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PLOS Neglected Tropical Diseases logoLink to PLOS Neglected Tropical Diseases
. 2024 Nov 6;18(11):e0012634. doi: 10.1371/journal.pntd.0012634

Serious adverse events reported with benzimidazole derivatives: A disproportionality analysis from the World Health Organization’s pharmacovigilance database

Pamella Modingam 1, Jean-Luc Faillie 2,3, Jérémy T Campillo 1,*
Editor: Eduardo José Lopes-Torres4
PMCID: PMC11573212  PMID: 39504320

Abstract

Background

Benzimidazole derivatives are widely used anthelmintic drugs, particularly in mass campaigns for intestinal parasitosis treatment. Despite their generally good safety profile, serious adverse reactions have been reported. This study aims to identify potential pharmacovigilance signals for benzimidazole derivatives using disproportionality analysis in the WHO database.

Methodology

A case/non-case study was conducted using data from the WHO VigiBase database (2000–2023). Cases were individual case safety reports (ICSRs) where at least one suspected serious adverse event of interest was reported, while non-cases were ICSRs reporting any adverse events other than the serious adverse events of interest. Reporting Odds Ratios (RORs) and 95% confidence intervals were calculated to assess disproportionate reporting. Analyses were adjusted for potential confounding factors and a sensitivity analysis with imputed missing data was performed.

Principal findings

Among 19,068 serious reports analyzed, significant disproportionality signals were found for benzimidazole derivatives compared to other anthelmintic drugs, notably for bone marrow failure and hypoplastic anemia (adjusted ROR 9.44 [5.01–18.9]), serious leukopenia (3.89 [2.64–5.76]), serious hepatic disorders (3.10 [2.59–3.71]), hepatitis (2.88, 95% CI 2.29–3.63) and serious urticaria (2.02, 95% CI 1.36–2.99). We have also highlighted a new signal not mentioned in the summaries of product characteristics for seizures with benzimidazole derivatives. Secondary analysis revealed these signals were primarily reported with albendazole.

Conclusions/Significance

This study identified potential pharmacovigilance signals for serious hematological and hepatic adverse events for benzimidazole derivatives, particularly albendazole. New signal for benzimidazole derivatives has been described for seizures. These findings underscore the need for vigilant monitoring during benzimidazole derivatives use and warrant further pharmacoepidemiologic studies to confirm these signals and investigate underlying mechanisms.

Author summary

Benzimidazole derivatives, including albendazole and mebendazole, are widely used anthelmintics known for their broad spectrum of activity and general tolerability. Some adverse reactions have been reported with benzimidazole derivatives, including hematological, immune, neurological, gastrointestinal, hepatobiliary, and skin disorders. This is the first analysis of serious adverse events reported with benzimidazole derivatives using the WHO global pharmacovigilance database, VigiBase. The study identifies potential pharmacovigilance signals for benzimidazole derivatives, including increased reporting of bone marrow failure, hypoplastic anemia, leukopenia, and hepatic disorders. It also reveals that albendazole is more frequently reported in several serious adverse events compared to other benzimidazole derivatives and anthelmintic drugs, particularly for hematological and hepatotoxic effects. We have also highlighted a new signal, not mentioned in the summaries of product characteristics, for benzimidazole derivatives. These findings highlight the importance of careful monitoring when using benzimidazole derivatives and suggest the need for further studies to confirm these observations and explore the underlying mechanisms.

Introduction

Anthelmintic drugs primarily include benzimidazole derivatives, ivermectin (IVM), and praziquantel (PZQ). These drugs are known for their broad spectrum of anthelmintic activity, effectiveness, and ease of use. The main benzimidazole derivatives used in human medicine include albendazole (ALB), flubendazole (FLU), triclabendazole (TRI), mebendazole (MEB), and thiabendazole (THIA) [1]. ALB and MEB are used in annual deworming campaigns for soil-transmitted helminth infections (roundworm, whipworm, and hookworm) in at-risk populations (preschool children, school-age children, women of reproductive age, and adults in certain high-risk occupations) living in endemic areas [2,3]. It is estimated that several hundred million doses of ALB and MEB have been administered since the inception of these control campaigns.

The broad spectrum of activity of benzimidazole derivatives is attributed to their ability to inhibit tubulin polymerization. This mechanism disrupts the biological processes of digestive tract parasites, including adults and larvae, leading to biochemical changes that result in parasite immobilization and death. In addition to its use in mass drug administration campaigns, ALB is indicated for a wide range of parasitic infections, while MEB and FLU are used for intestinal nematodes, and TRI for fascioliasis. THIA, formerly used for tissue nematodes and strongyloidiasis, was withdrawn from the French market due to high toxicity. PZQ is used for trematode and cestode infections, while IVM is indicated for various nematode infections and scabies [48].

While benzimidazole derivatives are generally considered well-tolerated, some adverse reactions have been reported, including hematological, immune, neurological, gastrointestinal, hepatobiliary, and skin disorders. These are documented in the official information and summaries of product characteristics (SPCs) in most countries.

Safety profiles of some anthelmintic drugs have already been analyzed using disproportionality analysis of the WHO pharmacovigilance database, including PZQ [9], levamisole [10] and IVM [1012]. However, despite their widespread use globally, to our knowledge, no disproportionality study has yet been conducted to assess the overall safety profile of benzimidazole derivatives and potentially detect new adverse events reported with this class.

