Ariceptâ„¢
Donepezil HCl
Cholinesterase Inhibitor
Pfizer
http://www.pfizer.com/pfizer/main.jsp
Aricept Monograph PDF download here.
CPS:PIS_m065200
Date of Preparation: August 8, 1997
Date of Revision: September 27, 2004
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Pharmacology
Donepezil is a piperidine-based, reversible
inhibitor of the enzyme acetylcholinesterase (AChE).
A consistent
pathological change in Alzheimer's disease is the degeneration of cholinergic
neuronal pathways that project from the basal forebrain to the cerebral cortex
and hippocampus. The resulting hypofunction of the cholinergic systems is
thought to account for some of the clinical manifestations of dementia.
Donepezil is postulated to exert its therapeutic effect by enhancing
cholinergic function. This is accomplished by increasing the concentration of
acetylcholine (ACh) through reversible inhibition of its hydrolysis by AChE. If
this proposed mechanism of action is correct, donepezil's effect may lessen as
the disease process advances and fewer cholinergic neurons remain functionally
intact.
There is no evidence
that donepezil alters the course of the underlying dementing process.
Pharmacokinetics
Absorption: Donepezil is well absorbed with a
relative oral bioavailability of 100% and reaches peak plasma concentrations (Cmax)
approximately 3 to 4 hours after dose administration. Plasma
concentrations and area under the curve (AUC) were found to rise in proportion
to the dose administered within the 1 to 10 mg dose range studied.
The terminal disposition half-life (t1/2) is approximately
70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 L/h/kg.
Following multiple dose administration, donepezil accumulates in plasma by 4-
to 7-fold and steady-state is reached within 15 days. The minimum, maximum
and steady-state plasma concentrations (C) and pharmacodynamic effect (E,
percent inhibition of acetylcholinesterase in erythrocyte membranes) of
donepezil in healthy adult male and female volunteers are given in Table 1.
CPS:Aricept_t1Click here for Table 1
Table 1: Aricept
Plasma Concentrations and Pharmacodynamic Effect
of Donepezil at Steady-state (Mean±S.D.)
|
Dose (mg/day)
|
Cmin
(ng/mL)
|
Cmax
(ng/mL)
|
CssaÂ
(ng/mL)
|
Emin
%
|
Emax
%
|
Essb
%
|
|
5
|
21.4±3.8
|
34.1±7.3
|
26.5±3.9
|
62.2±5.8
|
71.8±4.3
|
65.3±5.2
|
|
10
|
38.5±8.6
|
60.5±10.0
|
47.0±8.2
|
74.7±4.4
|
83.6±1.9
|
77.8±3.0
|
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 a Css: Plasma
concentration at steady-state.
 b Ess: Inhibition of
erythrocyte membrane acetylcholinesterase at steady-state.
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The range of inhibition
of erythrocyte membrane AChE noted in Alzheimer's disease patients in
controlled clinical trials was 40 to 80% and 60 to 90% for the
5 mg/day and 10 mg/day doses, respectively.
Pharmacokinetic
parameters from healthy adult male and female volunteers participating in a
multiple-dose study where single daily doses of 5 or 10 mg of
donepezil were administered each evening are summarized in Table 2. Treatment
duration was 1 month. However, volunteers randomized to the 10 mg/day
dose group initially received 5 mg daily doses of donepezil for
1 week before receiving the 10 mg daily dose for the next
3 weeks in order to avoid acute cholinergic effects.
CPS:Aricept_t2Click here for Table 2
Table 2: Aricept
Pharmacokinetic Parameters of Donepezil at
Steady-state (Mean±S.D.)
|
Dose
(mg/day)
|
tmax
(h)
|
AUC0-24
(ng.h/mL)
|
ClT/F
(L/h/kg)
|
Vz/F
(L/kg)
|
t1/2
(h)
|
|
5
|
3.0±1.4
|
634.8±92.2
|
0.110±0.02
|
11.8±1.7
|
72.7±10.6
|
|
10
|
3.9±1.0
|
1127.8±195.9
|
0.110±0.02
|
11.6±1.9
|
73.5±11.8
|
Legend:
tmax: Time to maximal plasma
concentration.
AUC0-24: Area under the plasma
concentration vs. time curve from 0 to 24 hours.
ClT/F: Mean apparent plasma
clearance.
Vz/F: Apparent volume of
distribution.
t1/2: Elimination half-life.
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Neither food nor time
of dose administration (i.e., morning vs evening dose) have an influence on the
rate and extent of donepezil absorption.
The effect of
achlorhydria on the absorption of donepezil is unknown.
Distribution: Donepezil HCl is about 96% bound
to human plasma proteins, mainly to albumins (∼ 75%) and α1-acid
glycoprotein (∼ 21%) over the concentration range of 2 to 1000 ng/mL.
Metabolism/Excretion: Donepezil HCl is
extensively metabolized and is also excreted in the urine as parent drug. The
rate of metabolism of donepezil is slow and does not appear to be saturable.
There are 4 major metabolites — 2 of which are known to be
active — and a number of minor metabolites, not all of which have
been identified. Donepezil is metabolized by CYP450 isoenzymes 2D6 and 3A4 and
undergoes glucuronidation. Following administration of a single 5 mg dose
of 14C-labelled donepezil, plasma radioactivity, expressed as a
percent of the administered dose, was present primarily as unchanged donepezil
(53%), and as 6-O-desmethyl 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% of the total
administered radioactivity was recovered from the urine and 15% was recovered
from the feces (total recovery of 72%) over a period of 10 days.
Approximately 28% of the labelled donepezil remained uncovered, with about 17%
of the donepezil dose recovered in the urine as parent drug.
Age and Gender: No formal pharmacokinetic study
was conducted to examine age and gender related differences in the
pharmacokinetic profile of donepezil. However, mean plasma donepezil
concentrations measured during therapeutic drug monitoring of elderly male and
female patients with Alzheimer's disease are comparable to those observed in
young healthy volunteers.
