EXPERT OPINION ON DRUG SAFETY
https://doi.org/10.1080/14740338.2021.1952980

ORIGINAL RESEARCH

Safety of elobixibat and lubiprostone in Japanese patients with chronic
constipation: a retrospective cohort study
Nobuhiro Ooba a, Yoshinori Takahashib, Marina Nagamuraa, Masao Takahashib, Makoto Ushidac, Eiji Kawakamib,
Masaomi Kimurad, Tsugumichi Satoe, Junichi Tokuyoshib, Choichiro Miyazakib and Mitsuaki ShimadabaDepartment of Clinical Pharmacy, Nihon University School of Pharmacy, Chiba, Japan; bJapan Pharmaceutical Association, Tokyo, Japan; cFacultyof Pharmacy, Meijo University, Aichi, Japan; dDepartment of Computer Science and Engineering, Shibaura Institute of Technology, Tokyo, Japan;eDepartment of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan
ABSTRACT

Background: We aimed to discuss and compare reported adverse reactions and drug add-ons asso­
ciated with elobixibat and lubiprostone use in chronic constipation treatment, as the safety of thesedrugs has not been well examined in post-marketing clinical settings.
Research Design and Methods: In this retrospective cohort study, using records of community
pharmacies in Japan, we identified new users of elobixibat and lubiprostone. The Japan
Pharmaceutical Association sent questionnaires regarding baseline and event data to community
pharmacists. The incidence of events and hazard ratio (HR) associated with the study drugs were
evaluated.
Results: New users of elobixibat (n = 979) and lubiprostone (n = 829) were identified (mean age: 74 and77 years; females: 59% and 53%, respectively). Although the crude risk ratio of adverse events for
elobixibat was 0.79 (95% confidence interval: 0.63–0.99), there was no significant difference in the HR
for any of the common events, including drug add-ons (n ≥ 5), compared with those for lubiprostone.
Conclusion: No new safety concerns have been raised in relation to elobixibat and lubiprostone use fortreating chronic constipation, although the HR of different events varied. Further larger-scale study isneeded as the estimates for events of small numbers were unstable

ARTICLE HISTORY

Received 1 March 2021
Accepted 5 July 2021
KEYWORDS

Community pharmacist;
new-user design; pharmacy
record; primary datacollection; retrospective
cohort study

1. Introduction
Chronic constipation is a common gastrointestinal condi­tion [1], the prevalence of which ranges from 1.9% to27.2% in North America [2] and is reportedly higher infemales and individuals older than 65 years [3]. The
Comprehensive Survey of Living Conditions in Japan
reported that the prevalence of constipation symptoms
has increased by approximately 1.4 times from 24.5 per
1,000 person-years in 2016 to 34.8 per 1,000 person-years
in 2019, and so has the prevalence in the elderly popula­tion (65.0 per 1,000 person-years in 2016 to 68.6 per
1,000 person-years in 2019) [4]. As the disease is associatedwith patients’ quality of life [1], mortality, and cardiovas­
cular disease prevalence [5,6], its management with appro­
priate treatment is important.
Among the laxatives used to treat constipation [7–11],
magnesium and stimulant laxatives are widely used inJapan [12]. Recently, novel drugs for chronic constipation
have been introduced. Lubiprostone was approved in2012, and it stimulates chloride secretion via the activationof type-2 chloride channels in the gastrointestinal tract[13]. Elobixibat, which inhibits the uptake of bile acids,
was approved in 2018 [14]. Lubiprostone has been mar­keted in some countries, including the United States,

whereas elobixibat is authorized only in Japan as ofMarch 2020. In a retrospective cohort study comparing
users of elobixibat and lubiprostone [15], the incidence ofnausea in users of lubiprostone 48 μg was 3.4 times higher
than that in users of elobixibat 10 mg. The incidence ofadverse events caused by elobixibat (9%) was significantly
lower than that caused by lubiprostone (15%) with a daily
dose of 24 μg. However, as this was a single-center study
with an observation period of 2 weeks, the generalizabilityof the findings may be limited.
Nausea is the most common adverse event associatedwith lubiprostone use [16], but serious adverse events havebeen rarely reported in association with elobixibat or lubi­
prostone use [17,18]. However, monitoring and evaluationof drug safety should be continued in actual clinical set­tings to identify the differences in the incidence propor­
tion of common adverse events such as diarrhea,
abdominal pain, and abdominal discomfort to benefit
patients suffering from constipation and ensure adherence
to treatment. The aim of this retrospective cohort study
involving community pharmacists was to examine thesafety of the new drugs elobixibat and lubiprostone post
marketing.

