A Comprehensive Safety Profile of Rabeprazole: Insights from a Real-World Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS) Database

Background: Rabeprazole is a widely used proton pump inhibitor whose long-term safety profile warrants further investi- gation. Based on the FAERS database, we systematically evaluated rabeprazole-associated adverse events (AEs). Methods: Data were extracted from FAERS (2004Q1 – 2025Q2), and four disproportionality methods including ROR, PRR, BCPNN and EBGM were applied for signal detection. Furthermore, we also conducted subgroup analyses by gender and patient out- comes, and evaluated the time to onset of AEs. Results: Among 3,696 rabeprazole-related cases, serious outcomes account for 59.9% of cases, including 6.4% fatalities. Females reported more AEs (45.7% vs 28.7%) with earlier onset (median 10 vs. 15 days, p=0.00054). Renal and urinary disorders were the only System Organ Class (SOC) meeting all signal criteria, showing significant associations with tubulointerstitial nephritis, acute kidney injury, and renal failure, which frequently asso- ciated with serious or fatal outcomes. Other notable signals involved gastrointestinal disorders (e.g., gastric/duodenal polyps, hemorrhagic enterocolitis), skin and subcutaneous tissue disorders (e.g., erythema multiforme, drug eruption), metabolism and nutrition disorders (e.g., hypomagnesemia, hypocalcemia, vitamin B 12 deficiency), respiratory and neurological AEs. Several rare but strong signal such as leukocyte adhesion deficiency (n = 3; ROR = 1103.35, 95% CI: 321.44–3787.3) were also detected.

This study identifies multi-system safety signals for rabeprazole, notably delayed renal toxicity and early gas- trointestinal or cutaneous reactions. Long-term users require regular monitoring of renal function, electrolytes and vitamin B 12, with prompt drug withdrawal upon serious adverse events. While FAERS provides critical real-world evidence, its inherent

necessitate further validation through prospective studies. 1. Introduction Rabeprazole sodium, a second-generation proton pump inhibitor (PPI), was first approved in Japan in 1997 and FDA-approved in the US in 1999. It has since gained widespread global use. By irreversibly in- hibiting parietal cell H+/K+-ATPase to suppress acid secretion, and exhibiting lower CYP2C19-dependent metabolism than some first-generation PPIs, this drug offers clinical benefits through reduced drug- interaction potential and more predictable inter-individual response [1-4]. It is indicated for the treatment of gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, and in combination with antibiotics for Helicobacter pylori eradication [5]. Rabeprazole is contraindicated in pa- tients with known hypersensitivity to benzimidazole derivatives, as well as in pregnant and breastfeeding women[6]. While the overall efficacy and safety profile of rabeprazole is comparable to other PPIs, some evidence indicates that it may offer a more rapid onset of symptomatic relief in specific patient groups [7-9]. Although generally well-tolerated over short-term use, long-term administration of rabeprazole has been associated with several safety concerns [10, 11] . Commonly reported adverse drug reactions (ADRs) include headache, gastrointestinal symptoms (e.g., nausea, constipation, diarrhea), and transaminase elevations [12]. Rare but 1 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. serious ADRs such as hypomagnesemia, interstitial pneumonia, hemolytic anemia, and renal impairment have also been documented[10-14]. More recent studies suggest potential associations between long-term PPI use, including rabeprazole, and increased risks of dementia, osteoporosis, and fractures [15]. Nonetheless, many existing studies remain limited by small sample sizes and short follow-up periods, under- scoring a scarcity of comprehensive real-world evidence regarding the long-term safety profile of rabeprazole. The FDA Adverse Event Reporting System (FAERS) is a well-established pharmacovigilance database that collects spontaneous adverse event reports worldwide, offering extensive real-world data for post-marketing drug safety monitoring. Its value lies in the detection of signals related to rare, severe, and long-term adverse events, thereby aiding in the identification of potential risk factors. Recent analyses of FAERS have identi- fied several