Pediatric Drugs

https://doi.org/10.1007/s40272-023-00612-8

ORIGINAL RESEARCH ARTICLE

Safety and Effectiveness of Prucalopride in Children with Functional

Constipation with and without Upper Symptoms
Alejandro Velez1 · Ajay Kaul1,2 · Khalil I. El‑Chammas1,2 · Lesley Knowlton1 · Erick Madis1 · Rashmi Sahay3 · Lin Fei3 ·
Sarah Stiehl4 · Neha R. Santucci1,2

Accepted: 6 December 2023

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024

Abstract
Introduction Pediatric prucalopride studies for treatment of gastrointestinal (GI) disorders have reported mixed results.
We aimed to assess the safety and effectiveness of prucalopride in functional constipation (FC) with and without upper GI
symptoms.
Methods Retrospective data on patients with FC receiving combined prucalopride and conventional therapy was compared
with those receiving conventional therapy alone within 12 months. Thirty patients on combined therapy and those on con-
ventional therapy were each matched on the basis of age, gender, race, and presence of fecal soiling. Response (complete,
partial, or no resolution) was compared. Similarly, response to concurrent functional upper GI symptoms (postprandial
pain, bloating, weight loss, vomiting, early satiety, or nausea) and dysphagia, as well as adverse effects, were evaluated in
the combined group.
Results Mean age of 57 cases was 14.7 ± 4.9 years and 68% were female. Comorbidities included functional upper GI
(UGI) symptoms (84%), dysphagia (12%), mood disorders (49%), and hypermobility spectrum disorder (37%). Unmatched
cases reported 63% improvement to FC; response did not differ between the matched cohorts (70% versus 76.6%, p = 0.84).
Cases showed a 56% improvement in functional UGI symptoms and 100% in dysphagia. Adverse effects were reported in
30%, abdominal cramps being most common. Four (7%) patients with a known mood disorder reported worsened mood, of
which two endorsed suicidal ideation.
Conclusion Prucalopride efficaciously treated concurrent UGI symptoms and dysphagia in constipated pediatric patients
and was overall well tolerated. Preexisting mood disorders seemed to worsen in a small subset of cases.

1 Introduction has investigated how these comorbidities respond to novel

promotility medications [7].
Functional constipation (FC) affects 16–25% of the As a highly selective serotonin receptor agonist, pru-
pediatric population [1, 2]. Current treatment modali- calopride has shown promise in the treatment of a myriad
ties include patient and family education about the dis- of gastrointestinal (GI) disorders [7–11]. Prucalopride is
ease process, behavioral/lifestyle modifications, and a US Food and Drug Administration (FDA)-approved for the
combination of oral and/or rectal laxatives [3]. However, treatment of chronic idiopathic constipation in adults [12]
these treatment modalities have limited efficacy [4] and with few side effects [13] and no appreciable cardiogenic
approximately a quarter of children with chronic consti- effects, unlike its non-selective predecessors —cisapride
pation have persistence of defecation problems in adult- [14, 15] and tegaserod [15]. While there is data on the
hood [5]. Additionally, recent studies have suggested that efficacy of prucalopride for adult GI disorders [10, 16],
comorbid conditions such as gastroesophageal reflux not the same is not the case in pediatrics. To date, there are
only exist in pediatric patients with FC but also respond few studies on the efficacy of prucalopride in pediatric GI
to the treatment of constipation [6]. These studies, how- disorders including two contradicting studies in pediatric
ever, have concentrated on the use of conventional treat- FC [8, 17], namely a favorable effect on the treatment of
ments for constipation, and to date, only one other study upper GI symptoms in children [7] and a case review of
its use in pediatric pseudo-obstruction [11]. Hirsch et al,
published the first and, to date, only study on pediatric
patients that evaluated the effect of prucalopride on upper
Extended author information available on the last page of the article

Vol.:(0123456789)
 A. Velez et al.

