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Current Drug Safety, 2022, 17, 350-356

RESEARCH ARTICLE

Event Monitoring and Evaluation by Community Pharmacists in Japan: A
Pilot Study on Fenofibrate and Pemafibrate
Masao Takahashi1, Nobuhiro Ooba2,*, Marina Nagamura2, Makoto Ushida3, Eiji Kawakami1, Masaomi Kimura4, Tsugumichi Sato5, Yoshinori Takahashi1, Junichi Tokuyoshi1, Hajime Hashiba1, Miwako Kamei6, Choichiro Miyazaki1, Mitsuaki Shimada1
1

Japan Pharmaceutical Association, Tokyo, Japan; 2Department of Clinical Pharmacy, Nihon University School of
Pharmacy, Chiba, Japan; 3Faculty of Pharmacy, Meijo University, Aichi, Japan; 4Department of Computer Science and Engineering, Shibaura Institute of Technology, Tokyo, Japan; 5Department of Pharmacy, Faculty of Pharmaceutical Sciences,
Tokyo University of Science, Chiba, Japan; 6Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
Abstract: Background: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected
events was performed in Japan.
Aim: In this study, the association between detected events and the use of pemafibrate, utilizing
pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events.
ARTICLE HISTORY
Received: August 08, 2021
Revised: December 17, 2021
Accepted: December 29, 2021
DOI:
10.2174/1574886317666220224142511

Methods: A retrospective cohort study using questionnaires regarding baseline and event data wasconducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards
model that was adjusted for confounding factors, such as age and sex.
Results: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on
drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug
has been used by pemafibrate users compared to fenofibrate users.
Conclusion: This study conducted by pharmacists can facilitate the safety assessment of newly
marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese
authority for pharmaceutical companies. However, further research is required.

Keywords: Retrospective cohort study, new-user design, event monitoring, concurrent control, primary data collection, community pharmacist.
1. INTRODUCTION
Information regarding a medicine’s safety is generally
limited during the early post-marketing period, even though
the approved medicine begins to be widely used in clinicalpractice. To provide complementary information on drug
safety, prescription-event monitoring (PEM) [1] was developed in the UK and, over time, evolved into modified PEM*Address correspondence to this author at the Department of Clinical Pharmacy, Nihon University School of Pharmacy, 7-7-1 Narashinodai,
Funabashi, Chiba 274-8555, Japan; Tel: +81-47-465-3548;
E-mail: ooba.nobuhiro@nihon-u.ac.jp1574-8863/22 $65.00+.00(M-PEM) [2,3]. Studies using similar methodologies havebeen conducted in New Zealand and Japan [2, 4]. PEM in
Japan (J-PEM) [5, 6], which was launched in 1997, has beensuspended in 2004. Instead, another investigation of drugrelated events, called drug event monitoring (DEM), has been
implemented in 2002 by community pharmacists under the purview of the Japan Pharmaceutical Association (JPA) [7] tomonitor events occurring in prevalent users of some preselected study drugs [8]. In real-world clinical practice, studies
using primary data obtained through event monitoring may help
generate study hypotheses, detect the safety signals of drugs,
and promote spontaneous reporting systems, even though thelimitations for hypothesis testing on safety concerns regarding©2022 Bentham Science Publishers