CONTACT Nobuhiro Ooba
ooba.nobuhiro@nihon-u.ac.jp
Nihon University School of Pharmacy, Chiba, Japan
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2021.1952980© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

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N. OOBA ET AL.

2. Patients and methods
2.1. Study design
This was a retrospective cohort study performed using the
new-user design [19]. Drug event monitoring (DEM) by theJapan Pharmaceutical Association (JPA) [20] includes both
event monitoring and reported event evaluation. For DEM,
the JPA sent paper-based questionnaires (Supplemental) to
48,382 community pharmacies affiliated to the JPA (as ofFebruary 2020); pharmacists in 5,562 pharmacies completed
the questionnaire. Study patients were then identified from2,343 pharmacies (Figure 1). The data from the questionnaires
were entered into a web-based online report form prepared inadvance. When pharmacists entered the data in the online
form, the information of individual patients was anonymized
using study identification data (ID) for each pharmacy. First,
the pharmacists identified new users of elobixibat and lubi­
prostone using pharmacy records; study patients were those
who had newly started taking the study drug in
September 2019 after 6 months of non-study drug use;patients who did not visit the pharmacy before
February 2019 were excluded. To prevent comparison
between patients with chronic constipation of different seve­
rities, we restricted our study to patients who did not takeeither elobixibat or lubiprostone. Although pharmacists incommunity pharmacies do not have the right to access the
medical records of patients in clinics or hospitals, pharmacy
records contain data on health insurance; prescription; followup during treatment by pharmacists; and demographic char­acteristics obtained from patients, including allergy, current
smoking, alcohol consumption, over-the-counter drug use,comedications, and comorbidities. According to Article 25–2of the Pharmacists Act in Japan, pharmacists as professional
service providers offer a patient or a person caring for thepatient the necessary guidance based on pharmaceuticalknowledge and monitor the effects of drugs and changes in
the patient’s physical condition during drug use.
Next, the pharmacists collected the baseline data (demo­
graphic data, co-medication [use of anti-hypertensives, antidiabetics, lipid-lowering drugs, steroids without external use,anti-ulceratives, anti-depressants/hypnotic drugs, antiParkinson’s drug, dabigatran, and digoxin], comorbidity[hypertension, diabetes mellitus, dyslipidemia, myocardial
infarction, and cancer], and a history of admission) for
6 months before the initiation of the study drugs (elobixibat
and lubiprostone), along with events data during the followup period between September 2019 and December 2019.
Whether or not there was a corresponding co-medication orcomorbidity in pharmacy records was described in thequestionnaire.

2.2. Definition of events
An event in the follow-up period included any suspecteddrug reaction, unexpected deterioration (or improvement)
in a concurrent illness, reasons for stopping the study druguse (if stopped), or adding a new drug (if added). Information
on add-on drugs may be used to characterize an event andan improvement in concurrent illness may complement theevent regarding drug discontinuation. The adverse eventswere partially defined using the methodology of Modified
Prescription-Event Monitoring (M-PEM) [21]. The pharmacists
involved in patient care at the pharmacies determineda suspected event due to a drug and deterioration of or
improvement in concurrent illness. We used the Medical
Dictionary for Regulatory Activities Terminology (MedDRA)
version 22.1 to encode reported events [22]. After selecting
the lowest level terms in the MedDRA, we converted them tothe preferred term level.

Japan Pharmaceutical Association (JPA) sent paper-based questionnaires to 48,382
community pharmacies (as of February 2020).

Among all patients using the study drugs in September 2019, pharmacists identified
patients who used the pharmacy more regularly than before February 2019 and thenselected patients who newly started taking study drugs after six months ofnon-study drug use.

Pharmacists completed the questionnaire regarding baseline data (demographic,
co-medication, and comorbidity) during the six months before the study start date
and the drug-event data during the follow-up period.

