Analysis of Drug-Induced Liver Injury from Bofutsushosan Administration Using Japanese Adverse Drug Event Report (JADER) Database

Tomoaki Ishida; Kei Kawada; Kohei Jobu; Tetsushi Kawazoe; Naohisa Tamura; Mitsuhiko Miyamura

doi:10.1248/bpb.b21-00887

Abstract

Bofutsushosan is a traditional Japanese Kampo medicine. In recent years, it has been reported to be effective in the treatment of lifestyle-related diseases, and its use is increasing. However, side effects from bofutsushosan administration are common, with drug-induced liver injury being the most frequently reported complication. In this study, we analyzed the Japanese Adverse Drug Event Report (JADER) database regarding the occurrence of liver injury after bofutsushosan administration. The results showed that bofutsushosan presented a significant reporting odds ratio (ROR) signal [crude ROR 14, 95% confidence interval (CI) 12–17; p < 0.001], indicating liver injury. Furthermore, the incidents of adverse events following bofutsushosan administration, as recorded in the JADER database, were higher in women aged between 30 and 59 years. The results of logistic regression analysis in patients taking this agent showed that females in the aforementioned age range had higher odds of developing drug-induced liver injury (adjusted ROR 5.5, 95% CI 2.8–11; p < 0.001). Therefore, although bofutsushosan is a useful drug for lifestyle-related diseases, it may be necessary to refrain from its overuse, and caution should be taken during its occasional use to avoid severe adverse events.

INTRODUCTION

Bofutsushosan is a traditional Japanese Kampo medicine. In recent years, it has been reported to be effective in the treatment of obesity,^1,2) non-alcoholic fatty liver disease,³⁾ hyperglycemia,⁴⁾ and hypertension.⁵⁾ Currently, its use is increasing because of its efficacy against the aforementioned lifestyle-related diseases.⁶⁾ However, side effects are commonly reported by patients taking bofutsushosan; these include drug-induced liver injury,⁷⁾ interstitial pneumonitis,⁸⁾ and pseudoaldsteronism.⁹⁾ It has been reported that liver damage is the most frequent side effect of Kampo medicines.⁶⁾ In addition, drug-induced liver injury can be fulminant, requiring organ transplant, and may even result in death.¹⁰⁾ The risk factors and the onset of drug-induced liver injury vary depending on the mechanism of occurrence. Therefore, it is important to understand the effect of each drug on the onset of liver injury to avoid aggravation. However, there are few reports on liver injury caused by Kampo medicines, and details regarding the overall safety of these agents are unknown. It may be difficult to investigate the side effects of Kampo medicines because they are often used in outpatient formulations. The Japanese Adverse Drug Report (JADER) database collects information on adverse drug reaction cases reported voluntarily by pharmaceutical companies, patients, clinicians, pharmacists, and other healthcare professionals to the Pharmaceuticals and Medical Devices Agency (PMDA), and this information is documented regardless of whether the log is associated with an inpatient or outpatient. Therefore, we believe that it would be useful to investigate the side effects and, thereby, determine the safety of Kampo medicines using information contained in the JADER database. In this study, we analyzed the JADER database regarding the occurrence of liver injury in patients taking Kampo medicines. In addition, we analyzed patient characteristics and the time of onset of liver injury related to bofutsushosan administration.

MATERIALS AND METHODS

Data Extraction

Data recorded from April 2004 to March 2020 in the JADER database were downloaded from the PMDA website (http://www.pmda.go.jp/). The JADER dataset consists of four tables containing the following information: 1) patient information, including gender, age, and body weight; 2) patient drug information; 3) patient adverse events and outcomes; and 4) medical history and primary illness. These four tables were integrated using the FUND E-Z Backup Archive (FUND E-Z Development Corporation, NY, U.S.A.).

