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Galantamine in Alzheimer’s
disease
Expert Rev. Neurotherapeutics 8(1), 9–17 (2008)

George Razay† and
Gordon K Wilcock
† leading to increased cholinergic neurotransmission in the CNS. Galantamine has a large volume
Author for correspondence
Launceston General Hospital,
School of Medicine,
University of Tasmania,
Launceston, Tasmania 7250,
Australia
Tel.: +61 363 487 111
Fax: +61 363 487 577
george.razay@dhhs.tas.gov.
au
Galantamine is a cholinesterase inhibitor with a dual mechanism of action. It is a reversible inhibitor
of acetylcholine esterase and enhances the intrinsic action of acetylcholine on nicotinic receptors,
clearance, low plasma protein binding and a high bioavailability. Short-term, double-blind, placebo-
controlled studies have shown that treatment with galantamine produces small improvements on
cognitive tests and global measures of change in selected patients with mild to moderately severe
Alzheimer’s disease. A dose of 16–24 mg/day appears to be the most efficacious, and is the licensed
maintenance dose range in most territories. The magnitude of the treatment effect is similar to that
of other cholinesterase inhibitors. Adverse events experienced by patients treated with galantamine
are usually mild, gastrointestinal and may improve with dose reduction.
KEYWORDS: Alzheimer’s disease • cholinesterase inhibitor • dementia • galantamine

Alzheimer’s disease (AD) is a chronic, progressive 6H-benzofuro[3a,3,2-ef ][2]benzazepin-6-ol

neurodegenerative disorder with an insidious
onset and prolonged course. It is the most com-
mon cause of dementia. The prevalence of AD has
been shown to double every 5 years in patients
over the age of 60 years. It afflicts an estimated
10% of individuals over the age of 65 years. A
recent delphi consensus study estimated that 24
million people had dementia worldwide in 2001,
and this figure is expected to double to 42 million
by 2020 [1]. AD reduces life expectancy, increases
years lived with disability and dramatically reduces
the quality of life (QoL) of patients and their fam-
ilies. In addition, it can pose a major economic
burden for families and the country [2,3].
There is no cure for AD and most of the avail-
able treatment has been based on providing
symptomatic treatment. The well-established
deficits in the cholinergic system in AD led to the
development of the cholinesterase inhibitors
(ChEIs) tacrine, donepezil, rivastigmine and gal-
antamine [4]. ChEIs have been the most widely
investigated and are the first drugs to be licensed
for the symptomatic treatment of mild to moder-
ately severe AD [5]. This article reviews the effi-
cacy of galantamine (Reminyl®, Razadyne™) in
mild-to-moderate AD.
Chemistry
Galantamine hydrobromide, (4aS, 6R,8aS)-
4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-
hydrobromide (FIGURE 1), is a tertiary alkaloid orig-
inally derived from bulbs of the Amaryllidaceae
family of plants, which include daffodils and the
common snowdrop (Galanthea woronowii). Gal-
antamine has three chiral centers; both the base
compound and its hydrobromide salt are levo-
rotatory. Galantamine can be synthetically pre-
pared in racemic or in enantiomerically pure
form, via two key reaction protocols, the phenol
oxidative coupling reaction and an intramolecu-
lar Heck reaction, with the first being used more
for industrial scale synthesis of the drug [6–8].
Pharmacodynamics
Galantamine is a ChEI with a dual mechanism
of action. It is a selective, reversible and competi-
tive inhibitor of acetylcholinesterase (AChE) [9],
the enzyme responsible for the breakdown of the
neurotransmitter acetylcholine (ACh) into ace-
tate and choline. This leads to increased concen-
trations of ACh in the synaptic cleft, and
enhanced cholinergically mediated neuro-
transmission, which can ameliorate some of the
cognitive deficits in AD.
In addition, galantamine acts as an allosteric
modulator of the neuronal nicotinic acetylcho-
line receptors (nAChRs), which have been shown
to be reduced in AD, and act synergistically with
ACh to increase nAChRs activation [6,10]. In vivo
human and animal studies have shown that

www.future-drugs.com 10.1586/14737175.8.1.9 © 2008 Future Drugs Ltd ISSN 1473-7175 9