A Pilot Study on Fenofibrate and Pemafibrate

drugs in the early phases after marketing are well known [9].
Collecting baseline information and information on the designof M-PEM [2] and setting a concurrent comparison group may
help overcome some of the limitations of the conventional
method of current DEM.
In a risk management plan (RMP) for newly marketeddrugs, severe or frequent adverse drug reactions are summarized as important specified risks. Although RMP [10] wasintroduced in 2013 in Japan, a comparison group is required
to evaluate whether the risk of known or unknown detected
events is associated with the use of a drug. We can expand
the event monitoring role of DEM by incorporating a component of retrospective cohort studies using the new-user
design in the schema of DEM.
Newly marketed drugs with indications for chronic diseases, such as hypertriglyceridemia, dispensed in many
pharmacies would be suitable as study drugs for DEM. Fibrates were recommended by therapeutic guidelines as they
have good efficacy in lowering fasting triglyceride levels[11,12]. Fenofibrate as a treatment has been marketed insome countries, including the United Kingdom and the United States, whereas pemafibrate, with the profile of a novel
selective peroxisome proliferator-activated receptor α modulator (SPPARMα) [13], is approved only in Japan as of May
2021 (Fig. 1). A phase III randomized controlled trial for
pemafibrate suggested a favorable benefit-risk balance incomparison to fenofibrate [14]. In addition, systematic reviews of pemafibrate reported no significant difference intotal adverse events between pemafibrate and placebo groups[15]. However, elevated low-density lipoprotein cholesterol(LDL) was indicated as a potential risk in the RMP for pemafibrate [16]. Safety information needs to be complemented
by observational studies, as randomized trials may not accurately represent patients in usual clinical practice [17].

Fig. (1). Chemical structures of pemafibrate and fenofibrate.

1.1. Aim of the Study
This study aimed to detect a drug-related event and evaluate the association between the event and drug use using a
retrospective cohort study for pemafibrate as a newly postmarketed drug and fenofibrate as an active comparison drugin the new schema of DEM in Japan.
2. MATERIALS AND METHODS
A retrospective cohort study using a new-user design was
conducted in February 2020 at 5562 of the 48382 community pharmacies belonging to the JPA [18]. The JPA sent questionnaires to all the community pharmacies, where pharmacists completed the forms using paper-based or electronic

Current Drug Safety, 2022, Vol. 17, No. 4351

health records, including the patients’ preferences, allergies,
prescriptions, and history of diseases. Except for pharmacies
with no study patients or pharmacies that refused to participate in the study, pharmacists from 2343 community pharmacies completed the questionnaires. They were anonymized using a study ID for each pharmacy into the webbased form that was prepared in advance. The questionnaire
included baseline data (demographic, co-medication, andcomorbidity) within six months before the starting date of
the use of the study drug and drug and events data during thefollow-up period between September and December 2019.
Study patients were restricted to new users of the study
drug, namely patients who were users of the pharmacy frombefore February 2019 and had newly started taking the study
drug in September 2019 after six months of non-study druguse. The observation period was from September 1st to December 31st, 2019, and follow-up was conducted fourmonths after the initiation of the drug. Since patients canfreely access any community pharmacy or medical institution without referral in Japan, we limited the study population to those who regularly used the same pharmacy by referring to visit records spanning more than seven months
before the start of the drug use to identify new users of the
drug and prevent the loss of participants before follow-up[19]. Patients who had only one visit on the start date of theprescription, including new users, were excluded because
they could not be followed up.
2.1. Exposure
Similar to J-PEM, our study design set a concurrent control [20]. To have similar indications for both test and active
comparator drugs, we selected a pair comprising a test drug
(pemafibrate) and a comparator drug (fenofibrate). The
drugs used as study targets had all been marketed for morethan one year because the supply of newly marketed drugs is
generally limited to 14 days to one year from the first day ofthe month as per the National Health Insurance Drug pricelisting in Japan [21].
Since determining which study drug (test or comparator)
caused the event is difficult, we did not include patients who
switched from the comparator to the test drug or from thetest drug to the comparator drug. In addition, we excluded
patients who had previously used any of the study drugs ineach drug pair to prevent the effect of bias [22], owing tomany test drug users having previously used the comparator
drug.
2.2. Data Collection of Events
We collected events data, including the incidence date of
the event from the health record of the pharmacy, wherein an
event was defined as any suspected drug reaction; unexpected deterioration (or improvement) in a concurrent illness; the reason for stopping the use of the study drug (ifstopped) or adding a new drug (if added). According to Article 25-2 of the Pharmacists Act in Japan, the pharmacist
provides the patient or a person caring for the patient thenecessary guidance based on pharmaceutical knowledge andmonitors the effects of the drugs and changes in physicalcondition during drug use. Information on add-on drugs may
be used to characterize the event. Adverse events were partly352