Renal: In a study of 4 patients with
moderate to severe renal impairment (Clcr
<22 mL/min/1.73 m2) the clearance of donepezil did not
differ from that of 4 age and sex matched healthy subjects.
Hepatic: In a study of 10 patients with
stable alcoholic cirrhosis, the clearance of donepezil was decreased by 20%
relative to 10 healthy age and sex matched subjects.
Race: No specific pharmacokinetic study was
conducted to investigate the effects of race on the disposition of donepezil.
However, retrospective pharmacokinetic analysis indicates that gender and race
(Japanese and Caucasian) did not affect the clearance of donepezil.
Clinical Trial Data
Donepezil has been studied in 3 Phase III trials
in patients with mild to moderate Alzheimer's disease and 1 Phase IIIb trial in
patients with moderate to moderately-severe Alzheimer's disease, and 2 Phase
III trials in patients with mild to moderate Vascular dementia.
Alzheimer’s Disease
24-Week Trials in Patients with Mild to Moderate
Alzheimer's Disease
Two 24-week studies were conducted in patients
with mild to moderate Alzheimer's disease (diagnosed by DSM III-R and NINCDS
criteria, Mini-Mental State Examination (MMSE) ≥ 10 and ≤ 26 as
well as a Clinical Dementia Rating of 1 or 2) and provided efficacy and safety
data for donepezil in this patient population. In these studies, the mean age
of patients was 73 years with a range of 50 to 94 years. Approximately 60% of
the patients were women and 40% were men. The racial distribution was as
follows: white: 97%, black: 2% and other races: 1%.
The primary efficacy of
treatment with donepezil was evaluated using a dual outcome assessment
strategy. The ability of donepezil to improve cognitive performance was
assessed with the cognitive subscale of the Alzheimer's Disease Assessment
Scale (ADAS-cog), a widely used and well validated multi-item instrument which
samples cognitive domains affected by the disease. The ability of donepezil to
produce an overall clinical effect was assessed using the semi-structured
CIBIC-Plus (Clinician's Interview Based Impression of Change that required the
use of caregiver information). The CIBIC-Plus evaluates 4 major areas of
functioning: general, cognition, behavior and activities of daily living. Among
the secondary measures of efficacy, the Clinical Dementia Rating Scale—Sum of
the Boxes (CDR-SB) or the Interview for Deterioration in Daily Functioning in
Dementia (IDDD) were used. The CDR-SB sums the ratings in each of 6 domains
(“boxesâ€) of the CDR to provide a clinical measure of global functioning in
patients. Information to rate each domain is obtained by semi-structured
clinical interviews with both the patients and a caregiver. The IDDD
questionnaire evaluates activities of daily living: self-care (e.g., dressing)
and complex tasks (e.g., finding things).
The data below
summarizes results from two 24-week trials and presents the primary, and the
secondary, outcome measures from the Intent-to-Treat population (ITT analysis,
i.e., all patients who were randomized to treatment, regardless of whether or
not they were able to complete the study. For patients unable to complete the
study, their last observation while on treatment was carried forward and used
at endpoint [week 24-LOCF]).
In each of the
controlled clinical trials, in order to reduce the likelihood of cholinergic
effects, the 10 mg/day treatment group received 5 mg/day for the first week
prior to receiving their first 10 mg daily dose.
Study 302: A 24-Week Study
In this Phase 3 study, 473 patients were
randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day
of donepezil for 24 weeks of double-blind active treatment followed by a
6-week, single-blind placebo washout period. Patients treated with donepezil
showed significant improvement in ADAS-cog score from baseline, and when
compared with placebo. The mean differences in the ADAS-cog change scores for
donepezil-treated patients compared to the patients on placebo at Week 24-LOCF
were (mean ± standard error) − 2.50±0.63 (p<0.0001) and
− 2.87±0.63 (p<0.0001) units for the 5 mg/day and 10 mg/day
treatments, respectively. Over the 24-week treatment period, 80% (5 mg) and 81%
(10 mg) of donepezil-treated patients versus 58% placebo-treated patients
showed an improvement or no evidence of deterioration (scores
≥ 0). A score ≥ 4 points in ADAS-cog was observed in 38% (5 mg) and
54% (10 mg) of donepezil-treated patients versus 27% for placebo. A ≥ 7
points improvement was observed in 15% (5 mg) and 25% (10 mg) of
donepezil-treated patients versus 8% for placebo. The mean drug-placebo
differences at Week 24-LOCF in CIBIC-Plus scores were 0.37±0.12 (p<0.0047)
and 0.47±0.11 (p<0.0001) units for 5 and 10 mg/day of donepezil,
respectively. Figure 1 represents the frequency distribution of CIBIC-Plus
scores achieved at Week 24-LOCF by patients assigned to each of the 3 treatment
groups.
Figure 1:
Aricept
Frequency Distribution of CIBIC-Plus Scores at
Week 24-LOCF by Patients Assigned to Each Treatment Group
For the CDR-SB, a
secondary efficacy measure, significant drug-placebo differences were observed
at Week 24-LOCF for both treatment groups (mean change from placebo: 5
mg=0.59±0.17 [p=0.0008]; 10 mg=0.59±0.17 [p=0.0007]).
Study 304: A 24-Week Study
In this Phase 3 multinational study, 818
patients were randomly assigned to treatment with placebo, 5 or 10 mg/day
of donepezil for 24 weeks followed by a 6-week, single-blind placebo washout.