Following a review of adverse reactions reports related to benzimidazole derivatives published in the literature, we investigated the WHO global pharmacovigilance database, VigiBase, for all suspected serious adverse events reported after anthelmintic treatment. We then conducted disproportionality analyses comparing benzimidazole derivatives to PZQ and IVM. Specifically, the aims of this study were: (i) to identify new potential pharmacovigilance signals (increased reporting of suspected adverse events after treatment with benzimidazole derivatives compared to PZQ and IVM), and (ii) to compare the safety profile of ALB to other benzimidazole derivatives.

Methods

Data source

Deduplicated data were specifically provided by the Uppsala Monitoring Centre upon request from the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database, VigiBase [13]. This database contains over 38 million cases of suspected adverse events reported by national pharmacovigilance centers from more than 130 countries participating in the WHO Program for International Drug Monitoring [14]. An ICSR is an anonymized report for a single individual who experienced adverse event(s) potentially linked to the use of one or more drugs. Each ICSR contains sociodemographic information (age, sex, reporter qualification, country of origin, year of report), drug administration details (frequency, dosage, co-medications), and information about the reported adverse event(s). The latter includes the seriousness criteria as defined by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) [15], verbatim description of the adverse event, and associated terms from the Medical Dictionary for Regulatory Activities (MedDRA) developed by the ICH [16].

Study design

We conducted disproportionality analyses using the case/non-case method to identify disproportionate reporting, defined as a higher-than-expected number of adverse events reports compared to other events recorded in the database. This was achieved by calculating Reporting Odds Ratios (RORs), which compare the odds of exposure to benzimidazole derivatives between cases and non-cases [17,18]. All ICSRs of serious adverse events reported with anthelmintic drugs between January 1, 2000, and December 31, 2023, were extracted from VigiBase. An ICSR can contain multiple adverse events. Duplicates and reports involving the concomitant administration of multiple anthelmintic drugs were excluded. Only ICSR in which anthelmintic drugs were suspected or implicated in interactions were included. Exposure to benzimidazole derivatives was determined by the mention of ALB, MEB, FLU, THIA, or TRI in the ICSR. Exposure to other anthelmintic drugs was determined by the mention of IVM or PZQ.

Drug exposure

Drugs were identified primarily by their active ingredients to ensure consistency and comparability between different formulations and trade names. The selected anthelmintics were benzimidazole derivatives (MEB, THIA, ALB, FLU, TRI) (Anatomical Therapeutic Chemical codes P02CA, D01AC, and P02BX) and IVM, and PZQ (P02BA). The latter two were chosen as comparators due to their similar indications.

Case definition

For each analysis, cases were ICSRs where at least one suspected serious adverse event of interest was reported, while non-cases were ICSRs reporting any adverse events other than the serious adverse events of interest. Each suspected serious adverse event of interest was identified by a selection of MedDRA terms (System Organ Class [SOC], High Level Term [HLT], and Preferred Term [PT]) reformulated into more specific terms (S1 Table). Serious adverse events of interest included hepatic disorders, hepatitis, cholecystitis, cholelithiasis, nausea and vomiting, cutaneous reactions, urticaria, toxidermias, drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous conditions, acute generalized exanthematous pustulosis, allergic disorders, seizures, leucopenia, marrow depression and hypoplastic anemias, headaches, dizziness.

Statistical methods

Only data concerning cases considered serious were used for statistical analysis. Descriptive statistics were used to summarize the basic characteristics of the ICSRs reporting serious adverse events after anthelmintic exposure according to sex, age group, geographic zone, reporting period, and reporter type, along with their numbers and frequency.

Our primary analysis consisted of calculating the ROR of each suspected adverse event of interest (and corresponding 95% confidence interval [95% CI]) for benzimidazole derivates compared to PZQ and IVM reported in VigiBase using logistic regression models. In the secondary analysis, adverse events were compared between ALB and all other benzimidazole drugs. Our analyses were adjusted for the potential confounders available in the line-listing extracted from Vigibase: sex, profession of the reporter (healthcare professional or not), age group (defined according to key life stages: 0–11 years, 12–17 years, 18–44 years, 45–65 years, and over 65 years), geographic area (Europe, Africa, Asia, North America, South America, Oceania), and reporting period (before 2016, 2016–2021, after 2021). To account for the presence of missing data, we performed a sensitivity analysis with imputation using the nearest neighbor’s method (KNN method) [19]. Analyses were conducted using R version 4.3.3 software.

Results

Descriptive analysis of the serious ADRs reported with benzimidazole derivatives

Among the 257,898 ICSRs reporting adverse events after anthelmintic exposure registered in the database, 81,480 ICSRs that matched our criteria were reported from January 1, 2000, to December 31, 2023. We excluded 49 duplicates and 391 cases with no available MedDRA terms. Of the remaining ICSRs, 19,068 contained a serious adverse event, of which 5,137 were reported after a benzimidazole derivative exposure (26.91%) and 13,931 cases were reported after another anthelmintic drug exposure (73.09%). Table 1 shows the characteristics of the ICSR reporting serious adverse events according to anthelmintic drug exposure by age group, sex, reporter type, geographical area, active ingredient name, and reporting period. In benzimidazole derivatives-exposed patients, the sex distribution was balanced, with 51% of cases being female. Adults aged 18–44 were the most represented (38%), followed by the 45–65 age group (23%) and children aged 0–11 (21%). Reports from Europe dominated with 38% of cases, followed by North America (28%). Africa and Asia represented 16% and 15% of cases, respectively. Notifications before 2016 and for the period 2016–2021 represented 40% and 44% of cases, respectively. ALB exposure accounted for two-thirds of the serious cases (67%), followed by mebendazole exposure at 28%. Others benzimidazole derivatives (FLU, THIA, TRI) were marginal. Healthcare professionals reported 76% of the cases.