The data from questionnaires were entered into a web-based online form bypharmacists at 5,562 community pharmacies, and study patients were identified at
2,343 community pharmacies.

Figure 1. Drug-event monitoring study design and process

EXPERT OPINION ON DRUG SAFETY

2.3. Statistical analysis
Summary statistics describe demographic characteristics,
comorbidities, and co-medications of study patients. We pre­sent the number and proportion of patients with these cov­
ariates at baseline. The standardized difference [23] was used
to evaluate the difference in baseline characteristics between
the drug groups. The absolute standardized difference greaterthan 0.1 suggested imbalances between the groups.
The incidence proportion of reported events including dis­continuation in patients during treatment with the study
drugs was calculated, and the crude risk ratio (RR) was esti­
mated for adverse reactions. The hazard ratio (HR) and its 95%
confidence interval (CI) were estimated for common eventsusing the Cox proportional hazards model, with the incidence
rate of an event for lubiprostone as the reference.
Adjustments for age, sex, anti-diabetic usage, and laxative
usage were made using the Cox proportional hazards model.
Confounding factors with absolute standardized differences
greater than 0.1 were incorporated in the Cox regression
model. The observation period for the assessment of anevent was defined as the period from the start date of elobix­
ibat or lubiprostone to the incidence date, date of switching or
stopping the study drug, last visit date, or 31 December 2019,
whichever came first. Results with p < 0.05 were considered
statistically significant. All analyses were conducted using SAS,version 9.4 (SAS Institute, Cary, NC, USA).

2.4. Ethical consideration
This retrospective cohort study adhered to the tenets of the
Declaration of Helsinki and the study protocol was approvedby the ethics review committee of the JPA (no. 2019–002). The
ethics committee waived the need for individual informed
consent as the study data were fully anonymized.

3. Results
There were 2,866 prevalent elobixibat users and 4,056 lubi­
prostone users during the study period. Of these, 979 patientsusing elobixibat (34%) and 829 using lubiprostone (20%) wereidentified as new users of the drugs.

3

Table 1. Baseline characteristics of new users of elobixibat or lubiprostone.
Elobixibat
Lubiprostone Standardized(n = 979)(n = 829)
difference
Mean age, years (SD)74 (15.2)
77 (13.1)−0.182
Female (%)
573 (58.5)
440 (53.1)
0.110
Mean daily dose
8.7 mg34.1 μg
Mean observation period
81.1
83.6
0.039
(days)
Current smoking (%)
78 (8.0)49 (5.9)
0.081
Alcohol drinking (%)
188 (19.2)
132 (15.9)
0.081
Comorbidity (%)
Hypertension
536 (54.7)
474 (57.2)−0.049Diabetes mellitus
183 (18.7)
188 (22.7)−0.099Dyslipidemia
315 (32.2)
268 (32.3)−0.003
Myocardial infarction
23 (2.3)
34 (4.1)−0.099Cancer75 (7.7)
60 (7.2)
0.016
Co-medication (%)
Anti-hypertensives
534 (54.5)
491 (59.2)−0.095Anti-diabetics
183 (18.7)
193 (23.3)−0.113
Lipid-lowering drugs
337 (34.4)
278 (33.5)
0.019
Laxatives without
416 (42.5)
411 (49.6)−0.143
elobixibat/lubiprostoneAnti-ulceratives
363 (37.1)
347 (41.9)−0.098
Steroids, except for external
31 (3.2)
28 (3.4)−0.012use
Anti-depressants/ hypnotic
303 (30.9)
270 (32.6)−0.035drugs
Anti-Parkinson’s drug
41 (4.2)
36 (4.3)−0.008Dabigatran etexilate
3 (0.3)1 (0.1)
0.040
Digoxin
7 (0.7)6 (0.7)−0.001
History of admission (%)
44 (4.5)
45 (5.4)−0.043SD, standard deviationthat for lubiprostone. Treatment discontinuation due toimprovements was observed in 8.7% (n = 85) of 257 patientsin the elobixibat group and 5.9% (n = 49) of 174 patients inthe lubiprostone group, and the crude RR was 1.47 (1.05–2.06).
Discontinuation due to any suspected adverse drug reaction
was reported in 7.3% (n = 71) of patients in the elobixibat
group and 8.6% (n = 71) of patients in the lubiprostone group,and the crude RR was 0.85 (0.62–1.16). Among the remaining
patients in the elobixibat group, 68 discontinued treatment
due to a lack of response (7.0%) and 33 discontinued treat­ment for unknown reasons (3.4%), whereas in the lubipros­
tone group, 49 discontinued treatment due to a lack of
response (5.9%) and 25 discontinued treatment for unknown
reasons (3.0%).