rare adverse reactions associated with PPIs, including rhabdomyolysis and dementia, which are typically undetectable within the scope of conventional clinical trials [16, 17] . Therefore, this study aims to utilize disproportionality analysis algorithms to mine the FAERS database to identify and evaluate potential safety signals associated with rabeprazole. The findings will provide crucial real-world evidence to inform clinical practice on the safe use of rabeprazole and address the gap in systematic research on its long-term and specific serious ADRs. 2. Methods 2.1 Data source and cleaning Data were obtained from the FAERS database, a publicly available pharmacovigilance database containing records since the first quarter of 2004. As FAERS relies on spontaneous reporting, it includes duplicate and occasionally retracted entries. Therefore, this study followed FDA-recommended procedures for data deduplication and applied official exclusion criteria to ensure data integrity. 2.2 Data filtering and processing All adverse events (AEs) were coded using Preferred Terms (PTs) and mapped to the highest-level System Organ Class (SOC) according to the Medical Dictionary of Regulatory Activities version 27.1 (MedDRA v27.1). Reports spanning from Q1 2004 to Q2 2025 were included, yielding an initial total of 23,168,942 cases. These data comprised seven structured files: demographic and administrative details (DEMO), pa- tient outcomes (OUTC), drug reactions (REAC), drug information (DRUG), indications (INDI), therapy dates (THER), and reporting sources (RPSR). After removing 3,824,146 duplicate entries, 19,344,796 cases remained. Cases involving rabeprazole were identified using both the brand name (PARIET, ACIPHEX) and the generic name (RABEPRAZOLE). A total of 3,696 reports listing rabeprazole as the primary suspect (PS) drug, encompassing 9,811 PTs, were extracted. The selection workflow is summarized in Figure 1. 2.3 Disproportionality analysis Disproportionality analysis was conducted to identify potential adverse drug reaction (ADR) signals within the dataset. Four established algorithms were applied: Reporting Odds Ratio (ROR), Proportional Re- porting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Detailed computational criteria and thresholds for each method are provided inSupplementary Table 1. Signal strength was considered positively associated with higher metric val- ues. A conservative approach was adopted: only signals meeting all four algorithm thresholds concurrently were deemed significant. 2.4 Subgroup analysis To examine gender and outcome differences in AEs, we conducted additional signal analyses on all 122 positive AEs at the PT level using the ROR method. These AEs were further categorized by SOC to provide a systematic overview of the signals. It should be noted that the ROR method applied here does not strictly 2 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. adhere to the conventional pharmacoepidemiologic definition of ROR; the specific calculation formula and detection criteria are detailed in Supplementary Table 2 . 2.5 Statistical analysis All analyses were performed using SAS 9.4 and R 4.2.1. A p-value < 0.05 was considered statistically significant. 3. Results 3.1 Descriptive characteristics After screening, we identified a total of 3,696 cases and 9,811 AE reports of rabeprazole from the first quarter of 2004 to the second quarter of 2025. Figure 2 provides a comprehensive overview of the demographic characteristics of these cases. The annual number of reports generally ranged between 100 and 200, showing an overall upward trend. The highest number of reports occurred in 2018 (n = 900), while the lowest was recorded in 2013 (n = 4). The countries with the most rabeprazole-related AE reports were the United States (n = 1,607), Japan (n = 477), France (n = 429), and China (n = 332). The majority of reports were submitted by physicians (23.3%), lawyers (21.9%), consumers (16.7%), pharmacists (6.5%) and other Health-professional (27.7%). Females accounted for a higher proportion of cases (45.7%) than males (28.7%). The most affected age groups were 18–64 years (32.3%) and 64–85 years (24.1%), while those under 18 years constituted the smallest group (0.7%). Serious outcomes were reported in 59.9% of patients, including hospitalization (18.9%), death (6.4%), life-threatening (1.5%), disability (1.2%), and other serious outcomes (32.0%). 