 Drug Profile Razay and Wilcock
inhibition of nicotinic receptors impairs cognition, whereas selec-
tive positive stimulation or modulation on nicotinic receptor
subtypes improves cognitive function and memory [8,11–13].
Studies have also shown that galantamine enhances the release
of glutamate, serotonin, dopamine and γ-aminobutyric acid
(GABA) via modulation of the nAChRs activity. The release of
these neurotransmitters may contribute to psychological and
behavioral improvement in AD regarding anxiety, disinhibition
and hallucinations [10,14]. These galantamine effects may be the
basis for the improvement of behavior seen in some AD patients,
since dopamine and serotonin, as well as ACh, are involved in
these symptoms.
Pharmacokinetics & metabolism
Galantamine has a low clearance (plasma clearance of
∼300 ml/min), a moderate volume of distribution and a low
plasma protein binding (18%). The disposition of galantamine is
biexponential, with a terminal half-life in the order of 7–8 h [15].
The pharmacokinetics of galantamine are linear over the recom-
mended daily dose range of 8–24 mg/day for the immediate-
release formulation. Galantamine prolonged-release capsules (max-
imum maintenance dose: 24 mg/day; also available as 8- and
16-mg doses) are bioequivalent to the immediate-release tablets
(12 mg twice daily) with respect to AUC24h and Cmin at steady
state.
Absorption
Immediate-release tablets
Galantamine is rapidly absorbed and reaches peak plasma con-
centrations with a Tmax of approximately 1–2 h. The absolute
bioavailability of galantamine is high and co-administration of
food has little effect on galantamine absorption, delaying the
rate (Tmax ) and reducing Cmax by approximately 25%, without
affecting the extent of absorption (AUC).
Prolonged release capsules
Galantamine is well absorbed with a peak plasma concentration
(Tmax) of approximately 4.4 h.
Metabolism
Galantamine is primarily metabolized in the liver to clinically
inactive metabolites by the cytochrome P-450 isoenzymes 2D6
(CYP2D6) and 3A4 (CYP3A4) [15,16]. Drugs that substantially
inhibit CYP3A4 and CYP2D6, such as paroxetine, ketocona-
zole and erythromycin, could increase galantamine concentra-
tions, and dose reductions may be considered in patients taking
CYP3A4- or CYP2D6- inhibiting drugs.
Excretion
Renal clearance of galantamine after oral administration
accounts for approximately 20–25% of total plasma clearance and
elimination of galantamine decreases with decreased creatinine
clearance [15].
10
The metabolism of galantamine has been shown to be
reduced in patients with renal and/or hepatic impairment, and
dose reductions have been recommended.
Clinical efficacy
Seven large, randomized, double-blind, placebo-controlled stud-
ies have been published (TABLE 1). Patients who were selected had
a diagnosis of probable AD according to the National Institute
of Neurologic and Communicative Disorders and Stroke and
the Alzheimer’s Disease and Related Disorders Association
(NINCDS-ADRDA) criteria [17], with mild-to-moderate
dementia defined as a Mini-Mental State Examination (MMSE)
score of 10–24, and an Alzheimer’s Disease Assessment Scale,
cognitive subscale (ADAS-cog) score of 12 at baseline [18]. Other
causes of dementia were excluded. More than 4500 patients
were randomized to take various maintenance doses of galan-
tamine ranging from 8 to 36 mg/day (the majority took
24–32 mg/day) over 3–6 months.
Efficacy measures
Improvement of symptoms was assessed in several domains:
• Cognitive function as measured by the ADAS-cog, which
assesses memory, attention, language, praxis and orientation
[18]. The ADAS-cog scale ranges from 0 to 70 with higher
scores indicating greater cognitive impairment.
• A global clinical assessment was measured by the Clinician’s
Interview Based Impression of Change plus Caregiver Input
(CIBIC-plus), which measures overall improvement or deteri-
oration of cognitive function and activity of daily living [19].
Scores range from 1 to 7 (1, markedly improved relative to
baseline; 4, no change; 7, markedly worse).
• Patients’ activities of daily living (ADL) were assessed by the
Disability Assessment for Dementia scale (DAD) [20] or the
Alzheimer Disease Cooperative Study-Activities of Daily Liv-
ing inventory (ADCS-ADL) [21]. These scales assess three cat-
egories of daily living: the basic ADLs comprise dressing,
hygiene, continence and eating; the instrumental ADLs con-
sist of meal preparation, telephoning, housework, taking care
of finance and correspondence, and the ability to safely stay
at home; and leisure activities. The maximum score on the
DAD is 100 and ADCS-ADL is 78. Lower scores indicate
greater functional impairment.
• Behavioral symptoms were assessed in some studies and uti-
lized the Neuropsychiatric Inventory (NPI) [22]. This
parameter covers ten domains of behavior, including hallu-
cination, delusion, agitation/aggression, dysphoria, anxiety,
euphoria, apathy, disinhibition, irritability and aberrant
motor behavior. In addition to assessing the severity and fre-
quency of each symptom, the NPI also assesses the amount
of caregiver distress engendered by each of the symptoms.
The maximum score of the NPI is 120, lower scores indicate
improvement.
Expert Rev. Neurotherapeutics 8(1), (2008)

