Drugs (2013) 73:19351950

DOI 10.1007/s40265-013-0140-1

ADIS DRUG EVALUATION

Prucalopride: A Review of Its Use in the Management of Chronic

Constipation
Gillian M. Keating

Published online: 6 November 2013

Springer International Publishing Switzerland 2013

Abstract The highly selective serotonin 5-HT4 receptor

agonist prucalopride (Resolor, Resotran, Resotrans) is
indicated for the treatment of chronic constipation. In four
randomized, double-blind, multicentre, 12-week trials in
patients (predominantly women) with chronic constipation,
oral prucalopride 2 mg once daily improved bowel function to a significantly greater extent than placebo, with a
significantly greater proportion of prucalopride than placebo recipients achieving an average of C3 spontaneous,
complete bowel movements per week (primary endpoint).
Significantly greater improvements in health-related quality of life, patient satisfaction with treatment and bowel
habit, and a range of constipation-related symptoms were
also seen with prucalopride than with placebo. Satisfaction
with treatment and bowel habit was maintained with prucalopride in the longer term. Prucalopride was generally
well tolerated in patients with chronic constipation, with
the most commonly reported adverse events (headache,
nausea, abdominal pain, diarrhoea) primarily occurring on
the first day of treatment. During the clinical trials, no

cardiovascular safety issues have arisen in patients with

chronic constipation receiving prucalopride. In conclusion,
prucalopride is an important option for use in patients with
chronic constipation who have not experienced adequate
relief with laxatives.

Prucalopride in chronic constipation: a summary

Highly selective serotonin 5-HT4 receptor agonist
Improves bowel function, health-related quality of life,
patient satisfaction with treatment and bowel habit,
and constipation-related symptoms
Satisfaction with treatment and bowel habit maintained
in the longer term
Generally well tolerated
No cardiovascular safety issues have arisen

1 Introduction
The manuscript was reviewed by: S.A. Muller-Lissner, Department
of Internal Medicine, Park-Klinik Weissensee, Berlin, Germany;
E.M.M. Quigley, Alimentary Pharmabiotic Centre, University
College Cork, Cork, Ireland; C. Scarpignato, Clinical Pharmacology
& Digestive Pathophysiology Unit, Department of Clinical &
Experimental Medicine, University of Parma, Parma, Italy; M.
Simren, Department of Internal Medicine & Clinical Nutrition,
Institute of Medicine, Sahlgrenska Academy, University of
Gothenburg, Gothenburg, Sweden; V. Stanghellini, Department of
Digestive Diseases and Internal Medicine, University of Bologna, St
Orsola-Malpighi Hospital, Bologna, Italy.
G. M. Keating (&)
Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
North Shore 0754, Auckland, New Zealand
e-mail: demail@springer.com

Chronic constipation is a common condition, affecting an

estimated 227 % of the population [1], with a higher
prevalence in women and the elderly [2, 3]. According to
ROME criteria, chronic constipation (i.e. functional or
idiopathic constipation) is diagnosed if at least two of the
following symptoms are present: fewer than three bowel
movements per week; hard or lumpy stools in C25 % of
defecations; straining during C25 % of defecations; a
sensation of incomplete evacuation in C25 % of defecations; a sensation of anorectal obstruction or blockage in
C25 % of defecations; and use of manual manoeuvres to
assist defecation in C25 % of defecations [4]. In addition,

1936

G. M. Keating

[17] enrolled women. Some of the studies discussed in this

section are only available as abstracts [11, 12, 18].

2.1 Mechanism of Action and Receptor Binding

N
O
OH
HO
HN

Cl
NH2

Prucalopride is a dihydrobenzofurancarboxamide derivative with gastrointestinal (GI) prokinetic activity [2]. Prucalopride stimulates GI motility via its activation of
intestinal 5-HT4 receptors [19, 20]. It acts as a potent,
highly specific and selective 5-HT4 receptor agonist [19];
5-HT4 receptors are expressed throughout the entire GI
tract [21]. Prucalopride binds to 5-HT4 receptors with high
affinity, with Ki values at human 5-HT4a and 5-HT4b
receptors of 2.5 and 8 nmol/L, respectively [19].
Measurable binding affinity was not seen (i.e. Ki values of
[10,000 nmol/L) for most other receptors (including
monoamine, opioid and peptide receptors, most other 5-HT
receptor subtypes besides 5-HT4, ion channels and transporters) [19]. Prucalopride had weak binding affinity (Ki
values of 2.353.82 lmol/L) at human dopamine D4 receptors, human r1 receptors and murine 5-HT3 receptors [19].

Fig. 1 Chemical structure of prucalopride succinate

2.2 Effects on Gastrointestinal Motility

loose stools should be rarely present without the use of
laxatives, and there should be insufficient criteria for irritable bowel syndrome. These criteria need to have been
fulfilled for the last 3 months, with symptom onset
C6 months prior to diagnosis [4].
Traditional treatment approaches for chronic constipation include lifestyle and dietary changes and the use of
laxative agents [1, 5]. More recently, novel pharmacological agents have become available for use in the treatment
of chronic constipation, such as the enterokinetic agent
prucalopride (Resolor, Resotran, Resotrans). Prucalopride is a highly selective serotonin 5-HT4 receptor agonist
indicated for use in the treatment of laxative-resistant
chronic constipation, and is available (as prucalopride
succinate; Fig. 1) in a film-coated tablet formulation [6].
This article reviews the efficacy and tolerability of
prucalopride in chronic constipation, as well as summarizing its pharmacological properties.

2 Pharmacodynamic Properties
This section summarizes the pharmacodynamic properties
of prucalopride. Randomized, double-blind, placebo-controlled studies were conducted in healthy volunteers [713]
and patients with chronic constipation [1417], with several studies using a crossover design [7, 8, 1012, 16].
Where specified, aside from four studies [7, 8, 10, 13],
these studies predominantly [9, 12, 1416] or exclusively

2.2.1 In Preclinical Studies

The agonist activity of prucalopride at 5-HT4 receptors
enhanced acetylcholine release from cholinergic neurons
and stimulated contractions in longitudinal muscle strips
from human and canine colon [22]. Relaxation of circular
muscle strips from human [23] and canine [24] colon was
also seen with prucalopride, mediated via 5-HT4 receptors.
This suggests that 5-HT4 receptor agonists improve GI
motility by promoting contraction of longitudinal smooth
muscle and suppressing the resistance to propulsion associated with the contraction of circular smooth muscle [2, 22].
The effect of prucalopride on GI motility in conscious
dogs appeared to be co-ordinated and region-specific [25].
Prucalopride increased contractile activity in the proximal
colon, with reduced contractility seen in the distal colon,
facilitating the propulsion of luminal contents [20, 25].
Giant migrating contractions propagating along the entire
length of the colon were also induced by prucalopride [25].
The effects of prucalopride on GI motility were blocked by
administration of a 5-HT4 receptor antagonist [25].
2.2.2 In Healthy Volunteers
Administration of prucalopride for 1 week generally
accelerated GI transit in healthy volunteers [79]. The
orocaecal transit time was significantly (p = 0.007) shorter
with prucalopride 1 mg once daily, but not 2 mg once
daily, versus placebo [7]. Moreover, the colonic transit