3.1. Patient characteristics

3.3. Proportion of events

Table 1 shows the baseline characteristics of the study parti­
cipants. The average observation period was approximately
80 days for both drugs. The mean age was 74 years for
elobixibat users and 77 years for lubiprostone users; the pro­portion of females was 58.5% among elobixibat users and53.1% among lubiprostone users. Age, sex, and anti-diabetic
and laxative usage had absolute standardized differences
greater than 0.1 between the groups.

The incidence proportion of highly reported events among
elobixibat and lubiprostone users is shown in Table 2. Some
events, including diarrhea, abdominal pain, and laxative andanti-hypertensive use, were common in both groups. For elo­
bixibat, the proportion of any adverse reaction was 12.4%,
with diarrhea (2.9%), abdominal pain (1.4%), and constipation(0.8%) being the most frequent adverse events. Other drugs
were added for 19.7% of elobixibat users; of these, the mostreported were laxatives without lubiprostone (11.3%), antihypertensives (1.8%), and lubiprostone (1.4%), in that order.
The occurrence of any adverse reaction was 15.7% for lubi­
prostone, with diarrhea (4.0%), constipation (1.5%), andabdominal pain (1.1%) being the most reported adverse
events. Other drugs were added to 21.2% of lubiprostone

3.2. Proportion of discontinuation and improvement
The treatment was discontinued by 26.3% (n = 257) of theelobixibat users and 21.0% (n = 174) of the lubiprostone users,
and the crude RR was 1.25 (95% CI: 1.06–1.48) compared with

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N. OOBA ET AL.

Table 2. Events* reported frequently for elobixibat and lubiprostone usage.

Event
Any adverse reaction
Diarrhea
Abdominal pain
Constipation
Blood pressure increased
Soft feces
Hospitalization
NauseaAny drug add-on
Laxative except lubiprostone†/elobixibat‡
Anti-hypertensive
Lubiprostone
Elobixibata
Anti-ulcerative
AntacidNon-steroidal anti-inflammatory
drug
Antibiotic
Anti-allergic
Diuretic
Hypnotic
Anti-flatulent
Analgesic

Number (%)
Elobixibat
Lubiprostone(n = 979)(n = 829)
121 (12.4)
130 (15.7)
28 (2.9)33 (4.0)
14 (1.4)
9 (1.1)8 (0.8)12 (1.5)
7 (0.7)3 (0.4)5 (0.5)6 (0.7)4 (0.4)7 (0.8)1 (0.1)6 (0.7)193 (19.7)
176 (21.2)
111 (11.3) †97 (11.7) ‡18 (1.8)
14 (1.4)
0 (-)
11 (1.1)
6 (0.6)5 (0.5)14 (1.7)
0 (-)
11 (1.3)
7 (0.8)7 (0.8)7 (0.8)5 (0.5)5 (0.5)0 (-)
0 (-)
4 (0.4)3 (0.3)6 (0.7)3 (0.4)10 (1.2)
7 (0.8)5 (0.6)5 (0.6)*n ≥ 5 reported or serious eventsusers, and the most reported were laxatives without elobixibat(11.7%), anti-hypertensives (1.7%), and elobixibat (1.3%) inthat order. The top three adverse events (diarrhea, abdominal
pain, and constipation) and added drugs (laxatives, antihypertensives, and study drugs) after the initiation of thestudy drugs were similar. The pre-identified risk of nausea
was 0.72% (n = 6) for lubiprostone and 0.1% (n = 1) for
elobixibat. Details of events related to hospitalization in both
drug groups were unknown.