Current Drug Safety, 2022, Vol. 17, No. 4

defined using the definition of M-PEM [2]. Although ourbasic study design refers to M-PEM, the process of data collection and definition of an event was slightly different. The
questionnaires for M-PEM were sent to prescribers, while
community pharmacists collected the necessary data fromthe health records of the pharmacies included in our study.
Therefore, the definition of an event could not include thediagnosis by a medical doctor. However, we collected complementary information regarding the judgement of causality
by pharmacists for the reported event, such as “unlikely,”“probable,” and “not assessable” [23].
The Medical Dictionary for Regulatory Activities Terminology (MedDRA) version 22.1 was used to encode the reported event; we selected the lowest level terms in the
MedDRA [24], which were converted to the preferred termlevel and counted as an event.
2.3. Statistical Analysis
We described summary statistics for demographic characteristics, current smoking, alcohol consumption, taking
over-the-counter drugs, comorbidities (dyslipidemia, hypertension, diabetes mellitus, myocardial infarction, and cancer), co-medications (anti-hypertensives, lipid-loweringdrugs, anti-diabetes drugs, anti-ulceratives, steroids [except
those for external use], laxatives and anti-depressants/hypnotic drugs), and history of hospital admission at a sixmonth baseline period. A standardized difference was calculated between paired drugs and was considered meaningfulwhen greater than 0.1 [25].
We calculated the incidence proportions of the events inpatients during treatment with test or comparator drugs andestimated the risk ratio and its 95% confidence interval (CI).
If the same event was reported more than once, only the firstevent was considered. For some events, time-to-event occurrence was depicted using a Kaplan–Meier curve and compared using a log-rank test. The Cox proportional hazards
model was used to estimate the unadjusted and adjusted hazard ratio (HR) of the test drug on the event compared to thecomparator drug. To adjust the HR, we used covariates witha standardized difference of 0.1 or more. In this analysis, wedefined the observation period for assessing the event asfollows: the period from the start date of the study drug tothe incidence date, date of switching or stopping the study
drug, last visit date, or the end of the observation period
date, i.e., December 31st, 2019, whichever came first.
Results with a p-value <0.05 were considered statisticallysignificant. All analyses were conducted using SAS version
9.4 (SAS Institute Inc., Cary, NC, USA).
3. RESULTS
Commonly dispensed drugs in the study period werepemafibrate (n=5020) as the test drug and fenofibrate(n=2825) as the comparator drug. Of these, 1294 patientsusing pemafibrate (26%) and 508 patients using fenofibrate(18%) were identified as new users of the drugs. Table 1
shows the data on the baseline characteristics of the study
patients. Standardized differences in age, smoking, myocardial infarction, lipid-lowering drugs, and history of hospitalization were greater than 0.1.

Takahashi et al.

Table 1. Baseline characteristics of new pemafibrate or fenofibrate users.

-

Pemafibrate(n = 1,294)

Fenofibrate(n = 508)

Standardized Difference

Median age (years, IQR)

64 (53−72)

67(56−76)–0.240Male (%)

835 (64.5)

317(62.4)

0.044

Mean daily dose (mg)

0.3

99.2

-

Number of missing doses

7

0

-

Mean observation period(days)

99.5

101

-

Current smoker (%)

262 (20.2)

81 (15.9)

0.112

Current drinker (%)

503 (38.9)

190(37.4)

0.030

Comorbidity (%)

-

-

-

Dyslipidemia

849 (65.6)

332(65.4)

0.005

Hypertension

798 (61.7)