Prucalopride: A Review

time was significantly (p \ 0.05) shorter with prucalopride

0.5 mg [9], 1 mg [8], 2 mg [8, 9] or 4 mg [9] once daily
than with placebo, and the whole-gut transit time was
significantly (p \ 0.05) shorter with prucalopride 1 or
2 mg once daily than with placebo [7]. Proximal colonic
emptying was also significantly (p \ 0.05) shorter with
prucalopride 0.5 or 2 mg once daily than with placebo [9].
The percentage decrease in mean colonic transit time
with prucalopride 1 or 2 mg once daily versus placebo did
not significantly differ between women and men (38.3 vs.
35.1 %), according to the results of a study enrolling equal
numbers of women (n = 12) and men (n = 12) [8]. During
the placebo phase of this study, mean colonic transit time
was significantly shorter in men than in women (31.1 vs.
46.6 h; p = 0.01) [8].
Prucalopride 0.54 mg once daily did not significantly
affect gastric emptying or small bowel transit in healthy
volunteers in one study [9]. However, another study in
healthy volunteers found that compared with placebo,
administration of prucalopride 4 mg once daily for 6 days
significantly (p \ 0.05) accelerated gastric emptying and
reduced oesophageal acid exposure [11].
Prucalopride 1 or 2 mg once daily did not affect anorectal function in healthy volunteers [7, 8].
Significant (p \ 0.05) increases in the number of bowel
movements were seen in healthy volunteers receiving
prucalopride 1 mg [7], 2 mg [8] or 4 mg [10] once daily
versus placebo. Stools also became significantly (p \ 0.05)
looser [7, 8, 10], and volunteers had to strain significantly
(p \ 0.05) less [10], with prucalopride than with placebo.
2.2.3 In Patients with Chronic Constipation
In patients with chronic constipation, administration of
prucalopride 1 mg [17] or 4 mg [15] once daily for 1 [15]
or 4 [17] weeks significantly (p \ 0.05) accelerated overall
gastric emptying [15], small bowel transit [15], orocaecal
transit [17], overall colonic transit [15] and whole-gut
transit [17], compared with placebo, in two studies. However, in two other studies, no significant difference was
seen between patients receiving prucalopride 1 mg [16],
2 mg [16] or 4 mg [14] once daily and those receiving
placebo for 2 [16] or 4 [14] weeks in the mean colonic [16]
or total gut [14] transit times. In one of these studies, the
lack of a significant between-group difference may reflect
the fact that the mean total gut transit time during the runin period was &92 h in prucalopride recipients versus
&80 h in placebo recipients (values estimated from a
graph) [14].
Two weeks treatment with prucalopride 1 or 2 mg once
daily did not significantly affect anorectal function in
patients with chronic constipation [16]. However, in a
4-week study, rectal sensitivity to balloon distension and

1937

electrical stimulation was significantly (p B 0.01)

increased with prucalopride 1 mg once daily versus placebo [17].
Significant (p B 0.05) improvements in the frequency of
spontaneous bowel movements [16, 17], the time to first
bowel movement [14, 17], bowel movement consistency
[14, 16, 17] and straining [14, 16] were seen with prucalopride 1 mg [16, 17] or 4 mg [14] once daily versus placebo in patients with chronic constipation.
A pooled analysis of three randomized, placebo-controlled, phase II trials found that, as expected, the increase
in spontaneous bowel movements in patients with chronic
constipation who received prucalopride was associated
with the decrease in colonic transit time [18].
Results of large, pivotal, clinical trials investigating the
effect of prucalopride on bowel function in patients with
chronic constipation are discussed in Sect. 4.
2.3 Cardiovascular Effects
Prucalopride blocked human ether a`-go-go related gene
(hERG) cardiac potassium channels at relatively high
concentrations (50 % inhibitory concentration [IC50] of
4.122 lmol/L) [2628]. Via the 5-HT4 receptor, prucalopride also acted as a partial agonist of the L-type calcium
current (ICaL) in human atrial cells, with a significant
(p \ 0.05) increase in ICaL amplitude seen with prucalopride 10 lmol/L, as well as prolongation of the early phase
of action potential repolarization, but not late repolarization [29]. Although prucalopride demonstrated inotropic,
chronotropic and/or lusitropic effects on the heart in vitro
[3032], these effects were of small magnitude [31].
Importantly, prucalopride appeared devoid of arrhythmic
activity [20, 29].
Results of a thorough QT study indicated that therapeutic (2 mg) and supratherapeutic (10 mg) doses of prucalopride did not have a clinically significant effect on
cardiac repolarization in healthy volunteers [13]. For
example, prucalopride 2 or 10 mg once daily was found to
be noninferior to placebo in terms of its effect on the studyspecific corrected QT (QTc) interval [13]. Changes in heart
rate of 25 beats per min were seen with prucalopride 2 or
10 mg [13].
Similarly, no differences were seen between healthy
volunteers receiving prucalopride (up to 20 mg once daily)
and those receiving placebo in the Fridericia-corrected QT
(QTcF) interval, according to an analysis of two randomized, double-blind, placebo-controlled, crossover, phase I
studies [12]. There were no reports of QTcF intervals of
[500 ms or increases in the QTcF interval of[60 ms [12].
QTc interval prolongation was also generally not seen in
patients with chronic constipation who received prucalopride in pivotal clinical trials (see Sect. 5).

1938

3 Pharmacokinetic Properties
This section summarizes the pharmacokinetic properties of
prucalopride. Some studies are only available as abstracts
[3335].
3.1 Absorption and Distribution
Prucalopride 2 mg tablets have an absolute oral bioavailability of 93.2 %, with no appreciable first-pass metabolism [33]. Food does not affect the bioavailability of oral
prucalopride to a clinically significant extent [34].
Following administration of a single dose of oral prucalopride 2 mg in the fasting state, a mean maximum
plasma prucalopride concentration (Cmax) of 4.34 ng/mL
was reached in &2 h [34]. The mean area under the prucalopride plasma concentration-time curve (AUC) from
time zero to infinity (AUC?) was 99.2 ng
h/mL [34].
Steady-state was reached within 34 days with oncedaily administration of prucalopride, with an accumulation
ratio of 1.92.3 [6]. The pharmacokinetics of prucalopride
are dose-proportional, and are time dependent during prolonged treatment [6].
Plasma protein binding of prucalopride is &30 % [6]
and, at steady-state, the prucalopride volume of distribution
averaged 567 L [33].
3.2 Metabolism and Elimination
Metabolism is not the major route of elimination for prucalopride [6]. Only small amounts of eight prucalopride
metabolites were detected in the urine and faeces, with
R107504 (the major metabolite) accounting for \4 % of
the dose [6]. Following administration of a radiolabelled
dose of prucalopride, the parent drug accounted for &85 %
of total radioactivity in plasma; R107504 was only a minor
plasma metabolite [6].
Approximately 60 % of the administered prucalopride
dose is excreted unchanged in urine, with C6 % excreted
unchanged in faeces [6]. The parent drug is eliminated
renally by both passive filtration and active secretion [6].
The mean clearance of prucalopride 2 mg was &19 L/h
and its mean terminal elimination half-life (t) was 21.2 h
[33, 34].
3.3 Special Patient Populations
The pharmacokinetics of prucalopride 2 mg in healthy
Chinese volunteers were similar to those seen in Caucasians [36].
At steady state, the AUC was 28 % higher in elderly
patients (aged 6581 years) than in younger adults (aged
2032 years) who received prucalopride 1 mg once daily

G. M. Keating

[35]. Mean creatinine clearance was 132 and 78.6 mL/min

in younger and older volunteers, respectively [35]. The
increased prucalopride exposure seen in the elderly was
attributed to the diminished renal function seen in this age
group [6]. A prucalopride starting dosage of 1 mg once
daily is recommended in elderly patients aged [65 years
[6, 37, 38].
Administration of a single dose of oral prucalopride
0.03 mg/day to paediatric patients aged 412 years resulted in a mean Cmax of 3.8 ng/mL (i.e. similar to that seen in
adults receiving a single 2 mg dose), although the mean
AUC? was 65.3 ng
h/mL [6, 39]. Prucalopride had a
mean t of &19 h in paediatric patients [39]. Prucalopride
is not currently recommended for use in patients aged
\18 years [6, 37, 38].
In terms of the prucalopride AUC?, there was no significant difference between individuals with normal renal
function and individuals with mild renal impairment who
received a single dose of prucalopride 2 mg [40]. However,
in individuals with moderate or severe renal impairment,
the prucalopride AUC? was 1.5- and 2.3-fold higher,
respectively, than in individuals with normal renal function
(p \ 0.01) [40]. No dosage adjustment is needed in patients
with mild to moderate renal impairment [6, 37]. The recommended prucalopride dosage in patients with severe
renal impairment (glomerular filtration rates of \30 mL/
min/1.73 m2) is 1 mg once daily [6, 37, 38].
No dosage adjustment is needed in patients with mild to
moderate hepatic impairment [6, 37]. The recommended
dosage of prucalopride in patients with severe hepatic
impairment is 1 mg once daily in the EU and Australia [6,
37], which may be increased to 2 mg once daily if needed
to improve efficacy (and if the 1 mg/day dosage is well
tolerated) [6]. However, Canadian prescribing information
states that no dosage adjustment is needed in patients with
hepatic impairment [38].
3.4 Potential Drug Interactions
Prucalopride has low potential for drug interactions [6].
Cytochrome P450 (CYP) enzymes were not inhibited by
prucalopride in vitro, and prucalopride did not inhibit
P-glycoprotein (P-gp) at clinically relevant concentrations,
although it may be a weak substrate for P-gp [6].
Coadministration of prucalopride increased erythromycin concentrations by 30 %; the mechanism of this interaction is not clear [6]. However, coadministration of
prucalopride did not have a clinically significant effect on
the pharmacokinetics of ethinylestradiol/norethisterone in
healthy women [41], or on the pharmacokinetics of warfarin, digoxin, paroxetine or alcohol [6].
Although ketoconazole (a potent inhibitor of CYP3A4
and P-gp) increased the systemic exposure of prucalopride

Prucalopride: A Review

by &40 %, this was not considered clinically relevant [6].