O H
O the placebo group. Galantamine doses of 8 mg/day [26] and
OH
N 24 mg/day [25] and 24–32 mg/day [24] failed to show a statistically
Figure 1. Galantamine.
Clinical efficacy was assessed using several outcome mea-
sures, although the ADAS-cog and CIBIC-plus were the main
primary outcomes assessed in most studies.
Clinical studies
A recent Cochrane review of galantamine in AD has been pub-
lished [23]. In this review, we only report the results from the
intention-to-treat data, which was calculated using the last
observation carried forward (LOCF) method.
Effects of galantamine on cognition
A statistically significant difference favoring galantamine treat-
ment was detected between treatment groups in the mean change
from baseline on the ADAS-cog scale at 3 months [24,25], 5 [26]
and 6 months [27–30] of treatment. In the 6-month trials, there
was statistically significant improvement in the mean change
from baseline on the ADAS-cog for patients who received galan-
tamine 8 mg/day (weighted mean difference [WMD]: 1.3 points;
95% confidence interval [CI]: 0.03–2.6) [26], 24 mg/day (WMD:
3.1 points; 95% CI: 2.6–3.7) [26–29] and 32 mg/day (WMD: 3.3
points; 95% CI: 2.4–4.1) [27,28], compared with patients who
received placebo, who experienced cognitive decline. Similar
findings were observed in patients who received galantamine
prolonged release 16–24 mg/day (WMD: 2.5 points; 95%
CI: 1.6–3.4) [30]. In the 3-month trials, there was improvement
in the mean change from baseline on the ADAS-cog for patients
who received galantamine 16–24 mg/day (WMD: 2.7 points;
95% CI: 1.9–3.6), 16–24 mg/day prolonged release (WMD: 1.8;
95% CI: 0.9–2.7) [30], 24 mg/day (WMD: 3.0 points; 95%
CI: 0.8–5.2) [25], 24–32 mg/day (WMD: 1.7 points; 0.6–2.8) [24]
or 36 mg/day (2.3; 0.4–4.2) [25].
Effects of galantamine on global response
The global rating results were significantly better in patients
treated with galantamine (16–32 mg/day), compared with
patients receiving placebo. More patients remained stable or
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Galantamine Drug Proflie
improved on the CIBIC-plus scores over 6 months treatment
with galantamine 16 mg/day (odds ratio [OR]: 2.0; 95% CI:
1.4–2.9) [26], 24 mg/day (OR: 1.9; 95% CI: 1.6–2.3) [26–29] or
32 mg/day (OR: 1.8; 95% CI: 1.3–2.4) [27,28], compared with
16–24 mg/day (twice daily or prolonged release) [30] failed to
show any significant effects. In the 3-month trials, there were sta-
tistically significant effects in favor of treatment with galan-
tamine 18 mg/day (OR: 2.4; 95% CI: 1.2–5.0) and 36 mg/day
(OR: 2.7; 95% CI: 1.2–6.2) [25], but galantamine doses of
significant effect.
Effects of galantamine on ADCS-ADL & DAD
Patients who were treated with galantamine were more likely to
maintain their functional ability. In one 5-month trial, there was
statistically significant improvement in the mean change from
baseline on the ADCS-ADL for patients who received galan-
tamine 16 mg/day (WMD: 3.1 points; 95% CI: 1.6–4.6) and
24 mg/day (WMD: 2.3 points; 95% CI: 0.6–4.0), compared
with patients who received placebo [26]. An analysis of the change
in the DAD score demonstrated that there was a statistically sig-
nificant improvement in the mean change from baseline for
patients who received galantamine 24–32 mg/day in a 3-month
trial (WMD: 4.8 points; 95% CI: 2.1–7.6) [24], and galantamine
24 mg/day (WMD: 3.7 points; 95% CI: 1.4–5.9) [27,29], galan-
tamine 32 mg/day (WMD: 3.5 points; 95% CI: 0.5–6.5) [27] in
the 6-month trials.
Effects of galantamine on behavior
Galantamine stabilized behavior in one study [26]. At 5 months,
patients receiving galantamine 16 mg/day showed significant
benefit in behavioral symptoms, as indicated by the difference in
mean change from baseline in NPI score between the galan-
tamine-treated group and placebo (WMD: 2.1 points; 95% CI:
0.2–4.0) [26]. However, no statistically significant treatment
effect was found at 3 months for patients receiving
24–32 mg/day [24], and at 6 months for 8 mg/day [26],
24 mg/day [26,29] and 16–24 mg/day twice daily or prolonged
release [30].
Long-term studies
There are no long-term, double-blind placebo-controlled studies
on the efficacy of galantamine. However, there are two open-
labeled extension studies, each without a placebocontrolled arm.
The placebo effect was estimated with the Stern equation [31].
The cognitive decline in patients was compared with mathe-
matical modeling of cognitive decline in untreated patients.
Patients who were treated with galantamine had less deteriora-
tion on cognitive function based on ADAS-cog scores, com-
pared with mathematically predicted deterioration in untreated
patients after 3 years [32,33]. Although the first 6–12 months of
galantamine therapy appear to provide some protection against
11
 Drug Profile Razay and Wilcock

Table 1. Phase III randomized, double-blind placebo-controlled clinical studies in Alzheimer’s disease.
Study Treated Duration Dose (mg/day) Inclusion criteria Efficacy measures Ref.
patients (months)

Wilkinson 285 3 6, t.i.d. MMSE 13–24 ADAS-cog [25]

(2001) 8, t.i.d. CIBIC-plus
12, t.i.d. IADL

Rockwood 386 3 12, b.i.d. MMSE 11–24 ADAS-cog [24]

(2001) 16, b.i.d. ADAS-cog >11 ADCS-CGIC
DAD
NPI

Tariot (2000) 978 5 4, b.i.d. MMSE 10–22 ADAS-cog [26]

8, b.i.d. ADAS-cog >17 ADCS-ADL
12, b.i.d. NPI

Raskind 636 6 12, b.i.d. MMSE 11–24 ADAS-cog [28]

(2000) 16, b.i.d. ADAS-cog >11 ADCS-CGIC
DAD

Wilcock 653 6 12, b.i.d. MMSE 11–24 ADAS-cog [27]

(2000) 16, b.i.d. ADAS-cog >11 ADCS-CGIC
DAD

Brodaty 971 7 8–12, b.i.d. MMSE 10–24 ADAS-cog/11 [30]

(2005) 8–12, PR ADAS-cog11 ≥18 CIBIC-plus ADCS-ADL
NPI

Erkinjuntti 592 7 12, b.i.d. MMSE 10–24 ADAS-cog [29]

(2002) CIBIC-plus
DAD
NPI

ADAS-cog: Alzheimer’s Disease Assessment Scale, cognitive subscale; ADCS-CGIC: AD Cooperative Study – Clinical Global Impression of Change; b.i.d.: Two-times
daily; CIBIC-plus: Clinician’s Interview Based Impression of Change plus Caregiver Input; DAD: Disability Assessment for Dementia scale; IADL: Instrumental activities of
daily living; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; PR: Prolonged release; t.i.d.: Three-times daily.