Table 1. Characteristics of ICSRs containing serious adverse events reported with benzimidazole derivatives and others anthelmintics in VigiBase.

Characteristics (n, %) Benzimidazole derivatives (n = 5,137) Others anthelmintic drugs (n = 13,931) Total (n = 19,068)
Sex
    Female 2,463 (51.0%) 6,897 (49.0%) 4 889 (49.0%)
    Male 2,372 (49.0%) 6,499 (51.0%) 4 910 (51.0%)
    Unknown 302 535 837
Age group (years old)
    0–11 954 (21.0%) 581 (5.1%) 1,535 (9.6%)
    12–17 308 (6.9%) 552 (4.8%) 860 (5.4%)
    18–44 1,701 (38.0%) 4,417 (38.0%) 6,118 (38.0%)
    45–65 1,019 (23.0%) 3,739 (33.0%) 4,758 (30.0%)
    >65 459 (10.0%) 2,208 (19.0%) 2,667 (17.0%)
    Unknown 696 2,434 3,130
Geographic area
    Europe 1,964 (38.0%) 3,553 (26.0%) 5,517 (29.0%)
    Africa 843 (16.0%) 3,096 (22.0%) 3,939 (21.0%)
    Asia 789 (15.0%) 1,181 (8.5%) 1,970 (10.0%)
    North America 1,451 (28.0%) 5,439 (39.0%) 6,890 (36.0%)
    Oceania 21 (0.4%) 102 (0.7%) 123 (0.6%)
    South America 69 (1.3%) 560 (4.0%) 629 (3.3%)
Reporting period
    Before 2016 2,041 (40.0%) 4,769 (34.0%) 6,810 (36.0%)
    2016–2021 2,277 (44.0%) 5,741 (41.0%) 8,018 (42.0%)
    After 2021 819 (16.0%) 3,421 (25.0%) 4,240 (22%)
Active ingredients name
    Mebendazole 1,425 (28.0%) 1,425 (7.5%)
    Albendazole 3,421 (67.0%) 3,421 (18.0%)
    Flubendazole 81 (1.6%) 81 (0.4%)
    Tiabendazole 156 (3.0%) 156 (0.8%)
    Triclabendazole 54 (1.1%) 54 (0.3%)
    Ivermectin 13,011 (93.0%) 13,011 (68.0%)
    Praziquantel 920 (6.6%) 920 (4.8%)
Reporter type
    No health professional 1,106 (24.0%) 3,260 (25.0%) 4,366 (25.0%)
    Health Professional 3,478 (76.0%) 9,757 (75.0%) 13,235 (75%)
    Unknown 553 914 1,467

n, number of ICSRs

An analysis of literature data (S1 Material) and an initial analysis of the frequencies of adverse events reported with anthelmintics (S2 Table) enabled us to construct the list of effects of interest presented with their corresponding MedDRA terms in S1 Table. Table 2 describes the serious adverse events of interest according to anthelmintic drugs use. Serious cases reported after benzimidazole derivatives exposure reveals a preponderance of cutaneous reactions (11.41%), followed by hepatic disorders (7.42%) and nausea and vomiting (5.96%). No cases of acute generalized exanthematous pustulosis were reported after benzimidazole derivatives exposure.

Table 2. Serious adverse events of interest according to anthelminthic drug exposure.

Serious adverse events (n, %) Benzimidazole derivatives Others anthelminthic drugs Total
Hepatobiliary
    Hepatic disorders 381 (7.42%) 327 (2.35%) 708(3.71%)
    Hepatitis 216 (4.20%) 188 (1.35%) 404(2.12%)
    Cholecystitis and cholelithiasis 8 (0.16%) 6 (0.04%) 14(0.07%)
Gastro-intestinal
    Serious nausea and vomiting 306 (5.96%) 405 (2.91%) 711(3.73%)
Allergic and dermatological
    Cutaneous reactions 586 (11.41%) 1,430 (10.26%) 2,016(10.57%)
    Urticaria 70 (1.36%) 72 (0.52%) 142(0.74%)
    Toxidermias 52 (1.01%) 252 (1.81%) 304(1.59%)
    Drug reaction with eosinophilia and systemic symptoms 3 (0.06%) 39 (0.28%) 42(0.22%)
    Stevens-Johnson syndrome 23 (0.45%) 59 (0.42%) 82(0.43%)
    Toxic epidermal necrolysis 8 (0.16%) 62 (0.44%) 70(0.37%)
    Bullous conditions 49 (0.95%) 188 (1.35%) 237(1.24%)
    Acute generalized exanthematous pustulosis 0 (0.00%) 25 (0.18%) 25(0.13%)
    Serious allergic disorders 71 (1.38%) 217 (1.56%) 288(1.51%)
Neurological
    Seizures 73 (1.42%) 79 (0.57%) 152(0.80%)
    Headaches 154 (3.00%) 387 (2.78%) 541(2.84%)
    Dizziness 123 (2.39%) 224 (1.61%) 347(1.82%)
Hematological
    Leucopenia 81 (1.58%) 56 (0.40%) 137(0.72%)
    Marrow depression and hypoplastic anemias 50 (0.97%) 16 (0.11%) 66(0.35%)

n, number of ICSRs containing the adverse event of interest

A same ICSR can contain multiple adverse events of interest

Disproportionality analyses

Table 3 shows the main disproportionality analyses of the serious adverse events of interest reported with benzimidazole derivatives compared to other anthelmintic drugs. The table also shows the results of the secondary analyses for each event of interest.