Other potent P-gp inhibitors (e.g. verapamil, ciclosporin,
quinidine) may be associated with interactions of similar
magnitude [6].
Prucalopride pharmacokinetics were not affected by
therapeutic doses of probenecid, cimetidine, erythromycin
or paroxetine [6].

4 Therapeutic Efficacy
4.1 Comparisons with Placebo
Five randomized, double-blind, multicentre trials compared the efficacy of prucalopride with that of placebo in
patients with chronic constipation [4246]. The approval of
prucalopride was based on the results of three 12-week
registration trials of identical design [4244]. Approximately 90 % of the patients enrolled in these registration
trials were Caucasian [4244], and a subsequent 12-week
trial was conducted in the Asia-Pacific region to examine
the efficacy of prucalopride in Asian patients (&90 % of
the trial population) [45]. In addition, a 4-week trial
examined the efficacy of prucalopride in elderly patients
aged C65 years [46]. The majority of patients enrolled in
all of these trials were women and the majority were dissatisfied with previous treatments (Table 1). Additional
patient baseline characteristics and trial design details are
shown in Table 1.
Patients in the registration trials were randomized to
receive prucalopride 2 or 4 mg once daily or placebo [42
44], patients in the Asia-Pacific study were randomized to
receive prucalopride 2 mg once daily or placebo [45] and
elderly patients in the 4-week study were randomized to
receive prucalopride 1, 2 or 4 mg once daily or placebo
[46]. Although results for all treatment arms in the registration trials are shown in Tables 2 and 3, the text discussion focuses on the approved prucalopride dosage of 2 mg
once daily. In general, no meaningful, incremental benefit
was seen with the prucalopride 4 mg/day dosage compared
with the 2 mg/day dosage in these trials [42, 44]. Recent
meta-analyses (available as abstracts) also found prucalopride 4 mg once daily to be no more effective than prucalopride 2 mg once daily [47, 48].
Rescue medication comprising bisacodyl was allowed in
patients who had not had a bowel movement for C3 consecutive days, with an enema permitted if bisacodyl was
unsuccessful [4246].
The primary endpoint was the proportion of patients
with an average of C3 spontaneous, complete bowel
movements (SCBMs) per week during weeks 112 [4245]
or over 4 weeks [46]. Key secondary endpoints included
the proportion of patients with an average increase from

1939

baseline of C1 SCBMs per week [4244] and the proportion of patients with an average of C3 SCBMs per week
during the first 4 weeks of treatment [45]. Efficacy was
assessed in the modified intent-to-treat (ITT) population
[4246].
Integrated analyses [49, 50] of the three registration
trials [4244] compared the effect of 12 weeks treatment
with prucalopride 2 mg once daily (n = 458) with that of
placebo (n = 478) on bowel function [49] (Sect. 4.1.1.1)
and Patient Assessment of Constipation Symptoms (PACSYM) scores [50] (Sect. 4.1.2.1) in women reporting
inadequate relief from laxatives. Women were asked if
they had used dietary measures, bulk-forming agents and/
or other laxatives in the prior 6 months and, if so, whether
they would rate the overall effects of these measures as
inadequate or adequate [49, 50].
Results are also available from a subgroup analysis
[51] of Chinese patients (n = 313) with chronic constipation included in the Asia-Pacific study [45]. This analysis compared the effect of prucalopride 2 mg once daily
with that of placebo on symptoms and health-related
quality of life (HR-QOL) [Sect. 4.1.2]. Almost 90 % of
patients included in this analysis (which is available as
an abstract and poster) were female, mean age was
&41 years and the mean duration of constipation was
&11 years [51].
4.1.1 Effects on Bowel Function
Bowel function improved to a significantly greater extent
in patients receiving prucalopride 2 mg once daily than in
those receiving placebo in the 12-week trials enrolling
predominantly Caucasian [4244] or Asian [45] patients.
Over weeks 112, the proportion of patients with an
average of C3 SCBMs per week was significantly higher
with prucalopride 2 mg once daily than with placebo
(Table 2) [4245]. The proportion of patients with an
average of C3 SCBMs per week over weeks 14 was also
significantly higher with prucalopride 2 mg once daily than
with placebo (Table 2) [4245].
In addition, the proportion of patients with an average
increase from baseline of C1 SCBMs per week over weeks
112 was significantly higher with prucalopride 2 mg once
daily than with placebo (Table 2) [4245]. The mean
number of SCBMs per week was significantly higher with
prucalopride 2 mg once daily than with placebo, and the
median time to first SCBM after the first intake of study
drug was significantly shorter with prucalopride 2 mg once
daily than with placebo (Table 2) [4245].
The mean proportion of bowel movements with normal
consistency was significantly higher with prucalopride
2 mg once daily than with placebo [4244], and the mean
proportion of bowel movements with no straining was

1940

G. M. Keating

Table 1 Design details and baseline patient characteristics in randomized, double-blind, placebo-controlled, multicentre trials in patients with
chronic constipation
Camilleri
et al. [42]
(n = 620)

Quigley
et al. [43]
(n = 641)

Tack
et al. [44]
(n = 716)

Ke et al. [45]
(n = 501)

Muller-Lissner
et al. [46] (n = 303)

58.376.3

Baseline pt characteristicsa
Women (% of pts)

87.9

86.6

90.8

89.8

Mean age (years)

48.3

47.9

43.9

41.6

75.677.1

Duration of constipationb
(years)

21.1

22.0

17.5

12.9

10.015.5

0
[0 and B1

37.4
37.7

44.0
31.8

38.5
32.3

22.8
27.1

21.034.2

[1 and B2 [45] or B3
[4244]

23.4

22.8

26.0

50.1

[3

1.5

1.4

3.2

Pts dissatisfied with

previous treatment (%)

83.7

80.3

83.2

Treatment regimen

No. of spontaneous stools

per week (% of pts)

55.3

71.487.3

PRU 2 or 4 mg or PL od for
12 weeks

PRU 2 mg or PL od for 12 weeks

PRU 1, 2 or 4 mg or PL od for
4 weeks

Inclusion criteria

Adults aged C18 years; chronic

constipationc; very hard or hard
stools, a sense of incomplete
evacuation or straining during
defecation with C25 % of BMs

Adults aged 1865 years; chronic

constipation for C6 months before
screeningd

Adults aged C65 years; history

of constipatione

Exclusion criteria

Constipation secondary to drugs,

endocrine disorders, metabolic
disorders, neurological disorders;
surgery or organic disorders of
the large intestine; uncontrolled
cardiovascular, liver, psychiatric
or lung diseases; serum creatinine
level of [2 mg/dL; clinically
significant laboratory
abnormalities; pregnant or
breastfeeding women

Drug-induced constipation;
secondary cause of constipation
(e.g. endocrine, metabolic or
neurological disorders, surgical
obstruction, megacolon or
megarectum, pseudo-obstruction),
uncontrolled cardiovascular, liver
or lung diseases; serum creatinine
level of [2 mg/dL; clinically
significant laboratory abnormalities