3.2. Time to onset analysis After excluding reports that were incomplete, inaccurate, or erroneous, a total of 884 cases were included in the time to onset analysis. As shown in Figure 3A , the majority of rabeprazole-related AEs occurred within 30 days of drug exposure (n = 581; 65.7%). Notably, a subset of adverse events still occurred even after 360 days of rabeprazole treatment (n = 126; 14.3%). The overall median time to onset was 12 days (interquartile range [IQR]: 5–75 days) ( Figure 3B ). To further investigate factors influencing the time to onset of rabeprazole-related AEs, we performed stratified analyses by sex, age group, patient outcome, and primary SOCs. The results revealed that the median time to onset was significantly longer in male patients (15 days; IQR: 6–118 days) than in female patients (10 days; IQR: 4–51 days) (p = 0.00054; Figure 3C ). Patients aged [?]85 years had the shortest median time to onset (7 days; IQR: 2–32.5 days), while those under 18 years had the longest (25 days; IQR: 9.5–75.8 days) (p = 0.0081;Figure 3D ). With regard to patient outcomes, the median time to onset was significantly shorter in the group with serious outcomes (9 days; IQR: 4–19 days) compared to the non-serious outcome group (34 days; IQR: 7–254 days) (p < 0.0001; Figure 3E ). By primary SOC category, skin and subcutaneous tissue disorders had the shortest median time to onset (8 days; IQR: 3–13 days), while Renal and urinary disorders had the longest (70.5 days; IQR: 14.2–268.2 days) (p < 0.0001; Figure 3F ). 3.3 Signal mining at the SOC level As depicted inFigure 4A , AEs associated with rabeprazole were distributed across 27 System Organ Classes (SOCs). The top five SOCs by report count were renal and urinary disorders (n = 1395), gastrointestinal disorders (n = 1338), general disorders and administration site conditions (n = 1188), skin and subcutaneous tissue disorders (n = 891), and nervous system disorders (n = 689). Signal detection was performed across all 27 SOCs. As illustrated in Figure 4B , only renal and urinary disorders met all four signal detection criteria. Metabolism and nutrition disorders and endocrine disorders satisfied three criteria (ROR, MGPS, and BCPNN). Gastrointestinal disorders, skin and subcutaneous tissue disorders, blood and lymphatic system disorders, and hepatobiliary disorders met two criteria (ROR and BCPNN). Immune system disorders met only the ROR criterion, while the remaining SOCs did not meet any of the signal detection thresholds. 3 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. 3.4. Signal mining at the PT level At the PT level, disproportionality analysis was performed on 1,506 adverse events. A total of 122 AEs met the signal detection criteria across all four analytical methods ( Supplementary Table 3 ). These 122 positive signals were subsequently categorized by SOC, the main categories identified were gastrointestinal disorders, investigations, skin and subcutaneous tissue disorders, renal and urinary disorders, and metabolism and nutrition disorders (Table 1 ). Rabeprazole showed particularly notable positive signals within renal and urinary disorders, including sig- nificant associations with tubulointerstitial nephritis and uveitis syndrome, allergic nephritis, chronic kidney disease, tubulointerstitial nephritis, and renal failure ( Table 2 ). In the domain of gastrointestinal disorders, rabeprazole was significantly associated with gastric polyps, gastric mucosal hypertrophy, duodenal polyp, haemorrhagic enterocolitis, and gastrointestinal polyp haem- orrhage (Table 3 ), which may be related to its primary site of action in the gastrointestinal tract. Regarding skin and subcutaneous tissue disorders, data analysis indicated that rabeprazole increased the risk of adverse events such as erythema annulare, erythema multiforme, drug eruption, macule, and allergic dermatitis (Table 4 ). These findings suggest clinicians should monitor patients’ skin conditions to prevent severe allergic reactions. Within metabolism and nutrition disorders, significant signals were observed for rabeprazole-related adverse events including hypomagnesaemia, hypocalcaemia, hypovitaminosis, vitamin B12 deficiency, and hypona- traemia (Table 5), indicating potential effects on micronutrient absorption and metabolism. In respiratory system-related adverse events, significant