as indicated. Patients with gastrostomy, gastrojejunostomy,

Key Points and cecostomies without any other GI surgeries, ventricu-
loperitoneal shunt, organic GI disorders (eosinophilic dis-
We show that prucalopride may provide most improve- orders, celiac disease, and inflammatory bowel disease),
ment in patients with difficulty swallowing (dysphagia) mood disorders (anxiety and/or depression), neurogenic
and patients with indigestion (dyspeptic) symptoms that disorders or developmental delay (autism spectrum disorder,
are often associated with functional constipation. Down syndrome, etc.), Ehlers Danlos Syndrome, and other
Here we also noted that while generally a safe medica- hypermobility disorders were included. Patients who were
tion to use, prucalopride may worsen mood disorders on concurrent laxatives as part of the conventional therapy
and suicidal ideation in some patients. were included. We excluded patients with Hirschsprung dis-
ease, sacral nerve stimulation, gastric electrical stimulation,
myelomeningocele, anorectal malformations, and tethered
cord syndrome. For the defined study period, after apply-
ing exclusion criteria, a total of 57 prucalopride-treated
patients could be enrolled and analyzed. Demographics,
GI symptoms and concluded that those with enteral tubes symptoms, duration of symptoms, medical and medication
saw the most improvement in their symptoms [7]. Thus, history, clinical investigations, and dose of prucalopride
the objective of this study was to assess the safety and were collected from the initial visit. Clinical response to
effectiveness of prucalopride in children and adolescents constipation, functional UGI symptoms and dysphagia, dose,
with FC with and without upper GI symptoms such as duration of prucalopride treatment, and adverse effects were
meal-associated abdominal pain, nausea, vomiting, bloat- documented at the follow-up visit within 12 months. The
ing, early satiety, weight loss, and difficulty swallowing conventional therapy cohort constituted of 90 patients with
at our institution. a diagnosis of FC at their baseline visit who were started
on conventional medical management alone. Conventional
management included rectal disimpaction, bowel cleanout,
maintenance laxatives (subdivided as osmotic—e.g., poly-
2 Methods ethylene glycol—or stimulant—e.g., senna), pelvic floor
physical therapy, and behavioral modifications. Conducting
After obtaining institutional research board (IRB) approval, propensity score matching between those on combined pru-
we reviewed charts of all consecutive patients who were pre- calopride and conventional therapy and conventional therapy
scribed prucalopride between December 2018 and Decem- alone cohorts (stated below) resulted in a final sample size
ber 2020 and diagnosed with FC at the Cincinnati Children’s of 30 patients in each group.
Hospital Medical Center pediatric gastroenterology clinics.
We identified patients with FC from our database using
ICD-10 codes (K59.00, K59.01, K.59.04, and/or K59.09). 3 Outcomes
Patients met Rome criteria for FC. We included children and
young adults aged 0–24 years diagnosed with FC with or 3.1 Primary Outcome
without concomitant functional UGI symptoms and/or dys-
phagia who were treated with prucalopride at their baseline The primary outcome was defined as the clinical response, as
visit, along with conventional therapy for FC (referred to evaluated by their primary GI provider, to combined therapy
as combined therapy from now on) and had a documented (prucalopride AND conventional therapy) for FC and was
follow-up within 1 year after commencement of treatment captured as: complete improvement, partial improvement
(in the form of clinic visit, emergency room visit, or phone [response in some symptoms (straining, stool character,
call/email communication with parent documented in the greater than three spontaneous bowel movements per week,
patient’s chart). The definition of functional UGI symptoms sensation of incomplete evacuation) but not complete reso-
included meal-associated abdominal pain, nausea, vomit- lution], and no improvement. The combined therapy group
ing, bloating, early satiety, and/or weight loss. Dysphagia was then compared with matched conventional therapy alone
was defined as symptoms of difficulty swallowing and food cohort and examined within 3 months, 6 months, and 12
getting stuck in the chest. Per institutional standard of care, months from starting prucalopride treatment.
patients with dysphagic symptoms underwent further evalu-
ation including a contrast study (either as an esophagram or
an upper GI series) and an endoscopy. Those with inconclu-
sive or normal findings, underwent manometric evaluation
Safety and Effectiveness of Prucalopride in Children