Drug-induced constipation;
secondary cause of constipation
(e.g. uncontrolled endocrine,
metabolic or neurological
disorders, surgery, organic
disorders of the large bowel or
other serious illnesses); main
complaint of abdominal pain

BM bowel movement, od once daily, PL placebo, PRU prucalopride, pts patients, SCBM spontaneous, complete BM
a

Overall values [4245] or range of values across treatment groups [46]

Mean [4245] or median [46] values

Chronic constipation was defined as B2 SCBMs per week for C6 months before screening. A BM was considered spontaneous when it
occurred [24 h after the last intake of laxative

Chronic constipation was defined as an average of B2 spontaneous BMs per week, with at least one of the following occurring in [25 % of
BMs: very hard or hard stools; a sense of incomplete evacuation; straining during defecation; sensation of anorectal obstruction or blockade; and
need for digital manipulation to facilitate evacuation. A BM was considered spontaneous when it occurred [24 h after the last intake of laxative
or use of an enema
e

Constipation was defined as B2 SCBMs per week, with at least one of the following occurring in [25 % of BMs: very hard or hard stools; a
sense of incomplete evacuation; straining during defecation. A BM was considered spontaneous when it occurred [24 h after the last intake of
laxative, enema or treatment other than PRU

significantly higher with prucalopride 2 mg once daily than

with placebo in one trial [43], with no significant betweengroup difference seen in a second trial [44] (Table 2).
The mean number of bisacodyl tablets taken per week
[42, 43, 45] and the mean number of days per week with
bisacodyl or enema use [4345] was significantly lower in

patients receiving prucalopride 2 mg once daily than in

those receiving placebo (Table 2).
A pooled analysis of the three registration trials (available as an abstract) reported that clinical benefit was seen
in 73.0 % of prucalopride 2 mg once daily recipients,
74.6 % of prucalopride 4 mg once daily recipients and

28.4***

12.0

PRU 4 [204]

PL [209]

33.3***

10.3

PL [252]

9.6

PRU 2 [249]

PL [240]

23.6***

PRU 4 [237]

12.1

PL [212]

19.5**

23.5**

PRU 4 [215]

PRU 2 [236]

23.9**

PRU 2 [214]

11.1d

34.5***

10.4

26.6***

23.7***

11.5

28.9***

29.2***

10.0

36.3***

33.8***

During
weeks
14

1.9*** [0.5]
1.0 [0.4]

44.1***d
20.9d

27.4

1.1 [0.3]

2.4*** [0.3]

1.6*** [0.4]

38.1***d

57.2***

1.2 [0.4]

27.5d

1.9*** [0.4]
2.0*** [0.5]

1.2 [0.4]

3.0*** [0.5]

46.6***d

42.6***

25.8d

46.6***

2.6*** [0.5]

47.3***d
d

Mean no. of
SCBM per
weeka
[baseline]

Average increase
from baseline of C1
SCBMs per weeka (%
of pts)

12.6

1.6***

20.5

2.1***

4.7***

13.0

1.9***

2.3***

12.6

1.0***

1.3***

Median time to first

SCBM after first
intake of study drug
(days)

33.7 [21.4]

41.6** [23.9]

40.0* [23.2]

35.7 [23.4]

46.4*** [26.0]

41.7** [21.6]

35.5 [21.9]

45.4*** [23.7]

46.6*** [23.5]

Mean % BMs
with normal
consistencya
[baseline]

Key secondary endpoint

Primary endpoint

Bisacodyl tablets

Assessed over weeks 112

* p B 0.05, ** p B 0.01, *** p B 0.001 vs. PL

BM bowel movement, od once daily, PL placebo, PRU prucalopride, pts patients, SCBM spontaneous, complete BM

Ke et al. [45]
(Asia-Pacific
study)

Tack et al.
[44]
(registration
trial)

Quigley et al.
[43]
(registration
trial)

30.9***

PRU 2 [207]

Camilleri
et al. [42]
(registration
trial)

During
weeks
112c

Average of C3
SCBMs per week
(% of pts)

Treatment
(mg od) [no.
of pts]

Study

14.8 [17.8]

19.6* [17.9]

16.4 [15.5]

19.0 [20.0]

27.3** [26.5]

26.6** [23.0]

Mean % BMs
with no
straininga
[baseline]

1.3 [1.6]

0.6*** [1.7]

1.7 [1.8]

1.2*** [2.2]

1.4** [2.1]

1.9 [2.1]

1.0*** [1.8]

0.9*** [1.9]

Mean no. of
laxativesb taken
per weeka
[baseline]

0.7 [0.9]

0.3*** [1.0]

0.8 [1.0]

0.5*** [0.8]

0.4*** [0.8]

0.7 [0.8]

0.5*** [1.0]

0.6* [0.9]

Mean use of
laxativesb or
enemasa (days per
week) [baseline]

Table 2 Effect of oral prucalopride on bowel function in patients with chronic constipation. Results of randomized, double-blind, placebo-controlled, multicentre, 12-week trials

Prucalopride: A Review
1941

1942

48.8 % of placebo recipients [52]. Clinical benefit was

defined as at least an increase of C1 spontaneous bowel
movement per week. In terms of best response among
prucalopride 2 mg once daily, prucalopride 4 mg once
daily and placebo recipients, 23.6, 24.7 and 11.3 %,
respectively, had an average of C3 SCBMs per week; 18.0,
19.4 and 12.7 %, respectively, had an average increase of
C1 SCBM per week; 14.4, 14.4 and 8.4 %, respectively,
had a C1-point improvement in the Patient Assessment of
Constipation Quality of Life (PAC-QOL) satisfaction
subscale score (see also Sect. 4.1.2), and 17.0, 16.1 and
16.4 %, respectively, had an average increase of C1
spontaneous bowel movement per week [52].
In the 4-week trial in elderly patients with chronic
constipation, the proportion of patients with an average of
C3 SCBMs per week was significantly higher with prucalopride 4 mg once daily than with placebo at week 1
(48.7 vs. 26.1 %; p \ 0.05), with no significant differences
between patients receiving prucalopride 1 or 2 mg once
daily and those receiving placebo [46]. In terms of this
endpoint, no significant differences were seen between
prucalopride 1, 2 or 4 mg once daily recipients and placebo
recipients at weeks 2, 3 or 4 [46].
Significantly more elderly patients receiving prucalopride 1, 2 or 4 mg once daily than those receiving placebo
had an average increase from baseline of C1 SCBM per
week at week 1 (61.8, 63.0 and 68.4 vs. 40.6 %; p \ 0.05)
[46]. No significant differences were seen between prucalopride and placebo recipients at weeks 2 or 3, although
at week 4, significantly more prucalopride 1 mg once daily
recipients than placebo recipients had an average increase
from baseline of C1 SCBM per week (59.2 vs. 33.8 %;
p \ 0.05) [46].
After 4 weeks treatment, the mean change from baseline in the number of SCBMs per week was significantly
higher in elderly patients receiving prucalopride 1, 2 or
4 mg once daily than in those receiving placebo (?1.9,
?1.7 and ?1.8 vs. ?0.6; p B 0.05) [46].
4.1.1.1 In Women With Inadequate Relief from Laxatives Prucalopride 2 mg once daily improved bowel
function in women reporting inadequate relief from laxatives, according to the results of the integrated analysis [49]
of the three registration trials [4244]. Over weeks 112,
significantly (p \ 0.0001) more prucalopride than placebo
recipients had an average of C3 SCBMs per week (24.7 vs.
9.2 %), an average increase from baseline of C1 SCBMs
per week (44.2 vs. 22.6 %), and an average increase from
baseline of C1 spontaneous bowel movements per week
(68.3 vs. 37.0 %) [49]. The increase from baseline in the
number of SCBMs per week was also significantly
(p \ 0.0001) greater (1.60 vs. 0.63), and the median time
to first SCBM was significantly (p \ 0.01) shorter (2.1 vs.