ADAS-cog mean change scores for the donepezil-treated patients compared to the
patients on placebo at Week 24-LOCF were (mean±standard error) − 1.55±0.48
(p=0.0021) and − 3.01±0.49 (p<0.0001) units for the 5 mg/day and 10
mg/day treatments, respectively. On the CIBIC-Plus, statistically significant
mean changes scores were observed in both the donepezil 5 mg (0.27±0.09;
p=0.0072) and 10 mg/day (0.39±0.10; p=0.0002) at Week 24-LOCF groups in
comparison to the placebo-treated group. Figure 2 presents the frequency
distribution of CIBIC-Plus scores achieved at Week 24-LOCF by patients assigned
to each of the 3 treatment groups.
Figure 2:
Aricept
Frequency Distribution of CIBIC-Plus Scores
Achieved at Week 24-LOCF by Patients Assigned to Each of the 3 Treatment Groups
With respect to
secondary efficacy measures, statistically significant differences over placebo
were noted at Week 24-LOCF for both treatment groups in CDR-SB scores (mean
change from placebo: 5 mg=0.32±0.14 [p<0.0033]; 10 mg=0.42±0.14
[p<0.0344]) and for the 10 mg donepezil group over placebo in the
IDDD-complex task measure (mean change from placebo: 2.15±0.89 p=0.0072).
Following 6 weeks of
placebo washout, scores on the ADAS-cog and CIBIC-Plus for both the donepezil
treatment groups were indistinguishable from those patients who had received
only placebo for 30 weeks. This suggests that the beneficial effects of
donepezil abate over 6 weeks following discontinuation of treatment and
therefore, represents symptomatic benefits of treatments. There was no evidence
of a rebound effect 6 weeks after abrupt discontinuation of therapy. This is in
line with the pharmacokinetics of donepezil (i.e., ~70 hour half-life) which
preclude an abrupt reduction in drug plasma levels.
Overall, data from
these controlled clinical trials showed that the beneficial symptomatic effects
of donepezil versus placebo were more consistently apparent after 12 weeks of
continuous treatment. Once treatment is discontinued, the effects of donepezil
were shown to abate within 6 weeks of treatment discontinuation.
54-Week Trial in Patients with Mild to Moderate
Alzheimer's Disease
Time to Clinically-Evident Loss of Function: A
double-blind, placebo-controlled, multicenter 1-year study was conducted in 432
patients with mild to moderate Alzheimer's disease. The study assessed time to
clinically-evident loss of function.
Patients were
randomized to receive single daily doses of either donepezil (n=214) or placebo
(n=217) for 54 weeks; treatment was initiated at 5 mg/day for 4 weeks, then
maintained at 10 mg/day. The mean age of patients was 75 years with a range of
49 to 94 years. 74% of patients were >70 years. Approximately 95% of
patients in both treatment groups took at least 1 concomitant medication during
the study.
Functional capacities
were evaluated using 2 scales: the Alzheimer's Disease Functional Assessment
and Change Scale (ADFACS) scale and the Clinical Dementia Rating (CDR). The
ADFACS scale assesses basic activities of daily living (ADL), such as dressing,
as well as instrumental ADLs (IADL), such as using the telephone. The CDR
assesses cognition and ADLs. Patients were assessed at nine 6-week intervals,
and were attrited from the study when any of the following 3 criteria were met:
1) decline in ability to perform 1 or more of the ADLs present at baseline; 2)
decline in ability to perform 20% or more of IADLs present at baseline; 3)
decline in CDR score. The primary outcome was the median time to
“clinically-evident loss of function†for each arm (Kaplan-Meier Survival
Function). The criteria provided a minimum threshold for consideration of
withdrawal, with attrition ultimately left to clinical judgement.
The proportion of
patients attrited was significantly greater for the placebo arm (56%) in
comparison to the donepezil arm (41%). The median time to loss of
clinically-evident function in this 1-year study was significantly longer in
the donepezil-treated patients (357 days) than in the placebo-treated patients
(208 days).
 Figure 3 displays the
survival curves for time to clinically-evident loss of function for both
treatment groups. The vertical axis represents the probability of survival to
functional decline (in other words, the proportion of individuals remaining in
the study at various times following treatment initiation), and the horizontal
axis indicates duration of treatment. The 2 survival curves were demonstrated
to be significantly different by Wilcoxon and log rank tests, such that the
overall risk of clinically-evident functional decline for patients treated with
donepezil was approximately 62% of that of patients who received placebo
(hazard ratio 0.62).
Figure 3:
Aricept
Survival Curves of Time to Clinically-Evident
Loss of Function for Both Treatment Groups
Study 324: A 24-Week Phase 3b Study in Patients
with Moderate to Moderately-Severe Alzheimer's Disease
This 24-week, randomized, double-blind,
placebo-controlled, multicenter study was conducted in 290 patients with
moderate to moderately-severe Alzheimer's disease (MMSE ≥ 5 and ≤
17; and a Functional Assessment Staging (FAST) score ≥ 6) who resided at
home or in an intermediate care-assisted living setting. Patients were
randomized 1:1 to receive either a single daily dose of placebo or donepezil
for 24 weeks. Patients received 5 mg/day for the first 4 weeks, after which the
dose could be increased to 10 mg/day, according to clinical judgement.
The CIBIC-Plus score at
the 24-week endpoint was the primary efficacy measure in this study, providing
a clinical global assessment of change. For the total patient population,
ranging from moderate to moderately-severe, statistically significant mean
change scores were observed in the donepezil-treated patients in comparison to
the placebo-treated patients (0.538±0.117; p<0.00001).
Post-Hoc Subgroup Analysis (MMSE ≥ 5 and
<10)
A post-hoc analysis was performed for the
moderately-severe subgroup (MMSE ≥ 5 and <10) with more advanced
Alzheimer's disease (n=83). Approximately half the patients in the subgroup
received donepezil (n=42).
CIBIC-Plus scores
showed statistical significant differences of donepezil over placebo at weeks
4,8,12, and 18 (p<0.03) and numerical superiority at Week 24 (p=0.072).Â
Figure 4 presents the distribution of CIBIC-Plus scores achieved at Week 24 by
patients assigned to each of the treatment groups.