deterioration of ADL, in patients with mild-to-moderate AD,
DAD scores began to deteriorate after 12 months of galan-
tamine treatment [33]. Moreover, a recent open-label, long-term
extension (up to 48 months) trial suggests that patients with
AD show variable long-term cognitive and functional decline:
ranging from very little, quite marked and in between. Patients
with the least initial impairment showed the least decline [34].
However, these open-labeled studies must be interpreted
cautiously because they were not conducted in a double-blind
controlled manner and are thus subject to bias in reporting.
Comparison between ChEIs
There have been several reviews comparing galantamine with
other ChEIs, including donepezil and rivastigmine.
Cochrane reviews of all ChEIs, including galantamine, con-
cluded that all ChEIs result in significant overall benefit for
patients with mild to moderately severe AD, with specific
improvement in cognition and global status for at least
6 months [23]. However, a recent meta-analysis of the three
ChEIs by Kaduszkiewicz et al. concluded that although there
were significant differences between patients treated with any
of the ChEIs and placebo, indicating a beneficial effect of
ChEIs, the benefits were minimal and the methodological
quality of the studies was poor [35]. This study conclusion is at
odds with all previous reviews, which report a clinical benefit
for ChEIs [23,36–39]. Several researchers have criticized Kaduszk-
iewicz and colleague’s review and responded to the points they
raised. First, the criticism of the failure of analyses to correct for
multiple testing is misplaced and rests on their mis-
understanding of trial methodology [101,102]. Examination of the
Cochrane meta-analyses shows that the effect of ChEIs would
remain statistically significant even if Bonferroni corrections
(which is the most conservative of several post hoc adjustments
for multiple comparisons) were applied to the multiple pooled
outcomes in the meta-analysis [101]. Second, Kaduszkiewicz

12 Expert Rev. Neurotherapeutics 8(1), (2008)

 Galantamine Drug Proflie

et al. were also critical about the use of the LOCF approach to
address missing data; other reviews (e.g., Cochrane Reviews)
examined this issue carefully and also utilized a retrieved drop-out
analysis [101–103].
There was also a debate on the cost–effectiveness of ChEIs,
and attempts to apply health economic analysis in terms of the
quality-adjusted life year (QALY) to people with dementia [40].
However, measures of QoL for people with dementia are few
and many are not validated [41,42]. One approach is to record the
time until patients with AD require full-time care. One study
suggested that treatment with galantamine delayed the time
before patients required full-time care by almost 10%, resulting
in savings especially in patients with moderate disease [43].
A recent cost–effectiveness analysis of all ChEIs suggests that
treatment with galantamine, donepezil or rivastigmine reduces
the mean time spent in full-time care (i.e., delays the progres-
sion of AD) by 1.4–1.7 months (over a 5-year period). Cost sav-
ings associated with this reduction do not seem to offset the cost
of treatment sufficiently to make treatment cost effective [39].
More recently, an independent analysis of ChEIs concluded
that those with moderate AD (defined by a MMSE score of
10–20) showed a substantially greater cognitive response than
those with mild disease, and this could bring QALY estimates
within the cost-effective range [104].
Galantamine in mild cognitive impairment
In two randomized, placebo-controlled trials of 2 years’ duration
in subjects with mild cognitive impairment (MCI), there was no
statistical significant treatment effect on cognition as assessed by
ADAS-cog and ADL measures at 24 months. However, there was
less conversion to dementia (change of the Clinical Dementia
Rating [CDR] score from 0.5 to ≥1) [44] for patients who received
galantamine 12–24 mg/day, compared with patients who
received placebo at 24 months in the two trials combined (15 vs
20%; OR: 0.74; 95% CI: 0.6–0.9) [23,105,106].
Safety & tolerability
Galantamine appears to be well tolerated. Most of the reported
adverse events (AEs) were mild to moderate in severity and
were related to cholinergic stimulation. The incidence of these
AEs was greater in the treatment group than in the placebo
group, with a probable dose–response effect [23,26–30]. The
majority of AEs occurred during dose escalation. The most
common AEs were gastrointestinal (nausea, vomiting, diarrhea,
abdominal pain and dyspepsia), and tended to resolve on con-
tinuing treatment (TABLE 2). Other AEs included anorexia, weight
loss, headache, dizziness, insomnia, confusion, agitation, uri-
nary tract infection, tremor and syncope, and rarely, severe
bradycardia [15]. Withdrawals due to AEs tended to be higher
for participants receiving galantamine than placebo over
6 months at a daily dose of 24 mg (25 vs 16%; OR: 1.7; 95%
CI: 1.3–2.2) [26–28], and 32 mg (34 vs 16%; OR: 2.6; 95% CI:
1.9–3.5) [27,28].
AEs from clinical trials and post-marketing experience that
have been reported in patients treated with galantamine include
depression, hypertension, asthenia, fever and malaise [15].
There was no evidence of an increased risk of mortality in the
galantamine-treated groups compared with placebo groups in
short-term studies. However, data from the two MCI trials
found significantly higher mortality in the galantamine groups
[105,106]. The deaths were due to various causes that may be
expected in an elderly population and approximately half of the
galantamine deaths appeared to result from various vascular
causes and sudden death.