G. M. Keating

18.4 days), with prucalopride 2 mg once daily than with

placebo [49].
The proportion of bowel movements with normal consistency (42.7 vs. 33.5 %) or no straining (21.5 vs. 18.1 %)
was significantly (p \ 0.001) greater with prucalopride
than with placebo [49]. In addition, the reduction from
baseline in the number of bisacodyl tablets taken per week
was significantly greater in prucalopride recipients than in
placebo recipients (-0.89 vs. -0.11; p \ 0.0001) [49].
The average weekly number of SCBMs and spontaneous
bowel movements was significantly (p \ 0.05) reduced by
0.4 and 1.3, respectively, among women with prucalopride
intake on 25 versus 7 days per week [49].
4.1.2 Effects on Health-Related Quality of Life Outcomes,
Symptoms and Patient Satisfaction
After 12 weeks treatment, overall PAC-QOL scores
improved to a significantly greater extent in patients
receiving prucalopride 2 mg once daily than in those
receiving placebo [4345], including in the Asia-Pacific
subgroup analysis in Chinese patients [51] (Table 3).
Patient dissatisfaction was high at baseline [4345, 51],
and PAC-QOL satisfaction subscale scores (assessing
patient satisfaction with treatment and bowel habit)
improved to a significantly greater extent with prucalopride
2 mg once daily than with placebo (Table 3) [4245, 51].
A C1-point improvement in the PAC-QOL satisfaction
subscale score (i.e. a clinically relevant response [43]) was
seen in significantly (p B 0.001) more prucalopride 2 mg
once daily than placebo recipients at 12 weeks (33.544.9
vs. 16.426.0 %) [4244]. PAC-QOL physical discomfort,
psychosocial discomfort, and worries and concerns subscale scores also improved to a significantly (p \ 0.05)
greater extent with prucalopride 2 mg once daily than with
placebo [4345, 51], although in one study there was no
significant difference between prucalopride 2 mg once
daily recipients and placebo recipients in the PAC-QOL
psychosocial discomfort subscale score [43].
Overall PAC-SYM scores improved to a significantly
greater extent with prucalopride 2 mg once daily than
with placebo after 12 weeks treatment [4245], including
in the Asia-Pacific subgroup analysis in Chinese patients
[51] (Table 3). PAC-SYM stool and abdominal symptoms
scores improved to a significantly (p B 0.05) greater
extent with prucalopride 2 mg once daily than with placebo [4245, 51]. The change in the PAC-SYM rectal
symptoms score did not significantly differ between prucalopride 2 mg once daily recipients and placebo recipients in one study [42], with a significantly improved PACSYM rectal symptoms score seen with prucalopride 2 mg
once daily versus placebo in the remaining studies [4345,
51].

-0.6*** [1.5]
-0.4 [1.7]

PRU 2 [155]

PL [158]

-0.4 [1.9]

-0.38 [2.07]

PL [240]

PL [252]

-0.66*** [1.88]

PRU 4 [237]
-0.8*** [1.8]

-0.47 [2.11]
-0.65*** [2.04]

PL [212]
PRU 2 [236]

PRU 2 [249]

-0.86*** [2.09]

PRU 4 [215]

-0.2 [2.9]

-0.9*** [3.0]

-0.2 [3.0]

-0.9*** [3.0]

-0.30 [3.17]

-0.87*** [3.08]

-0.44 [3.43]
-0.76*** [3.12]

-0.97*** [3.37]

-0.93*** [3.38]

NR
-0.85*** [2.18]

PRU 2 [214]

PL [207]

-0.6*** [1.9]

-0.4 [1.4]

-0.6*** [1.3]

-0.4 [1.5]

-0.7*** [1.5]

-0.37 [2.06]

-0.71*** [2.00]

-0.45 [1.97]
-0.66*** [2.12]

-0.56* [1.84]

-0.78*** [2.04]

-0.4 [2.0]

-0.7*** [1.9]

8.8

32.9***

18.7

36.1***

20.1
34.6***

37.0***

38.9***

17.0

37.7***

33.3***

Pt assessment
of efficacyc
(%)

-0.31 [2.74]

-0.92*** [2.72]

-0.37 [2.69]
-0.76*** [2.66]

-0.80*** [2.72]

-0.98*** [2.85]

Mean change from baseline

in pt assessment of
constipation severityd [baseline]

Subgroup analysis of the Asia-Pacific study in Chinese pts. Available as an abstract and poster

Scored on a 5-point Likert scale ranging from 0 (none/absent) to 4 (very severe)

Proportion of pts rating treatment as quite a bit or extremely effective. Scored on a 5-point Likert scale ranging from 0 (not at all effective) to 4 (extremely effective)

PAC-SYM scores 12 constipation-related symptoms on three subscales (stool, abdominal or rectal symptoms), with scores ranging from 0 (symptoms absent) to 4 (symptoms very severe)

PAC-QOL scores 28 items relating to the effects of constipation on daily lives on four subscales (physical discomfort, psychosocial discomfort, worries and concerns, satisfaction) with scores
ranging from 0 to 4 (lower scores indicate better health-related quality of life)

* p B 0.05, ** p B 0.01, *** p B 0.001 vs. PL

NR values not reported, od once daily, PAC-SYM Patient Assessment of Constipation Symptoms; PAC-QOL Patient Assessment of Constipation Quality of Life; PL placebo, PRU prucalopride,
pt(s) patient(s)

Ke et al. [51]e (Chinese pts)

Ke et al. [45] (Asia-Pacific

study)

Tack et al. [44] (registration

trial)

Quigley et al. [43]

(registration trial)

NR***
NR***

Mean change from baseline

in overall PAC-SYM scoreb
[baseline]

treatment in randomized, double-blind, multicentre trials [4245], and a subgroup analysis

[51], in chronic constipation

Mean change from baseline

in PAC-QOL satisfaction
subscale scorea [baseline]

PRU 2 [207]

Camilleri et al. [42]

(registration trial)

Mean change from baseline

in overall PAC-QOL scorea
[baseline]

PRU 4 [203]

Treatment (mg od)

[no. of pts]

Study

Table 3 Effect of prucalopride on health-related quality of life, patient satisfaction,

symptoms and patient-rated efficacy and constipation severity. Outcomes after 12 weeks

Prucalopride: A Review
1943

1944

After 12 weeks of treatment, patients receiving prucalopride 2 mg once daily were significantly more likely to
rate their treatment as being quite a bit or extremely
effective [4245], and reported a significantly greater
reduction in the severity of their constipation symptoms
[43, 44], than placebo recipients (Table 3).
In the 4-week trial in elderly patients, significantly
(p B 0.05) more prucalopride 1 mg once daily than placebo recipients had an improvement in the PAC-QOL
satisfaction subscale score of C1, and significantly
(p B 0.05) more prucalopride 1 or 4 mg once daily than
placebo recipients had an improvement in the PAC-SYM
stool symptoms score of C1 [46]. Elderly patients receiving prucalopride 1, 2 or 4 mg once daily were significantly
more likely than placebo recipients to rate treatment as
being quite a bit or extremely effective (42, 24 and 39
vs. 16 % of patients; p \ 0.05). Moreover, the improvement in constipation severity was significantly (p \ 0.05)
greater in patients receiving prucalopride 1 or 4 mg once
daily than in those receiving placebo [46].
4.1.2.1 In Women With Inadequate Relief From Laxatives Prucalopride 2 mg once daily improved PAC-SYM
scores in women reporting inadequate relief from laxatives,
according to the results of the integrated analysis [50] of
the three registration trials [4244]. The mean reduction
from baseline in the total PAC-SYM score was significantly (p \ 0.001) greater with prucalopride than with
placebo at both weeks 4 (-0.69 vs. -0.34) and 12 (-0.70
vs. -0.36) [mean baseline scores were 2.10 in prucalopride
recipients and 2.07 in placebo recipients]. In addition,
significantly (p \ 0.001) more prucalopride than placebo
recipients had an improvement in the total PAC-SYM
score of C1 at weeks 4 (34.3 vs. 15.9 %) and 12 (34.9 vs.
20.8 %) [50].
PAC-SYM stool, abdominal and rectal symptoms scores
improved to a significantly (p \ 0.05) greater extent with
prucalopride than with placebo at both weeks 4 and 12
[50]. Moreover, significantly (p \ 0.01) more prucalopride
than placebo recipients had improvements in PAC-SYM
stool, abdominal and rectal symptoms scores of C1 at
weeks 4 and 12 [50].
4.1.3 Longer-Term Follow-Up
Following completion of the three 12-week registration
trials, 1,455 patients received prucalopride in two openlabel long-term follow-up studies [53]. In both follow-up
studies, patients could self-titrate prucalopride up to a
maximum dosage of 4 mg once daily. The median duration
of prucalopride exposure was 308 days in the follow-up
studies, yielding a total prucalopride exposure of 1,464
patient-years when prucalopride exposure during the