signals were detected for eosinophilic bronchitis, malignant pleural effusion, eosinophilic pneumonia, laryngeal pain, and obstructive airways disorder ( Table 6 ), suggesting cautious use in patients with pre-existing pulmonary conditions. With respect to nervous system disorders, rabeprazole was significantly associated with multiple adverse events, including muscle tone disorder, Wernicke’s encephalopathy, tongue biting, clonus, clumsiness, and parkinsonism (Table 7 ). Additionally, several other rabeprazole-associated adverse events demonstrated particularly strong signals and warrant attention, such as: leukocyte adhesion deficiency (n = 3; ROR = 1103.35, 95% CI: 321.44– 3787.3), blood gastrin increased (n = 7; ROR = 355.25, 95% CI: 165.62–761.97), anticoagulation drug level decreased (n = 6; ROR = 330.08, 95% CI: 145.01–751.34), vitamin D abnormal (n = 5; ROR = 78.9, 95% CI: 32.64–190.71) and device-related thrombosis (n = 9; ROR = 55.9, 95% CI: 28.99–107.8) ( Supplementary Table 3 ). These findings strongly indicate the necessity of establishing a comprehensive multi-system safety monitoring system during rabeprazole therapy, along with the development of corresponding risk prevention and control strategies. 3.5 Subgroup analysis To further investigate differences in the incidence of rabeprazole-related AEs across genders and outcomes, disproportionality analysis using the ROR method was conducted. Figure 5 presents 24 significant signals associated with gender. Some AEs including dyspepsia, abdominal pain, vomiting, drug ineffective, swelling face, feeling abnormal, anaphylactic reaction, product use in unapproved indication, weight increased, and arthritis were more frequently reported in female patients. In contrast, AEs such as tachycardia, chest pain, drug interaction, hepatic function abnormal, blood pressure increased, hypomagnesaemia, hypocalcaemia, insomnia, acute kidney injury, interstitial lung disease, and angioedema were associated with higher risk in male patients. Figure 6 displays 49 positive signals associated with the severity of patient outcomes. AEs including inappropriate antidiuretic hormone secretion, gastric polyps, haemorrhagic enterocolitis, microscopic coli- 4 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. tis, hepatic function abnormal, hypomagnesaemia, hypocalcaemia, hypokalaemia, and pruritus were more common among patients with serious outcomes. On the other hand, events such as arrhythmia, diarrhoea, nausea, inflammation, myalgia, headache, dysgeusia, tremor, loss of consciousness, and depression were more frequently reported in non-serious outcomes. As illustrated in Figure 7 , patients with fatal outcomes exhibited higher risks of AEs including drug hypersensitivity, renal failure, chronic kidney disease, and acute kidney injury compared to those with non- fatal outcomes. These findings suggest that rabeprazole may induce severe renal toxicity. 4.Disscussion Although the efficacy and safety of rabeprazole were established in rigorous pre-marketing clinical trials, concerns regarding its long-term safety have emerged due to its widespread and often prolonged global use. Therefore, we conducted an in-depth signal mining and comparative analysis to explore rabeprazole- associated AEs, aiming to identify potential high-risk signals and inform optimized clinical management strategies. 4.1 Epidemiological characteristics Based on data from the FAERS database, this study included 3,696 cases and 9,811 rabeprazole-associated AE reports, providing a comprehensive description of the drug’s ADR epidemiology. The annual number of reports generally ranged between 100 and 200, showing an overall increasing trend. The majority of reports originated from the United States, Japan, France, and China, reflecting differences in national reporting practices and regulatory environments. Physicians, lawyers, and consumers were the most frequent reporters, underscoring the need for heightened clinical vigilance regarding drug-related AEs. Additionally, a substantial proportion of cases (59.9%) involved serious outcomes, including hospitalization (18.9%) and death (6.4%), consistent with the tendency of spontaneous reporting systems to capture more severe or unexpected events. In our study, the proportion of AE reports was numerically higher in female patients (45.7%) than in males (28.7%). Time to onset analysis