Drug Safety Evaluation

Safety and tolerability of

transdermal and oral rivastigmine
in Alzheimer’s disease and
1. Introduction Parkinson’s disease dementia
2. Pharmacology
3. Clinical applications Taher Darreh-Shori† & Vesna Jelic
†
Karolinska University Hospital, Karolinska Institute, Department of Neurobiology, Care Sciences
4. Safety and tolerability
and Society, Division of Alzheimer Neurobiology, Novum, 4th Floor, Room 4F23:10, 141 86,
evaluation
Huddinge, Stockholm, Sweden
5. Conclusions
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Windsor on 08/29/14

6. Expert opinion Importance of the field: Cholinesterase inhibitors are the mainstay of symp-
tomatic therapy for Alzheimer’s disease (AD). Rivastigmine, an inhibitor of
both acetylcholinesterase and butyrylcholinesterase, is available as a trans-
dermal patch and in oral forms. It is also approved for the treatment of
Parkinson’s disease dementia (PDD) in many countries. The objective of this
article is to review the safety and tolerability profile of transdermal and oral
rivastigmine in AD and PDD patients.
Areas covered in this review: Articles were identified by searching MEDLINE in
July 2009using the terms rivastigmine, Exelon, ENA713and clinical trial. Alldouble-
blind, placebo-controlled randomized trials in which rivastigmine monotherapy
For personal use only.

was administered to AD or PDD patients for longer than 2 weeks were included.
What the reader will gain: This article provides a comprehensive summary of
currently available safety data on rivastigmine.
Take home message: The main adverse events reported with rivastigmine
therapy are gastrointestinal in nature. However, the transdermal patch appears
to reduce these side effects, allowing more patients to access higher therapeutic
doses. Overall, the safety profile of rivastigmine is favorable and the improved
tolerability offered by the rivastigmine patch suggests that transdermal delivery
may be the best way to deliver this drug in AD and PDD patients.

Keywords: Alzheimer’s disease, Parkinson’s disease dementia, rivastigmine, safety, tolerability

Expert Opin. Drug Saf. (2010) 9(1):167-176

1. Introduction

Alzheimer’s disease (AD) is the most common form of dementia and represents 80%
of all cases [1]. It is characterized by loss of memory and cognitive function,
behavioral disorders and an impaired ability to perform activities of daily living.
Sufferers of Parkinson’s disease (PD) are particularly susceptible to dementia; the
incidence of cognitive impairment in this population is up to six times that seen in
healthy people [2]. Dementia affects about 40% of patients with PD [3].
Rivastigmine (Box 1) is a cholinesterase inhibitor that was first licensed in oral form
(capsules or liquid solution) for the treatment of mild to moderate dementia of the
Alzheimer type in 1997. Cholinesterase inhibitors form the mainstay of treatment
for AD, with galantamine (Razadyne
/Reminyl
) and donepezil (Aricept
) being the
other two commonly-used drugs in this class. However, galantamine and donepezil are
approved for the treatment of AD only, while rivastigmine was also approved in many
countries for the treatment of mild to moderate Parkinson’s disease dementia (PDD) in
2006. The highest recommended dose of rivastigmine capsules is 12 mg/day (6 mg
administered twice-daily).

10.1517/14740330903439717 © 2010 Informa UK Ltd ISSN 1474-0338 167

All rights reserved: reproduction in whole or in part not permitted
 Rivastigmine

Box 1. Drug summary. both lipophilic and hydrophilic properties) are characteristics
that allow a drug to readily pass through the skin, enter the
Drug name Rivastigmine
(generic)
bloodstream and cross the BBB [4]. Rivastigmine’s potency is
also advantageous as it allows the rivastigmine patch to
Phase (for indications Phase IV
under discussion) be small (which is associated with improved skin tolerability)
Indication (specific to Alzheimer’s disease and
and discreet.
discussion) Parkinson’s disease dementia
Pharmacology Acetylcholinesterase and 2.2 Mechanism of action
description/ butyrylcholinesterase inhibition The degeneration of cholinergic neurons in the AD brain
mechanism
of action results in decreased levels of the neurotransmitter acetylcho-
line (ACh), which correlates with the development of disease
Route of Oral (capsules or solution) or
administration transdermal patch symptoms [5]. Inhibition of the hydrolysis of ACh by rivas-
tigmine increases the level of ACh in the brain or prolongs its
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Chemical structure
N action at synapses, thereby enhancing cholinergic function [6].
Unlike other widely-used cholinesterase inhibitors, rivastig-
N O
mine inhibits two enzymes, acetylcholinesterase (AChE)
and butyrylcholinesterase (BuChE) [6,7]. Both enzymes are
O involved in the hydrolysis of ACh, and represent rational
Pivotal trial(s) [18–20,22,23]
treatment targets in AD, according to the conventional
cholinergic hypothesis [6].
Pharmaprojects - Copyright to Citeline Drug Intelligence (an Informa It has been hypothesized more recently that BuChE
business). Readers are referred to Informa-Pipeline (http://informa-
inhibition may affect the underlying disease pathology of
pipeline.citeline.com) and Citeline (http://informa.citeline.com).
AD [8]. As well as having enzymatic effects on synaptic ACh,
BuChE is also thought to affect extracellular ACh. Extra-
For personal use only.