G. M. Keating

double-blind phase of the registration trials was also

included. During follow-up, 12, 18 and C24 months of
study data were available in 788, 516 and 216 patients,
respectively [53].
Patient satisfaction with bowel function was maintained in
the longer term with prucalopride [53]. At month 18, the mean
PAC-QOL satisfaction subscale score was 1.67, which was
significantly (p \ 0.001) lower (i.e. better) than the score at
the start of the double-blind phase of the registration trials. At
month 18, the mean PAC-QOL satisfaction subscale score
was 1.38 among the 249 patients who had not used laxatives
and 1.95 among the 256 patients with laxative use [53].
Among the patients who responded to prucalopride in
the registration trials, only 10.3 % discontinued treatment
because of insufficient response in the open-label studies
[53].
4.2 Comparison with PEG-3350/Sodium Chloride/
Sodium Bicarbonate/Potassium Chloride
The efficacy of PEG-3350/sodium chloride/sodium bicarbonate/potassium chloride (hereafter referred to as PEG3350 plus electrolytes [PEG-3350 ? E]) was compared
with that of prucalopride in a randomized, double-blind,
single-centre, 4-week trial in women with chronic constipation [54]. The trial was conducted in the controlled
environment of a Phase I unit [54].
The study included women aged 1875 years (mean age
&40 years) with at least 6 months of chronic constipation
and dissatisfaction with previous laxative treatment [54].
Chronic constipation was defined as \3 successful bowel
movements per week with at least one additional symptom
(straining, lumpy or hard stools, sense of incomplete
evacuation or anorectal blockage, or manual manoeuvres to
facilitate defecation) in C25 % of defecations, and \3
SCBMs during the last week of the 14-day run-in period
[54].
Patients were randomized to receive two sachets per day
of PEG-3350 ? E in a split dose (each sachet contained
PEG-3350 13.13 g, sodium chloride 0.35 g, sodium
bicarbonate 0.18 g and potassium chloride 0.05 g)
[n = 120] or prucalopride (initial dosage of 2 mg once
daily in those aged B65 years and 1 mg once daily in those
aged [65 years) [n = 120] for 4 weeks [54].
Rescue medication comprising a sodium dioctyl sulfosuccinate microenema could be administered up to twice
daily in patients with no bowel movement for C3 consecutive days [54].
The primary endpoint was the proportion of patients
with C3 SCBMs during the last week of the study, assessed
in the per-protocol population [54]. PEG-3350 ? E was
shown to be noninferior to prucalopride if the lower limit
of the 97.5 % CI for the between-group difference in the

Prucalopride: A Review

primary endpoint was greater than -20 %. If noninferiority

was shown, superiority was also assessed in the modified
ITT population [54].
PEG-3350 ? E was noninferior to prucalopride in
women with chronic constipation [54]. In the per-protocol
population, 66.7 % of PEG-3350 ? E recipients and
56.5 % of prucalopride recipients had C3 SCBMs during
the last week of the study. The lower limit of the 97.5 % CI
for the between-group difference was -2.7 %, demonstrating noninferiority. Superiority was not shown in the
modified ITT population (the lower limit of the 97.5 % CI
for the between-group difference was -3.1 %) [54].
As a weekly average, the proportion of patients with C3
SCBMs was significantly higher in PEG-3350 ? E recipients than in prucalopride recipients (58.3 vs. 35.3 %;
p = 0.0007) [54]. During the 4 weeks of treatment, the
mean number of SCBMs was significantly higher with
PEG-3350 ? E than with prucalopride (13.1 vs. 9.0;
p \ 0.001). However, the mean time to first SCBM did not
significantly differ between PEG-3350 ? E and prucalopride recipients (4.8 vs. 5.0 days) [54].
The proportion of bowel movements associated with
severe or very severe straining was significantly lower in
patients receiving PEG-3350 ? E than in those receiving
prucalopride (weekly average of 6.3 vs. 14.8 %;
p \ 0.0001) and significantly fewer PEG-3350 ? E than
prucalopride recipients reported a feeling of incomplete
evacuation (43.3 vs. 52.4 %; p = 0.0159) [54].
Rescue medication was used in 0.8 % of PEG-3350 ? E
recipients and in 3.4 % of prucalopride recipients [54].

5 Tolerability and Safety

Data concerning the tolerability and safety of prucalopride
in patients with chronic constipation were obtained from
the clinical trials discussed in Sect. 4. In addition, the
tolerability and safety of prucalopride was evaluated in a
randomized, double-blind, multicentre, phase II study
conducted in 89 elderly (aged 6598 years) nursing home
residents (65 women and 24 men) with chronic constipation who received prucalopride 0.5, 1 or 2 mg once daily or
placebo for 4 weeks; 88 % of patients in this study had a
history of cardiovascular disease and 78 % were being
treated for a cardiovascular condition [55].
Oral prucalopride was generally well tolerated in patients
with chronic constipation [4245], including in the elderly
[46, 55]. The majority of adverse events were of mild to
moderate severity and of transient duration, occurring primarily on the first day of treatment [4244, 46, 55].
Across the randomized, double-blind, multicentre, placebo-controlled, 12-week trials discussed in Sect. 4.1,
adverse events were reported in 57.080.8 % of patients

1945

receiving prucalopride 2 mg once daily [4245],

74.878.4 % of patients receiving prucalopride 4 mg once
daily [4244] and 36.571.3 % of placebo recipients [42
45]. Adverse events considered to be possibly, probably
or very likely related to the study drug were reported in
36.1 % of patients receiving prucalopride 2 mg once daily
and in 13.1 % of patients receiving placebo [45].
The most commonly reported adverse events included
nausea, abdominal pain, diarrhoea and headache [4246,
55]. For example, in the prucalopride 2 mg once daily [42,
44, 45], prucalopride 4 mg once daily [42, 44] and placebo
[42, 44, 45] arms of the 12-week, placebo-controlled trials,
nausea occurred in 11.623.9 %, 21.623.5 % and
3.214.2 % of patients, respectively, abdominal pain
occurred in 6.823.1 %, 18.522.5 % and 2.419.1 % of
patients, respectively, diarrhoea occurred in 13.022.1 %,
12.618.6 % and 5.37.9 % of patients, respectively, and
headache occurred in 12.426.6 %, 29.429.8 % and
2.016.7 % of patients, respectively.
When adverse events reported on day 1 were excluded,
the differences between prucalopride and placebo recipients in the incidence of these adverse events were attenuated [43, 44]. For example, after day 1 in prucalopride 2 or
4 mg once daily recipients and placebo recipients, the
incidence of headache was 15.1, 16.0 and 15.4 %,
respectively, the incidence of nausea was 13.0, 11.3 and
12.9 %, respectively, the incidence of abdominal pain was
17.2, 13.5 and 15.8 %, respectively, and the incidence of
diarrhoea was 8.0, 5.9 and 5.4 %, respectively [44].
Among elderly patients with chronic constipation
receiving prucalopride 1, 2 or 4 mg once daily or placebo
for 4 weeks, adverse events occurred in 48.7, 38.7, 47.5
and 44.4 % of patients, respectively [46]. In the corresponding treatment groups, abdominal pain was reported in
9.2, 4.0, 11.3 and 5.6 % of patients, respectively, headache
was reported in 6.6, 5.3, 8.8 and 4.2 % of patients,
respectively, diarrhoea was reported in 6.6, 1.3, 6.3 and
0 % of patients, respectively, and nausea was reported in
5.3, 1.3, 5.0 and 2.8 % of patients, respectively [46].
In the 4-week trial comparing prucalopride with PEG3350 ? E in women with chronic constipation, adverse
events (most of which were of mild to moderate severity)
were reported in 85.0 and 68.3 % of patients, respectively
[54]. Adverse events included headache (55.0 % of prucalopride recipients vs. 36.7 % of PEG-3350 ? E recipients), dysmenorrhoea (15.8 vs. 13.3 %), nausea (13.3 vs.
5.8 %), pharyngitis (10.8 vs. 5.8 %), vomiting (6.7 vs.
2.5 %), abdominal pain (5.8 vs. 2.5 %), urinary tract
infection (0.8 vs. 3.3 %) and back pain (0 vs. 5.0 %) [54].
Serious adverse events occurred in 1.21.9 % of prucalopride 2 mg once daily recipients [42, 43, 45] and
2.33.4 % of prucalopride 4 mg once daily recipients [42,
43] versus 2.03.8 % of placebo recipients [42, 43, 45] in