revealed that AEs emerged more rapidly in females, with a significantly shorter median onset time (10 days; IQR: 4–51 days) compared to males (15 days; IQR: 6–118 days; p = 0.00054). At the PT level, females were more likely to experience dyspepsia, abdominal pain, vomiting, drug ineffective, and facial swelling, whereas males exhibited higher risk of tachycardia, chest pain, drug interaction, abnormal hepatic function, and increased blood pressure. Recent studies indicate that women account for more than half of all PPI users and are generally more susceptible to adverse drug reactions (ADRs)[18]. Sex differences in absorption, distribution and hepatic metabolism can alter exposure and time-course of drug effects. For rabeprazole, population PK/PD modeling has identified gender differences including faster absorption and higher weight-adjusted Cmax in women, which may accelerate the onset of symptomatic adverse events or modify early drug effects [19]. Following long-term PPI use, females tend to exhibit a more pronounced increase in gastrin levels, which may exert trophic effects on gastric mucosa, potentially promoting morphological changes and rebound acid hypersecretion[20-23]. A recent Chinese study found that the incidence of gastric polyps was significantly higher in women than in men (with a ratio of 2.4:1), with 78% of cases occurring in patients using PPIs for more than five years [24]. However, no such gender disparity was observed in our study. A nationwide drug utilization study in Iceland reported a consistent increase in PPI use over time, particularly among older age groups, with higher usage rates observed across all age strata in women compared to men [25]. Furthermore, long-term PPI use (exceeding one year) was most prevalent among the elderly, a population especially vulnerable to polypharmacy and ADRs due to age-related metabolic changes [25, 26] . 4.2 Renal and urinary disorders A disproportionality analysis was conducted at both the SOC and PT levels to investigate AEs associated with rabeprazole. And we identified renal and urinary disorders as the only SOC that met all signal detection criteria. At the PT level, highly significant signals were observed for tubulointerstitial nephritis and uveitis 5 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. syndrome, allergic nephritis, chronic kidney disease, tubulointerstitial nephritis, and renal failure. Time to onset analysis revealed the longest median latency for renal and urinary events, at 70.5 days (IQR: 4.2–268.2). Subgroup analysis by patient outcome indicated that renal AEs such as renal failure and acute kidney injury were frequently associated with serious outcomes, including an elevated risk of mortality. These characteris- tics suggest that rabeprazole exhibits delayed yet potentially severe renal toxicity signals in real-world data. Our findings align with observational studies and drug safety reviews, which have reported associations be- tween PPIs and acute interstitial nephritis (AIN), acute kidney injury (AKI), and new-onset or progressive chronic kidney disease (CKD) in large cohorts and case-control studies [14, 27-29] . This accumulated evidence underscores a significant association between rabeprazole and renal adverse events in post-marketing surveil- lance. The renal impairment linked to rabeprazole/PPIs may be mediated through several pathways: (1) idiosyncratic, immune-mediated acute interstitial nephritis driven by drug hypersensitivity [30, 31] ; (2) cumu- lative renal damage resulting from recurrent AKI episodes, leading to fibrosis and CKD progression [32, 33] ; and (3) metabolic and electrolyte disturbances, such as hypomagnesemia, which can indirectly impair renal function during long-term use [34, 35] . Therefore, we recommend avoiding unnecessary long-term PPI pre- scriptions and periodically reassessing their indications. Baseline renal function and electrolyte levels should be evaluated in patients planned for prolonged therapy, with regular monitoring recommended for high-risk individuals. 