cellular ACh has roles in processes such as inflammation,

More recently, a rivastigmine transdermal patch has been
developed, the first transdermal treatment to be approved
for AD. The rivastigmine transdermal patch is also licensed for
the treatment of PDD in many parts of the world, including
the US. The rivastigmine transdermal patch is approved in the
EU and US in two dosage strengths: an initial dose 5 cm2
patch that releases 4.6 mg/24 h, and a maintenance dose
10 cm2 patch that releases 9.5 mg/24 h.
Here, we review the current literature on the safety and
tolerability of rivastigmine transdermal patch and oral forms
in both approved indications, AD and PDD. Articles were
identified by searching MEDLINE in July 2009 using the
terms rivastigmine, Exelon, ENA 713 and clinical trial. All
double-blind, placebo-controlled randomized trials in which
rivastigmine monotherapy was administered to AD or PDD
patients for longer than 2 weeks were included.
2. Pharmacology
2.1 Chemistry
Rivastigmine is a pseudo-irreversible cholinesterase inhibitor
known chemically as (S)-3-[1-(dimethylamino)ethyl]phenyl
ethylmethylcarbamate. As a base, its empirical formula is
C14H22N2O2, which has a molecular mass of 250.34 g/
mol. Its structure and chemical class are distinct from other
cholinesterase inhibitors approved for AD.
Rivastigmine has a number of chemical properties that
make it particularly well-suited to transdermal delivery.
Low molecular mass and amphipathic nature (possessing
which are believed to affect amyloid pathology. BuChE may
also interact with apolipoprotein E e4 (APOE e4), a risk
factor for AD, affecting the aggregation of toxic b-amyloid in
the brain [8-11].
2.3 Pharmacodynamics
Rivastigmine is classified as a pseudo-irreversible inhibitor
due to its long inhibition of AChE of up to 10 h [12].
Rivastigmine inhibits AChE and BuChE by binding to the
catalytic site, where it is hydrolyzed. The carbamyl moiety
of rivastigmine remains attached to the enzyme for hours,
causing long inactivation of the enzyme. However, the enzyme
is reactivated once the carbamyl moiety is released. Other
cholinesterase inhibitors are classified as reversible, as upon
binding to AChE they are not hydrolyzed but are released
intact within minutes. The enzymatic activity of AChE
and BuChE in the plasma can be used as a marker of
rivastigmine’s target enzyme inhibition over time. In a
pharmacodynamic study of rivastigmine, two distinct
peak-troughs of BuChE inhibition were seen when rivastig-
mine was orally administered; this was due to the twice-daily
dosing regimen [13]. The first trough was observed between 2
and 6 h after the morning dose and the second occurred
between 2 and 5 h after the evening dose. In contrast,
transdermal administration provided a smoother, more con-
tinuous reduction in plasma BuChE activity [13]. With the
9.5 mg/24 h patch, BuChE activity reached maximum
inhibition after ~ 12 h, and was then sustained at near
to the peak inhibition over the remainder of the 24 h patch