Figure 4:
Aricept
Frequency Distribution of the CIBIC-Plus Scores
Achieved at Week 24-LOCF for Patients With MMSE ≥ 5 to <10 Assigned to
Each Treatment Group
These findings in a
small number of more advanced Alzheimer's disease patients, although promising,
are considered to be hypothesis-generating and must be confirmed by additional
studies.
Vascular dementia
The efficacy of donepezil as a treatment for
Vascular dementia has been evaluated in 2 Phase III randomized, double-blind,
placebo-controlled clinical trials. One of the 2 studies showed significant
treatment differences between the active treatment and placebo groups for both
primary endpoints (ADAS-cog and CIBIC-Plus). The validity of the assessment
scales used in these studies has not been established for evaluating treatment
effects in Vascular dementia. Although these data are promising, they are
considered to be hypothesis-generating and confirmatory trials are required.
The initial safety profile from controlled clinical trials in Vascular dementia
patients indicates that the rate of occurrence of adverse events overall was
higher in Vascular dementia patients (91%) than in Alzheimer's disease patients
(75%), however this was seen in both donepezil-treated subjects and
placebo-treated subjects and may relate to the greater number of comorbid
medical conditions in the Vascular dementia population (see Adverse Effects,
Vascular Dementia section).
Study 308: A 24-Week Study in Vascular Dementia
Patients
This 24-week study was conducted in 616 patients
who met criteria for probable or possible Vascular dementia as defined by the
NINDS-AIREN criteria, modified to require neuroradiological evidence of
cerebrovascular disease for all patients. Seventy six (76%) per cent of
patients were classified as probable and 24% as possible. MMSE scores ranged
between ≥ 10 and ≤ 26. The mean (± SD) Hachinski Ischemic Scale
(HIS) score was 9.7 ± 0.08. The HIS is a 13-criteria tool on which a score of
greater than 4 is suggestive of cerebrovascular disease. Patients were
randomized to receive either a single daily dose of placebo, 5 mg donepezil or
10 mg donepezil for 24 weeks. Patients randomized to 10 mg/day donepezil
received 5 mg daily for the first 28 days, then 10 mg daily thereafter.
Primary efficacy
measures were the ADAS-cog and CIBIC-Plus. Secondary efficacy endpoints were
the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), CDR-SB
and MMSE. Results are presented for outcome measures from the Intent-to-Treat
population [ITT analysis, ie, all patients who were randomized to treatment,
regardless of whether or not they were able to complete the study. For patients
unable to complete the study, their last observation while on treatment was
carried forward and used at endpoint (Week 24)].
Patients treated with
donepezil showed significant improvement in ADAS-cog scores from baseline and
when compared with placebo. The mean differences in the ADAS cog change scores
for donepezil treated patients compared to the patients on placebo at Week 24
were − 1.75 (95% C.I. − 2.71 to − 0.59; p=0.003) for the 5
mg/day and − 2.19 units (95% C.I. − 3.16 to − 1.02; p=0.0002)
for the 10 mg/day treatment groups.
The mean drug-placebo
differences at Week 24-LOCF in CIBIC-Plus scores were 0. 34 ± 0.11 (p=0.004)
and 0.19 ± 0.11 (p=0.047) units for 5 and 10 mg/day of donepezil, respectively.
The global assessment provided by the CIBIC-plus in this population is
potentially confounded by the underlying comorbidities (eg, cardiovascular
disease, physical disabilities following stroke) of the subjects. Figure 5
presents the frequency distribution of CIBIC-Plus scores achieved at Week
24-LOCF by patients assigned to each of the 3 treatment groups.
Figure 5:
Aricept
Frequency Distribution of the CIBIC-Plus Scores
Achieved at Week 24-LOCF for Patients Assigned to Each Treatment Group
With respect to
secondary efficacy measures, scores did not reach statistical significance for
the 5 mg group (95% C.I. − 0.66 to 0.03; p=0.072) for the CDR SB, which
measured global functioning but, a statistically significant benefit was
observed for the 10 mg group (95% C.I. − 0.71 to − 0.03; p=0.034).
The ADFACS was used to measure basic and instrumental ADLs (IADL). The change
from baseline in the IADL sub-scale scores for Week 24 as compared to placebo
revealed no significant difference between the 5 mg donepezil group and placebo
and a marginally significant effect in the 10 mg group (95% C.I. − 1.61
to 0.01; p=0.056).
Indications
For the symptomatic treatment of patients with
mild to moderate dementia of the Alzheimer's type.
Efficacy of donepezil
in patients with mild to moderate Alzheimer's disease was established in two
24-week and one 54-week placebo-controlled trials.
Donepezil should only
be prescribed by (or following consultation with) clinicians who are
experienced in the diagnosis and management of Alzheimer's disease.
Contraindications
In patients with known hypersensitivity to
donepezil or to piperidine derivatives.
Warnings
Anesthesia: Donepezil, as a cholinesterase
inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation
during anesthesia.
Neurological Conditions: Seizures: Some cases of
seizures have been reported with the use of donepezil in clinical trials and
from spontaneous Adverse Reaction reporting. Cholinomimetics can cause a
reduction of seizure threshold, increasing the risk of seizures. However,
seizure activity may also be a manifestation of Alzheimer's disease. The
risk/benefit of donepezil treatment for patients with a history of seizure
disorder must therefore be carefully evaluated.
Donepezil has not been
studied in patients with Parkinsonian features. The efficacy and safety of
donepezil in these patients are unknown.
Pulmonary Conditions: Because of their
cholinomimetic action, cholinesterase inhibitors should be prescribed with care
to patients with a history of asthma or obstructive pulmonary disease.