3.2 Secondary Outcomes 5 Results

• Response of functional UGI symptoms (meal-associated 5.1 Patient Characteristics of the Unmatched
abdominal pain, nausea, vomiting, bloating, early satiety, Cohort at Baseline (N = 57)
and/or weight loss) and dysphagia (symptoms of esopha-
geal dysphagia including difficulty swallowing and food Of 57 patients on combined therapy (prucalopride and con-
getting stuck in chest) to prucalopride. ventional), the mean age was 14.7 ± 4.9 years (2–24 years);
• Association of prucalopride dose with primary response, 68% were female and 90% Caucasian (Table 1). All patients
adverse effects, and baseline characteristics. met at least two of the Rome criteria items for the diagnosis
• Distribution of adverse effects. of FC. Ten patients (20%) reported less than three bowel
movements (BMs) per week, 20/57 (35%) had hard stools,
and 13/57 (23%) had fecal incontinence. All patients in the
combined therapy treated group were on at least one concur-
4 Data Analysis rent laxative, 80% of patients were on a stimulant laxative,
60% were on an osmotic laxative, and 39% were on both a
To examine the primary outcome (response to FC) between stimulant and an osmotic laxative.
combined therapy treated patients and conventional therapy A total of 48 (84%) patients had concurrent functional
treated cohort, propensity score matching (PSM) was per- UGI symptoms and 7/57 (12%) had concurrent dysphagia.
formed to eliminate selection bias between the two study Of those with concurrent dysphagia, none had a baseline
groups. PSM was done using “MatchIt” package in R statis- organic GI disorder, two had endoscopic findings (chronic
tical environment (R Foundation for Statistical Computing, gastritis, duodenitis), and one had delayed 4-h gastric emp-
Vienna, Austria) [18]. The ratio was defined as 1:1 match tying study. All seven patients with dysphagia underwent
with a caliper width of 0.1 based on nearest neighbor-match- esophageal manometry testing, which was abnormal. Of
ing method without replacement. The covariates used for these, five had ineffective esophageal motility (IEM), one
matching were age, gender, race, and fecal incontinence. had poor esophageal reserve based on failed augmentation
Baseline characteristics for continuous variables were on rapid drink challenge, and one had inadequate bolus
summarized as mean (standard deviation) or median (first clearance.
and third quartile) and group differences examined using Four patients (7%) had organic GI disorders at baseline
Wilcoxon rank sum test. Categorical variables were pre- [celiac disease, 2 (3.5%), and eosinophilic esophagitis, 2
sented as frequency counts and percentages, and group dif- (3.5%)]; these patients were noted to be in endoscopic remis-
ferences were examined using the chi-squared or Fisher’s sion at the time of follow-up. Hypermobility spectrum disor-
exact tests. der was noted in 21/57 (37%), and 28/57 (49%) had a docu-
The response to FC was labeled as “complete improve- mented mood disorder. The most common mood disorders
ment,” “partial improvement,” and “no-improvement.” included anxiety in 45% and depression in 14% of patients.
Complete improvement denoted complete resolution of One patient had developmental delay, one had ventriculo-
symptoms while partial improvement corresponded with peritoneal (VP) shunt and seven had enteral feeding tubes.
improvement in some symptoms only. The association
between clinical response to FC and study groups was 5.2 Response to Prucalopride in FC (N = 57)
then examined at defined timepoints using chi-squared
statistics. Response to secondary outcomes (functional Of 57 patients on combined therapy (prucalopride and con-
UGI symptoms and dysphagia) in the combined therapy ventional), 36 (63%) reported improvement of FC. Specifi-
cohort were reported as frequency counts and percentages. cally, 20/57 (35%) had complete resolution, 16/57 (28%)
Association between prucalopride dose/day (0.5, 1, responded partially, while 21/57 (37%) were non-responders.
and 2 mg) in relation to age was examined using the pro-
portional odds model. The odds ratio [95% confidence 5.3 Response to Prucalopride in the Matched
interval (CI)] was analyzed for being on 2 mg/day dose Case‑Conventional Therapy Cohort (N = 30)
in comparison with 1 and 0.5 mg/day. All analyses were
conducted as two-sided tests with p ≤ 0.05 considered to After matching, 30 subjects in each group were examined
be statistically significant, and SAS 9.4 (SAS Institute Inc., (Table 1). In the matched combined therapy group, the
Cary, NC) was used. mean age was 11.7 ± 4.1 years; 63% were females and
97% were Caucasian. In the matched conventional ther-
apy group, the mean age was 11.7 ± 4.3 years; 57% were
 A. Velez et al.