168 Expert Opin. Drug Saf. (2010) 9(1)


application period [13]. AChE activity was not measured in
this study.
2.4 Pharmacokinetics
Oral rivastigmine is absorbed from the gastrointestinal tract,
while the transdermal patch delivers the drug through the skin
into the bloodstream. In an open-label, ascending dose study
of 51 AD patients, rivastigmine capsule was rapidly absorbed,
with a median tmax of 1 h for all doses [13]. These findings were
consistent with earlier studies, which indicated a tmax of
0.8 – 1.7 h with the rivastigmine capsule [12]. In comparison,
tmax with the rivastigmine patch was reached at ~ 8 h for all
patch sizes, reflecting the more gradual increase in plasma
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concentration with transdermal administration. The mean
Cmax with transdermal administration was consistently lower
than with capsules (mean Cmax 8.7 ng/ml with the 9.5 mg/24 h
patch compared to 21.6 ng/ml with 12 mg/day capsules) [14].
There was also less variation in peak-trough rivastigmine
concentrations with the rivastigmine transdermal patch, with
a fluctuation index of 0.8 with the 9.5 mg/24 h patch
compared with 4.2 with 12 mg/day capsules, demonstrating
a smoother, continuous drug delivery with transdermal
administration [13].
Pharmacokinetic studies with the rivastigmine capsule
For personal use only.
have shown that the drug is not significantly metabolized
by hepatic oxidative CYP isoenzymes; instead, it is rapidly
and extensively metabolized by its target enzymes, AChE and
BuChE, resulting in production of the inactive metabolite
NAP-226-90 [12]. NAP-226-90 then undergoes rapid renal
elimination [12]. Because of this, there is no accumulation of
rivastigmine or NAP-226-90 even after repeated administration,
and the potential for drug–drug interactions is very low [12].
Protein binding of rivastigmine is ~ 40%, with about 40 – 50%
of rivastigmine bound with red blood cells. Rivastigmine has
a volume of distribution of ~ 1.8 – 2.7 l/kg [12,15].
In the open-label pharmacokinetic study of the rivastigmine
patch and capsule, assessments of drug exposure, assessed
by measuring the AUC, showed that the starting dose
4.6 mg/24 h patch provided comparable drug exposure to
6 mg/day capsules, while the target dose 9.5 mg/24 h patch
provided comparable exposure to the highest recommended
dose of capsules, 12 mg/day [14]. The efficacy of rivastigmine is
dose-dependent, but a 6 mg/day dose of rivastigmine capsules
has been shown to provide therapeutic drug levels [16]. Body
application site has been shown to have an effect on the
pharmacokinetics of the rivastigmine patch, with bioavailabil-
ity being greatest when the patch is applied to the upper back,
upper arm or chest [17]. In a pharmacokinetic study comparing
five different application sites, mean exposure following
a single 24-h application of the 9.5 mg/24 h patch was
122 (ng.h)/ml when the patch was applied to the upper
back, 123 (ng.h)/ml when applied to the chest and 116
(ng.h)/ml when applied to the upper arm. Exposure was
lower when the patch was applied to the thigh (88 (ng.h)/
ml) and the abdomen (101 (ng.h)/ml) [17].
Expert Opin. Drug Saf. (2010) 9(1)
Darreh-Shori & Jelic
3. Clinical applications
The efficacy of rivastigmine capsules in mild to moderate AD
has been well-established in > 3000 patients in numerous
randomized, double-blind, placebo-controlled clinical trials
[18-21]. Significant treatment benefits have been consistently
observed on measures of cognition, global impression of change,
activities of daily living and disease severity [18-21]. The rivas-
tigmine capsule has also been evaluated in a randomized,
double-blind placebo-controlled trial in 541 PDD patients, in
which significant improvements in cognition, activities of daily
living, behavior, attention and executive function were seen with
rivastigmine treatment compared with placebo (Table 1) [22].
The efficacy of the rivastigmine transdermal patch was
evaluated in a single, 24-week, international, randomized,
double-blind trial of 1195 patients with mild to moderate
AD [23]. All rivastigmine treatment groups (patch and capsule)
showed significant improvements compared with placebo at
week 24 with respect to the primary outcomes (the Alzheimer’s
Disease Assessment Scale–Cognitive subscale and the
Alzheimer’s Disease Cooperative Study–Clinical Global
Impression of Change), as well as many of the secondary
outcomes, including measures of activities of daily living,
cognition and attention. The 9.5 mg/24 h patch provided
similar efficacy to the highest doses of capsules (12 mg/day) on
these outcome measures. The trial also evaluated a larger patch
releasing 17.4 mg/24 h rivastigmine; these data are not
reported here as this dose is not approved in the EU or US.
Cost-effectiveness studies of cholinesterase inhibitors in AD
have shown that healthcare costs for patients are generally
similar for all three commonly-used cholinesterase inhibi-
tors [24-26]. These analyses were based on rivastigmine capsules;
however, they may also be applicable to rivastigmine trans-
dermal patch in countries such as the US, where rivastigmine
patch is similarly priced and is available on a flat-price basis.
A modeling study of the incremental costs and benefits
associated with the rivastigmine patch versus best supportive
care has demonstrated a favorable cost-effectiveness profile [27].
Further analyses using healthcare data from other countries
would of course be required to confirm cost-effectiveness
according to each national model.
4. Safety and tolerability evaluation
4.1 Most frequently-reported adverse events
The incidences of the most frequently-reported adverse events
during the five major clinical trials of rivastigmine are shown
in (Table 2). As with all cholinesterase inhibitors, the most
common side effects were gastrointestinal adverse events, trig-
gered by rapid increases in ACh levels in the brain [28]. These side
effects (primarily nausea and vomiting) were particularly fre-
quent during the dose-escalation phase, but tended to decrease
over time [18,28,29]. The target dose 9.5 mg/24 h rivastigmine
transdermal patch was associated with three times fewer events
of nausea and vomiting compared with the capsule in the clinical
169
 Rivastigmine