Donepezil has not been studied in patients under treatment for these conditions
and should therefore be used with particular caution in such patients.
Cardiovascular
Because of their pharmacological action,
cholinesterase inhibitors may have vagotonic effects on heart rate (e.g.,
bradycardia). The potential for this action may be particularly important to
patients with “sick sinus syndrome†or other supraventricular cardiac
conduction conditions.
In clinical trials in
Alzheimer’s disease, most patients with serious cardiovascular conditions were
excluded. Patients such as those with controlled hypertension (DBP
<95 mmHg), right bundle branch blockage, and pacemakers were included.
Therefore, caution should be taken in treating patients with active coronary
artery disease and congestive heart failure. Syncopal episodes have been
reported in association with the use of donepezil. It is recommended that
donepezil should not be used in patients with cardiac conduction abnormalities
(except for right bundle branch block) including “sick sinus syndrome†and those
with unexplained syncopal episodes.
Gastrointestinal
Through their primary action, cholinesterase
inhibitors may be expected to increase gastric acid secretion due to increased
cholinergic activity. Therefore, patients at increased risk for developing ulcers,
e.g., those with a history of ulcer disease or those receiving concurrent
NSAIDs including high doses of ASA, should be monitored for symptoms of active
or occult gastrointestinal bleeding. Clinical studies of donepezil have shown
no increase, relative to placebo in the incidence of either peptic ulcer
disease or gastrointestinal bleeding (see Adverse Effects).
Donepezil, as a
predictable consequence of its pharmacological properties, has been shown to
produce, in controlled clinical trials in patients with Alzheimer's disease,
diarrhea, nausea and vomiting. These effects, when they occur, appear more
frequently with the 10 mg dose than with the 5 mg dose. In most
cases, these effects have usually been mild and transient, sometimes lasting
1 to 3 weeks and have resolved during continued use of donepezil (see
Adverse Effects). Treatment with the 5 mg/day dose for 4 to 6 weeks prior to
increasing the dose to 10 mg/day dose is associated with a lower incidence of
gastrointestinal intolerance.
Genitourinary
Although not observed in clinical trials of
donepezil, cholinomimetics may cause bladder outflow obstruction.
Precautions
Concomitant Use with Other Drugs:
Anticholinergics: Because of their mechanism of action, cholinesterase
inhibitors have the potential to interfere with the activity of anticholinergic
medications.
Cholinomimetics and Other Cholinesterase
Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors
are given concurrently with succinylcholine, similar neuromuscular blocking
agents or cholinergic agonists such as bethanechol.
Other Psychoactive Drugs: Few patients in
controlled clinical trials received neuroleptics, antidepressants or
anticonvulsants. There is thus limited information concerning the interaction of
donepezil with these drugs.
Patients ≥ 85 years old: In
controlled clinical studies with 5 and 10 mg of donepezil,
536 patients were between the ages of 65 to 84, and 37 patients
were aged 85 years or older. In Alzheimer's disease patients, nausea, diarrhea,
vomiting, insomnia, fatigue and anorexia increased with dose and age and the
incidence appeared to be greater in female patients. Since cholinesterase
inhibitors as well as Alzheimer's disease can be associated with significant
weight loss, caution is advised regarding the use of donepezil in low body
weight elderly patients, especially in those ≥ 85 years old.
Geriatrics with Comorbid Disease: There is
limited safety information for donepezil in patients with mild to moderate
Alzheimer's disease and significant comorbidity. The use of donepezil in
Alzheimer's disease patients with chronic illnesses common among the geriatric
population, should be considered only after careful risk/benefit assessment and
include close monitoring for adverse events. Caution is advised regarding the
use of donepezil doses above 5 mg in this patient population.
Renally and Hepatically Impaired: There is
limited information regarding the pharmacokinetics of donepezil in renally and
hepatically impaired Alzheimer's disease patients (see Pharmacology,
Pharmacokinetics).
Close monitoring for
adverse effects in patients with renal or hepatic disease being treated with
donepezil is therefore recommended.
Drug Interactions
Pharmacokinetic studies, limited to short-term,
single-dose studies in young subjects evaluated the potential of donepezil for
interaction with theophylline, cimetidine, warfarin and digoxin administration.
No significant effects on the pharmacokinetics of these drugs were observed.
Similar studies in elderly patients were not done.
Drugs Highly Bound to Plasma Proteins: Drug
displacement studies have been performed in vitro between donepezil, a highly
bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin.
Donepezil at concentrations of 0.3 to 10 µg/mL did not affect the
binding of furosemide (5 µg/mL), digoxin (2 ng/mL) and warfarin
(3 µg/mL) to human albumin. Similarly, the binding of donepezil to human
albumin was not affected by furosemide, digoxin and warfarin.
Effect of Donepezil on the Metabolism of Other
Drugs: In vitro studies show a low rate of donepezil binding to CYP3A4 and
CYP2D6 isoenzymes (mean Ki about 50 to 130 µM), which, given the
therapeutic plasma concentrations of donepezil (164 nM), indicates little
likelihood of interferences. In a pharmacokinetic study involving
18 healthy volunteers, the administration of donepezil at a dose of 5
mg/day for 7 days had no clinically significant effect on the pharmacokinetics
of ketoconazole. No other clinical trials have been conducted to investigate
the effect of donepezil on the clearance of drugs metabolized by CYP3A4 (e.g.,
cisapride, terfenadine) or by CYP2D6 (e.g., imipramine).
It is not known whether
donepezil has any potential for enzyme induction.
Effect of Other Drugs on the Metabolism of
Donepezil: Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively,
inhibit donepezil metabolism in vitro. In a pharmacokinetic study, 18 healthy
volunteers received 5 mg/day donepezil together with 200 mg/day ketoconazole
for 7 days. In these volunteers, mean donepezil plasma concentrations were
increased by about 30 to 36%.