332(65.4)-0.077

Diabetes mellitus

440 (34.0)

151(29.7)

0.092

Myocardial infarction

29 (2.2)

3 (0.6)0.140

Cancer33 (2.6)

10 (2.0)

0.039

Co-medication (%)

-

-

-

Anti-hypertensives

824 (63.7)

340(66.9)-0.068

Lipid-lowering drugs except fibrates

525 (40.6)

170(33.5)

0.148

Anti-diabetes drugs

449 (34.7)

156(30.7)

0.085

Anti-ulceratives

286 (22.1)

96 (18.9)

0.079

Steroids except those forexternal use

16 (1.2)

4 (0.8)0.045

Laxatives

104 (8.0)

39 (7.7)

0.0113Anti-depressants/ hypnotic
drugs

192 (14.8)

71 (14.0)

0.025

History of admission (%)

8 (0.6)

0 (0)

0.112

IQR, interquartile range.

The proportion of patients who discontinued the drug
was 3.9% (n=50) for pemafibrate and 6.3% (n=32) for fenofibrate. Discontinuation because of any suspected adverse
drug reaction was 1.5% for pemafibrate and 2.0% for fenofibrate, while the proportion of improvement was 1.4% forpemafibrate and 2.8% for fenofibrate.

A Pilot Study on Fenofibrate and Pemafibrate

Current Drug Safety, 2022, Vol. 17, No. 4

In pemafibrate, the incidence proportion (95% CI) of any
event was 11.8% (10.2% to 13.7%), while that for fenofibrate was 8.3% (6.2% to 11.0%). The crude risk ratio of
any event was higher for pemafibrate users than for fenofibrate users [1.43 (1.03 to 1.98)]. Tables 2 and 3 show thefive most reported events and incidence proportions of the
drug. For pemafibrate, increased blood pressure (1.3%), myalgia (0.6%), and pain in the extremities (0.5%) were reported. Nasopharyngitis (0.6%), pruritus (0.6%), and dizziness(0.6%) were reported for fenofibrate, and the reported number of cases (incidence proportion) of increased blood pressure was 2 (0.4%).
Table 2.

Number (%) of Events in
Pemafibrate Users (n=1,294)

Adverse reaction-

Increased blood pressure

17 (1.3)

Myalgia8 (0.6)

Pain in extremity

7 (0.5)

Pruritus

5 (0.4)

Abdominal discomfort

5 (0.4)Add-on drug-

Lipid-lowering drug

48 (3.7)

Anti-hypertensive

47 (3.6)

Anti-diabetes drug

35 (2.7)

Non-steroid anti-inflammatory drug

13 (1.0)

Anti-ulcerative

12 (0.9)

Table 3.

We have presented the unadjusted and adjusted HR forthe common events, including the drug added after the initiation of the test or comparator drug, compared to the fenofibrate as reference (Table 4). No significant differenceswere found in the events except for the add-on of an antihypertensive (adjusted HR=3.20; 95 % CI, 1.36–7.52).
Table 4.

Unadjusted and adjusted hazard ratios for the
events reported most in both pemafibrate and fenofibrate users.

Event

The five most reported events in pemafibrate users.
Event

The five most reported events in fenofibrate users.
Event

Number (%) of Events infenofibrate Users (n=508)

Adverse reaction-

Nasopharyngitis

3 (0.6)

Pruritus

3 (0.6)

Dizziness

3 (0.6)

Increased blood pressure

2 (0.4)

Myalgia2 (0.4)

Renal impairment

2 (0.4)Cough

2 (0.4)Hypoesthesia

2 (0.4)

Abnormal hepatic function

2 (0.4)Add-on drug-

Lipid-lowering drug

10 (2.0)

Anti-diabetes drug

6 (1.2)Anti-hypertensive

6 (1.2)Anti-ulcerative

4 (0.8)Laxative

3 (0.6)

353

Unadjusted HR (95% CI)