Table 3. Disproportionality analysis of serious adverse events of interest reported after benzimidazole derivatives exposure.

Serious adverse events of interest Cases* Non-cases Analysis 1a Analysis 2b Analysis 3c
ROR (IC95%) P-value aROR (IC95%) P-value aROR (IC95%) P-value
Hepatic disorders
Benzimidazole derivatives 381 4,756 3.33 (2.87–3.88) <0.001 3.10 (2.59–3.71) <0.001 3.23 (2.74–3.80) <0.001
Other anthelminthic drugs 327 13,604 Ref. Ref. Ref.
Albendazole 336 3,085 4.04 (2.98–5.62) <0.001 5.70 (3.88–8.59) <0.001 4.53 (3.22–6.49) <0.001
Other benzimidazole derivatives 45 1,671 Ref. Ref. Ref.
Hepatitis
Benzimidazole derivatives 216 4,921 3.21 (2.63–3.91) <0.001 2.88 (2.29–3.63) <0.001 2.95 (2.38–3.64) <0.001
Other anthelminthic drugs 188 13,743 Ref. Ref. Ref.
Albendazole 190 3,231 3.82 (2.58–5.92) <0.001 4.82 (2.98–8.16) <0.001 4.16 (2.70–6.66) <0.001
Other benzimidazole derivatives 26 1,690 Ref. Ref. Ref.
Cholecystitis et cholelithiasis
Benzimidazole derivatives 8 5,129 3.62 (1.26–11.0) 0.017 1.89 (0.14–26.0) 0.600 1.33 (0.30–6.29) >0.900
Other anthelminthic drugs 6 13,925 Ref. Ref. Ref.
Albendazole 1 3,420 0.07 (0.00–0.40) 0.014 4,857,903(0.00-Inf) >0.900 2.15 (0.04–192) 0.700
Other benzimidazole derivatives 7 1,709 Ref. Ref. Ref.
Nausea and vomiting
Benzimidazole derivatives 306 4,831 2.12 (1.82–2.46) <0.001 1.50 (1.22–1.83) <0.001 1.56 (1.31–1.85) <0.001
Other anthelminthic drugs 405 13,526 Ref. Ref. Ref.
Albendazole 197 3224 0.90 (0.71–1.15) 0.400 0.61 (0.43–0.87) 0.006 0.75 (0.56–1.01) 0.060
Other benzimidazole derivatives 109 1,607 Ref. Ref. Ref.
Cutaneous disorders
Benzimidazole derivatives 586 4,551 1.13 (1.02–1.25) 0.023 0.81 (0.71–0.92) 0.001 0.84 (0.75–0.94) 0.002
Other anthelminthic drugs 1430 12,501 Ref. Ref. Ref.
Albendazole 365 3,056 0.81 (0.68–0.97) 0.019 0.64 (0.50–0.82) <0.001 0.73 (0.59–0.91) 0.006
Other benzimidazole derivatives 221 1495 Ref. Ref. Ref.
Urticaria
Benzimidazole derivatives 70 5,067 2.66 (1.91–3.70) <0.001 2.02 (1.36–2.99) <0.001 1.92 (1.34–2.74) <0.001
Other anthelminthic drugs 72 13,859 Ref. Ref. Ref.
Albendazole 38 3,383 0.59 (0.37–0.95) 0.030 0.56 (0.30–1.07) 0.076 0.62 (0.35–1.10) 0.100
Other benzimidazole derivatives 32 1,684 Ref. Ref. Ref.
Toxidermias
Benzimidazole derivatives 52 5,085 0.56 (0.41–0.74) <0.001 0.36 (0.25–0.51) <0.001 0.33 (0.24–0.46) <0.001
Other anthelminthic drugs 252 13,679 Ref. Ref. Ref.
Albendazole 26 3,395 0.50 (0.29–0.86) 0.012 0.23 (0.11–0.46) <0.001 0.26 (0.13–0.51) <0.001
Other benzimidazole derivatives 26 1,690 Ref. Ref. Ref.
Drug reaction with eosinophilia and systemic symptoms
Benzimidazole derivatives 3 5,134 0.21 (0.05–0.57) 0.009 0.14 (0.03–0.43) 0.002 0.15 (0.03–0.42) 0.002
Other anthelminthic drugs 39 5,134 Ref. Ref. Ref.
Albendazole 1 3,420 0.25 (0.01–2.62) 0.300 0.08 (0.00–1.69) 0.130 0.08 (0.00–1.74) 0.130
Other benzimidazole derivatives 2 1,714 Ref. Ref. Ref.
