baseline and throughout the study. At 24 weeks of treatment, in
patients on concomitant donepezil treatment, the mean difference in the SIB
change scores for the memantine hydrochloride extended-release 28 mg-treated
patients compared to patients on placebo (2.7 units) was similar to that
observed for the entire study population (2.6 units).
Effects of Clinician's Interview-Based Impression of
Change Plus Caregiver Input (CIBIC-Plus)
Figure 3 shows the time course for the CIBIC-Plus score
for patients in the two treatment groups completing the 24 weeks of the study.
At 24 weeks of treatment, the mean difference in the CIBIC-Plus scores for the
memantine hydrochloride extended-release 28 mg/AChEI-treated patients compared
to the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis,
memantine hydrochloride extended-release 28 mg/AChEI treatment was
statistically significantly superior to placebo/AChEI.
Figure 3: Time course of the CIBIC-Plus score for
patients completing 24 weeks of treatment.
Figure 4 is a histogram of the percentage distribution of
CIBIC-Plus scores attained by patients assigned to each of the treatment groups
who completed 24 weeks of treatment.
Figure 4: Distribution of CIBIC-Plus ratings at week
Effects on CIBIC-Plus in the Subset of Patients on
Concomitant Donepezil Therapy
Approximately 68% of the patients randomized to receive
either memantine hydrochloride extendedrelease 28 mg or placebo were taking
donepezil at baseline and throughout the study. At 24 weeks of treatment, in
patients on concomitant donepezil, the mean difference in the CIBIC-Plus scores
for the memantine hydrochloride extended-release 28 mg-treated patients
compared to patients on placebo (0.3 units) was similar to that observed for
the entire study population (0.3 units).
The effectiveness of donepezil hydrochloride as a
treatment for patients with severe Alzheimer's disease was based on the results
of two double-blind, placebo-controlled trials.
6-Month Study Of Donepezil Hydrochloride
This was a randomized, double-blind, placebo-controlled
clinical study conducted in Sweden in patients with probable or possible
Alzheimer's disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range
of 1-10. Two hundred and forty eight (248) patients with severe Alzheimer's
disease were randomized to donepezil hydrochloride or placebo. For patients
randomized to donepezil hydrochloride, treatment was initiated at 5 mg once
daily for 28 days and then increased to 10 mg once daily. At the end of the 6
month treatment period, 90.5% of the donepezil hydrochloride treated patients were
receiving the 10 mg/day dose. The mean age of patients was 84.9 years, with a
range of 59 to 99. Approximately 77% of patients were women, and 23% were men.
Almost all patients were Caucasian. Probable AD was diagnosed in the majority
of the patients (83.6% of donepezil hydrochloride treated patients and 84.2% of
placebo treated patients).
Study Outcome Measures
The effectiveness of treatment with donepezil
hydrochloride was evaluated using a dual outcome assessment strategy that
evaluated cognitive function using an instrument designed for more impaired patients
and overall function through caregiver-rated assessment. This study showed that
patients on donepezil hydrochloride experienced significant improvement on both
measures compared to placebo.
The ability of donepezil hydrochloride to improve
cognitive performance was assessed with the SIB.
Daily function was assessed using the Modified
Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for
Severe Alzheimer's Disease (ADCS-ADL-severe). The ADCS-ADLsevere is derived
from the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory,
which is 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 ADCS-ADL-severe is a
subset of 19 items, including ratings of the patient's ability to eat, dress,
bathe, use the telephone, get around (or travel), and perform other activities
of daily living; it has been validated for the assessment of patients with
moderate to severe dementia. The ADCS-ADLsevere has a scoring range of 0 to 54,
with the lower scores indicating greater functional impairment. The
investigator performs the inventory by interviewing a caregiver, in this study
a nurse staff member, familiar with the functioning of the patient.
Effects On The SIB
Figure 5 shows the time course for the change from
baseline in SIB score for the two treatment groups over the 6 months of the
study. At 6 months of treatment, the mean difference in the SIB change scores for
donepezil hydrochloride treated patients compared to patients on placebo was
5.9 points. Donepezil hydrochloride treatment was statistically significantly
superior to placebo.
Figure 5: Time Course of the Change from Baseline in
SIB Score for Patients Completing 6 months of Treatment.
Figure 6 illustrates the cumulative percentages of
patients from each of the two treatment groups who attained the measure of
improvement in SIB score shown on the X-axis. While patients assigned both to donepezil
hydrochloride and to placebo have a wide range of responses, the curves show
that the donepezil hydrochloride group is more likely to show a greater
improvement in cognitive performance.
Figure 6: Cumulative Percentage of Patients Completing
6 Months of Double-blind Treatment with Particular Changes from Baseline in SIB
Figure 7: Time Course of the Change from Baseline in
ADCS-ADL-Severe Score for Patients Completing 6 Months of Treatment.
Effects on the ADCS-ADL-severe
Figure 7 illustrates the time course for the change from
baseline in ADCS-ADL-severe scores for patients in the two treatment groups
over the 6 months of the study. After 6 months of treatment, the mean difference
in the ADCS-ADL-severe change scores for donepezil hydrochloride treated
patients compared to patients on placebo was 1.8 points. Donepezil
hydrochloride treatment was statistically significantly superior to placebo.
Figure 8 shows the cumulative percentages of patients
from each treatment group with specified changes from baseline ADCS-ADL-severe
scores. While both patients assigned to donepezil hydrochloride and placebo
have a wide range of responses, the curves demonstrate that the donepezil hydrochloride
group is more likely to show a smaller decline or an improvement.
Figure 8: Cumulative Percentage of Patients Completing
6 Months of Double-blind Treatment with Particular Changes from Baseline in
24-Week Study Of Donepezil Hydrochloride
In a randomized, double-blind, placebo-controlled study
conducted in Japan, 325 patients with severe Alzheimer's disease received doses
of 5 mg/day or 10 mg/day of donepezil hydrochloride, administered once daily,
or placebo. Patients randomized to treatment with donepezil hydrochloride were
to achieve their assigned doses by titration, beginning at 3 mg/day, and
extending over a maximum of 6 weeks. Two hundred and forty eight (248) patients
completed the study, with similar proportions of patients completing the study
in each treatment group. The primary efficacy measures for this study were the
SIB and CIBIC-plus.
At 24 weeks of treatment, statistically significant
treatment differences were observed between the 10 mg/day dose of donepezil
hydrochloride and placebo on both the SIB and CIBIC-plus. The 5 mg/day dose of
donepezil hydrochloride showed a statistically significant superiority to
placebo on the SIB, but not on the CIBIC-plus.