Table 2. Percentage of patients with adverse events on galantamine (placebo) in Phase III clinical studies
in Alzheimer’s disease.
Galantamine Number of patients % of patients with adverse events Ref.
dose Galantamine Placebo Nausea Vomiting Diarrhea Anorexia Weight Dizziness
loss
8 mg/day 140 286 6 (5) 4 (1) 5 (6) 6 (3) 0 (0) 0 (0) [26]

16 mg/day 279 286 13 (5)* 6 (1)* 12 (6)‡ 7 (3) 0 (0) 0 (0) [26]

24 mg/day 705 714 29 (9)* 17 (6)* 8 (6) 10 (6)‡ 10 (3)* 12 (8)‡ [26–28]

32 mg/day 429 427 42 21 (8)* 16 (9)* 15 (3)* 8 (3)* 15 (8)* [27,28]

(25)*
16–24 mg/day 326 320 14 (5)* 9 (2)* 7 (7) 7 (3)‡ 5 (1)‡ 7 (4) [30]

16–24 mg/day 319 320 17 (5)* 7 (2)* 5 (7) 10 (6)‡ 4 (1)‡ 10 (4)‡ [30]
prolonged release
*p < 0.001
‡
p < 0.05

www.future-drugs.com 13
 Drug Profile Razay and Wilcock
Safety and tolerability data from two open-label extension
studies over 36 months of treatment suggested that galan-
tamine was well tolerated [32,33]. Most AEs were mild to moder-
ate in severity. The most common AEs in the two trials com-
bined, were agitation (20%), insomnia (13%), depression
(15%), falls (13%) and urinary tract infection (11%).
Dosage & administration
Galantamine can be administered as prolonged-release capsules
once daily or immediate-release tablets twice daily. The recom-
mended starting dose is 8 mg/day for 4 weeks. The initial main-
tenance dose is 16 mg/day and patients should be maintained
on this dose for at least 4 weeks. An increase to the maximum
recommended maintenance dose of 24 mg/day should be con-
sidered after appropriate assessment, including evaluation of
clinical benefit and tolerability [15].
Regulatory affairs
Galantamine has been approved for the treatment of mild to
moderately severe AD in many countries, including Europe,
North America and Australia. In Australia, the use of ChEIs,
including galantamine, is approved for the initial treatment of
mild to moderately severe AD, with up to 6 months’ therapy
provided. However, confirmation of the diagnosis must be
made by a specialist with written confirmation that includes an
MMSE score. The baseline MMSE must be a score of 10 or
more, and if the score is at least 25 points, the result of the base-
line ADAS-cog must also be specified. Continuation of treat-
ment, following initial therapy, will be based on demonstrating
improvement in cognitive function, as measured by an increase
of at least 2 points from baseline on the MMSE, or a decrease of
at least 4 points from baseline on the ADAS-cog for patients
with an MMSE baseline score of at least 25 points [45].
In the UK, the original National Institute for Health and
Clinical Excellence (NICE) guidelines in 2001 approved the
use of ChEIs, including galantamine, for the treatment of mild
to moderately severe AD (defined by an MMSE score of ≥12).
The treatment was only to be continued in those deemed to be
responders at 3 months, in terms of cognitive improvement or
stability combined with some measure of functional or behav-
ioral improvement. However, NICE has recently reviewed its
guidelines and recommends their use for moderate stages of
AD only (i.e., for those with an MMSE score of between 10
and 20 points). In addition, each patient should be reviewed
every 6 months, including an MMSE score and global, func-
tional and behavioral assessment. The ChEI should be contin-
ued while the patient’s MMSE score remains at or above 10
points, and their global, functional and behavioral condition
remains at a level where the drug is considered to be having a
worthwhile effect [104].
Galantamine has been approved by the US FDA for first-line
use in patients with mild to moderately severe AD.
14
Conclusion
Galantamine is a ChEI with a dual mechanism of action. It is a
reversible inhibitor of AChE and enhances the intrinsic action of
ACh on nicotinic receptors. Short-term, 3–6-month, double-
blind, placebo-controlled trials of galantamine in the treatment
of mild to moderately severe AD have demonstrated efficacy on
cognitive tests and global rating, but mixed results were reported
on measurements of functionality and behavior. There have been
no long-term, placebo-controlled studies, and our knowledge is
mainly based on open-labeled trials that are difficult to interpret.
A dose of 16–24 mg/day appears to be the most efficacious. The
prolonged-release, once-daily formulation of galantamine was
found to have a similar efficacy and side-effect profile as the
equivalent twice-daily regime. The magnitude of the treatment
effect appears to be similar to other ChEIs, including donepezil
and rivastigmine. The adverse events are usually mild, reversible,
cholinergic-induced and often gastrointestinal in nature, such as
nausea, vomiting and diarrhea.
Expert commentary
Galantamine, similar to other ChEIs, produces small improve-
ments on cognitive tests and global measures of change in
selected patients with mild-to-moderate AD over a period of
6 months. Patients who experience some benefit might go on
long-term treatment; however, the optimum duration of
treatment is uncertain and patients will require regular reviews.
A number of questions still need to be addressed. These
include the use of a different ChEI if galantamine is not effective
in a particular patient, and the effect of withdrawing treatment
when it appears that galantamine may be ineffective. Moreover,
there is lack of good QoL, cost–effectiveness data and head-to-
head comparisons between different ChEIs, although a few
industry sponsored trials, which generally support the sponsoring
company’s product, have been undertaken. A recent randomized,
rater-blinded, head-to-head trial found significant advantages in
treatment response to donepezil compared with galantamine on
cognition and ADL [46]. However, the study was criticized for the
short duration of the trial (3 months), poor methodological
design, the lack of clearly validated outcome measures and the
inconsistency of previous donepezil literature [47]. The cholin-
ergic hypothesis, which suggests that the cognitive impairment of
AD is due to a disorder predominantly affecting cholinergic neu-
rones, led to the development of ChEIs. However, cholinergic
enhancement therapy has produced only modest results. This
could be partly explained by the multiple neurotransmitter defi-
cits in AD, including disruption of glutamatergic, serotoninergic,
dopaminergic and noradrenergic systems, all of which might
contribute to cognitive decline in AD. It has been shown that, in
AD, continuous stimulation of NMDA receptors by glutamate
triggers neurodegeneration [48]. This has led to the development
of NMDA receptor antagonists, such as memantine, which have
been shown to be effective in moderate-to-severe AD [49,50].
Expert Rev. Neurotherapeutics 8(1), (2008)
 Galantamine Drug Proflie

