Donepezil, rivastigmine, galantamine and memantine for ...

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Clinical effectiveness
clinical trials and some comparisons can be
made between treatment and placebo groups.
● Some adverse events that occur in the short
term and that are obvious to participants and
carers have the potential to unblind participants,
carers and physicians, even if trials are placebo
controlled and participants are not told which
treatment they are receiving. Such unblinding
could produce biased assessments of treatment
effects when the outcomes are self-assessed.
● Some adverse events may lead to
discontinuation of a participant in a trial or
reduction in the dosage of the treatment. This
has the potential to increase the likelihood of
bias in the reporting of the outcomes.
Various event rates for selected adverse events
were reported in 11 of the included trials and are
given in Table 10. In general, the quality of
reporting of adverse events is variable and is not
consistent across trials, with few descriptions of
how clinical adverse events were defined.
Descriptions of those adverse events that are most
commonly reported between the included trials
are given here. Severity, where noted, is as
reported in each of the individual trials. Very few
included studies made statistical comparisons of
the rates of adverse events in treatment groups
with those in the placebo groups. Table 11 shows
the number of withdrawals due to adverse events.
A range of adverse events were reported in the 11
included studies. One study did not present data
for each type of event individually, but rather gave
overall incidence rates. 45 Another, a cross-over
study, only reported adverse events for all
participants receiving donepezil treatment. These
studies are not discussed further here but are
reported in Appendix 7. Most events presented in
the studies were reported as mild or moderate in
nature.
Adverse events that were most consistently
reported were generally related to the
gastrointestinal system.
Nausea and vomiting
Nausea was reported in seven studies. 41,44,46,47,50–52
Rates of nausea in the donepezil groups ranged
from around 4 to 24% and in the placebo groups
from 1 to 9%. Three included studies report that
nausea was statistically significantly greater in
those treated with donepezil than those with
placebo. 46,50,51 Vomiting was reported in five
studies. 41,44,50–52 Rates of vomiting in the
donepezil groups ranged from around 1 to 16%
and in the placebo groups from 2 to 5%. Two
included studies report vomiting incidence that
was statistically significantly greater in those
treated with donepezil than in those treated with
placebo, although in both cases this was only with
the higher (10 mg) dose of donepezil. 50,51
Nausea/vomiting was reported in one study, which
also showed the same trend with rates being
higher in the donepezil treated groups compared
to the placebo groups. 53
Diarrhoea
Diarrhoea was reported in seven
studies. 41,44,46,47,50–52 In all studies the incidence of
diarrhoea was greater in the donepezil-treated
groups, although the magnitude of this difference
was less in two studies. 44,47 Three of these seven
studies tested the difference in rates statistically
and noted significant differences between the
groups. Rates of diarrhoea ranged from around 4
to 17% in the donepezil groups and from 3 to 7%
in the placebo groups.
Other adverse events that were more consistently
reported related to mental and neurological
systems.
Headache and dizziness
In six of the included studies rates of headache
were reported. 41,44,46,47,52,53 Incidence ranged from
around 3 to 13% in the donepezil-treated groups
and around 1 to 9% in the placebo-treated groups.
No studies report statistically significant
differences in the rates of headaches reported
between the groups. Dizziness was reported in six
studies. 41,47,50–53 In all studies the occurrence of
dizziness was greater in the donepezil-treated
groups, although the magnitude of this difference
was generally small.
Agitation/restlessness
Four included studies reported data on
agitation/restlessness. 44,46,52,53 In the donepeziltreated
groups this ranged from 0 to 13% and in
the placebo-treated groups from 2 to 10%. In
general, rates within studies were similar between
those in the donepezil-treated group and those in
the placebo-treated group. Agitation in
participants may, in particular, have an effect on
the burden on the caregiver; however, in these
studies it would appear that donepezil has a
minimal effect on agitation.
Serious adverse events
Rates of ‘serious’ adverse events were reported in
six studies. 41,43,46,47,50,52 In many cases these were
classed as being unrelated to the study treatment
by assessors; however, in all studies it can be