3.4. Comparison of common events between the drugs
The crude RR of any adverse reaction for elobixibat was 0.79
(95% CI: 0.63–0.99) compared with that of lubiprostone. Table

3 shows unadjusted and adjusted HRs for the common events
including the event of drug add-on after the initiation of
elobixibat, using those of lubiprostone as the reference. No
significant difference was found for each of the common
events, including drug add-on (n ≥ 5), between the study
drug groups. The adjusted HR of nausea for lubiprostone
was 7.09 (0.85–58.8) compared with that for elobixibat,
although the CIs were wide.

4. Discussion
Using data from the Japan system of DEM, which plays thedual role of collecting and evaluating reported events, thesafety of elobixibat and lubiprostone usage in chronic consti­
pation treatment was examined by community pharmacists.
Although the proportion of any adverse reaction associatedwith elobixibat was 21% lower than that with lubiprostone,
the proportion of common events including new drug addons and discontinuation owing to any suspected adverse drug
reaction in both groups was similar and not significantly dif­ferent. Events with symptoms of constipation or laxativeassociated diarrhea are most commonly reported with theuse of laxatives. Furthermore, diarrhea caused by other
newly commercialized drugs (e.g. linaclotide) is common[24]; it is also associated with lubiprostone use, althoughmultiple electrolyte abnormalities, hypovolemia, and diarrhea
have been reported to be associated with magnesium in con­ventional drugs [25]. In addition to paying attention to the comedication and comorbidity related to constipation, better
patient care for chronic constipation is recommended, taking
into account the expected events.
In randomized placebo-controlled phase II and III trials for
elobixibat, the frequently reported adverse events wereabdominal pain (12%–26%) and diarrhea (5%–15%), although
no severe adverse drug reactions occurred [14,26]. Diarrhea(6%) and abdominal pain (5%) were reported as common
events in a retrospective cohort study without a comparatorgroup [27]; these results are consistent with our findings for

Table 3. HR of common events reported in both elobixibat and lubiprostone users.
Event
Any adverse reaction
Diarrhea
Abdominal pain
Constipation
Increased blood pressure
Soft feces
Hospitalization
Any drug add-on
Laxative
Anti-hypertensive
Anti-ulcerative
Antacid
Antibiotic
Non-steroidal anti-inflammatory drug
Anti-allergic
Anti-flatulent
AnalgesicaUnadjusted HR (95% CI)
Lubiprostone
Elobixibat

Adjusted a HR (95% CI)
Lubiprostone
Elobixibat

1.0
1.0
1.0
1.0
1.0
1.0

0.72 (0.44–1.20)
1.34 (0.58–3.11)
0.58(0.24–1.42)
2.07 (0.54–8.00)
0.72 (0.22–2.36)
0.50 (0.15–1.71)

1.0
1.0
1.0
1.0
1.0
1.0

0.71 (0.43–1.18)
1.28 (0.55–2.99)
0.60 (0.25–1.48)
2.18 (0.56–8.45)
0.75 (0.23–2.46)
0.49 (0.14–1.69)

1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0

1.00 (0.76–1.31)
1.14 (0.57–2.28)
1.38 (0.53–3.55)
0.74 (0.25–2.21)
0.74 (0.23–2.42)
0.63 (0.20–2.00)
1.46 (0.35–6.11)
0.69 (0.19–2.58)
0.53 (0.13–2.21)

1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0

1.02 (0.77–1.34)
1.21 (0.60–2.45)
1.35 (0.52–3.52)
0.71 (0.23–2.13)
0.73 (0.22–2.41)
0.67 (0.21–2.12)
1.48 (0.35–6.22)
0.57 (0.15–2.19)
0.56 (0.13–2.36)

Adjusted for age, sex, and antidiabetic and laxative usage
HR, hazard ratio, CI, confidence interval