Adjusted* HR (95% CI)

Fenofibrate Pemafibrate Fenofibrate Pemafibrate---

3.39 (0.78–
14.68)

1.0

3.40 (0.77–
14.93)

Adversereaction-

Increased
blood pressure

1.0

Pruritus

1.0

0.66 (0.16–
2.74)

1.0

0.77 (0.18–
3.29)

Dizziness

1.0

0.52 (0.12–
2.34)

1.0

0.46 (0.09–
2.01)

Add-on drug

-

-

-

-

Lipidlowering drug

1.0

1.93 (0.97–
3.81)

1.0

1.87 (0.94–
3.71)

Antihypertensive

1.0

3.15 (1.35–
7.37)

1.0

3.20 (1.36–
7.52)

Anti-diabetes
drug

1.0

2.33 (0.98–
5.54)

1.0

2.11 (0.88–
5.05)

Antiulcerative

1.0

1.19 (0.38–
3.68)

1.0

1.10 (0.35–
3.51)

Laxative

1.0

0.99 (0.19–
5.08)

1.0

1.03 (0.18–
5.70)*Adjusted for age, sex, current smoking, lipid-lowering drug, and history of admission.
Abbreviations: HR, hazard ratio; CI, confidence interval.

To examine the event of increased blood pressure withthe use of pemafibrate, we used the Kaplan-Meier curves forthe event during the study period (Fig. 2). A log-rank test
revealed that the time to the event did not significantly differ
between the pemafibrate and fenofibrate groups (p=0.08).
Furthermore, of the 17 events of increased blood pressure
reported for pemafibrate, eight events were determined bypharmacists to be unlikely due to the use of pemafibrate.
4. DISCUSSION
The DEM design in Japan could play the dual role ofevent monitoring and evaluating the detected events [26].
Generally, event monitoring helps generate test hypotheses
and strengthen the safety signal of drugs [3]. Groups must becompared in terms of the risk of events to assess the association between newly marketed drugs and events. We identified new users of test or comparator drugs using electronic
dispensing data maintained by each pharmacy and followed354

Current Drug Safety, 2022, Vol. 17, No. 4

the study cohort for at least three months. In addition, community pharmacists were able to collect information regarding the event using pharmacy records, demographic data,
including over-the-counter drugs for outpatients, and healthinformation about the patients. This process may help evaluate detected signals in the real-world post-marketing ofdrugs. In the Revision of Good Post-Marketing Study Practice Ordinance implemented in Japan as of April 2018 [27],post-marketing database surveillance and drug use investigation with a comparator group using primary data were newly
added to the conventional post-marketing surveillance required by the Japanese authority for pharmaceutical companies. However, in the fiscal year 2018, no drug use investigations were conducted with comparator groups as an additional pharmacovigilance plan of the RMP [28]. DEM bycommunity pharmacists can serve as an option for postapproval safety studies.

Takahashi et al.

multivariate-adjusted HR for both events of pemafibrate wasapproximately 3.0, the 95% CI was wide and inconclusive.
Our findings for increased blood pressure need to be further
replicated in larger sample sizes.
Details of the mechanism for hypertension in pemafibrate
are unknown. Gilbert et al. suggest that the anti-hypertensive
effect of fenofibrate as a comparator drug, such as that observed in our study, results from an action downstream from
PPARα activation [31]. In contrast, Yamashita et al. reported
that pemafibrate showed high selectivity for PPARα compared to conventional fibrates [32]. In our findings, the incidence of increased blood pressure in pemafibrate users was
not significant; however, the add-on of anti-hypertensive forpemafibrate may characterize the effect on blood pressure. If
the anti-hypertensive effect of fenofibrate is related to
PPARα activation, the increase in blood pressure by pemafibrate, which is highly selective for PPARα, may be inconsistent.
This study has several strengths. First, in our retrospective cohort study using primary data from pharmacies, weused a concurrent comparator group comprising new drug
users. Therefore, we could estimate the measure of effect, in
addition to the identification or confirmation of drug safety
signals. Second, we could collect information on comorbidity, co-medication, and lifestyle factors for current smoking,alcohol consumption, and over-the-counter drugs. This isuseful as these factors can be adjusted to strengthen or refine
the detected signals. Third, the generalizability of our findings is high. As of March 2019, the number of pharmacies inJapan was 59613 [33]. As of February 2020, 48382 pharmacies belonged to JPA, 11.5% of which participated in ourstudy.