4.3 Gastrointestinal disorders Gastrointestinal ADRs represent another notable safety concern for rabeprazole. Time to onset analysis revealed a relatively short latency for rabeprazole-associated gastrointestinal adverse events, with a median time of 14 days. At the SOC level, disproportionality analysis revealed a strong signal for gastrointestinal disorders, which met the detection thresholds of both ROR and BCPNN. At the PT level, 23 positive sig- nals were identified, including gastric polyps, gastric mucosal hypertrophy, duodenal polyp, haemorrhagic enterocolitis, and gastrointestinal polyp haemorrhage. According to the drug label and clinical studies, com- monly observed and generally mild gastrointestinal adverse effects of rabeprazole include nausea, vomiting, abdominal pain, abdominal discomfort, bloating, dyspepsia, diarrhea, and constipation [4, 36] . These mani- festations may be attributed to the drug’s direct influence on gastrointestinal motility and secretion, or to altered symptom thresholds following gastric acid suppression [37]. Long-term use of rabeprazole and other PPIs elevates gastric pH, leading to hypergastrinemia. Gastrin stimulates the proliferation of gastric mu- cosa and enterochromaffin-like (ECL) cells, thereby increasing the risk of fundic gland polyps (FGPs) [38, 39] . Rabeprazole-specific cohort studies and case reports have described the emergence of new FGPs or gastric mucosal hypertrophy during treatment, with some patients experiencing polyp hemorrhage or severe gas- trointestinal bleeding, particularly when combined with NSAIDs [40-42]. These conditions often improved or resolved after drug discontinuation [43, 44] . Polyps or vulnerable mucosa in an acid-suppressed environment may be more prone to bleeding, and concomitant use of antiplatelet agents or NSAIDs further increases this risk[45]. Moreover, PPIs can compromise the gastric acid barrier and alter the gut microbiota, increasing susceptibility to enteric infections such as Clostridium difficile, severe infections may present as hemorrhagic enterocolitis[46]. Therefore, clinicians should carefully evaluate the indications for long-term rabeprazole therapy. In cases of severe diarrhea or gastrointestinal bleeding, testing for pathogens such as Clostridium difficile and considering PPI use as a potential risk factor is strongly recommended. 4.4 Skin and subcutaneous tissue disorders In our FAERS analysis, skin and subcutaneous tissue disorders emerged as common adverse events with the most rapid onset, exhibiting a median time to on- set of only 7 days. Signals detected at the PT level included erythema annulare, erythema multiforme, drug eruption, macule, and allergic dermatitis. Consistent with previous literature, rabeprazole has been associated with a spectrum of cutaneous adverse reactions, ranging from mild maculopapular and annular erythema to rare but severe conditions such as fixed drug eruption, drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [47-49]. The underlying mechanisms primarily involve IgE-mediated immediate hypersensitivity and T-cell–mediated delayed immune responses, potentially triggered by haptens formed via covalent binding of the drug or its metabolites to host proteins [50, 51] . Early recognition and immediate discontinuation of the suspected drug 6 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. are critical in clinical practice to prevent progression to severe cutaneous adverse reactions. 4.5 Metabolism and nutrition disorders Long-term use of rabeprazole have been linked to various metabolic and nutritional disturbances. Our analysis revealed notable signals connecting rabeprazole to hypomagnesaemia, hypocalcaemia, vitamin B12 deficiency, other hypovitaminoses, and hyponatraemia. The underlying mechanisms may include the fol- lowing: long-term acid suppression impairs the release of dietary vitamin B12 from food proteins and its subsequent binding to intrinsic factor, leading to malabsorption that can manifest as anaemia and neu- rological symptoms [52]. Additionally, PPIs are thought to interfere with active magnesium absorption in the gut, mediated by TRPM6/TRPM7 channels [35, 53] . The resulting hypomagnesaemia can in turn induce hypocalcaemia and impair parathyroid function. Previous cohort analyses have indicated an increased risk of hyponatraemia with rabeprazole, with mechanisms likely involving fluid-electrolyte shifts, SIADH-like reactions, or diuretic interactions [54-56]. Long-term rabeprazole users (particularly elderly, on diuretics, or with prior deficiencies) should be periodically monitored for serum electrolytes and vitamin B12, with severe deficiencies warranting drug discontinuation or alternative treatment. 