Table 1  Baseline characteristics before and after propensity matching at 12-month follow-up
Variable Before matching After matching
Conventional therapy Prucalopride p value Conventional therapy Prucalopride p value
with conventional with conventional
therapy therapy
N = 200 N = 57 N = 30 N = 30

Age
Years, median (Q1–Q3) 7 (3–10) 16 (11-19) < 0.0001 11 (9–15) 12 (9–16) 0.97
Age group
≤5 84 (42%) 2 (3.5%) < 0.0001 2 (6.7%) 2 (6.7%) 1
>5 116 (58%) 55 (96.5%) 28 (93.3%) 23 (93.3%)
Gender
Male 106 (53%) 18 (31.6%) 0.004 13 (43.3%) 11 (36.7%) 0.60
Race
White 174 (87%) 51 (89.5%) 0.79 30 (100%) 29 (96.7%) 1
Black 13 (6.5%) 2 (3.5%) 0 (0%) 1 (3.3%)
Other 13 (6.5%) 4 (7.0%) 0 (0%) 0 (0%)
Baseline bowel movements per N = 176 N = 51 N = 27 N = 27
week
< 3/week 46 (26.1%) 10 (19.6%) 0.34 7 (25.9%) 6 (22.2%) 0.75
Fecal incontinence N = 200 N = 57 N = 30 N = 30
Yes 67 (33.5%) 13 (22.8%) 0.12 8 (26.7%) 9 (30%) 0.77
Stool consistency N = 200 N = 57 N = 30 N = 30
Hard 100 (50%) 20 (35%) 0.0003 16 (53%) 9 (30%) 0.03
Laxative use
Stimulant laxative N = 196 N = 44 N = 30 N = 22
98 (50%) 35 (79.6%) 0.004 19 (63.3%) 18 (81.8%) 0.15
Osmotic laxative N = 196 N = 45 N = 30 N = 23
185 (94.4%) 27 (60%) < 0.0001 28 (93.3%) 12 (52.2%) 0.006
Any laxative N = 196 N = 45 N = 30 N = 23
192 (98%) 45 (100%) 1 30 (100%) 23 (100%) NA
Both laxatives N = 196 N = 44 N = 30 N = 22
91 (46.4%) 17 (38.6%) 0.35 17 (56.7%) 7 (31.8%) 0.08

females and all were Caucasian. Since these were propen- follow-up, 12/55 (22%) increased their laxatives at follow-up
sity-matched cohorts, the demographic data did not differ (e.g., increase in dose, addition of another laxative), 19/55
between matched combined therapy and conventional ther- (35%) made no changes to their laxatives, and 24/55 (44%)
apy cohorts (p > 0.05). For the conventional therapy group, either reduced (n = 14) or stopped (n = 10) their concomi-
93% of patients were on osmotic laxatives and 63% were on tant laxatives. Response between the matched combined
stimulant laxatives at baseline. More than half (57%) were therapy and the conventional therapy group did not differ
noted to be on both stimulant and osmotic laxatives. At base- when separated by follow-up within 3 months (p = 0.41),
line, 30% of the combined therapy patients and 63% of the within 6 months (p = 0.59), or within 12 years (p = 0.84,
matched conventional therapy patients were found to have Fig. 1).
hard stool consistency; this was statistically significant (p
= 0.01). In the matched combined therapy group, 70% of 5.4 Response to Functional UGI Symptoms (N = 57)
patients showed either a complete (40%) or partial (30%)
improvement in FC within the 12-month period. Meanwhile, In the combined therapy group at baseline, 48 (84%) patients
in the conventional therapy group, 77% of patients showed reported at least one functional UGI symptom. Among these,
either complete (43.3%) or partial improvement (33.3%) 56% noted improvement in their symptoms (25% complete,
(p = 0.84; Fig. 1). In the combined therapy group, when 31% partial). In subgroup analysis, patients with hyper-
comparing laxative use at baseline and within the 12-month mobility syndrome that were identified to have comorbid
Safety and Effectiveness of Prucalopride in Children