Stevens-Johnson syndrome
Benzimidazole derivatives 23 5,114 1.06 (0.64–1.59) 0.800 0.90 (0.51–1.57) 0.700 0.79 (0.45–1.33) 0.400
Other anthelminthic drugs 59 13,872 Ref. Ref. Ref.
Albendazole 15 3,406 0.93 (0.41–2.34) 0.900 0.35 (0.13–1.06) 0.050 0.37 (0.14–1.05) 0.051
Other benzimidazole derivatives 8 1,708 Ref. Ref. Ref.
Toxic epidermal necrolysis
Benzimidazole derivatives 8 5,129 0.35 (0.15–0.69) 0.005 0.32 (0.13–0.69) 0.007 0.26 (0.11–0.55) <0.001
Other anthelminthic drugs 62 13,869 Ref. Ref. Ref.
Albendazole 5 3,416 0.84 (0.20–4.08) 0.800 0.45 (0.07–2.88) 0.400 0.54 (0.09–3.38) 0.500
Other benzimidazole derivatives 3 1,713 Ref. Ref. Ref.
Bullous conditions
Benzimidazole derivatives 49 5088 0.70 (0.51–0.96) 0.029 0.44 (0.30–0.64) <0.001 0.41 (0.29–0.59) <0.001
Other anthelminthic drugs 188 13,743 Ref. Ref. Ref.
Albendazole 25 3,396 0.52 (0.29–0.92) 0.022 0.24 (0.12–0.48) <0.001 0.27 (0.14–0.54) <0.001
Other benzimidazole derivatives 24 1,692 Ref. Ref. Ref.
Allergic disorders
Benzimidazole derivatives 71 5,066 1.52 (1.13–2.03) 0.005 1.31 (0.89–1.92) 0.200 1.12 (0.81–1.54) 0.500
Other anthelminthic drugs 127 13,804 Ref. Ref. Ref.
Albendazole 35 3,386 0.48 (0.30–0.77) 0.002 0.24 (0.12–0.47) <0.001 0.35 (0.20–0.62) <0.001
Other benzimidazole derivatives 36 1,680 Ref. Ref. Ref.
Seizures
Benzimidazole derivatives 73 5,064 2.53 (1.83–3.48) <0.001 1.92 (1.29–2.85) 0.001 1.75 (1.23–2.48) 0.002
Other anthelminthic drugs 79 13,852 Ref. Ref. Ref.
Albendazole 38 3,383 0.54 (0.34–0.86) 0.009 0.52 (0.28–0.99) 0.043 0.65 (0.36–1.16) 0.140
Other benzimidazole derivatives 35 1,681 Ref. Ref. Ref.
Leucopenia
Benzimidazole derivatives 81 5,056 3.97 (2.83–5.61) <0.001 3.89 (2.64–5.76) <0.001 4.62 (3.24–6.64) <0.001
Other anthelminthic drugs 56 13,875 Ref. Ref. Ref.
Albendazole 76 3,345 7.77 (3.48–22.2) <0.001 14.3 (4.25–89.0) <0.001 5.57 (2.37–16.4) <0.001
Other benzimidazole derivatives 5 1,711 Ref. Ref. Ref.
Marrow depression and hypoplastic anemias
Benzimidazole derivatives 50 5,087 8.55 (4.98–15.50) <0.001 9.44 (5.01–18.9) <0.001 10.7 (6.01–20.0) <0.001
Other anthelminthic drugs 16 13,915 Ref. Ref. Ref.
Albendazole 49 3,372 24.9 (5.46–441) 0.001 11.1 (2.31–199) 0.019 11.9 (2.52–212) 0.015
Other benzimidazole derivatives 1 1,715 Ref. Ref. Ref.
Headaches
Benzimidazole derivatives 154 4,983 1.08 (0.89–1.30) 0.400 1.35 (1.08–1.68) 0.007 1.25 (1.01–1.53) 0.034
Other anthelminthic drugs 387 13,544 Ref. Ref. Ref.
Albendazole 130 3,291 2.78 (1.83–4.42) <0.001 1.72 (1.00–3.06) 0.056 1.77 (1.08–3.01) 0.027
Other benzimidazole derivatives 24 1,692 Ref. Ref. Ref.
Dizziness
Benzimidazole derivatives 123 5,014 1.50 (1.20–1.87) <0.001 1.56 (1.20–2.02) <0.001 1.46 (1.14–1.86) 0.002
Other anthelminthic drugs 224 13,707 Ref. Ref. Ref.
Albendazole 95 3,326 1.72 (1.14–2.68) 0.012 0.84 (0.49–1.46) 0.500 0.98 (0.60–1.64) >0.900
Other benzimidazole derivatives 28 1,688 Ref. Ref. Ref.