4.6 Respiratory, thoracic and mediastinal disorders In this study, rabeprazole showed significant associations with several respiratory AEs, including eosinophilic bronchitis, malignant pleural effusion, eosinophilic pneumonia, laryngeal pain, and obstructive airways dis- order. Multiple epidemiological studies and meta-analyses have indicated that PPIs are associated with an increased short-term risk of both community-acquired and hospital-acquired pneumonia, which may progress to conditions such as empyema [57, 58] . Furthermore, studies have described PPI-induced eosinophilic lung disease (including eosinophilic bronchitis/pneumonia), primarily mediated by immune-mediated hypersen- sitivity reactions [59]. Additionally, both immediate and delayed hypersensitivity reactions to PPIs may manifest as bronchospasm or obstructive airway symptoms [47, 60] . 4.7 Nervous system disorders Neurological AEs associated with rabeprazole also warrant attention. Our study detected significant sig- nals for nervous system disorders including muscle tone disorder, Wernicke’s encephalopathy, tongue bit- ing, clonus, clumsiness, and parkinsonism, which have been sporadically documented in previous liter- ature. PPI-induced hypomagnesaemia can increase neuromuscular excitability, manifesting as tremor, hypertonia, clonus, or seizures; and subsequent hypocalcaemia may contribute to ataxia or movement abnormalities[13, 35, 61] . Rare cases suggest that refractory hypergastrinaemia secondary to PPI use can lead to persistent vomiting, resulting in vitamin B1 deficiency and ultimately triggering Wernicke’s encephalopathy[62]. Additionally, several studies have reported associations between PPIs (including rabepra- zole) and acute neuropsychiatric syndromes or reversible parkinsonian manifestations, potentially related to immune-mediated hypersensitivity reactions or alterations in neurotransmitter activity [63-65]. 4.8 leukocyte adhesion deficiency Our analysis of the FAERS database identified three cases coded as ”leukocyte adhesion deficiency (LAD)” (ROR = 1103.35, 95% CI: 321.44–3787.3), though these findings require cautious interpretation. Classical LAD is a congenital disorder caused by defects in integrins/adhesion molecules (e.g., ITGB2/CD18 muta- tions) rather than drug-induced effects [66]. Notably, numerous experimental and translational studies have shown that proton pump inhibitors can functionally inhibit neutrophil-endothelial interactions by downregu- lating adhesion molecules such as CD11b/CD18, thereby reducing neutrophil adhesion and transendothelial migration[67, 68] . However, evidence confirming clinically significant acquired LAD due to PPI exposure in humans remains very limited. Therefore, the high ROR observed in FAERS more likely reflects rare, re- versible PPI-induced impairment of leukocyte adhesion/migration functions rather than new-onset genetic LAD. 5. Strengths and Limitations 7 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. The FAERS database serves as a cornerstone of post-marketing drug safety surveillance, offering extensive population coverage and extended temporal windows that enable detection of rare, severe, or unexpected adverse events often missed in randomized controlled trials. Its strength lies in supporting signal detection

such as disproportionality analysis and early identification of potential risks. However, FAERS has inherent limitations as a spontaneous reporting system: it lacks reliable denominator data, suffers from substantial underreporting and notoriety bias, contains inconsistent or incomplete reports, includes potential duplicates, and is susceptible to confounding by indication and protopathic bias. Therefore, signals identified in FAERS can only suggest associations and require further validation through well-designed cohort or case-control studies, active surveillance, medical record verification, and mechanistic investigations before informing regulatory decisions or clinical practice. Despite these constraints, this study implemented rigorous data cleaning protocols and cross-validated multiple signal detection algorithms to enhance result reliability, thereby providing valuable evidence to support the safe clinical use of rabeprazole and laying the groundwork for further risk-benefit assessment. 