Recent clinical trials have shown that co-administration of
memantine with ChEIs (donepezil or rivastigmine) results in
better outcomes than either of these drugs alone [51,52]. However,
to date, there have not been clinical trials of galantamine with
memantine, in particular. Recent in vitro studies suggest that gal-
antamine potentiates NMDA receptors [53], and memantine
blocks nAChRs [54]. However, co-administration of galantamine
and memantine has been shown to have an additive or synergis-
tic efficacy [53]. Thus, co-administration of galantamine and
memantine merits further clinical trials.
Five-year view
AD is now recognized as a multigenetic disorder and has several
risk factors that might contribute to its development. This may
account for some of the interindividual variation in treatment
responses in many drug trials. Group treatment effects can
appear modest because a very positive response in a subgroup of
patients may be masked by the nonresponse of others. In addi-
tion, AD patients treated with galantamine showed variable
long-term decline over 48 months, approximately a third of
patients showed little decline, while a third showed important
decline [34]. However, to date, no distinguishing characteristics
have been identified to help predict which patient will benefit,
but this should remain one of the goals of drug trials. Future
treatment of AD will probably include combinations of treat-
ments with different modes of action, which will have a broad
effect across different systems and some of which may be effec-
tive at neuroprotection. Examples include drugs that inhibit the
production and accumulation, or increase the clearance, of the
toxic β-amyloid, and also reduce tau hyperphosphorylation and
tangle formation in the brain.
However, new treatments for AD will first have to demon-
strate worthwhile improvements in the progression of disability,
behavior, patient and caregiver health-related QoL, health
resource use, institutionalization or a combination of these
before application to the regulatory bodies for a license.
Financial & competing interests disclosure
GK Wilcock has received honoraria from the companies that have been
involved in the production and development of galantamine, and has been
the principal investigator for two clinical trials involving galantamine.
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Galantamine is effective in improving cognition and global rating in some patients with mild to moderately severe
Alzheimer’s disease.
• Patients should be reviewed to assess the efficacy of the treatment, and a trial of treatment withdrawal should be considered
if the drug appears to be ineffective.
• Adverse events are mild, mainly gastrointestinal and may improve with dose reduction.

of geriatric memory dysfunction. 9 Maelicke A, Albuquerque EX.

References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 Ferri CP, Prince M, Brayne C et al.
Global prevalence of dementia:
a Delphi consensus study. Lancet 366,
2112–2117 (2005).
2 World Health Organisation.
World Health Report 2003 – Shaping the
Future. WHO, Geneva, Switzerland
(2003).
3 Coma-Herrera A, Wittenberg R,
Pickard L, Knapp M. MRC-CFAS.
Cognitive impairment in older people:
its implications for future demands for
services and costs. In: Report to the
Alzheimer’s Research Trust, PSSRU
Discussion Paper. London School of
Economics, London, UK 1728, (2005).
4 Bartus RT, Dean RL III, Beer B,
Lippa AS. The cholinergic hypothesis
Science 217, 408–414 (1982)
5 Cummings JL. Use of cholinesterase
inhibitors in clinical practice: evidence-
based recommendation. Am. J. Geriatr.
Psychiatry 11, 131–145 (2003).
6 Kueenburg B, Czollner L, Froehlich J,
Jordis U. Development of a pilot scale
process for the anti-alzheimer drug
(-)-galanthamine using large-scale
phenolic oxidative coupling and
crystallisation-induced chiral conversion.
Org. Progress Res. Dev. 3, 425–431
(1999).
7 Marco-Contelles J, doCarmo Carreiras MDC,
Rodriguez C et al. Synthesis and
pharmacology of galantamine.
Chem. Rev. 106, 116–133 (2006).
•• Provides historical accounts of the
development of galantamine.
8 Farlow MR. Clinical pharmacokinetics of
galantamine. Clin. Pharmacokinet. 42(15),
1383–1392 (2003).
New approach to drug therapy in
Alzheimer’s dementia. Drug Disc. Today
1, 53–59 (1996).
10 Samochocki M, Hoffle A, Fehrenbacher A
et al. Galantamine is an allosteric
potentiating ligand of neuronal nicotinic
but not of muscarenic acetylcholine
receptors. J. Pharmacol. Exp. Ther. 305,
1024–1036 (2003).
11 Arthur D, Levin ED. Chronic inhibition of
α4β2 nicotinic receptors in the ventral
hippocampus of rats: impacts on memory
and nicotine response. Psychopharmacology
16, 140–145 (2002).
12 Levin ED, Rezvani AH. Development of
nicotinic drug therapy for cognitive disorders.
Eur. J. Pharmacol. 393, 141–146 (2000).
13 Woodruff-Pak DS, Vogel RW, Wenk GL.
Galantamine: effect on nicotinic receptor
binding, acetylcholinesterase inhibition,
and learning. Proc. Natl Acad. Sci. USA 98,
2089–2094 (2001).