Inducers of CYP2D6 and
CYP3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin and
phenobarbital) could increase the rate of elimination of donepezil.
Pharmacokinetic studies
demonstrated that the metabolism of donepezil is not significantly affected by
concurrent administration of digoxin or cimetidine.
Pregnancy
The safety of donepezil during pregnancy and
lactation has not been established and therefore, it should not be used in
women of childbearing potential or in nursing mothers unless, in the opinion of
the physician, the potential benefits to the patient outweigh the possible
hazards to the fetus or the infant.
Teratology studies
conducted in pregnant rats at doses of up to 16 mg/kg/day and in pregnant
rabbits at doses of up to 10 mg/kg/day did not disclose any evidence for a
teratogenic potential of donepezil.
Lactation
See Pregnancy.
Children
There are no adequate and well-controlled trials
to document the safety and efficacy of donepezil in any illness occurring in
children. Therefore, donepezil is not recommended for use in children.
Adverse Effects
Alzheimer’s disease: A total of
747 patients with mild to moderate Alzheimer's disease were treated in
controlled clinical studies with donepezil. Of these patients, 613 (82%)
completed the studies. The mean duration of treatment for all donepezil groups
was 132 days (range 1 to 356 days).
Adverse Events Leading to Discontinuation: The
rates of discontinuation from controlled clinical trials of donepezil due to adverse
events for the donepezil 5 mg/day treatment groups were comparable to
those of placebo-treatment groups at approximately 5%. The rate of
discontinuation of patients who received the 10 mg/day dose after only a
1-week initial treatment with 5 mg/day donepezil was higher at 13%.
The most common adverse
events leading to discontinuation, defined as those occurring in at least 2% of
patients and at twice the incidence seen in placebo patients, are shown inÂ
Table 3.
CPS:Aricept_t3Click here for Table 3
Table 3: Aricept
Most Frequent Adverse Events Leading to
Withdrawal from Controlled Clinical Trials by Dose Group
|
Dose Group
|
Placebo
|
5 mg/day Aricept
|
10 mg/day Aricept
|
|
|
Number of Patients Randomized
|
355
|
350
|
315
|
|
|
Events/% Discontinuing
|
|
Nausea
|
1%
|
1%
|
3%
|
|
|
Diarrhea
|
0%
|
<1%
|
3%
|
|
|
Vomiting
|
<1%
|
<1%
|
2%
|
|
Â
Most Frequent Adverse Clinical Events Seen in
Association with the Use of Donepezil: The most common adverse events, defined
as those occurring at a frequency of at least 5% in patients receiving
10 mg/day and twice the placebo rate, are largely predicted by donepezil's
cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting,
muscle cramp, fatigue and anorexia. These adverse events were often of mild
intensity and transient, resolving during continued donepezil treatment without
the need for dose modification.
There is evidence to
suggest that the frequency of these common adverse events may be affected by
the duration of treatment with an initial 5 mg daily dose prior to
increasing the dose to 10 mg/day. An open-label study was conducted with
269 patients who received placebo in the 15- and 30-week studies. These
patients received a 5 mg/day dose for 6 weeks prior to initiating
treatment with 10 mg/day. The rates of common adverse events were lower
than those seen in controlled clinical trial patients who received
10 mg/day after only a 1-week initial treatment period with a 5 mg
daily dose, and were comparable to the rates noted in patients treated only
with 5 mg/day.
The comparison of the
most common adverse events following 1- and 6-week initial treatment
periods with 5 mg/day donepezil is shown in Table 4.
CPS:Aricept_t4Click here for Table 4
Table 4: Aricept
Comparison of Rates of Adverse Events in
Patients Treated with 10 mg/day after 1 and 6 weeks of Initial
Treatment with 5 mg/day
|
Adverse Event
|
No Initial Treatment
|
1-Week Initial
Treatment with 5 mg/day
|
6-Week Initial
Treatment with 5 mg/day
|
|
Placebo
(N=315)
%
|
5 mg/day
(N=311)
%
|
10 mg/day
(N=315)
%
|
10 mg/day
(N=269)
%
|
|
|
Nausea
|
6
|
5
|
19
|
6
|
|
|
Diarrhea
|
5
|
8
|
15
|
9
|
|
|
Insomnia
|
6
|
6
|
14
|
6
|
|
|
Fatigue
|
3
|
4
|
8
|
3
|
|
|
Vomiting
|
3
|
3
|
8
|
5
|
|
|
Muscle cramps
|
2
|
6
|
8
|
3
|
|
|
Anorexia
|
2
|
3
|
7
|
3
|
|
Â
Adverse Events Reported in Controlled Trials:
The events cited reflect experience gained under closely monitored conditions
of clinical trials in a highly selected patient population. In actual clinical
practice or in other clinical trials, these frequency estimates may not apply,
as the conditions of use, reporting behavior, and the kinds of patients treated
may differ. Table 5 lists treatment emergent signs and symptoms (TESS) that
were reported in at least 2% of patients from placebo-controlled clinical
trials who received donepezil and for which the rate of occurrence was greater
for donepezil than placebo assigned patients. In general, adverse events
occurred more frequently in female patients and with advancing age.