Table 1. Mean changes from baseline at week 24 for of rivastigmine include: sweating, allergy, hypertension, som-
primary and secondary efficacy measures in the IDEAL nolence, flatulence, dyspepsia, sinusitis, agitation, anxiety,
study (ITT-LOCF population) [23]. hemorrhoids, falls, hypotension, constipation, confusion,
orthostatic hypotension and decreased appetite [18,20,22,23].
Mean 24-week change from baseline Extension studies of the PDD and rivastigmine patch trials
Rivastigmine Rivastigmine Placebo
have demonstrated that rivastigmine has a favorable long-term
9.5 mg/24 h 12 mg/day
tolerability profile [33-35].
patch capsules
4.2 Skin tolerability with transdermal therapy
Primary measures As with any medical patch, some patients treated with the
ADAS-cog -0.6‡ -0.6‡ 1 rivastigmine transdermal patch will probably develop skin
‡
ADCS-CGIC 3.9 3.9‡ 4.2 reactions [36]. These typically take the form of mild erythema
Secondary measures (redness) and pruritus (itching), caused by contact irritation, and
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MMSE 1.1‡ 0.8‡ 0 should not present a serious medical problem (Figure 2). Allergic
Trail Making -12.3 §
-9.8§ 7.7
dermatitis with the rivastigmine patch is rare, and typically
Test part A manifests as localized redness with swelling, which may ‘spread’
ADCS-ADL -0.1‡ -0.5* -2.3 beyond the border of the patch. In the clinical trial of the
NPI-12 -1.7 -2.2 -1.7
rivastigmine patch, skin irritation was evaluated at every visit
by the investigator using a 5-point rating scale ranging from no
*p £ 0.05. reaction through to slight, mild, moderate and severe irritation.
‡
p £ 0.01. The majority (89.6%) of patients in the 9.5 mg/24 h patch group
§
p £ 0.001 versus placebo.
experienced no, slight or mild application site skin reactions, and
Negative change scores on ADAS-cog, Trail Making Test part A and NPI-12
indicate improvement.
the incidence of severe skin reactions was low (2.2%) [23]. In
Negative change scores on MMSE and ADCS-ADL indicate deterioration. total, 7.6% of patients reported moderate or severe erythema
For personal use only.