www.future-drugs.com 15
 Drug Profile Razay and Wilcock
14 Albuquerque EX, Pereira EF, Mike A
et al. Neuronal nicotinic receptors
in synaptic functions in human and
rats: physiological and clinical relevance.
Behav. Brain Res. 113, 131–141 (2000).
15 Reminyl® (galantamine), product
information. Janssen–Cilag Pty Ltd, NSW,
Australia (2007).
16 Bachus R, Bickel U, Thomsen T et al.
The O-demethylation of the anti-dementia
drug galantamine is catalysed by
cytochrome P450 2D6. Pharmacogenetics 9,
661–668 (1999).
17 McKhann G, Drachman D, Folstein M
et al. Clinical diagnosis of Alzheimer’s
disease: report of the NINCDS-ADRDA
work group under auspices of Department
of Health and Human Services Task Force
on Alzheimer’s disease. Neurology 4,
939–944 (1984).
18 Rosen W, Mohs R, Davis K. A new rating
scale for Alzheimer’s disease. Am. J.
Psychiatry 141, 1356–1364 (1984).
19 Schneider LS, Olin JT, Doody RS et al.
Validity and reliability of the Alzheimer’s
Disease Cooperative Study-Clinical Global
Impression of Change (ADC-CGIC).
Alzheimer Dis. Assoc. Disord. 11, S22–S32
(1997).
20 Gelinas I, Gauthier L. McIntyre M et al.
Development of a functional measure for
persons with Alzheimer’s disease: the
disability assessment for dementia. Am. J.
Occup. Ther. 53, 471–481 (1999).
21 Galasko D, Bennet D, Sano M et al.
Alzheimer’s Disease Cooperative Study:
an inventory to assess activities of daily
living for clinical trials in Alzheimer’s
disease. Alzheimer Dis. Assoc. Disord. 11,
S33–S39 (1997).
22 Cummings JL. The Neuropsychiatric
Inventory: assessing psychopathology in
dementia patients. Neurology 48(Suppl. 6),
S10–S16 (1997).
23 Loy C, Schneider L. Galantamine for
Alzheimer’s disease and mild cognitive
impairment (review). Cochrane Database
Sys. Rev. (1)CD001747 (2006).
•• Comprehensive analysis of clinical efficacy
and adverse events using observed cases
and intention-to-treat analyses.
24 Rockwood K, Mintzer J, Truyen L et al.
On behalf of the Galantamine
International-2 Study Group. Effects of a
flexible galantamine dose in Alzheimer’s
disease: a randomised, controlled trial.
J. Neurol. Neurosurg. Psychiatry 71(5),
589–595 (2001).
16
25 Wilkinson D, Murry J. Galantamine:
a randomised, double-blind, dose
comparison in patients with Alzheimer’s
disease. Int. J. Geriatr. Psychiatry 16,
852–857 (2001).
26 Tariot PN, Solomon PR, Morris JC et al.
Galantamine USA-10 Study Group.
A 5-month, randomised, placebo-
controlled trial of galantamine in AD.
Neurology 54(12), 2261–2276 (2000).
27 Wilcock GK, Lilienfeld S, Gaens E.
Efficacy and safety of galantamine in
patients with mild to moderate Alzheimer’s
disease: multicentre randomised controlled
trial. Br. Med. J. 321, 1445–1449 (2000).
28 Raskind MA, Peskind ER, Wessel T,
Yuan W. Galantamine USA-1 Study
Group. Galantamine in AD: a 6-month
randomised placebo-controlled trial with a
6-month extension. Neurology 54(12),
2261–2276 (2000).
29 Erkinjuntti T, Kurz A, Gauthier S et al.
Efficacy of galantamine in probable
Vascular dementi and Alzheimer’s disease
combined with cerebrovascular disease.
A randomised trial. Lancet 359, 1283–1290
(2002).
30 Brodaty H, Corey-Bloom J, Potocnik FCV
et al. Galantamine prolonged-release
formation in the treatment of mild to
moderate Alzheimer’s disease. Dement.
Geriatr. Cogn. Disord. 20(2–3), 120–132
(2005).
31 Stern RG, Mohs RC, Davidson M et al.
A study of Alzheimer’s disease:
measurement, rate, and predictors of
cognitive deterioration. Am. J. Psychiatry
151(3), 390–394 (1994).
32 Raskind MA, Peskind ER, Truyen L et al.
The cognitive benefits of galantamine are
sustained for at least 36 months: a long
term extension trial. Arch. Neurol. 61,
252–256 (2004).
33 Pirttila T, Wilcock G, Truyen L,
Damaraju V. Long-term efficacy and safety
of galantamine in patients with mild to
moderate Alzheimer’s disease: multicentre
trial. Eur. J. Neurol. 11, 734–741 (2004).
34 Rockwood K, Dai D, Mitnitski A. Patterns of
decline and evidence of subgroups in patients
with Alzheimer’s disease taking galantamine
for up to 48 months. Int. J. Geriatr. Psychiatry
(2007) (Epub ahead of print).
35 Kaduszkiewicz H, Zimmermann T,
Beck-Bornholdt HP et al. Cholinesterase
inhibitors for patients with Alzheimer’s
disease: systematic review of randomised
clinical trials. Br. Med. J. 331, 321–327
(2005).
36 Birks J, Harvey R. The efficacy of donepezil
for mild and moderate Alzheimer’s disease.
Cochrane Database Sys. Rev. 1, CD001190
(2005).
37 Birks J, Grimley Evans J, Iakividou V,
Tsolaki M. Rivastigmine for Alzheimer’s
disease. Cochrane Database Sys. Rev. 4,
CD001191 (2005)
38 Clegg A, Bryant J, Nicholson T et al.
Clinical and cost–effectiveness of
donepezil, rivastigmine, and galantamine
for Alzheimer’s disease. Int. J. Technol.
Assess Health Care 18(3), 497–507 (2002).
39 Loveman E, Green C, Kirby J et al.
The clinical and cost–effectiveness of
donepezil, rivastigmine, galantamine and
memantine for Alzheimer’s disease. Health
Technol. Assess. 10(1), iii–iv, ix–xi, 1–160
(2006).
40 O’Brien JT. NICE and anti-dementia
drugs: a triumph of health economics over
clinical wisdom? Lancet Neurol. 5(12),
994–996 (2006).
41 Fossey J, Lee L, Ballard C. Dementia care
mapping as a research tool for measuring
quality of life in care setting: psychometric
properties. Int. J. Geriatr. Psychiatry 17,
1064–1070 (2002).
42 Smith SC, Lamping DL, Banerjee S
et al. Measurement of health-related quality of
life for people with dementia: development of
a new instrument (DEMQOL) and an
evaluation of current methodology.
Health Technol. Assess. 9, 10 (2005).
43 Gestios D, Caro JJ, Caro G et al.
Assessment of health economics in
Alzheimer’s disease (AHEAD): galantamine
treatment in Canada. Neurology 57,
972–978 (2001).
44 Morris JC. The Clinical Dementia Rating
(CDR): current version and scoring rules.
Neurology 43, 2412–2414 (1993).
45 Department of Health and Ageing, Australian
Government. Pharmaceutical Benefit Advisory
Committee (PBAC) Recommendations for the
Use of Anticholinesterases in Alzheimer’s Disease
(2005).
46 Jones RW, Soininen H, Hager K et al.
A multinational, randomised, 12-week
study comparing the effects of donepezil
and galantamine in patients with mild to
moderate Alzheimer’s disease. Int. J. Geriatr.
Psychiatry 20 (1), 85–87 (2004).
47 Bullock R, Truyen L. Not all head-to-head
trials are created equal: results from an
open-label, short-term study seem
inconsistent with previous donepezil
literature. Int. J. Geriatr. Psychiatry 20,
85–87 (2005).
Expert Rev. Neurotherapeutics 8(1), (2008)