Selection of Cases in Each Analysis

For the analysis of each adverse event associated with bofutsushosan administration, we selected complications for which more than 10 cases had been reported in the JADER database, and the crude reporting odds ratios (RORs) and 95% confidence intervals (CIs) were calculated. Furthermore, for the analysis of each Kampo medicine in relation to the onset of drug-induced liver injury, we selected 22 Kampo formulae as suspected drugs, for which more than 40 cases had been reported in the JADER database, and the RORs and 95% CIs of liver injury were calculated. These analyses were performed on all reported cases (641736) in the JADER database (relative odds ratio vs. total cases in the JADER database) with reference to previous reports.^11,12) From the patient drug information, the drugs associated with the adverse events were categorized into three groups: “suspected drug,” “concomitant drug,” and “interaction.” The category “suspected drug” was examined in the present study.

For the analysis of possible factors associated with liver injury in patients taking bofutsushosan, we selected cases in which this agent was the suspected causative drug (423 cases). Cases in which data on sex and age were missing (13 cases, 3.1% of the total number of bofutsushosan cases) were excluded. Thus, 410 cases (97% of the total number of bofutsushosan cases) were included in the study.

Calculation of the Ratio of Cases by Sex and Age

For cases associated with Kampo medicines reported in the JADER database, the percentage occurrence was calculated by age and sex. The data included the ratio of each sex and age to all reported cases for a particular drug. Furthermore, we selected the cases that were excluded because of missing sex and age data (bofutsushosan, 410 cases; other Kampo formulations, 4937 cases).

Analysis of the Reporting Odds Ratio

The calculation method for crude ROR is outlined herein. First, the cases were classified into groups (a) to (d) as follows: (a) Individuals who received the drug of interest and exhibited an adverse event of interest; (b) Individuals who received the drug of interest and exhibited other adverse events (of no interest); (c) Individuals who received other drugs (of no interest) and exhibited an adverse event of interest; and (d) Individuals who received other drugs (of no interest) and exhibited other adverse events (of no interest). Next, the crude ROR was calculated using the following calculation method:

A signal was detected when the lower limit of the 95% CI of the crude ROR exceeded 1. The RORs were expressed as point estimates with 95% CIs. The data were analyzed using Fisher’s exact test.

We calculated the adjusted ROR according to previous reports.^13,14) In addition, the cases were stratified by age as follows: 0–19, 20–29, 30–39, 40–49, 50–59, 60–69, and ≥70 years. To construct the logistic model, sex (female), reporting year, and stratified age groups were coded. The following logistic model was used for analysis:

The 60–69-year group was used as a reference group to calculate RORs adjusted for age variations, with the results being considered statistically significant at p ≤ 0.05. These analyses were performed using the JMP 14.0 software (SAS Institute, Cary, NC, U.S.A.).

Analysis of Onset of Adverse Events

We selected those cases in which bofutsushosan was the suspected causative drug for drug-induced liver injury (221 cases). Cases in which data on sex and age were missing were excluded from the analysis. Records with complete liver injury occurrence and prescription start date were used for the time-to-onset analysis (146 cases, 66% of the total 221 cases). The onset of adverse events was calculated from the time the patient received their first prescription to the occurrence of liver injury. It was necessary to consider the right truncation during evaluation of the time-to-onset of liver injury. We determined an analysis period of 365 d after the start of administration.¹⁵⁾ The median duration, quartiles (IQR), and Weibull shape parameters (WSP) were used to evaluate the onset data. The scale parameter α of the Weibull distribution determines the scale of the distribution function. A larger scale value (α) stretches the distribution, whereas a smaller scale value (α) shrinks the data distribution. The WSP β of the Weibull distribution determines the shape of the distribution function. Larger and smaller shape values produce left- and right-skewed curves, respectively. The shape parameter β of the Weibull distribution was used to indicate the level of hazard over time without a reference population. When β is equal to 1, the hazard is estimated to be constant over time. If β is greater than 1 and the 95% CI of β excludes the value 1, the hazard is considered to increase with time.¹⁶⁾

These analyses were performed using JMP 14.0 (SAS Institute).