1946

the 12-week trials. In one of the trials in the elderly, serious

adverse events were reported in one patient each receiving
prucalopride 1 mg once daily, prucalopride 4 mg once
daily or placebo [46]. No deaths were reported during the
12-week studies [4245]. In the elderly, one placebo recipient died of a myocardial infarction in one study [46], and
two deaths occurred in prucalopride recipients in the other
study, although neither death was considered related to the
study drug [55].
Study drug discontinuation because of adverse events
occurred in 3.28.2 % of prucalopride 2 mg once daily
recipients [4245] and 615.1 % of prucalopride 4 mg
once daily recipients [4244] versus 1.26.7 % of placebo
recipients [4245] in the 12-week trials. Adverse events
leading most commonly to study drug discontinuation
included diarrhoea [42, 44, 45], headache [44], abdominal
pain [44], nausea [44] and vomiting [44], often occurring in
the first days of treatment [44].
Prucalopride was well tolerated in the longer term,
according to the results of open-label, follow-up studies of
the three 12-week registration trials [53]. During the first
3 months of the follow-up studies, discontinuation of prucalopride because of adverse events occurred in 2.5 % of
patients originally randomized to prucalopride and in 6.9 %
of patients originally randomized to placebo (reflecting the
higher incidence of adverse events that occurs in the first
few days of prucalopride treatment). Over the entire duration of follow-up, 8.0 % of patients discontinued prucalopride because of adverse events. The adverse events most
commonly responsible for discontinuation were headache
(1.0 % of prucalopride recipients), nausea (0.9 %),
abdominal pain (1.2 %) and diarrhoea (1.2 %) [53].
In one study, the incidence of prespecified adverse events
of interest was low in both prucalopride 2 mg once daily
recipients and placebo recipients, with pregnancy-associated events occurring in 0 and 0.4 % of patients, respectively, palpitations occurring in 1.6 and 1.2 % of patients,
respectively, and ECG signs of myocardial ischaemia
occurring in 0.4 and 0 % of patients, respectively [45].
In terms of other clinically significant cardiovascular
events, supraventricular tachycardia was reported in a
patient receiving prucalopride 2 mg once daily in one of
the registration trials; the patient had mitral valve prolapse
and a history of supraventricular tachycardia [42].
No clinically relevant differences were seen between
prucalopride recipients and placebo recipients in terms of
laboratory parameters, vital signs and ECG recordings [42
45], including in the elderly [46, 55].
In particular, the incidence of QTc interval prolongation
was low and similar among patients with chronic constipation who received prucalopride 0.54 mg once daily or
placebo [4246, 55], including in elderly patients with a
history of cardiovascular disease [55]. For example, no

G. M. Keating

significant changes from baseline in the QTcF interval

were seen in patients with chronic constipation after
12 weeks therapy with prucalopride 2 or 4 mg once daily
in one of the registration trials [42]. At any time during the
study, a maximum QTcF interval of 470500 ms was seen
in 0.5 % of prucalopride 2 mg once daily recipients, in
1.0 % of prucalopride 4 mg once daily recipients and in
0.5 % of placebo recipients, with a maximum QTcF
interval of [500 ms seen in 0, 0 and 0.5 % of patients in
the corresponding treatment groups [42].

6 Dosage and Administration

The approved indication for prucalopride differs between
regions/countries. For example, in the EU [6] and Canada
[38], prucalopride is approved for the symptomatic treatment of women with chronic constipation in whom laxatives have failed to provide adequate relief. By contrast, in
Australia and Switzerland, the label is not restricted to
women [37, 56]. Rather, prucalopride is indicated for the
treatment of chronic functional constipation in adults in
whom laxatives fail to provide adequate relief [37, 56].
The recommended dosage of prucalopride is 2 mg once
daily [6, 37]. Exceeding a prucalopride dosage of 2 mg
once daily is not expected to increase efficacy [6, 37, 38].
In terms of dosage adjustments, a starting dosage of
prucalopride 1 mg once daily is recommended in the
elderly; the dosage may be increased to 2 mg if needed [6,
37, 38]. The recommended prucalopride dosage in patients
with severe renal impairment is 1 mg once daily [6, 37,
38]. The recommended dosage of prucalopride in patients
with severe hepatic impairment is 1 mg once daily in the
EU and Australia [6, 37], which may be increased to 2 mg
once daily if needed to improve efficacy (and if the 1 mg/
day dosage is well tolerated) [6]. However, Canadian
prescribing information states that no dosage adjustment is
needed in patients with hepatic impairment [38].
Prucalopride tablets may be taken with or without food
at any time of the day [6]. If efficacy has not been demonstrated after 4 weeks of once-daily prucalopride therapy,
the patient should be re-examined and the benefit of
continuing treatment reconsidered [6, 37, 38].
Local prescribing information should be consulted for
contraindications, special warnings and precautions relating to prucalopride.

7 Place of Prucalopride in the Management of Chronic

Constipation
Chronic constipation is a common disorder that has a significant impact on HR-QOL, as well as being associated

Prucalopride: A Review

with a significant economic burden [2, 5, 57]. Constipation

can have many different causes [58]. The medical history,
examination and test results should allow a patients constipation to be classified (e.g. as normal-transit constipation, constipation-predominant irritable bowel syndrome,
slow-transit constipation, evacuation disorder or idiopathic/
organic/secondary constipation) [58]. After organic or
secondary causes of constipation have been excluded, most
cases of chronic constipation can be managed using a
symptomatic, graded approach to treatment [5, 58].
Initial treatment of constipation usually involves dietary
and lifestyle changes, such as increasing fibre intake
(either in the diet or with preparations such as psyllium or
methylcellulose) [5, 5860]. The next step usually
involves treatment with osmotic laxatives (e.g. polyethylene glycol, lactulose, sorbitol, magnesium hydroxide,
magnesium salts) [5, 58, 60]. Stimulant laxatives (e.g.
anthraquinone derivatives such as senna and diphenylmethane derivatives such as bisacodyl and sodium
picosulfate), softening agents (e.g. sodium dioctyl sulfosuccinate, glycerine, liquid paraffin) and probiotics may
also be used for the treatment of constipation [5, 59, 60].
Newer pharmacological options include prucalopride and
prosecretory agents (e.g. linaclotide, lubiprostone) [59,
60]. The availability of these newer agents differs between
markets, and prucalopride is currently the only agent
specifically approved for use in patients with laxativeresistant chronic constipation [61]. Nonpharmacological
treatment options for laxative-resistant chronic constipation include physical manipulation, colonic lavage, enemas and, rarely, surgery [61]. Biofeedback and pelvic
floor training is also an option for patients with an evacuation disorder [5, 58, 59].
Prucalopride 2 mg once daily improved bowel function
to a significantly greater extent than placebo in patients
with chronic constipation (Sect. 4.1). Although stringent,
the primary endpoint used in these studies (average of C3
SCBMs per week) is considered clinically meaningful and
combines the objective measure of the number of bowel
movements with the subjective measure of the completeness of evacuation [42, 43]. Significantly greater
improvements in HR-QOL, patient satisfaction with treatment and bowel habit, and a range of constipation-related
symptoms were also seen with prucalopride than with
placebo. Treatment effects were generally seen by 4 weeks
[42, 43]. It is recommended that if efficacy is not seen after
4 weeks treatment with prucalopride, the patient should be
re-examined and the benefit of continuing treatment
reconsidered (Sect. 6).
In elderly patients with chronic constipation, the primary endpoint (average of C3 SCBMs per week) was only
achieved in significantly more prucalopride than placebo
recipients at one time point (week 1) in patients receiving

1947

the highest dosage (prucalopride 4 mg once daily) [Sect.