a, crude analysis

b, adjusted analysis on age, sex, reporter type, reporting period and geographical zone

c, adjusted analysis on age, sex, reporter type and geographical zone with imputed data for missing values (KNN method).

* Cases are ICSRs where at least one suspected serious adverse event of interest is reported after the drug exposure. An ICSR can be used in multiple analysis if it contains multiple events of interest.

In the main analyses, a significant pharmacovigilance signal, in the sense of an over-reporting, was found with benzimidazole derivatives for the following serious adverse events, ranked by decreasing adjusted ROR (aROR): bone marrow failure and hypoplastic anemia (aROR 9.44, 95% CI 5.01–18.9), leukopenia (aROR 3.89, 95% CI 2.64–5.76), hepatic disorders (aROR 3.10, 95% CI 2.59–3.71, hepatitis (aROR 2.88, 95% CI 2.29–3.63), urticaria (aROR 2.02, 95% CI 1.36–2.99), seizures (aROR 1.92, 95% CI 1.29–2.85), dizziness (aROR 1.56, 95% CI 1.20–2.02), nausea and vomiting (aROR 1.50, 95% CI = 1.22–1.83), and headaches (aROR 1.35, 95% CI 1.03–1.68).

As for the secondary analysis comparing ALB to other benzimidazole derivatives, disproportionality analysis revealed an over-reporting of certain serious adverse events, ranked by decreasing adjusted ROR: leukopenia (aROR 14.3, 95% CI 4.25–89.0), bone marrow failure and hypoplastic anemias (aROR 11.1, 95% CI 2.31–199), hepatic disorders (aROR 5.70, 95% CI 3.88–8.59) and hepatitis (aROR 4.82, 95% CI 2.98–8.16). There was no disproportionate reporting for the other adverse events analyzed.

The sensitivity analysis with data imputation showed similar disproportionate reporting than those of the main analyses, except for a new signal of serious headache observed after ALB exposure (aROR 1.77, 95% CI 1.08–3.01).

Discussion

This research established a detailed assessment of serious adverse events reported after the use of benzimidazole derivatives, using a case/non-case approach, analyzing data collected from the WHO Adverse Drug Reaction database, spanning 2000 to 2023. Our analyses revealed statistically significant pharmacovigilance signals for several serious adverse events, including bone marrow failure, hypoplastic anemia, leukopenia, hepatic disorders and hepatitis, with particularly strong signals reported after ALB exposure. The signal observed for seizures after benzimidazole derivatives exposure was not previously known nor mentioned in official information and constitutes a new pharmacovigilance signal.

While Bagheri et al. (2004) described various adverse reactions to anthelmintic drugs recorded in the French pharmacovigilance database from 1988 to 1999, our study is the first to examine serious adverse events associated with benzimidazole derivatives in the WHO pharmacovigilance database through disproportionality analyses [20].

Our main hypothesis, that there were new signals of serious adverse events reported with benzimidazole derivatives compared to other anthelmintic drugs, is supported by our analyses. Our results revealed pharmacovigilance signals, indicated by statistically significant disproportionate reporting, for bone marrow failure and hypoplastic anemia, leukopenia, liver disorders, hepatitis, hepatic disorders, urticaria, convulsions/seizures, dizziness, nausea and vomiting, and headaches in patients exposed to benzimidazole derivatives, with strong signals observed for the first six. Specifically, the analysis within class comparing ALB with other benzimidazole derivatives (i) showed that pharmacovigilance signals for bone marrow failure and hypoplastic anemias, leukopenia, liver disorders, hepatitis, and hepatic disorders were strongly reported after ALB exposure.

Placing these results in the context of existing literature, our findings align with previous studies highlighting the hematological and hepatotoxic risks associated with ALB, corroborating existing safety concerns [4]. Although these effects are rare, Fernandez et al. (1996) were the first to report a case of pancytopenia (bone marrow failure) associated with ALB in a 75-year-old woman treated for hepatic hydatidosis [21]. Additionally, Bagheri et al. (2004) reported pancytopenia with ALB and MEB treatments as part of a long course of treatment for echinococcosis, with high doses of medicinal products [20]. Xing et al. (2018) also reported a case of fatal pancytopenia after 15 days of ALB treatment [22]. Several studies are consistent with our findings of disproportionality observed for the hepatotoxic risks associated with ALB [2329]. Although ALB excellent safety profile underpins mass drug distribution campaigns, it is essential to remain aware of and vigilant about the serious adverse reactions it can potentially induce. As the signals highlighted in our study were based on findings from existing data, it would be valuable to conduct a real-world pharmacoepidemiologic study to confirm these signals.

The pathophysiological mechanisms underlying the suspected adverse events following exposure to benzimidazole derivatives remain incompletely understood. For hematological disorders such as bone marrow failure, hypoplastic anemia, leukopenia, and pancytopenia, the primary hypothesis is that this class of drugs can inhibit tubulin polymerization, potentially impairing cell turnover and leading to a depletion of cell lineages [21]. Additionally, benzimidazoles may interfere with folate metabolism, further contributing to hematological toxicity [30]. Hepatic disorders, which are well-known adverse drug reactions, might be linked to the drug’s metabolites, primarily eliminated via the biliary route [4]. The mechanisms underlying seizures and skin disorders are unclear and need further investigations. One hypothesis is that these effects might involve the direct action of the drug on parasites in the blood (such as loiasis) or in brain (such as taeniasis), provoking allergic and/or neurologic reactions due to parasite death, circulation of their remains, or embolization in brain capillaries. The limitations of this study include the under-reporting of suspected adverse reactions (and the potential differences in this under-reporting between countries), as well as the lack of information on drug exposure in the population. These limitations, inherent in studies using pharmacovigilance databases [31,32], restrict the measurement of the true incidence of adverse reactions. Although under-reporting may be less significant since we focused on serious adverse events (which are more likely to be reported) [33], our analyses cannot measure the actual risk of adverse reactions but only differences in reported events. Indeed, the subjects in our "control" (non-case) group are not healthy controls, but patients who have reported other adverse events. Given the multiplicity of statistical analyses performed, which increases the risk of Type I errors, we did not apply formal corrective methods for multiple comparisons. However, we focused on 17 specific adverse events selected based on a comprehensive literature review and preliminary frequency analysis in our dataset. The consistent findings across various sub-analyses suggest that the risk of random statistically significant results is low. Moreover, it is crucial to consider the potential for protopathic bias in interpreting our results. Several adverse effects, such as liver disorders, seizures, or urticaria can also be symptoms of parasitic infections for which benzimidazole derivatives are prescribed. This could lead to misattribution of disease symptoms to the drug, potentially inflating the apparent association with benzimidazole use.). Another limitation is the possibility of indication bias: not all anthelmintic drugs are used in the same situations, and the signals found with benzimidazole derivatives could be partly explained by these differences. Unfortunately, the precise indication was not available in the database and could not be considered. However, indication bias is less important when comparing drugs in the same therapeutic area (which we did) than when comparing the drugs of interest to all other drugs reported in the database across all therapeutic areas and indications. Additionally, by eliminating reports recording the concomitant role of our drugs, we have reduced the impact of competition bias on the drug-event combination of interest [34]. Nevertheless, these results must be interpreted with caution due to potentially missing information.