functional UGI symptoms noted a 47% (n = 48) improve- (SD): 0.031 ± 0.016 versus 0.03 ± 0.015 mg/kg/day, median
ment in symptoms. and interquartile range (IQR): 0.029 (0.02–0.044) versus
0.031 (0.019–0.041) mg/kg/day]. Examining the relation-
5.5 Response to Dysphagia (N = 57) ship between prucalopride dose/day and the patient’s age,
a unit increase in age (years) was found to be significantly
Dysphagia was reported in seven (12%) of the patients in associated with 17% higher odds of being on 2 mg/day of
the combined therapy group at baseline. At follow-up, all of prucalopride in comparison with 1 or 0.5 mg/day [odds
those that reported swallowing issues saw improvement in ratio (OR) (95% CI): 1.17 (1.04–1.31), p = 0.01]. However,
their symptoms, with most (5/7, 71%) having complete reso- prucalopride dose was not associated with gender (p = 1.0)
lution while on prucalopride. All five patients that improved or response to FC (p = 0.21).
had esophageal manometry pre-prucalopride initiation with The starting and follow-up prucalopride dose did not
these respective findings: three had ineffective esophageal differ for children younger than 12 years of age [mean ±
motility disorder, one had poor esophageal reserve (failed SD: 0.041 ± 0.016 versus 0.036 ± 0.017 mg/kg/day, median
peristaltic augmentation during rapid drink challenge), and (IQR): 0.044 (0.027–0.05) versus 0.04 (0.026–0.047) mg/kg/
one had inadequate bolus clearance. day]. The most common dose at follow-up for this age group
(N = 18) was 2 mg (44.4%) and the least common dose was
5.6 Prucalopride Dose and Associations (N = 57) 0.5 mg per day (16.7%).
There was no statistically significant difference in dose
The most common dose/day initiated was 2 mg (49.1%) fol- between responders and non-responders for the dyspha-
lowed by 1 mg (35.1%) and 0.5 mg (15.8%, Table 2). Dose gia [mean ± SD: 0.027 ± 0.012 versus 0.030 ± 0.016 mg/
was increased in 12% and decreased in 4% of patients at kg/day, median (IQR): 0.028 (0.019–0.038) versus 0.032
follow-up. The dose did not differ significantly between (0.019–0.043) mg/kg/day] and functional upper GI symptom
baseline and follo- up visit [mean ± standard deviation groups [mean ± SD: 0.029 ± 0.014 versus 0.033 ± 0.021

Fig. 1  Response of functional

constipation to prucalopride at
3-, 6-, and 12-month follow-
up Response was graded as
complete improvement, partial
improvement, or no improve-
ment over baseline constipation.
Conventional therapy cohort are
patients with primary diagno-
sis of FC that only received
standard of care conventional
therapies. Data represents per-
cent improvement

Table 2  Prucalopride dosing (n = 57)

Dose (mg/kg/day) Baseline Follow-up p ­value§

Mean ± SD 0.031 ± 0.016 0.03 ± 0.015

Median (Q1–Q3) 0.029 (0.02–0.044) 0.031 (0.019–0.041) 0.79
Dose/day Baseline Follow-up p ­valueѰ
n (%) n (%) 0.34

0.5 mg 9 (15.8%) 5 (8.8%)

1 mg 20 (35.1%) 17 (29.8%)
2 mg 28 (49.1%) 35 (61.4%)
§
Wilcoxon rank-sum test, Ѱchi-squared test
 A. Velez et al.