Definitions of Side Effects and Medications

The ICH Medical Dictionary (MedDRA) ver. 24.0 for regulatory activities was used to extract the adverse events listed in the JADER database. Each adverse event was defined by preferred terms (PT) that were included in the standardized MedDRA queries (SMQ), viz. “hepatic disorder (SMQ: 20000005),” “interstitial lung disease (SMQ: 20000042),” “pseudoaldosteronism (decrease in potassium levels [PT: 10005724], hypokalemia [PT: 10021015], or pseudoaldosteronism [PT: 10037113]), and “mesenteric phlebosclerosis (PT: 10074525).”

Kampo medicines were defined as those that were listed in the PMDA’s prescription drug information in March 2020 as “Kampo medicine” (Japanese standard product classification number: 875200). The OTC Kampo medicines were included in this study.

RESULTS

Crude RORs and Number of Cases of Each Adverse Event Associated with Bofutsushosan Administration

The crude ROR (95% CI) of each adverse event associated with bofutsushosan in the JADER database was calculated. Signals were detected for liver injury (ROR: 14; 95% CI: 12–17), interstitial lung disease (ROR: 5.6; 95% CI: 4.4–6.9), pseudoaldosteronism (ROR: 5.2; 95% CI: 2.7–9.2), and mesenteric phlebosclerosis (ROR: 90; 95% CI: 60–138) (Table 1).

Table 1. Number of Reported Cases and ROR (95% CI) of Each Adverse Event Resulting from Bofutsushosan Administration

Adverse events	Total	Case	Ratio (%)	Crude ROR (95% CI)	p-Value
Number of total reported cases	641736	423
Liver injury	48947	228	54	14 (12–17)	<0.001
Interstitial lung disease	37842	109	26	5.6 (4.4–6.9)	<0.001
Pseudoaldosteronism	3602	12	2.8	5.2 (2.7–9.2)	<0.001
Mesenteric phlebosclerosis	197	10	2.7	90 (60–138)	<0.001

RORs and Number of Cases of Liver Injury Associated with Each Kampo Medicine

Among the 641736 cases reported from April 2004 to March 2020, 48947 patients developed liver injury. Based on the analysis of the ROR for each Kampo medicine, significant ROR signals were detected for 22 drugs of which, the ROR of bofutsushosan was 14 (95% CI: 12–17) (Table 2). There were 423 cases including 50 OTC drug cases in which bofutsushosan was the suspected drug for adverse events, and drug-induced liver injury was reported in 228 cases including 25 OTC drug cases.

Table 2. Number of Reported Cases and ROR (95% CI) of Drug-Induced Liver Injury Resulting from Administering Kampo Medicines

Drugs (OTC drug cases, n)	Total	Case	Ratio (%)	Crude ROR (95% CI)	p-Value
Total	641736	48947	7.6
Bofutsushosan	423 (50)	228 (25)	54	14 (12–17)	<0.001
Saikokaryukotsuboreito	171 (8)	91 (2)	53	14 (10–19)	<0.001
Hangekobokuto	55 (0)	26 (0)	47	11 (6.1–19)	<0.001
Tokishakuyakusan	51 (0)	24 (0)	47	11 (5.9–19)	<0.001
Keishibukuryogan	71 (0)	29 (0)	41	8.4 (5.0–14)	<0.001
Saireito	390 (0)	150 (0)	38	7.6 (6.1–9.3)	<0.001
Daikenchuto	236 (0)	88 (0)	37	7.2 (5.5–9.5)	<0.001
Hangeshasinto	187 (1)	64 (1)	34	6.3 (4.6–8.6)	<0.001
Orengedokuto	199 (1)	65 (0)	33	5.9 (4.3–8.0)	<0.001
Goreisan	94 (0)	30 (0)	32	5.7 (3.6–8.9)	<0.001
Kakkonto	286 (63)	85 (13)	30	5.1 (3.9–6.6)	<0.001
Maoto	104 (2)	31 (0)	30	5.1 (3.3–7.9)	<0.001
Hachimijiogan	48 (7)	14 (1)	29	5.0 (2.5–9.5)	<0.001
Bakumondoto	166 (5)	40 (2)	24	3.8 (2.6–5.5)	<0.001
Kamishoyosan	153 (4)	35 (2)	23	3.6 (2.4–5.3)	<0.001
Shoseiryuto	140 (0)	31 (0)	22	3.4 (2.2–5.2)	<0.001
Juzentaihoto	65 (0)	14 (0)	22	3.3 (1.7–6.1)	<0.001
Shosaikoto	128 (1)	27 (1)	21	3.2 (2.0–5.0)	<0.001
Gosyajinkigan	144 (0)	26 (0)	18	2.7 (1.7–4.1)	<0.001
Hochuekkito	187 (0)	33 (0)	18	2.6 (1.7–3.8)	<0.001
Yokukansan	314 (0)	45 (0)	14	1.7 (1.2–2.4)	0.001
Shakuyakukanzoto	544 (3)	57 (1)	10	1.4 (1.1–1.9)	0.015