Fig. (2). Probability of blood pressure increase among users of
pemafibrate and fenofibrate. Survival probability at a time point isthe unadjusted probability of not developing blood pressure increase by that time point.

The incidence of LDL increase mentioned as an important potential risk in RMP [16] for pemafibrate was small(n=3, 0.2%), while no event was reported for fenofibrate.
However, lipid-lowering drug was additionally used 1.9
times more by pemafibrate users than by fenofibrate users;
however, this difference is not statistically significant.
Therefore, monitoring of lipid levels and recommendations
for lifestyle changes may be needed for patients during pemafibrate use.
Gremmels et al. suggest that studies on fibrates show inconsistent results related to blood pressure [29]. In addition,some randomized controlled studies did not mention the adverse events on blood pressure [14, 30]. However, in ourstudy, the use of pemafibrate was not related to the risk forevents of increased blood pressure, while the add-on of ananti-hypertensive increased significantly in pemafibrate users compared to users of fenofibrate (Table 4). Although

Nevertheless, this study has some limitations. First, as
our sample size was small, the estimates of the association
between drug and events were unstable, and their CIs were
wide. For events that were small in number, the Cox proportional hazards model may lack the power to detect the differences between drug groups due to the non-proportional hazard assumption. Second, the follow-up period in our study
was relatively short (approximately four months). The rare
events that may occur in the long term may have been
missed, although the events that may be likely to occur early
after the initiation of the drug were captured. Third, theevents related to laboratory test values, such as the elevationof creatine kinase, are underestimated. At pharmacies, laboratory test values can only be confirmed by some patients,
although some clinics and hospitals attach data of laboratory
test values to their prescriptions.
CONCLUSION
A retrospective cohort study involving the framework of
DEM with a comparison group comprising new users of
drugs was conducted by community pharmacists in Japan.
However, further study is needed as the sample size and thenumber of events were small for both pemafibrate and fenofibrate users. DEM may help monitor and evaluate safety
signals for newly marketed drugs in real-world clinical settings. This design may apply to drug use investigations witha comparison group in pharmacovigilance plans as an RMP
by pharmaceutical companies.

A Pilot Study on Fenofibrate and Pemafibrate

Current Drug Safety, 2022, Vol. 17, No. 4

ETHICS APPROVAL AND CONSENT TO PARTICIPATEThe study protocol was approved by the ethics review
committee of the JPA (no. 2019-002).

[6]

HUMAN AND ANIMAL RIGHTS[7]

No animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national) and with the Helsinki
Declaration of 2013.
CONSENT FOR PUBLICATIONSThe ethical committee waived the need for individual informed consent, as the study data were fully anonymized.
STANDARDS OF REPORTING

[8]

[9]

[10]
[11]

STROBE guidelines were followed in this study.
AVAILABILITY OF DATA AND MATERIAL
The authors confirm that the data supporting the findingsof this research are available within the article.

[12]

[13]

FUNDING
This work was financially supported by the Japan Pharmaceutical Association.

[14]

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial orotherwise.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the pharmacists ofparticipating pharmacies for providing data. The authors
thank the staff of the Japan Pharmaceutical Association fordata collection and management. They also wish to thankProfessor Naoki Harikai at Nihon University School of
Pharmacy for useful comments regarding this study.

[15]

[16]

[17]

[18]

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