ADCS-CGIC is scored as a judgement of change, with a score of 4 indicating
no change, < 4 indicating improvement and > 4 indicating deterioration.
ADAS-cog: Cognitive subscale of the Alzheimer’s disease assessment scale;
ADCS-ADL: Alzheimer’s disease cooperative study activities of daily living
scale; ADCS-CGIC: Alzheimer’s disease cooperative study clinical global
impression of change; MMSE: Mini-mental state examination;
NPI-12: 12-Item neuropsychiatric inventory.
trial in patients with AD [23], presumably due to the smoother
pharmacokinetic profile of the patch. This was reflected by the
fact that the majority (95.9%) of patients in the rivastigmine
9.5 mg/24 h patch group who underwent maintenance phase
treatment had reached their target dose by the last assessment of
the maintenance phase, compared with 64.4% in the capsule
group (Figure 1) [30,31]. The 9.5 mg/24 h rivastigmine patch
tolerability profile compares favorably to the other commonly-
used cholinesterase inhibitors, donepezil and galantamine,
which are both administered orally (Table 3).
In addition to fluctuations in plasma drug concentration that
occur with oral administration, the incidence of nausea and
vomiting in the initial clinical trials of rivastigmine capsule in
AD may have been further increased by the short length of the
intervals (2 weeks) between each titration step [18,19]. It has since
been shown that extending the time interval to 4 weeks, or longer
in certain patients, can reduce gastrointestinal tolerability
problems considerably [32]. A 4-week titration regimen was,
therefore, used in subsequent trials [22,23].
Other than gastrointestinal side effects, the most common
adverse events reported during rivastigmine therapy were
neurological in nature and include headache, dizziness and
fatigue [29]. Other adverse events reported during clinical trials
with the 9.5 mg/24 h patch, and < 2.5% of patients discontinued
due to adverse skin reactions [23].
Simple steps may be taken to minimize the occurrence of
skin reactions, such as application site rotation, moisturizing
skin, and trimming rather than shaving excess hair at the
application site. Topical corticosteroids may be used in some
rare cases of severe allergic dermatitis [37]; however, if the signs
and symptoms of dermatitis are not tolerable by the patient at
any point, patch treatment should be discontinued. In general,
appropriate management and treatment will help to ensure
that any signs and symptoms of skin reactions, should they
occur, will most likely be transient, mild-to-moderate and
cause minimal discomfort to the patient.
The rivastigmine transdermal patch has not yet been tested
in a large clinical trial of patients with PDD. Patients with
PDD are prone to excessive perspiration, caused by autonomic
nervous system dysfunction [38], and some PD medications
can also affect sweating [38]. Excessive sweat might increase
the risk of skin irritation. However, the clinical trial of the
rivastigmine transdermal patch in patients with AD included a
number of countries with hot climates where heavy perspira-
tion may have been expected (for example, Chile, Taiwan and
Venezuela), and the patch exhibited a favorable skin tolera-
bility profile. This suggests that the rivastigmine patch may be
suitable for PDD patients despite increased perspiration.
4.3Cardiac safety
Studies have shown that the predominant effect on the heart
from the peripheral action of accumulated ACh is bradycardia.
All labels for marketed cholinesterase inhibitors include
warnings that cholinesterase inhibitors may have vagotonic

170 Expert Opin. Drug Saf. (2010) 9(1)

 Table 2. Most commonly-reported adverse events in clinical trials of rivastigmine in AD and PDD patients (reported in ‡ 10% patients).
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AD PDD

Rösler et al. [19] Corey-Bloom et al. [18] Feldman et al. [20] Winblad et al. [23] Emre et al. [22]

Placebo 6 – 12 mg/day Placebo 6 – 12 mg/day Placebo 2 – 12 mg/day 2 – 12 mg/day Placebo 9.5 mg/24 h Placebo 3 – 12 mg/day
(n = 239) capsules* (n = 234) capsules* (n = 222) b.i.d. capsules* t.i.d. capsules* (n = 302) patch (n = 179) capsules
(n = 242) (n = 231) (n = 228) (n = 227) (n = 291) (n = 362)

Nausea 10% 50% 11% (T), 48% (T), 20% (M) 14% 54% 48% 5% 7% 11% 29%
3% (M)
Vomiting 6% 34% 3% (T), 27% (T), 16% (M) 6% 39% 30% 3% 6% 2% 17%
Expert Opin. Drug Saf. (2010) 9(1)

2% (M)
For personal use only.

Diarrhea 9% 17% – – 9% 18% 17% 3% 6% 5% 7%

Weight – – 1% (T) 4% (T) – – – 1% 3% – –
decreased
Dizziness 7% 20% 13% (T), 24% (T), 14% (M) 7% 18% 17% 2% 2% 1% 6%
4% (M)
Tremor – – – – – – – – – 4% 10%
Anorexia 2% 14% 3% (T) 20% (T) 3% 21% 19% – – 3% 6%
Headache 8% 19% – – 10% 18% 16% 2% 3% – –
Abdominal 3% 12% – – 5% 15% 12% – – – –
pain
Fatigue 3% 10% 4% (T) 10% (T) – – – – – – –
Malaise 2% 10% 1% (T) 3% (T) – – – – – – –
Asthenia – – 2% (T) 10% (T) – – – 1% 2% – –
Hallucin- – – – – – – – – – 5% 10%
ations

*Two-weekly titration.
–: Not reported due to low occurrence or no difference in incidence compared with placebo.