Ratio of Cases Associated with Bofutsushosan and Other Kampo Medicines Stratified by Sex and Age

We stratified the cases associated with bofutsushosan and other Kampo formulations according to sex and age. Regarding bofutsushosan-associated complications, the ratio of females aged 30–59 years taking this agent were higher than those taking other Kampo medicines. On the other contrary, the ratio of patients ≥70 years of age taking bofutsushosan was lower than of those taking other Kampo medicines (Fig. 1).

Fig. 1. Ratio of Bofutsushosan Cases and Other Kampo Medicines Reported in the JADER Database by Sex and Age

A) bofutsushosan and B) other Kampo medicines; the cases reported in the JADER database were tabulated by sex and age, and the percentage of all cases for the drug is shown.

Analysis of the Characteristics of Patients with Drug-Induced Liver Injury Caused by Administrating Bofutsushosan

The adjusted RORs and 95% CIs are presented in Table 3. Female sex (adjusted ROR: 5.5; 95% CI: 2.8–11; p < 0.001) was detected as a characteristic of drug-induced liver injury by bofutsushosan. In the evaluation of age, signals for drug-induced liver injury, using the 60–69 years old group as reference, were detected in the 30–39 years old (adjusted ROR: 5.5; 95% CI: 2.3–13; p < 0.001), 40–49 years old (adjusted ROR: 2.4; 95% CI: 1.3–4.7; p = 0.008), and 50–59 years old (adjusted ROR: 3.3; 95% CI: 1.7–6.1; p < 0.001) groups.

Table 3. Analysis of Possible Factors Associated with Drug-Induced Liver Injury in Patients Taking Bofutsushosan

Characteristic	Liver injury (n = 221)	No liver injury (n = 189)	Crude ROR (95% CI)	Adjusted ROR (95% CI)	p-Value
Reporting year	—	—	—	0.97 (0.92–1.03)	0.36
Sex, female, n (%)	197 (89)	111 (59)	5.8 (3.4–13)	5.5 (2.8–11)	<0.001
Age, n (%)
0–19 years	1 (0.5)	3 (1.6)	0.28 (0.01–3.6)	0.85 (0.07–9.9)	0.90
20–29 years	10 (4.5)	3 (1.6)	2.9 (0.74–16)	4.0 (0.97–17)	0.055
30–39 years	43 (18)	9 (1.8)	4.8 (2.2–12)	5.5 (2.3–13)	<0.001
40–49 years	54 (24)	27 (14)	1.9 (1.1–3.4)	2.4 (1.3–4.7)	0.008
50–59 years	75 (34)	33 (17)	2.4 (1.5–4.0)	3.3 (1.7–6.1)	<0.001
60–69 years	35 (16)	48 (25)	0.55 (0.33–0.93)	Reference	—
≥70 years	3 (1.4)	66 (35)	0.03 (0.01–0.08)	0.08 (0.02–0.27)	<0.001

Onset of Drug-Induced Liver Injury in Patients Taking Bofutsushosan

The number of cases in the JADER database of drug-induced liver injury associated with bofutsushosan administration at the onset is shown in Fig. 2. The onset of drug-induced liver injury was analyzed using Weibull distribution. The scale parameters were α = 77, 95% CI: 66–89; β = 1.14, 95% CI: 0.99–1.28, and the median of onset was 57, IQR: 26–101. The onset of liver injury occurred after the second day of bofutsushosan administration, and in 71% of the cases, this complication developed within 90 d from the start of bofutsushosan administration.