EXPERT OPINION ON DRUG SAFETY

the frequently reported events (diarrhea (3%) and abdominal
pain (1%)).
Randomized trials on lubiprostone [13,28–30] havereported nausea, diarrhea, and abdominal pain as the frequent
adverse events, whereas the proportion of events of head­ache, dizziness, and flatulence has been reported to be over
5% [28,29]. Nausea was reported as the most common adverse
event during treatment with lubiprostone [16]. In our study,
although the events of headache and dizziness were infre­
quent and the event of nausea was frequent, gastrointestinal
events were similar to those reported in previous studies[13,28–30].
Although co-medication with digoxin and dabigatran was
not frequent with elobixibat and lubiprostone use, less than
1% of patients used elobixibat in combination with thesedrugs. According to the package insert of elobixibat [31], theinhibitory effect on p-glycoprotein has been suggested toincrease the blood concentration of these drugs. As ourstudy included many elderly individuals, these drugs were
not frequently used in combination; nevertheless, the atten­
tion of medical staff including pharmacists should be on theonset of symptoms due to increased drug blood levels.
The generalizability of this study finding is high. Previous
studies on elobixibat and lubiprostone [16,18] used a small
number of patients (less than 500) and did not have an active
comparator group. Patients diagnosed with cancer or
Parkinson’s disease were not included in the clinical trials[26,29]. In addition, although the main population in ourstudy was an elderly population, populations in most previous
studies [16,18,26,28,29] included only a few elderly individuals,
except for some observational studies [15,27,32].
There are a few studies that have made a head-to-headcomparison of elobixibat and lubiprostone. In a retrospective
cohort study with 2-week follow-up using propensity scorematching by Eguchi et al. [15], any adverse events due toelobixibat (9%) with a daily dose of 10 mg were significantly
less than those due to lubiprostone (14.8%) with a daily doseof 24 μg (p = 0.03); the incidence of nausea caused by lubi­
prostone with a daily dose of 48 μg was approximately threetimes greater than that by elobixibat with a daily dose of
10 mg (p = 0.01). These findings are relatively consistent
with our findings, although there were some differences in
the observation period with the follow-up period of 3 months
and methodology using the new-user design [19].
The cost of treatment with these drugs (200.4 yen/day forelobixibat and 232 yen/day for lubiprostone; the drug price ofthe standard daily dose) is considerably higher than that ofconventional drugs for constipation (22.8 yen/day for magne­
sium and stimulant laxatives [11.4 yen/day for sennoside and14.4 yen/day for sodium picosulfate]). Furthermore, the gen­eric drugs can be selected as conventional drugs, but not asalternatives for elobixibat and lubiprostone, to reduce patientco-payments.
This study had some limitations. First, we did not have data
regarding the time of drug administration. For elobixibat, predinner administration has been suggested to reduce abdom­
inal pain and bloating [33]; the proportion of adverse reactions
may be different based on the time of drug administration.
Second, the follow-up period was approximately 3 months in5

our study; the events that might occur after a long-term will
be missed. However, several studies on laxatives (including
elobixibat and lubiprostone) have been conducted witha short period of observation (less than 3 months)[15,16,26,29,34]. Third, the proportion of reported events
such as diarrhea and abdominal pain might be slightly under­
estimated in our study as they may differ depending onwhether the study population included elderly individuals or
not. The proportion of adverse events in the elderly popula­tion tend to be lower than that in the non-elderly population[16,32,35]. In addition, events that patients may have experi­
enced but not reported or events that were treated ata hospital but not recognized as related to lubiprostone or
elobixibat use may have been missed, although we selected
the patients from the same pharmacy. Fourth, the estimate
regarding the pre-identified risk of nausea in lubiprostone
users may lack power. The adjusted HR of nausea for lubipros­
tone had a wide CI (HR = 7.09: 0.85–58.8) compared with thatfor elobixibat. However, the increasing trend of nausea risk
was consistent with that for lubiprostone. Fifth, there may beresidual confounding in this study, as the sample size andnumber of cases were relatively small. In further larger pro­pensity score-matched cohort study, hypothesis-generating
evidence of this study may have to be examined. Finally,
details of constipation as an event are unknown. Rather thanshowing constipation as an adverse effect, the data may indi­cate that the drug lacked sufficient therapeutic effect because
it was originally used in patients with constipation, although
the event was reported for both drugs.

5. Conclusions
The study did not raise any new safety concerns related to theuse of elobixibat and lubiprostone for treating chronic con­stipation in clinical settings; the relative risk of any adverse
reaction was lower for elobixibat and the risk of nausea
tended to be high in lubiprostone users. Nevertheless, thesafety of these drugs needs to be monitored and evaluatedcontinually over long periods. Taking into account the effects
of underlying diseases, comorbidities, and concomitant med­
ications and usual adverse reactions due to the use of laxa­
tives, chronic constipation in elderly individuals should betreated with care. As there were some limitations to ourstudy, including sample size, the findings as hypothesisgenerating evidence should be tested in further larger pro­pensity score-matched cohort studies.