CPS:Aricept_t5Click here for Table 5
Table 5: Aricept
Events Reported in Controlled Clinical Trials in
at Least 2% of Patients Receiving Aricept and at a Higher Frequency than
Placebo-treated Patients
|
Body System/Adverse Events
|
Placebo
n=355
|
Aricept
n=747
|
|
|
Percent of patients with any adverse event
|
72
|
74
|
|
|
Body as a Whole
|
|
Headache
|
9
|
10
|
|
|
Pain, various locations
|
8
|
9
|
|
|
Accident
|
6
|
7
|
|
|
Fatigue
|
3
|
5
|
|
|
Cardiovascular
|
|
Syncope
|
1
|
2
|
|
|
Digestive
|
|
Nausea
|
6
|
11
|
|
|
Diarrhea
|
5
|
10
|
|
|
Vomiting
|
3
|
5
|
|
|
Anorexia
|
2
|
4
|
|
|
Hemic and Lymphatic
|
|
Ecchymosis
|
3
|
4
|
|
|
Metabolic and Nutritional
|
|
Weight decrease
|
1
|
3
|
|
|
Musculoskeletal
|
|
Muscle cramps
|
2
|
6
|
|
|
Arthritis
|
1
|
2
|
|
|
Nervous System
|
|
Insomnia
|
6
|
9
|
|
|
Dizziness
|
6
|
8
|
|
|
Depression
|
<1
|
3
|
|
|
Abnormal dreams
|
0
|
3
|
|
|
Somnolence
|
<1
|
2
|
|
|
Urogenital
|
|
Frequent urination
|
1
|
2
|
|
Â
Other Adverse Events Observed During Clinical
Trials: During the pre-marketing phase, donepezil has been administered to over
1700 individuals for various lengths of time during clinical trials worldwide.
Approximately 1200 patients have been treated for at least 3 months,
and more than 1000 patients have been treated for at least 6 months.
Controlled and uncontrolled trials in the US included approximately 900 patients. In
regards to the highest dose of 10 mg/day, this population includes
650 patients treated for 3 months, 475 patients treated for
6 months and 115 patients treated for over 1 year. The range of
patient exposure is from 1 to 1214 days.
Treatment emergent
signs and symptoms that occurred during 3 placebo-controlled clinical
trials and 2 open-label trials were recorded as adverse events by the
clinical investigators using terminology of their own choosing. To provide an
overall estimate of the proportion of individuals having similar types of
events, the studies were integrated and the events were grouped into a smaller
number of standardized categories using a modified COSTART dictionary and event
frequencies were calculated across all studies. These categories are used in
the listing below. The frequencies represent the proportion of
900 patients from these trials who experienced that event while receiving
donepezil. All adverse events occurring at least twice are included. Adverse events
already listed in Table 4 and Table 5 are not repeated here (i.e., events
occurring at an incidence >2%). Also excluded are COSTART terms too general
to be informative, or events less likely to be drug caused. Events are
classified by body system and listed as occurring in ≥ 1% and
<2% of patients (i.e., in 1/100 to 2/100 patients: frequent) or in <1% of
patients (i.e., in 1/100 to 1/1000 patients: infrequent). These adverse events
are not necessarily related to donepezil treatment and in most cases were observed
at a similar frequency in placebo-treated patients in the controlled studies.
Adverse events
occurring in ≥ 1% and <2% or <1% of patients receiving donepezil:
Body as a Whole
(≥ 1% and <2%) influenza, chest pain,
toothache; (<1%) fever, edema face, periorbital edema, hernia hiatal,
abscess, cellulitis, chills, generalized coldness, head fullness, head
pressure, listlessness.
Cardiovascular
(≥ 1% and<2%) hypertension,
vasodilation, atrial fibrillation, hot flashes, hypotension; (<1%) angina
pectoris, postural hypotension, myocardial infarction, premature ventricular
contraction, arrhythmia, AV Block (first degree), congestive heart failure,
arteritis, bradycardia, peripheral vascular disease, supraventricular
tachycardia, deep vein thromboses.
Digestive
(≥ 1% and <2%) fecal incontinence,
gastrointestinal bleeding, bloating, epigastric pain; (<1%) eructation,
gingivitis, increased appetite, flatulence, periodontal abscess,
cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis,
irritable colon, tongue edema, epigastric distress, gastroenteritis, increased
transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena,
polydipsia, duodenal ulcer, stomach ulcer.
Endocrine
(< 1%) diabetes mellitus, goiter.
Hemic and Lymphatic
(<1%) anemia, thrombocythemia,
thrombocytopenia, eosinophilia, erythrocytopenia.
Metabolic and Nutritional Disorders
(≥ 1% and <2%) dehydration; (<1%)
gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase,
increased lactate dehydrogenase.
Musculoskeletal
(≥ 1% and <2%) bone fracture; (<1%)
muscle weakness, muscle fasciculation.
Nervous System
(≥ 1% and <2%) delusions, tremor,
irritability, paresthesia, aggression, vertigo, ataxia, libido increased,
restlessness, abnormal crying, nervousness, aphasia; (<1%) cerebrovascular
accident, intracranial hemorrhage, transient ischemic attack, emotional
lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait
abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia,
dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional
withdrawal, nystagmus, pacing, seizures.
Respiratory
(≥ 1% and <2%) dyspnea, sore throat,
bronchitis; (<1%) epistaxis, postnasal drip, pneumonia, hyperventilation,
pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary
collapse, sleep apnea, snoring.
Skin and Appendages
(≥ 1% and <2%) abrasion, pruritus,
diaphoresis, urticaria; (<1%) dermatitis, erythema, skin discoloration,
hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin
striae, night sweats, skin ulcer.
Special Senses
(≥ 1% and <2%) cataract, eye
irritation, blurred vision; (<1%) dry eyes, glaucoma, earache, tinnitus,
blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis
media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots
before eyes.
Urogenital
(≥ 1% and <2%) urinary incontinence,
nocturia; (<1%) dysuria, hematuria, urinary urgency, metrorrhagia, cystitis,
enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder,
breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.
Long-term Safety
Patients were exposed to donepezil in
2 open-label extension studies (n=885) of over 2 years. In 1 of the
studies, 763 patients who previously completed 1 of 2 placebo-controlled
studies of 15 or 30 week's duration continued to receive donepezil and were
evaluated for safety and neuropsychological evaluations for up to 152 weeks;
the safety profile of donepezil in this extension study remained consistent
with that observed in placebo-controlled trials. Following 1 and 2 years of
treatment, 76% (n=580) and 49% (n=374) of these patients, respectively, were
still receiving therapy (cumulative weeks 48 and 108).