Fig. 2. Numbers of Liver Injury Cases Associated with Bofutsushosan by Onset in the JADER Database

DISCUSSION

In this study, we investigated drug-induced liver injury following the administration of Kampo medicines using spontaneous reporting system (SRS). The obtained results suggest that significant ROR signal was detected for bofutsushosan causing liver injury. Furthermore, bofutsushosan-induced liver injury was observed to frequently occur in females aged between 30 and 59 years.

In recent years, due to increased health awareness, the use of health foods and natural medicines for lifestyle-related diseases has increased. A Kampo medicine is a traditional Japanese drug composed of natural medicines used for the management of diseases through self-medication or ethical medical treatment regimens.¹⁷⁾ The number of reports associated with adverse events resulting from the use of Kampo medicines has been increasing in recent years,⁶⁾ as their use has increased. Owing to this, adverse events, such as pseudoaldosteronism,¹⁸⁾ interstitial lung disease,¹⁹⁾ and liver injury,²⁰⁾ have been reported, with liver injury being reported as the most frequent complication.⁶⁾ In this study, the most common adverse event related to bofutsushosan was associated with liver damage, as reported in the JADER database (Table 1).

Bofutsushosan is known to be effective in the management of obesity.⁴⁾ Therefore, it is expected that many young people may be taking this drug (supplementary data 1) for weight loss. In this study, the ratio of women, especially in the age range of 30–59 years, taking bofutsushosan was higher than that of those taking other Kampo medicines (Fig. 1), which may be attributed to its reported effect on obesity. The risk of drug-induced liver injury varies with age due to differences in the activity of metabolic enzymes and volumes of distribution.^21,22) In addition, it is known that the age at which drug-induced hepatotoxicity occurs differs depending on the drug.²³⁾ In this study, significant ROR signals were detected for bofutsushosan, and this was more frequently reported in the age range of 30–59 years (Table 3). In previous reports, the average age of herb-induced liver damage was reported to be in the 50s,²⁴⁾ and the common age of the onset of liver injury in patients taking bofutsushosan may be similar to that of other herbs as reported in previous studies.

The incidence of drug-induced liver injury is thought to vary by sex.^25,26) Therefore, differences may be observed in incidences of drug-induced liver injury based on sex when investigating herbal medicines; previous studies on herbal medicines in China and Korea have reported a higher incidence in females.^27,28) In this study, it was observed that liver injury following the administration of bofutsushosan was more frequently reported in women (Table 3). Differences in responsiveness to hepatotoxicity by sex are thought to be due to differences in pharmacokinetics and immune response²⁹⁾; however, the detailed mechanisms underlying this are unknown.

Because the supplementary data showed that the total amount of bofutsushosan prescribed was much higher among women in the 40–59 years group, the current result may reflect a more prevalent prescription pattern in these populations. However, as the exact number of people taking the drug is unknown from the current data, further studies are needed to estimate the risk or incidence rate of liver injuries due to bofutsushosan in these subpopulations.

It has been reported that the pathogenesis of drug-induced liver injury usually involves the participation of a toxic drug or metabolite that either elicits an immune response or directly affects the liver cells.³⁰⁾ A Kampo medicine is a combination of several herbal medicines; therefore, drug-induced liver injury caused by Kampo medicines is thought to be due to the various interacting constituent ingredients. The occurrence of liver damage following administration of Kampo medicines has been widely reported in formulations containing Scutellariae Radix.^6,31) In this study, a signal of liver injury resulting from Kampo medicines containing Scutellariae Radix, such as bofutsushosan, saikokaryukotsuboreito, and saireito, was detected (Table 2), implying that drug-induced liver injury is likely to occur with the use of these Kampo medicines.