Acknowledgments
We express our appreciation to the participating pharmacists for provid­
ing reliable data. We also thank the staff of the Japan Pharmaceutical
Association for data collection and management.

Author contributions
All authors were involved in the conception and design of the study.
N. Ooba and M. Nagamura analyzed and interpreted the data. All authors
critically reviewed the manuscript, revised the paper for intellectual con­tent, provided detailed feedback, read and approved the final manuscript,
and agreed to be accountable for all aspects of the work.

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N. OOBA ET AL.

Funding
This work was supported by the Japan Pharmaceutical Association.

Declaration of interest
The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or otherrelationships to disclose.

ORCID
Nobuhiro Ooba

http://orcid.org/0000-0003-0579-3946

References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Belsey J, Greenfield S, Candy D, et al. Systematic review: impact ofconstipation on quality of life in adults and children. Aliment
Pharmacol Ther. 2010;31:938–949.
2. Higgins PDR, Johanson JF. Epidemiology of constipation in North
America: a systematic review. Am J Gastroenterol. 2004;99:750–759.
3. Paquette IM, Varma M, Ternent C, et al. The American Society of Colonand Rectal Surgeons’ clinical practice guideline for the evaluation andmanagement of constipation. Dis Colon Rectum. 2016;59:479–492.
4. Comprehensive survey of living conditions by the Ministry of
Health, Labor, and Welfare in Japan (In Japanese); [cited 2021 Jun24]. Available from: https://www.mhlw.go.jp/toukei/list/20-21.html
5. Sumida K, Molnar MZ, Potukuchi PK, et al. Constipation and risk ofdeath and cardiovascular events. Atherosclerosis 2019;281:114–120.
6. Salmoirago-Blotcher E, Crawford S, Jackson E, et al. Constipation
and risk of cardiovascular disease among postmenopausal women.
Am J Med. 2011;124:714–723.
7. Werth BL, Christopher SA. Laxative use in the community:
a literature review. J Clin Med. 2021;10:143.
8. Shah BJ, Rughwani N, Rose S. In the clinic. Constipation. Ann Intern
Med. 2015;162.
9. Snell DB, Faruqui S, Bosworth BP. A case-based approach to con­stipation in primary care. Med Clin North Am. 2021;105:55–73.
10. Gandell D, Straus SE, Bundookwala M, et al. Treatment of constipa­
tion in older people. CMAJ 2013;185:663–670.
11. Shin JE, Jung HK, Lee TH, et al. Guidelines for the diagnosis andtreatment of chronic functional constipation in Korea, 2015 revised
edition. J Neurogastroenterol Motil 2016;22:383–411.
12. Mihara H, Murayama A, Nanjo S, et al. Factors correlated with druguse for constipation: perspectives from the 2016 open Japanese
National Database. BMC Gastroenterol. 2020;20:284.
13. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubipros­
tone in patients with constipation-associated irritable bowel
syndrome--results of two randomized, placebo-controlled studies.
Aliment Pharmacol Ther. 2009;29:329–341.
14. Nakajima A, Seki M, Taniguchi S, et al. Safety and efficacy of elobixibat
for chronic constipation: results from a randomised, double-blind,placebo-controlled, phase 3 trial and an open-label, single-arm,
phase 3 trial. Lancet Gastroenterol Hepatol. 2018;3:537–547.
15. Eguchi T, Yoshizaki T, Ikeoka S, et al. Real-world comparison of
elobixibat and lubiprostone treatment in patients with chronic
constipation: a propensity score matched analysis. Dig Dis. 2020.
•• Observational study with active comparator in patients withchronic constipation