Darreh-Shori & Jelic

AD: Alzheimer’s disease; b.i.d.: Twice a day; M: Maintenance phase; PDD: Parkinson’s disease dementia; T: Titration phase; t.i.d.: Three times a day.
171
 Rivastigmine
Patients reaching target dose at study endpoint (%)
100 95.9%
90
80
70
60
50
40
30
20
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10
0 ities of daily living, were seen regardless of whether exacerbation
Rivastigmine
9.5 mg/24 h
n = 241
Figure 1. Percentage of patients who reached maintenance
phase and achieved target dose at study end point in a
clinical trial of rivastigmine patch and capsule in patients
with AD [31].
AD: Alzheimer’s disease.
For personal use only.
effects on the sinoatrial and atrioventricular nodes, manifest-
ing as bradycardia or heart block in patients both with and
without known underlying cardiac conduction [15,39]. How-
ever, ECG data from the original rivastigmine Phase III
database showed that the majority of patients (‡ 82% in any
treatment group) demonstrated < 10 or 15% maximum percent
change from baseline in PR, QRS or QTc intervals [15,40].
Marked autonomic dysfunction is a common feature of PD,
and may be associated with increased mortality due to cardiac
effects such as lowered heart rate variability [41]. The cardiac safety
profile of rivastigmine capsules was, therefore, closely monitored
during the randomized, placebo-controlled clinical trial in PDD
patients. No clinically meaningful treatment differences in ECG
abnormalities were apparent in this study [42], and compared
with placebo, rivastigmine appeared to be associated with sig-
nificantly fewer vascular disorder adverse events (p = 0.002) and
fewer adverse events of syncope (p = 0.018) [42].
4.4 Motor function in PDD
PD is primarily a movement disorder, characterized by motor
symptoms such as tremor, rigidity and bradykinesia. Because
anticholinergic drugs are often used in the management of
tremor in patients with PD, concerns have been raised that the
use of cholinergic drugs for PDD might worsen the motor
symptoms associated with PD. During the double-blind trial of
rivastigmine capsules in PDD patients, the adverse event of
emerging or worsening tremor was reported in 10.2% of
patients in the rivastigmine group, compared with 3.9% in
the placebo group (p = 0.012) [22]. However, tremor appeared to
be transient and was most frequently reported during the
172
titration phase of rivastigmine treatment. In the open-label
extension phase of the study, in which all patients received
rivastigmine capsules, tremor was reported by 6.9% of patients:
3.8 and 12.2% of whom had previously received double-
blind rivastigmine and placebo, respectively (p = 0.006) [43].
64.4% Together, these findings suggested that first exposure to
rivastigmine leads to a transient increase in tremor.
Incidences of worsening parkinsonism, bradykinesia and
rigidity all occurred in < 5% of patients in each treatment group
during the double-blind phase, with no significant differences
detected between rivastigmine and placebo-treated patients [43].
Overall, during the full 48-week observation of rivastigmine
treatment, there was no evidence of adverse long-term motor
outcomes. Post hoc analyses showed that improvements in the
symptoms of dementia, including the ability to perform activ-
Rivastigmine
12 mg/day capsules of tremor was reported during the study [43].
n = 250 The risk of clinically significant exacerbation of motor
dysfunction in patients with PDD treated with rivastigmine
is very low. Nevertheless, physicians should remain vigilant
during the time of rivastigmine initiation and dose titration, as
transient increases in tremor may occur. There is no indication
that exposure to long-term rivastigmine is associated with a
worsening of PD.
4.5 Special populations
Patients with a body weight below 50 kg may experience
more gastrointestinal adverse events during rivastigmine
capsule therapy and are also more likely to discontinue
due to adverse events [15]. The risk may be reduced with
the rivastigmine patch compared with the capsules; in the
rivastigmine patch clinical trial, the percentages of patients
reporting at least one adverse event did not differ signifi-
cantly between the 9.5 mg/24 h patch and placebo groups in
patients weighing < 50 kg (Figure 3) [44]. Nevertheless, it is
recommended that weight should be monitored carefully
throughout the course of rivastigmine treatment, and par-
ticular caution should be exercised in titrating low weight
patients above the recommended maintenance dose of riv-
astigmine. Although the pharmacokinetics of rivastigmine do
not appear to be meaningfully different in Japanese healthy
volunteers compared with Caucasians, special attention
should be paid to ethnic groups who are more likely to
have low body weight, such as Japanese patients [45].
Hepatically- and renally-impaired patients should also be
monitored carefully during rivastigmine therapy, as their
condition affects the rate of clearance of rivastigmine from
the body [15]. However, dosage adjustment is not necessary as
rivastigmine is titrated to individual tolerability levels. Addi-
tionally, as with other cholinergic substances, rivastigmine
may cause increased gastric acid secretions, and so care should
be exercised in treating patients with active gastric or duodenal
ulcers. Cholinesterase inhibitors should be prescribed with
care to patients with a history of asthma or obstructive
pulmonary disease [15].
Expert Opin. Drug Saf. (2010) 9(1)
 Darreh-Shori & Jelic

Table 3. Incidence of gastrointestinal cholinergic adverse events with commonly-used cholinesterase inhibitors.