The main strength of this study is the use of the WHO VigiBase database, which enables the study of adverse events reported worldwide and provides important information on the use of drugs in real-life situations. Our study is the first to evaluate the serious adverse events of benzimidazole derivatives in the WHO database using a disproportionality analysis. Moreover, the detection of emerging signals of serious adverse events, such as bone marrow failure, hypoplastic anemias, leukopenia, and hepatic disorders, is paramount to ensure patient safety. By comparing ALB with other benzimidazole derivatives, and more specifically with MEB, the study provides a detailed assessment of the specific risks associated with each drug within the same therapeutic class. This makes it possible to identify risks specific to certain drugs, rather than the entire class.

The discovery of statistically significant disparities for several serious adverse events, with particularly strong associations attributed to ALB, confirms the reliability of the results and highlights safety issues specific to this drug. The revelation of a significant association between ALB and headache, which had not been detected in the main analysis, underscores the value of the analysis conducted, capable of detecting potentially infrequent but clinically relevant adverse events. Finally, this research builds upon previous studies, such as those by Bagheri et al. (2004), by providing recent and extensive data on the adverse reactions of anthelmintic drugs, focusing specifically on benzimidazole derivatives [20].

Conclusion

This first study to disproportionate reporting of adverse events reported with benzimidazole derivatives in the WHO database, complements and extends previous work carried out on smaller national databases, suggests that ALB presents an increased risk for several serious adverse events compared to other benzimidazole derivatives. It also revealed new potential pharmacovigilance signal for benzimidazole derivatives: seizures. These results underline the need for constant vigilance and monitoring for patients taking benzimidazole derivatives, particularly ALB. These results call for further studies to confirm these links and examine the mechanisms underlying these adverse effects.

Supporting information

S1 Material. Review of the case reports in the literature.

(DOCX)

pntd.0012634.s001.docx (59.4KB, docx)
S1 Table. Adverse events of interest and corresponding MedDRA terms.

(DOCX)

pntd.0012634.s002.docx (32KB, docx)
S2 Table. Reported MedDRA System Organ Class (SOC) according to anthelmintic drugs type.

(DOCX)

pntd.0012634.s003.docx (36KB, docx)

Data Availability

Data cannot be shared publicly because of restriction of access to VigiBase. Data are available from the WHO Global Individual Case Safety Report (ICSR) database, VigiBase for researchers who meet the criteria for access to confidential data. Vigibase has the data we used and makes them available to people working in a hospital pharmacovigilance service via the email address CustomSearches@who-umc.org.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0012634.r001

Decision Letter 0

jong-Yil Chai, Eduardo José Lopes-Torres

9 Sep 2024

Dear Dr Campillo,

Thank you very much for submitting your manuscript "Serious adverse drug reactions associated with benzimidazole derivatives: a disproportionality analysis from the World Health Organization's pharmacovigilance database" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

The reviewers have acknowledged the novelty of your study, particularly the use of the World Health Organization's pharmacovigilance database to analyze benzimidazole derivatives. They noted that the manuscript is well-written and includes valuable sub-analyses. The objectives are clearly articulated, and the hypothesis is testable.

However, there are areas that require further attention:

Concerns were raised about the adequacy of the sample size in relation to the power of the analysis.

While the figures and tables are generally clear, there may be room for improvement in their presentation.

Given these points, the manuscript is being returned with a recommendation for Major Revision. Please address the reviewers' comments in detail and resubmit your revised manuscript for further consideration.

We look forward to receiving your revised submission.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

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Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Eduardo José Lopes-Torres, Ph.D.

Academic Editor

PLOS Neglected Tropical Diseases

Jong-Yil Chai

Section Editor

PLOS Neglected Tropical Diseases

***********************

Dear Authors,

Thank you for submitting your manuscript titled "Serious adverse drug reactions associated with benzimidazole derivatives: a disproportionality analysis from the World Health Organization's pharmacovigilance database" to PLOS Neglected Tropical Diseases. After careful consideration and review by our expert reviewers, we have reached a decision.

The reviewers have acknowledged the novelty of your study, particularly the use of the World Health Organization's pharmacovigilance database to analyze benzimidazole derivatives. They noted that the manuscript is well-written and includes valuable sub-analyses. The objectives are clearly articulated, and the hypothesis is testable.