16. Cryer B, Drossman DA, Chey WD, et al. Analysis of nausea in clinicalstudies of lubiprostone for the treatment of constipation disorders.
Dig Dis Sci. 2017;62:3568–3578.
17. Wilson N, Schey R. Lubiprostone in constipation: clinical evidence
and place in therapy. Ther Adv Chronic Dis. 2015;6:40–50.
18. Wong BS, Camilleri M. Elobixibat for the treatment of constipation.
Expert Opin Investig Drugs. 2013;22:277–284.
• Overview of elobixibat with a novel pharmacological effect.
19. Ray WA. Evaluating medication effects outside of clinical trials:
new-user designs. Am J Epidemiol. 2003;158:915–920.
• Methodology for a new-user design.
20. The Japan Pharmaceutical Association; [cited 2021 Jun 24].
Avalialble from https://www.nichiyaku.or.jp/assets/uploads/about/anuual_report2020j.pdf
21. Layton D, Hazell L, Shakir SA. Modified prescription-event monitor­
ing studies: a tool for pharmacovigilance and risk management.
Drug Saf. 2011;34(12):e1–e9.
•• Methodology for a cohort study using primary data collection
in clinical settings.
22. Yokotsuka M, Aoyama M, Kubota K. The use of a medical dictionaryforregulatory
activities
terminology(MedDRA)inprescription-event monitoring in Japan (J-PEM). Int J Med Inform.
2000;57:139–153.
23. Mamdani M, Sykora K, Li P, et al. Reader’s guide to critical appraisalof cohort studies: 2. Assessing potential for confounding. BMJ.
2005;330:960–962.
24. Fukudo S, Miwa H, Nakajima A, et al. Dose-finding study of linaclo­tide in Japanese patients with chronic constipation: a phase II
randomized, double-blind, and placebo-controlled study.
Neurogastroenterol Moti. 2018;12:e13442.
25. Brandt LJ, Prather CM, Quigley EMM, et al. Systematic review on the
management of chronic constipation in North America. Am
J Gastroenterol. 2005;100(Suppl 1):S5–S21.
26. Nakajima A, Seki M, Taniguchi S. Determining an optimal clinicaldose of elobixibat, a novel inhibitor of the ileal bile acid transpor­ter, in Japanese patients with chronic constipation: a phase II,multicenter, double-blind, placebo-controlled randomized clinical
trial. J Gastroenterol. 2018;53:525–534.
27. Abe T, Kunimoto M, Hachiro Y, et al. Efficacy and safety of elobix­
ibat in elderly patients with chronic constipation: a single-center,observational study. J Anus Rectum Colon. 2020;4:122–127.
28. Barish CF, Drossman D, Johanson JF, et al. Efficacy and safety of
lubiprostone in patients with chronic constipation. Dig Dis Sci.
2010;55:1090–1097.
29. Johanson JF, Morton D, Geenen J, et al. Multicenter, 4-week,
double-blind, randomized, placebo-controlled trial of lubiprostone,
a locally-acting type-2 chloride channel activator, in patients withchronic constipation. Am J Gastroenterol. 2008;103:170–177.
30. Shah ED, Suresh S, Jou J, et al. Evaluating when and why patients
discontinue chronic therapy for irritable bowel syndrome withconstipation and chronic idiopathic constipation. Am
J Gastroenterol. 2020;115:596–602.
31. Package insert of elobixibat (In Japanese). [cited 2021 Jun 24].
Available from: https://www.pmda.go.jp/PmdaSearch/iyakuSearch/
32. Tomie A, Yoshida N, Kugai M, et al. The efficacy and safety of
elobixibat for the elderly with chronic constipation: a multicenter
retrospective
cohortstudy.
Gastroenterol
Res
Pract.
2020;2020:9656040.
33. Odaka T, Tominaga K. Uncontrolled, open-label pre-dinner admin­
istration of elobixibat in Japanese adults with chronic constipation:a retrospective chart review. Curr Ther Res Clin Exp.
2020;93:100616.
34. Alsalimy N, Madi L, Awaisu A. Efficacy and safety of laxatives forchronic constipation in long-term care settings: a systematic
review. J Clin Pharm Ther. 2018;43:595–605.
35. Nakajima A, Taniguchi S, Kurosu S, et al. Efficacy, long-term safety,
and impact on quality of life of elobixibat in more severe constipa­
tion: post hoc analyses of two phase 3 trials in Japan.
Neurogastroenterol Motil. 2019;31:e13571.