mg/kg/day, median (IQR): 0.03 (0.019–0.04) versus 0.034 6 Discussion

(0.019–0.045) mg/kg/day].
Our study is one of few pediatric studies that compares the
5.7 Adverse Events (N = 57) effectiveness of combined prucalopride and conventional
therapy with conventional therapy alone for FC. In our
One or more adverse effects were reported by 17/57 (30%) study, prucalopride with conventional combination ther-
patients. These are summarized in Table 3. In brief, abdomi- apy showed a 70% response for FC that did not differ from
nal cramps were the most common adverse effects in 7/57 conventional therapy alone. This means that in our study
(12%) patients, followed by mood disturbances including population, both combined prucalopride and conventional
suicidal ideation, nausea, vomiting, headache, and dizziness. therapy and conventional therapy alone were noted to be
The 1 mg and 2 mg per day doses were associated with the equally efficacious. Two prior pediatric prospective clinical
bulk of discontinuation due to adverse events. Prucalopride studies have reported the response of FC to prucalopride [8,
was discontinued due to side effects in 30% of the patients 17]. The study by Mugie et al. [17] is the only randomized
and due to non-response in 7% (mean dose of 0.024 ± 0.014 double-blinded study of prucalopride in pediatric FC. They
mg/kg/day and 0.042 ± 0.016 mg/kg/day, respectively). A did not report any difference between the prucalopride and
total of 26 patients were noted to have an underlying mood placebo group (responder rates of 17% versus 17.8%, p =
disorder at baseline. Four (7%, N = 57) reported worsen- 0.90). On the other hand, Winter et al. used an open label
ing of their mood disorder, of which two had new onset of non-controlled design and demonstrated an improvement in
suicidal ideation and required drug discontinuation. These mean BM frequency (94.3% with ≥ 3 BMs per week) and
four patients were not on any medications for their mood reduced fecal incontinence (average number of episodes at
disorder. Most of the patients with worsening mood (3/4) week 1 of 5.6 versus 2.4 at week 8) with an adverse event
were on 1 mg/day and the remaining patient was on 0.5 mg/ rate of 26/37 (70%) in their pediatric patient population [8].
day dose of prucalopride. Adverse events associated signifi- However, both were clinical studies with short observation
cantly with response to FC (p < 0.001) and 81% of patients periods (4–8 weeks) and tight inclusion criteria. Our study,
with adverse effects demonstrated no improvement. There on the other hand, mirrored the real-world clinical setting as
was a positive association between adverse events and doses close as possible with follow-up over a longer time frame.
of prucalopride (p = 0.05) with most events occurring at The response to conventional therapy alone in our study is
either 1 mg/day (53%) or 2 mg/day (41%) dose. No associa- higher than previously reported (50–60%) [19], which may
tion was noted between adverse effects and age (p = 0.70) be explained by the fact that most were under the care of spe-
or gender (p = 0.39). cialists in neurogastroenterology. In the only other pediatric
study to have taken this approach, they found that 66% of
their patients with baseline constipation improved with use
of prucalopride [7]. It should be noted that both our study,
as well as that published by Hirsch et al., included patients
that were on laxatives and prucalopride therapy. This means
that the independent effect of prucalopride on FC is not
Table 3  Adverse effects and lack of response to prucalopride easily separated, and it is unclear whether the response in
Adverse effects N = 57 Mean ± SD
constipation relief is related to prucalopride alone. Thus, it
Dose (mg/kg/day) is difficult to ascertain whether the treatment response in
our study is an effect of prucalopride on FC or the effect
Adverse effects of concomitant use of laxatives. Another possibility for the
Abdominal cramping 7 (12%) 0.020 ± 0.017 difference in response between the two groups could be that
Worsened constipation 3 (5%) 0.026 ± 0.011 patients who were started on prucalopride may have had
Worsened mood (anxiety and 4 (7%) 0.020 ± 0.010 a more severe phenotype of constipation with worse rec-
depression)
tosigmoid dilation compared with the conventional therapy
Suicidal ideation 2 (4%) 0.020 ± 0.007
group.
Diarrhea 2 (4%) 0.038 ± 0.009
Prucalopride has been used for a number of GI disorders
Nausea and vomiting 3 (5%) 0.022 ± 0.021
and due to its receptor specificity is well tolerated [7–11].
Headache and dizziness 3 (5%) 0.032 ± 0.013
Selective agonism at the 5-HT4 receptors enhances the
Medication intolerable 3 (5%) 0.041 ± 0.020
release of neurotransmitters from their terminals and other
Drug discontinuation
terminals in the GI prokinetic reflex pathways [20]. Differ-
Due to adverse effects 17 (30%) 0.024 ± 0.014
ential distribution of 5-HT receptor subtypes enables the use
Due to non-response 4 (7%) 0.042 ± 0.016
Safety and Effectiveness of Prucalopride in Children