Immunogenic hepatotoxicity is thought to be caused by T-cell-dependent hepatocellular damage, in which the drug itself or its metabolites become haptens that bind to carrier proteins and acquire antigenicity.³²⁾ In Kampo medicines containing Scutellariae Radix, the antigenicity is assumed to cause an immune response because many patients who developed liver damage were positive for the drug-induced lymphocyte stimulation test⁷⁾ and the occurrence was not dose-dependent.³³⁾ Therefore, it is thought that this same mechanism of liver injury may be activated following the administration of bofutsushosan. It is thought that liver injury induced by immunogenic response occurs upon re-dosing of the drug³³⁾ and within 90 d of administration.³⁴⁾ In patients taking bofutsushosan, the onset of liver injury on the fourth day of drug administration was the most common. The cases that occurred within 90 d accounted for 71% of the total number of cases (Fig. 2). However, in the case of herbal medicines and health foods, the time elapsed before liver damage onset tends to be longer than that of other drugs.³⁴⁾ In this study, cases of liver injury after 90 d accounted for approximately 29% of the total number of cases (Fig. 2). This suggests that monitoring liver injury is necessary from the start of drug administration regimen, and periodic monitoring of side effects is necessary while taking bofutsushosan.

Kampo medicines are frequently used not only in hospitals but also as OTC drugs for outpatients. Because of the easy accessibility to herbal medicines, they are readily used, resulting in an increased probability of adverse events. In this study, there were 423 cases including 50 OTC drug cases in JADER in which bofutsushosan was the suspected drug for adverse events. Half of these cases were reported as drug-induced liver injury (Table 2). For bofutsushosan, the rate of liver injury cases reported was similar for both OTC and ethical pharmaceuticals, suggesting that there is a sufficient risk of drug-induced liver injury even when the drug is used as an OTC. Thus, drug-induced hepatotoxicity caused by Kampo medicines may often cause adverse reactions not only in hospitalized patients but also in outpatients. Therefore, it is difficult to collect data on drug-induced liver injury from Kampo medicines in a few centralized cohort studies. Nevertheless, in this study, we investigated liver injury following the administration of Kampo medicines using records in the JADER database, and we were able to obtain information on the characteristics and the onset of liver injury in patients taking bofutsushosan. Such a method may be useful in investigating the adverse events of drugs that are often prescribed to outpatients or purchased OTC.

Although bofutsushosan is a useful drug for the management of lifestyle-related diseases, it may cause adverse events, such as drug-induced liver injury. In particular, there have been many cases of drug-induced liver damage in women aged between 30 and 59 years taking this agent. It may, therefore, be necessary to refrain from its extensive use and administer it with caution to avoid the severity of adverse events.

Despite the findings highlighted in this study, certain limitations are to be noted. In the JADER database, it was not possible to obtain information on the quantitative values of age and biochemical test values in patients with liver injury. Furthermore, regarding the dose of Kampo medicines, temporary interruption or dose changes may not have been reflected in the database. In addition, the number of components and herbal medicines used in each Kampo medicine may differ depending on information, such as the manufacturer, lot, and differences between medical use and OTC or scheduled medicine use. Moreover, because cases in the JADER database are spontaneously reported, there may be some reporting bias as only data on patients presenting with side effects are available. There is a concern that the research data may target a patient group distinct from those generally encountered in actual clinical practice. Therefore, the results of this study need to be further evaluated through cohort studies and randomized controlled trials.

Overall, bofutsushosan was found to be associated with significant odds of liver injury, with many of these cases occurring in females aged between 30 and 59 years. Consequently, it is necessary to be mindful of drug-induced liver injury while taking bofutsushosan.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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