4.1]. This primary endpoint was considered an ambitious
target in this patient group [46]. However, several other
measures of bowel function and HR-QOL were improved
with prucalopride 1 mg once daily. For example, patients
receiving prucalopride 1 mg once daily were more likely
than placebo recipients to have an average increase from
baseline of C1 SCBMs per week at weeks 1 and 4, were
more likely to have an increase in the PAC-QOL satisfaction subscale score of C1 and had greater increases in
the number of SCBMs per week (Sect. 4.1). Given that the
efficacy of prucalopride 1 mg once daily appeared similar
to that of prucalopride 2 mg once daily in this population, a
starting dosage of prucalopride 1 mg once daily is recommended in the elderly (Sect. 6).
Prucalopride is only approved for use in women in a
number of regions/countries (e.g. the EU, Canada), as the
associated regulatory authorities decided that the registration trials included too few men for efficacy to be established in this population [28, 38]. However, some countries
(e.g. Australia, Switzerland) have approved prucalopride
for use in both men and women [37, 56]. The pharmacodynamic effects of prucalopride appeared similar in men
and women (Sect. 2) [28], and a randomized, double-blind,
placebo-controlled, phase III trial examining the efficacy of
prucalopride in men with chronic constipation is currently
underway [62]. Prucalopride is not currently approved in
the USA.
An integrated analysis (Sects. 4.1.1.1 and 4.1.2.1) of the
three registration trials confirmed the efficacy of prucalopride 2 mg once daily in women with constipation who
reported inadequate relief from laxatives (i.e. the indication
approved in the EU [6] and Canada [38]). Results of this
analysis suggest that intermittent use of prucalopride is
associated with decreased efficacy, emphasizing the
importance of adhering to the once-daily treatment regimen
[49].
Satisfaction with treatment and bowel habit was maintained with prucalopride in the longer term (1,464 patientyears of prucalopride exposure), according to the results of
open-label follow-up studies (Sect. 4.1.3).
Results of a 4-week study conducted in a Phase I unit in
women with chronic constipation who were dissatisfied
with their previous laxative treatment indicate that the
osmotic laxative PEG-3350 ? E was noninferior to prucalopride in terms of the proportion of patients with C3
SCBMs during the last week of the study (Sect. 4.2). Some
secondary endpoints improved to a significantly greater
extent with PEG-3350 ? E than with prucalopride.
Although the controlled environment in which this study
was set has some advantages (e.g. it allows for environmental factors to be standardized), its major disadvantage
is that it is an artificial environment [54]. In addition, the

1948

study was only of 4 weeks duration, as a longer study

duration in this controlled environment was not feasible
[54]. A randomized, crossover study comparing the effect
of prucalopride with that of PEG-3350 ? E on colonic
motility is currently underway [63]. Additional studies
comparing prucalopride with other laxatives and agents
such as linaclotide and lubiprostone would be of interest.
Prucalopride 2 mg once daily was generally well tolerated in the treatment of chronic constipation, including in
the elderly (Sect. 5). The most commonly reported adverse
events were headache, nausea, abdominal pain and diarrhoea. Adverse events were of usually of mild to moderate
severity and transient duration, and occurred on the first
day of treatment. The favourable tolerability profile of
prucalopride was maintained in the longer term.
It has been suggested that there may be a relationship
between the pharmacodynamic effects of prucalopride and the
occurrence of adverse events on day 1 of therapy [64]. For
example, the average number of spontaneous bowel movements on day 1 was significantly (p \ 0.05) higher among
patients who experienced headache and abdominal pain than
among those who did not experience these adverse events [64].
The nonselective 5-HT4 receptor agonists cisapride and
tegaserod were previously available in some markets for
use in constipation [2, 65]. However, both agents were
withdrawn from most markets because of concerns over an
increased risk of cardiovascular adverse events [65]. The
increased risk of cardiovascular events seen with cisapride
was attributed to its interaction with the hERG potassium
channel [2, 65]. Although the mechanism by which tegaserod may increase cardiovascular risk has not been
clearly established, its affinity for the 5-HT1 and 5-HT2b
receptor subtypes has been proposed as a possible mechanism [2, 65, 66].
Given the cardiovascular issues that arose with cisapride
and tegaserod, the cardiovascular safety profile of the
highly selective 5-HT4 receptor agonist prucalopride has
been thoroughly investigated [67]. A 30-fold margin
between the IC50 for the hERG potassium channel and
Cmax has been suggested, in order to limit the risk of cardiac arrhythmias such as torsade de pointes [68]. The
prucalopride IC50 for the hERG potassium channel is at
least 200-fold higher than its therapeutic plasma concentration [13]. By contrast, there was no discernible safety
margin between the hERG potassium channel IC50 and the
therapeutic plasma concentration of cisapride [13]. Moreover, the margin between the affinity of cisapride for 5-HT4
receptors and the hERG potassium channel was \10-fold,
whereas prucalopride is more than 200-fold more selective
for 5-HT4 receptors than for the hERG potassium channel
[13].
Clinically significant effects on the QT interval were not
seen in healthy volunteers receiving supratherapeutic

G. M. Keating

prucalopride doses of up to 20 mg (Sect. 2.3). Moreover,

no cardiovascular safety issues have arisen in patients with
chronic constipation receiving prucalopride (Sect. 5).
Ongoing assessment of the cardiovascular safety of prucalopride in large samples of patients is needed to ensure
that rare adverse cardiovascular events are ruled out [42,
43]. Pharmacoeconomic analyses assessing the cost effectiveness of prucalopride in chronic constipation would also
be of interest.
Prucalopride has also shown potential in the treatment of
patients with chronic noncancer pain and opioid-induced
constipation [69, 70] and relieved symptoms in selected
patients with chronic intestinal pseudo-obstruction [71].
Prucalopride is not currently recommended for use in
paediatric patients (Sect. 6). Prucalopride demonstrated
beneficial effects in a small study in paediatric patients
aged 412 years with functional constipation [39].
In conclusion, the highly selective 5-HT4 receptor agonist prucalopride is an effective, generally well tolerated
treatment for chronic constipation. In well designed,
12-week trials in patients (predominantly women) with
chronic constipation, oral prucalopride 2 mg once daily
improved bowel function, HR-QOL, patient satisfaction
with treatment and bowel habit, and a range of constipation-related symptoms to a significantly greater extent than
placebo. Satisfaction with treatment and bowel habit was
maintained with prucalopride in the longer-term. Prucalopride was generally well tolerated in patients with chronic
constipation, with the most commonly reported adverse
events including headache, nausea, abdominal pain and
diarrhoea. During the clinical trials, no cardiovascular
safety issues have arisen in patients with chronic constipation receiving prucalopride. Thus, prucalopride is an
important option for use in patients with chronic constipation who have not experienced adequate relief with
laxatives.
Data selection sources: Relevant medical literature (including
published and unpublished data) on prucalopride was identified
by searching databases including MEDLINE (from 1946) and
EMBASE (from 1996) [searches last updated 8 October 2013],
bibliographies from published literature, clinical trial registries/
databases and websites. Additional information was also
requested from the company developing the drug.
Search terms: Prucalopride, Resolor.
Study selection: Studies in patients with chronic constipation
who received prucalopride. When available, large, well designed,
comparative trials with appropriate statistical methodology were
preferred. Relevant pharmacodynamic and pharmacokinetic data
are also included.

Disclosure The preparation of this review was not supported by any

external funding. During the peer review process, the manufacturer of
the agent under review was offered an opportunity to comment on this
article. Changes resulting from comments received were made by the
author on the basis of scientific and editorial merit.

Prucalopride: A Review

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