of 5-HT4 agonists to specifically treat intestinal discomfort that may occur with prucalopride therapy. This is likely
and motility [20]. 5-HT4 stimulation in enteric cholinergic because studies tend to exclude patients with mood disor-
neurons results in acetylcholine release and smooth muscle ders and fail to elicit changes in mood as an adverse effect
contraction, and 5-HT4 stimulation in inhibitory enteric or unless identified by the patient directly. About half of our
nitrergic neurons results in nitric oxide release and smooth study population prior to matching was noted to have an
muscle relaxation [21]. As such, prucalopride may be an underlying mood disorder (anxiety, depression) and four
adjunctive therapy for patients with FC that may also be (7%) of these endorsed worsened mood after commencing
suffering from coexisting conditions such as functional UGI treatment with prucalopride. Alarmingly, two (4%) with pre-
symptoms and dysphagia. In the present study, more than existing mood disorder reported new onset suicidal ideation.
half of the prucalopride-treated patients had some resolu- As part of prescribing information for prucalopride, the FDA
tion in their functional UGI symptoms and all patients had includes the section “suicidal ideation and behavior” under
improvement in dysphagia with over 70% experiencing their “Adverse Reactions of Special Interest” section detail-
complete resolution of their swallowing issues. This find- ing that “one patient reported a suicide attempt 7 days after
ing parallels that of the Hirsch et al. study that reported the end of treatment with 2 mg once daily.” However, this
improvement in 65% of patients with upper GI symptoms has only been reported in one other pediatric study by Hirsch
(defined as feeding difficulties, nausea, vomiting, reflux, et al. [7]. Their study also included an assessment of base-
dysphagia, or abdominal pain) on prucalopride with those line and posttreatment psychiatric conditions in their pediat-
with enteral tube seeing the most improvement on symptoms ric cohort with one patient in the cohort (1/71; 1.4%) noted
while on prucalopride [7]. Additionally, half of our patients to have “psychosis” as a possible adverse event while on
with hypermobility syndrome and coexisting functional UGI prucalopride treatment. Our work and the Hirsch et al. study
symptoms, and the majority of those with concurrent dys- are the only two pediatric studies to include patients with
phagia, showed improvement in symptoms while on prucalo- mood disorders and report on the possible mood-altering
pride. This highlights the overlap in pediatric motility disor- properties of this drug (relatively higher prevalence in our
ders and the advantage of prucalopride’s prokinetic effect on study). This may be clinically relevant during the selection
various segments of the GI tract, making it a feasible choice of patients who would have more benefit than risk with pru-
for treating GI motility disorders affecting other segments calopride therapy. Caution should be taken when prescribing
of the GI tract other than just the colon. prucalopride in pediatric (especially adolescent) patients and
The safety and tolerability of prucalopride has been previ- a screening for mental health disorders instituted prior to
ously studied in adults and children [8, 15, 22, 23]. Prucalo- starting the medication and regularly while on prucalopride
pride has been noted to have better safety and side-effect pro- therapy.
file when compared with cisapride and tegaserod, likely due The advantage of our study was a cohort with a rela-
to its selectivity for the 5-HT4 receptor [22]. In children, the tively large sample size and inclusion of patients with vari-
most common reported side effects were headaches, abdomi- ous comorbidities, including upper GI symptoms, dysphagia,
nal pain, and nausea with none reporting cardiac side effects and mood disorders, which are often excluded from rand-
[7, 8, 17]. In the randomized controlled trial by Mugie et al., omized controlled trials. Second, we used propensity score
treatment-emergent adverse effects were reported in 65–70% matching to assess our outcomes allowing for more robust
patients on prucalopride versus 60–62% in placebo/Poly- conclusions similar to a prospective trial. We were able to
ethylene Glycol (PEG) groups [19]. In comparison, in our compare the two groups effectively by using propensity
study, 30% of patients had at least one adverse effect attribut- matching and our conclusions are likely stronger than earlier
able to prucalopride with the most common being abdominal studies where no propensity matching was done. In addi-
cramping, followed by mood disturbances including suicidal tion, a provider contemplating the use of prucalopride can
ideation, nausea, vomiting, headache, and dizziness. About assess patients for associated upper GI comorbidities and
a quarter of the prucalopride group discontinued the drug potential mood disorders as risk factors and make a more
due to adverse effects. The adverse effect rate reported in our informed decision about continuing conventional therapy
study was within the previously published pediatric range or the use prucalopride to target the UGI concerns with-
(19–70%) [7, 8, 17]. The variable rate of adverse events is out losing efficacy against constipation. Finally, our study
likely due to variability in the employed methods of report- included a thorough investigation of adverse effects which
ing. However, adverse effects of prucalopride are nonethe- allowed us to identify the potential effect of prucalopride on
less common and often lead to discontinuation of the drug. mood disorders.
Hence, patients and families should be made aware of this Our study had a few limitations. Due to its retrospec-
possibility at the commencement of treatment. tive design, we were unable to assess response on a symp-
Among the well-known adverse effects, our study is one tom–response scale or measure adherence. We were unable
of the two to date to report on the potential mood alterations to follow patients after a year to assess longer outcomes. We
 A. Velez et al.