Data from transdermal patch clinical trial [23] Data from Aricept
label [53] Data from Razadyne ER

label* [54]

Rivastigmine Rivastigmine capsules Placebo Donepezil tablets Placebo Galantamine Placebo

patch 9.5 mg/24 h 6 – 12 mg/day (n = 302) 5 or 10 mg/day (n = 355) tablets 24 mg/day (n = 286)
(n = 291) (n = 294) (n = 747) (n = 273)

Nausea 7% 23% 5% 11% 6% 17% 5%

Vomiting 6% 17% 3% 5% 3% 10% 1%
Diarrhea 6% 5% 3% 10% 5% 6% 6%

*ER: Extended-release formulation.

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administered for the next 24 h. In overdose accompanied

by severe nausea and vomiting, the use of antiemetics should
be considered, and symptomatic treatment for other adverse
events should be given as necessary [15].

5. Conclusions

Rivastigmine is the only commonly-used cholinesterase inhib-

itor to inhibit both AChE and BuChE. Rivastigmine helps
relieve the symptoms of dementia associated with AD and
For personal use only.

PDD. Rivastigmine has a favorable safety profile, despite the

3.5 cm
Figure 2. Example of localized mild erythema following
administration of a medical transdermal patch.
4.6 Drug–drug interactions
Consistent with rivastigmine’s rapid metabolism and excretion,
studies in healthy volunteers did not show any pharmacokinetic
interactions between rivastigmine and other common drugs,
including digoxin, warfarin, diazepam and fluoxetine [15,46,47].
However, as a cholinesterase inhibitor, rivastigmine may exag-
gerate the effects of succinylcholine-type muscle relaxants
during anesthesia, and in view of its pharmacodynamic effects,
rivastigmine should not be given concomitantly with other
cholinomimetic drugs [15].
4.7 Overdose
Most cases of accidental overdosage of rivastigmine have not
been associated with any clinical signs or symptoms, and
almost all of the patients concerned continued rivastigmine
treatment [15]. Where symptoms have occurred, they have
included nausea, vomiting and diarrhea, hypertension or hallu-
cinations. It is recommended that in cases of asymptomatic
overdose, no further dose of rivastigmine should be
target populations having a high incidence of concomitant
disease and frequently taking concurrent medications. In PDD
patients, worsening of the motor symptoms of PD was
generally transient and not regarded as clinically meaningful.
The development of the transdermal patch has led to a
considerable improvement in the gastrointestinal tolerability
profile of rivastigmine. Transdermal delivery provides a
smoother, more continuous drug delivery profile, limiting the
fluctuations in plasma concentration seen with oral administra-
tion and resulting in a reduced incidence of cholinergic adverse
events such as nausea and vomiting. This allows more patients to
access higher doses of rivastigmine, potentially leading to
improved patient compliance. The rivastigmine patch may be
the optimal way to deliver rivastigmine in the treatment of AD.
6. Expert opinion
The rivastigmine patch is the first transdermal therapy for AD,
representing a valuable and effective new tool for the treat-
ment of the disease. Due to the improved tolerability profile
and easier access to optimal therapeutic doses, the rivastigmine
patch has become a first-line treatment option for AD in many
countries. Additional benefits of transdermal therapy over oral
administration include improved medication management, as
the patch provides visual reassurance that the medication has
been taken, is applied once-daily and there is only one titration
step to the target dose. In a caregiver questionnaire adminis-
tered during the clinical trial of the rivastigmine patch, care-
givers expressed greater overall satisfaction and less interference
with daily life with patches compared with capsules, and

Expert Opin. Drug Saf. (2010) 9(1) 173

 Rivastigmine

A. the presence of b-amyloid in combination with the AD risk

factor APOE e4, suggesting an interaction between BuChE
Patients reporting adverse events (%)

50 Extreme low weight (< 50 kg)

Medium weight (50 – 80 kg) and APOE e4 [10,11,50]. Further, other cholinesterase inhibitors
40 High weight (> 80 kg) have been shown to increase the protein levels of AChE
variants in the cerebrospinal fluid and possibly in the brain
* parenchyma, while rivastigmine does not appear to have this
30 27.3% ‡
23.4%
effect. In vitro studies have shown that such increases in AChE
* protein levels may accelerate the deposition of b-amyloid
20 18.6%
peptides in the brain [51,52]. These findings suggest – at least
hypothetically – that other cholinesterase inhibitors have the
9.1%
10 7.6%
5.6%
potential to cause increased b-amyloid deposition. Until we
4.4% 3.7% 2.4% have a better understanding of these findings and their long-
0 term consequences in vivo, rivastigmine may be a prudent
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Windsor on 08/29/14

