$368 P.
4 Degenerative and neurological disorders
donepezil only and donepezil plus sertraline groups on Day 1.
The concurrent administration, of donepezil and sertraline did not
alter the PK parameters of donepezil on Day 15.
Conclusions: During the co-administration of donepezil and
sertraline, no unexpected adverse events were observed. In ad-
dition, no clinically meaningful pharmacokinetic interactions oc-
curred, suggesting that no dose adjustment is required for either
donepezil or sertraline when the two drugs are used in combina-
tion.
IP.4.0321 Donepezil improved or stabilized cognition
over one year in patients with mild and
moderate Alzheimer's disease
K. Engedall, H. Soininen2, E Verheya, G. Waldernar4, B.
Winblad5, A. Wimo6, A.-L. Wetterholm7, R. Zhanga, A.
Haglund7, P. Subbiaha. The Donepezil Nordic Study Group;
I Clinic for Geriatric Rehabilitation, Oslo, Norway; 2University
of Kuopio, Finland; 3Academic Hospital of Maastricht, The
Netherlands," 4The Neuroscience Center, Copenhagen, Denmark;
5Karolinska Institute, Huddinge; 6Dept. of Family Medicine,
Umed University; 7Pfizer AB, Taby, Sweden; 8Pfizer Inc, New
York, USA
Cholinesterase (ChE) inhibitors have been approved for use
in the symptomatic treatment of patients with mild to moder-
ate Alzheimer's disease (AD). Previous double-blind, placebo-
controlled studies of ChE inhibitors have demonstrated beneficial
effects on global function, cognition and activities of daily living
(ADLs) in AD patients for up to 6 months. This unique, double-
blind, placebo-controlled study evaluated the effÉcacy and safety
of once-daily donepezil, versus placebo, for the symptomatic
treatment of patients with mild to moderate AD over the course
of one year.
This trial included 286 patients with possible or probable AD
from 28 sites in five Northern European countries. Patients were
randomized to receive either donepezil (n = 142; 5 mg/day for 28
days followed by 10 rag/day as per the clinician's judgement) or
placebo (n = 144). In addition to the primary efficacy variable, the
Gottfries-Brfine-Steen scale (GBS), outcome measures included
the Mini-Mental State Examination (MMSE) and the Progressive
Deterioration Scale (PDS). Safety measures included monitoring
of treatment-emergent adverse events (AEs).
Significant differences in global function favouring donepezil
over placebo were observed for mean change from baseline on
GBS total scores at Weeks 24, 36 and 52 (p < 0.05). Significant
differences favouring donepezil over placebo were also observed
in cognition and ADLs for mean change from baseline on the
MMSE at Weeks 24, 36 and 52 (p < 0.02) and PDS total scores at
Week 52 (p < 0.05), respectively. Significant treatment differences
in MMSE scores favored donepezil compared with placebo in
patients with mild AD at Week 36 and Endpoint (p < 0.05) and at
Weeks 24, 52 and Endpoint (p < 0.002),for moderate AD patients.
At Week 24, 81% of donepezil-treated patients were rated as either
improved or stabilized according to the change from baseline on
either the MMSE or PDS compared to 63% of placebo-treated
patients (p < 0.0002). Similarly, 63% of donepezil-treated patients
compared with 37% of placebo-treated patients were rated as
improved or stabilized at Week 52 (p < 0.001) according to at least
one of these scales. Over the full one year treatment period, 66.9%
of donepezil- and 67.4% of placebo-treated patients completed
the study. AEs were observed for 81.7% donepezil- and 75.7%
placebo-treated patients and 7% donepezil- and 6.3% placebo-
treated patients discontinued due to AEs.
This double-blind study demonstrated the benefits of donepezil
in terms of global function, cognition and ADLs and that the drug
was well tolerated over the course of one year. Further, both mild
and moderate AD patients showed cognitive benefits during one
year of treatment. Stabilization or improvements in cognition or
ADLs were demonstrated in more patients receiving donepezil
than those receiving placebo o v e r a one year period.
1P.4.0331TolerabiUty and safety of donepezil in the
treatment of Alzheimer's disease: Results
from a Post Marketing Surveillance study
C.A. Sramko 1, E Berger 1, R Calabrese2, L. Fr61ich3. lEisai
GmbH, Medical Department, Lyoner Str. 14, 60528 Frankfurt;
2University of Bochum; 3University of Frankfurt, Germany
Background: In addition to the safety data obtained in pivotal
clinical trials of new drugs, monitoring of tolerability and safety is
required after regulatory approval, This can be formally conducted
as a Post Marketing Surveillance (PMS)study. These studies, with
larger cohorts of patients, either confirm the safvty profile of the
drug or potentially identify new adverse events (AE) associated
with its treatment.
Objective: To evaluate the tolerability and safety of donepezil
in patients with Alzheimer's disease (AD).
Methods: This was an open-label, observational post-marketing
surveillance study undertaken shortly after approval of the drug in
1997. The patients enrolled represented the population who would
be prescribed donepezil in everyday clinical practice. Physicians
were requested to record and assess causality for all AEs that
occurred during the 3-month treatment period. For patients of
special interest and those with serious AEs, emphasis was placed
on obtaining follow up and additional information. Because side-
effects are typically reported spontaneously in such surveillance
studies, a lower incidence of AEs than reported in clinical lrials
could be expected. At the end of the treatment period, an overall
assessment of tolerability was carried out by the physician based
on a 4-point rating scale ("not satisfactory", "moderate", "good",
and "very good").
Results: The majority (61%) of the 2094 enrolled patients were
female. The mean ages of female and male patients were 75 and 72
years, respectively. 128 patients (6%) discontinued the treatment
due to an AE. 12.2% of patients reported at least one AE (most
frequently: nausea 2.2%, diarrhoea 1.4%, trembling inside 1.4%,
vomiting 1.1%). During the observation period, 10 patients died.
None of the deaths was attributable to donepezil. The tolerability
of donepezil was assessed by the physician as "very good" or
"good" in more than 90% of patients.
Conclusions: This analysis of donepezil's safety and tolembil-
ity profile in clinical practice demonstrated reported AEs to be
consistent with the known cholinergic properties of donepezil or
with the signs and symptoms seen in AD. These results provide
additional information supporting the favorable safety profile of
donepezil in the treatment of patients with mild to moderate AD.