were also unable to compare our treatment populations to an Declarations

untreated population. However, we attempted to remove age,
gender, race, and presence of fecal incontinence as possible Funding This study was funded by pediatric gastroenterology divi-
sional funds.
interfering factors by making use of propensity matching.
The objective of this study was to assess the effectiveness
Conflict of Interest All authors certify that they have no affiliations
of prucalopride in FC and comorbid conditions. For the pri- with or involvement in any organization or entity with any financial
mary efficacy outcome, namely improvement of symptoms, interest or non-financial interest in the subject matter or materials dis-
a post hoc power analysis showed that we need about 100 cussed in this manuscript.
patients per group (as opposed to 30 per matched group) to
Ethics Approval This retrospective chart review study involving human
reach 80% power. Of course, going into the study, we did not participants was done in accordance with the ethical standards of the
have information regarding effect size, therefore this power institutional and national research committee and with the 1964 Hel-
analysis can serve as a guide for future studies. Additionally, sinki Declaration and its later amendments or comparable ethical
standards. The Human Investigation Committee (IRB) of the Cincin-
we aimed to study the safety of prucalopride in our pediatric
nati Children’s Hospital approved this study.
patient population but did not address the adverse event rate
of the conventional therapy cohort. Future studies should Informed Consent Not applicable.
consider comparing the adverse event rates of both therapies.
Consent for Publication Not applicable.
The next step in the evaluation of prucalopride should
be using a large prospective study design to better assess Data Availability The datasets generated during and/or analyzed dur-
the effects of prucalopride and prucalopride plus laxative ing the current study are available from the corresponding author on
effect on functional constipation and to better delineate the reasonable request.
effects on mood disorders by employing standardized meas-
Author Contribution Statement All authors contributed to the study
ures of anxiety, depression, and suicidal ideation. While we conception and design. Material preparation, data collection and analy-
observed worsening mood in a small number of patients in sis were performed by Lesley Knowlton, Erick Madis, and Alejandro
our study, factors determining causality or risk still need Velez Lopez supervised by Dr. Neha R Santucci. Dr. Rashmi Sahay
provided statistical expertise, Sarah Stiehl provided pharmaceutical
to be explored. Further studies are needed to assess the
expertise, while Drs. Kaul, El-Chammas and Santucci provided exper-
response of prucalopride in functional UGI symptoms and tise on functional constipation and other motility disorders. The first
dysphagia independent of FC and also assess the esophageal draft of the manuscript was written by Alejandro Velez Lopez and all
manometric changes with prucalopride. authors commented on previous versions of the manuscript. All authors
read and approved the final manuscript.

Previous Communications: As an abstract/poster for the 2021 North

7 Conclusion American Society for Pediatric Gastroenterology, Hepatology and
Nutrition (NASPGHAN) that only included the prucalopride cohort
results. As an abstract/poster for NASPGHAN 2022 that included the
Our study adds an important insight into the effective-
conventional therapy–prucalopride cohort analysis and the propensity
ness, safety, and tolerability of prucalopride in pediatric matched data. As an abstract/podium presentation for 2022 Pediatric
patients. We were unable to show the independent efficacy Colorectal and Pelvic Reconstruction Conference (PCPLC).
of prucalopride in functional constipation as there was no
direct comparison of patients on prucalopride alone versus
on conventional laxative therapy. We were, however, able
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Authors and Affiliations

Alejandro Velez1 · Ajay Kaul1,2 · Khalil I. El‑Chammas1,2 · Lesley Knowlton1 · Erick Madis1 · Rashmi Sahay3 · Lin Fei3 ·
Sarah Stiehl4 · Neha R. Santucci1,2

2
* Neha R. Santucci University of Cincinnati College of Medicine, Cincinnati,
[email protected]; [email protected] OH, USA
3
1 Biostatistics, Cincinnati Children’s Hospital Medical Center,
Gastroenterology, Hepatology and Nutrition, Pediatric
Cincinnati, OH, USA
Gastroenterology, Cincinnati Children’s Hospital Medical
4
Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, Division of Pharmacy, Cincinnati Children’s Hospital
OH 45229, USA Medical Center, Cincinnati, OH, USA