48 Danysz W, Parsons CG, Mobius H-J et al.
Neuroprotective and symptomatological
action of mementine relevant for
Alzheimer’s disease- a unified glutamatergic
hypothesis on the mechanism of action.
Neurotox. Res. 2, 85–97 (2000).
49 Areosa Sastre A, Sherriff F, McShane R.
Memantine for dementia. Cochrane
Database Sys. Rev. 2, CD003154
(2005).
50 Wilkinson D, Anderson HF. Analysis of the
effect of memantine in reducing the
worsening of clinical symptoms in patients
with moderate to severe Alzheimer’s disease.
Dement. Geriatr. Cogn. Disord. 24,
138–145 (2007).
51 Dantoine T, Auriacombe S, Sarazin M
et al. Rivastigmine monotherapy and
combination therapy with memantine in
patients with moderately severe Alzheimer’s
disease who failed to benefit from previous
cholinesterase inhibitor treatment.
Int. J. Clin. Pract. 60(1), 110–118 (2006).
52 Tariot PN, Farlow MR, Grossberg GT et al.
Memantine treatment in patients with
moderate to severe Alzheimer’s disease
already receiving donepezil: a randomised
controlled trial. JAMA 291, 317–324
(2004).
53 Zhao X, Marszalec W, Toth PT et al.
In vitro galantamine-memantine
co-application: mechanism of beneficial
action. Neuropharmacology 51, 1181–1191
(2006).
•• Discusses different mechanisms of actions
of galantamine and memantine.
www.future-drugs.com
54 Aracava Y, Pereira EFR, Maelicke A,
Albuquerque EX. Memantine blocks α7
nicotenic actylcholine receptors more
potently than NMDA receptors in rat
hippocampal neurons. J. Pharmacol. Exp.
Ther. 312, 1195–1205 (2005).
Websites
101 McShane R, Schneider L. The baby has
been thrown out with the bath water.
BMJ.com. 2 September (2005)
www.bmj.com/cgi/eletters/331/7512/
321#115586
102 Birks J. The Cochrane reviews of
cholinesterase inhibitors. BMJ.com. 5
September (2005)
www.bmj.com/cgi/eletters/331/7512/
321#115765
103 Wilkinson D. Evidence of cholinesterase
inhibitors in AD. BMJ.com. 13 August
(2005)
www.bmj.com/cgi/eletters/331/7512/
321#114284
104 Dementia. The NICE-SCIE Guidelines on
Supporting People with Dementia and their
Carers in Health and Social Care.
The British Psychological Society and The
Royal College of Psychiatrists. National
Clinical Practical Guidelines Number 42
(2007)
www.nice.org.UK/CG042
105 Gal-INT-11 DeKosky. A randomised
double-blind, placebo-controlled trial to
evaluate the efficacy and safety of
galantamine in subjects with mild cognitive
Galantamine Drug Proflie
impairment (MCI) clinically at risk for the
development of clinically probable
Alzheimer’s disease
www.clinicalstudyresults/documents/2004
106 Gal-INT-18 Winblad. A randomised
double-blind, placebo-controlled trial to
evaluate the efficacy and safety of
galantamine in subjects with mild cognitive
impairmrnt (MCI) clinically at risk for the
development of clinically probable
Alzheimer’s disease
www.clinicalstudyresults/documents/2004
Affiliations
• George Razay, MRCP, MD (UK), FRACP
University of Oxford, Nuffield Department
of Clinical Medicine, John Radcliffe
Hospital, Headington, Oxford, OX3 9DU,
UK
george.razay@dhhs.tas.gov.au
• Gordon K Wilcock, DM (OXON), FRCP
University of Oxford, Nuffield Department
of Clinical Medicine, John Radcliffe
Hospital, Headington, Oxford,
OX3 9DU, UK
Tel.: + 44 186 522 1339
Fax: + 44 186 561 7185
gordon.wilcock@ndm.ox.ac.uk
17