12 mg/day 9.5 mg/24 h Placebo

treatment choice, because it has been accompanied with
rivastigmine rivastigmine
capsules patch minimal changes in protein levels of AChE and BuChE.
Another potential advantage of rivastigmine is derived from its
B.
pseudo-irreversible nature, making it possible to tailor the level of
Patients reporting adverse events (%)

50 cholinesterase inhibition for each patient. Usually, physicians

titrate the dose of cholinesterase inhibitors up to the recom-
40 mended dose, and monitor the clinical response. If there is no
response, further dose increases might be considered. However,
30 because the efficacy of rivastigmine is dose-related, monitoring
the actual plasma inhibition levels might allow physicians to
‡
20 18.8% select the most appropriate dose for each patient. This could be
For personal use only.

particularly valuable in patients with a low body weight who may

12.1% 11.6%
10
4.5%
0 Currently ongoing studies of rivastigmine include a large
12 mg/day
rivastigmine
capsules
Figure 3. Effect of body weight on incidence of nausea and
vomiting with rivastigmine capsule and transdermal
patch [44].
*p < 0.05.
‡
p £ 0.001.
p-values are based on Fisher’s exact test and compare rivastigmine treatment
versus placebo.
preferred rivastigmine patches to capsules overall [48].
Improved convenience and satisfaction for both patients and
caregivers may lead to better patient compliance to treatment,
and to patients staying on therapy for a longer period, resulting
in better overall outcomes. Rivastigmine patch is also approved
for the treatment of PDD in many countries. Due to the
similarities between PDD and Lewy body dementia, rivastig-
mine patch may also benefit patients with Lewy body disease;
however, this is not an approved indication.
In contrast to selective AChE inhibitors, inhibition of
BuChE with rivastigmine may provide additional long-term
benefits. Two independent studies have shown correlations
between BuChE inhibition and improvements in cognitive
test results [7,49]. In addition, emerging data have shown that
BuChE activity in the cerebrospinal fluid may be boosted by
have poorer tolerability. Measurement of enzyme inhibition
6.3% 6.7% following administration of rivastigmine is simple and inexpen-
4.3%
sive, and should not present difficulties for hospital laboratories.
0.0% 0.0%
9.5 mg/24 h Placebo
rivastigmine clinical trial of the transdermal patch and capsule to demon-
patch strate longer term safety in PDD patients, and a study in
patients with AD to investigate the efficacy of a higher patch
dose (13.3 mg/24 h) in patients who show a cognitive decline.
These results will provide valuable information on the benefits
of higher doses of rivastigmine that could not previously be
elucidated with the capsule due to tolerability issues. Future
studies are anticipated to provide further evidence that the
transdermal patch can improve compliance to therapy.
Currently there are several agents under development that
target the underlying disease pathology of AD, which may offer
more substantial disease modification. Many of these therapies
are targeted at b-amyloid formation or aggregation. In the
future, combinations of these disease-modifying agents with
symptomatic treatments may become the optimal therapeutic
regimen. In particular, rivastigmine, due to its potential effect
on disease pathology, may be an ideal partner for combination
therapy with specific disease-modifying agents.
Declaration of interest
Novartis sponsored Alpha-Plus Medical Communications Ltd
(UK) to provide writing and editorial assistance with this
manuscript. The authors approved the final version of this
article and take full responsibility for the contents. The
authors have no conflicts of interest to disclose.

174 Expert Opin. Drug Saf. (2010) 9(1)


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Affiliation
Taher Darreh-Shori†1 PhD & Vesna Jelic2 PhD
†
Author for correspondence
1
Karolinska University Hospital,
Karolinska Institute,
Department of Neurobiology,
Care Sciences and Society,
Division of Alzheimer Neurobiology,
Novum, 4th Floor,
Room 4F23:10, 141 86,
Huddinge, Stockholm,
Sweden
Tel: +46 8585 836 12; Fax: +46 8585 854 70
E-mail: taher.darreh-shori@ki.se
2
Karolinska University Hospital,
Karolinska Institute,
Department of Neurobiology,
Care Sciences and Society,
Alzheimer Disease Research Centre, 141 86,
Huddinge, Stockholm,
Sweden