However, there are areas that require further attention:

Concerns were raised about the adequacy of the sample size in relation to the power of the analysis.

While the figures and tables are generally clear, there may be room for improvement in their presentation.

Given these points, the manuscript is being returned with a recommendation for Major Revision. Please address the reviewers' comments in detail and resubmit your revised manuscript for further consideration.

We look forward to receiving your revised submission.

Best regards,

Eduardo Torres

Academic Editor PLOS Neglected Tropical Diseases

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: Yes

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: Yes

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: Yes

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: (No Response)

Reviewer #2: The authors reported the results of a disproportionality analysis using the World Health Organization's pharmacovigilance database regarding benzimidazole derivatives for the first time. The manuscript is well written with several subanalyses.

I only had few comments:

- In the Discussion section, the authors stated “severe leukopenia, severe liver disorders, hepatitis, severe hepatic disorders, severe urticaria, severe convulsions/seizures, dizziness, severe nausea and vomiting”, which is misleading as the ADR in the Vigibase are “serious” and not “severe”. Indeed, an ADR could be considered serious in the Vigibase if it is a “medically important event or reaction”, independent of any notion of severity.

- The authors could elaborate on possible pathophysiological mechanisms at the origin of the ADR found, even if this not the purpose of a disproportionality analysis.

- The authors should discuss possible protopathic bias, as several ADR found can be symptoms of parasitic infections (liver disorders, seizures, urticaria…)

- The authors should provide further details on the literature review: which “expert pharmacovigilants”? which keywords? which search engines?…

- Some corrections need to be done: typos (a new signals, as well-tolerated, Table 2 shows describes, according anthelminthic drugs,…) ; inconsistencies (in abstract: aROR sometimes written, sometimes not) ; “other benzimidazole derivatives (i)” in the Discussion section?; legend 1 not explained in Supplementary Table 2; article 22 misquoted ; “of which 5,131 cases” instead of 5,137.

--------------------

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Reviewer #1: No

Reviewer #2: No

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Attachment

Submitted filename: PNTD-D-24-01059_Comments.docx

pntd.0012634.s004.docx (16.4KB, docx)
PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0012634.r003

Decision Letter 1

jong-Yil Chai, Eduardo José Lopes-Torres

16 Oct 2024

Dear Dr Campillo,

We are pleased to inform you that your manuscript 'Serious adverse events reported with benzimidazole derivatives: a disproportionality analysis from the World Health Organization's pharmacovigilance database' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted, you will need to address the changes suggested by Reviewer 1 and and complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Eduardo José Lopes-Torres, Ph.D.

Academic Editor

PLOS Neglected Tropical Diseases

Jong-Yil Chai

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: There is an improvement in the method section. However, here are some additional suggestions to improve the manuscript

Objective (introduction and abstract)

L28 & L99: It is more appropriate to say “potential pharmacovigilance signal”. Disproportionality analysis allows to identify potential quantitative signals. Further assessment is required to confirm as signals.

Methods

L105 states “Deduplicated data were extracted from … VigiBase”. You responded to reviewer that you “did not use the VigiLyze tool for data extraction. Instead, a de-duplicated dataset was specifically provided by the Uppsala Monitoring Centre upon request.” This last information needs to appear in the method section. It can explain discrepancies in case some readers extract data from VigiLyze for comparison.

L132 – 136: I would strongly suggest to remove these lines from Case definition and put them in the data source section. This will allow to focus on L136 to 146 for case definition.

Reviewer #2: Yes

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: The results are clearly presented.

Reviewer #2: Yes

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are supported by the data presented. The limitations have been discussed as well as the relevance of these findings.

However, the conclusion should be nuanced to present seizure as a new potential pharmacovigilance signal, since signal assessment was not part of this manuscript.

Reviewer #2: Yes

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: (No Response)

Reviewer #2: All comments have been made.

Please note the typo in supplementary materials: Encephlopathy

**********

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0012634.r004

Acceptance letter

jong-Yil Chai, Eduardo José Lopes-Torres

30 Oct 2024

Dear Dr Campillo,

We are delighted to inform you that your manuscript, "Serious adverse events reported with benzimidazole derivatives: a disproportionality analysis from the World Health Organization's pharmacovigilance database," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

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Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Material. Review of the case reports in the literature.

    (DOCX)

    pntd.0012634.s001.docx (59.4KB, docx)
    S1 Table. Adverse events of interest and corresponding MedDRA terms.

    (DOCX)

    pntd.0012634.s002.docx (32KB, docx)
    S2 Table. Reported MedDRA System Organ Class (SOC) according to anthelmintic drugs type.

    (DOCX)

    pntd.0012634.s003.docx (36KB, docx)
    Attachment

    Submitted filename: PNTD-D-24-01059_Comments.docx

    pntd.0012634.s004.docx (16.4KB, docx)
    Attachment

    Submitted filename: Revision Letter_Plos-PV-Alb jlf+jc.docx

    pntd.0012634.s005.docx (29.1KB, docx)

    Data Availability Statement

    Data cannot be shared publicly because of restriction of access to VigiBase. Data are available from the WHO Global Individual Case Safety Report (ICSR) database, VigiBase for researchers who meet the criteria for access to confidential data. Vigibase has the data we used and makes them available to people working in a hospital pharmacovigilance service via the email address CustomSearches@who-umc.org.


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