Postmarketing Reports
Voluntary reports of adverse events temporally
associated with donepezil that have been received since market introduction
that are not listed above, and that there is inadequate data to determine the
causal relationship with the drug include the following: abdominal pain,
agitation, cholecystitis, confusion, convulsions, hallucinations, heart block
(all types), hemolytic anemia, hepatitis, hyponatremia, pancreatitis, and rash.
Vascular Dementia
The initial safety profile from controlled
clinical trials in Vascular dementia patients indicates that the rate of
occurrence of adverse events overall was higher in Vascular dementia patients
(91%) than in Alzheimer’s disease patients (75%), however this was seen in both
donepezil-treated subjects and placebo-treated subjects and may relate to the
greater number of comorbid medical conditions in the Vascular dementia population
(see Pharmacology, Clinical Trial Data, Vascular dementia section). A
comparison of the Alzheimer’s disease and Vascular dementia studies shows that
the type of donepezil-associated adverse events was similar in the 2 patient
populations
A total of 827 patients
with Vascular dementia were treated in controlled clinical studies with
donepezil. Of these patients, 639 (77%) completed the studies. The mean
duration of treatment for all donepezil groups was 152 days (range 1-428 days).
In controlled clinical
trials in Vascular dementia patients, the rates of discontinuation due to
adverse events were 10.6 % for donepezil 5 mg and 19% for donepezil 10 mg
compared to 9.9% for placebo. The most common adverse event leading to
discontinuation, defined as those occurring in at least 2% of patients and at
twice the incidence seen in placebo patients was nausea. Other less common
events leading to discontinuation include cerebrovascular accident, confusion,
dizziness, diarrhea, and vomiting.
The most common serious
adverse events were cerebrovascular accident (3.4%) and pneumonia (1.6%). The
most common adverse events were infection (14.4%), diarrhea (13.9%), accidental
injury (13.0%) and nausea (11.3%). Most adverse events were judged by the
investigator to be mild to moderate in intensity and not related to study
medication.
Overdose
For management of a
suspected drug overdose, CPhA recommends that you contact your regional
Poison Control Centre. See the CPS Directory section for a list ofÂ
Poison Control Centres.
Symptoms
Overdosage with cholinesterase inhibitors can
result in cholinergic crisis characterized by severe nausea, vomiting,
salivation, sweating, bradycardia, hypotension, respiratory depression,
collapse and convulsions. Increasing muscle weakness is a possibility and may
result in death if respiratory muscles are involved.
Treatment
The elimination half-life of donepezil at
recommended doses is approximately 70 hours, thus, in the case of
overdose, it is anticipated that prolonged treatment and monitoring of adverse
and toxic reactions will be necessary. As in any case of overdose, general
supportive measures should be utilized.
Tertiary
anticholinergics such as atropine may be used as an antidote for donepezil
overdosage. I.V. atropine sulfate titrated to effect is recommended: an initial
dose of 1 to 2 mg i.v. with subsequent doses based upon clinical
response. Atypical responses in blood pressure and heart rate have been
reported with other cholinomimetics when coadministered with quaternary
anticholinergics such as glycopyrrolate. It is not known whether donepezil
and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal
dialysis, or hemofiltration).
Dose-related signs of
toxicity observed in animals included reduced spontaneous movement, prone
position, staggering gait, lacrimation, clonic convulsions, depressed
respiration, salivation, miosis, fasciculation, and lower body surface
temperature.
Dosage
Donepezil tablets should only be prescribed by
(or following consultation with) clinicians who are experienced in the
diagnosis and management of Alzheimer's disease.
Adults: The recommended initial dose of
donepezil is 5 mg taken once daily. Therapy with the 5 mg dose should
be maintained for 4 to 6 weeks before considering a dose increase, in
order to avoid or decrease the incidence of the most common adverse reactions
to the drug (see Adverse Effects) and to allow plasma levels to reach
steady-state. Based on clinical judgement, the 10 mg daily dose may be considered
following 4-6 weeks of treatment at 5 mg/day. The maximum recommended
maintenance dose is 10 mg taken once daily.
Following initiation of
therapy or any dosage increase, patients should be closely monitored for
adverse effects.
Donepezil should be
taken once daily in the morning or evening. It may be taken with or without
food.
Special Populations: Adverse events are more
common in individuals of low body weight, in patients ≥ 85 years old and
in females. It is recommended that donepezil be used with caution in these
patient populations. In elderly women of low body weight, the dose should not
exceed 5 mg/day.
In a population of
cognitively impaired individuals, safe use of this and all other medications
may require supervision.
Supplied
5 mg
Each white, film-coated tablet, embossed with
the name “ARICEPT†and the strength, contains: donepezil HCl 5 mg
equivalent to donepezil free base 4.56 mg. Nonmedicinal ingredients:
cornstarch, hydroxypropylcellulose, lactose monohydrate, magnesium stearate and
microcrystalline cellulose; film-coating: hypromellose, polyethylene glycol,
talc and titanium dioxide. HDPE bottles of 30. Boxed blister strips of 28
(2 strips of 14).
10 mg
Each yellow, film-coated tablet, embossed with
the name “ARICEPT†and the strength, contains: donepezil HCl 10 mg
equivalent to donepezil free base 9.12 mg. Nonmedicinal ingredients:
cornstarch, hydroxypropylcellulose, lactose monohydrate, magnesium stearate and
microcrystalline cellulose; film-coating: hypromellose, iron oxide,
polyethylene glycol, talc and titanium dioxide. HDPE bottles of 30. Boxed
blister strips of 28 (2 strips of 14).
Store at controlled room temperature, 15 to 30°C and away from moisture.