6.Conclusion This large-scale analysis of the FAERS database comprehensively characterizes the real-world safety profile of rabeprazole. The most prominent signals involved renal and urinary disorders such as tubulointerstitial nephritis, acute kidney injury, and renal failure, which demonstrated prolonged median onset times and strong associations with serious outcomes. Other clinically relevant signals included gastrointestinal disorders (e.g., gastric/duodenal polyps, mucosal hypertrophy, hemorrhagic enterocolitis), rapidly emerging skin and subcutaneous tissue disorders, metabolism and nutrition disorders (e.g., hypomagnesemia, hypocalcemia, vitamin B12 deficiency), respiratory disorders, and several neurological disorders. Sex-based differences were observed, with females more frequently reporting gastrointestinal and cutaneous reactions, whereas males showed higher risks of electrolyte disturbances and renal injury. These findings underscore the importance of systematic and individualized monitoring for patients receiving rabeprazole, particularly during long-term therapy. Clinicians should periodically reassess the need for continued treatment and implement tailored surveillance strategies in high-risk populations—such as the elderly and those on polypharmacy—including evaluations of renal function, electrolyte levels, and nutritional status. This study provides critical real-world evidence for post-marketing safety regulation of rabeprazole and highlights priorities for further mechanistic research and risk-minimization measures. Funding Not applicable. Declaration of competing interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Author Contributions Conception and design: Qining He Provision of study materials: Qining He Collection and assembly of data: Qining He, Tao Zheng Data analysis and interpretation: Qining He, Tao Zheng Manuscript writing: All authors Final approval of manuscript: All authors Data availability statement 8 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. This study utilized data from the FDA Adverse Event Reporting System (FAERS) database (https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers), a widely accessible resource for AEs research. Ethics statement Not applicable.

[1] Furuta T, Iwaki T, Umemura K. Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes [J]. Br J Clin Pharmacol, 2010, 70(3): 383-92.[2] Wu J, Jia L T, Shao L M, et al. Drug-drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers [J]. Eur J Clin Pharmacol, 2013, 69(2): 179-87.[3] Freedberg D E, Kim L S, Yang Y X. The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association [J]. Gastroenterology, 2017, 152(4): 706-15.[4] Baldwin C M, Keam S J. Rabeprazole: a review of its use in the management of gastric acid-related diseases in adults [J]. Drugs, 2009, 69(10): 1373-401.[5] Sharara A I. Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication [J]. Expert Rev Anti Infect Ther, 2005, 3(6): 863-70.[6] Savarino V, Marabotto E, Zentilin P, et al. Proton pump inhibitors: use and misuse in the clinical setting [J]. Expert Rev Clin Pharmacol, 2018, 11(11): 1123-34.[7] Moayyedi P, Eikelboom J W, Bosch J, et al. Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin [J]. Gastroenterology, 2019, 157(3): 682-91.e2.[8] Nehra A K, Alexander J A, Loftus C G, et al. Proton Pump Inhibitors: Review of Emerging Concerns [J]. Mayo Clin Proc, 2018, 93(2): 240-6.[9] Xia B, He Q, Smith F G, et al. Individualized prevention of proton pump inhibitor related adverse events by risk stratification [J]. Nat Commun, 2024, 15(1): 3591.[10] Haastrup P F, Thompson W, Søndergaard J, et al. Side Effects of Long-Term Proton Pump Inhibitor Use: A Review [J]. Basic Clin Pharmacol Toxicol, 2018, 123(2): 114-21.[11] Castellana C, Pecere S, Furnari M, et al. Side effects of long-term use of proton pump inhibitors: practical considerations [J]. Pol Arch Intern Med, 2021, 131(6): 541-9.[12] Arnold R. Safety of proton pump inhibitors–an overview [J]. Aliment Pharmacol Ther, 1994, 8 Suppl 1: 65-70.[13] Gommers L M M, Hoenderop J G J, De Baaij J H F. Mechanisms of proton pump inhibitor-induced hypomagnesemia [J]. Acta Physiol (Oxf), 2022, 235(4): e13846.[14] Kamal F, Khan M A, Molnar M Z, et al. The Association Between Proton Pump Inhibitor Use With Acute Kidney Injury and Chronic Kidney Disease [J]. J Clin Gastroenterol, 2018, 52(6): 468-76.[15] Nehra A K, Alexander J A, Loftus C G, et al. Proton Pump Inhibitors: Review of Emerging Concerns [J]. Mayo Clin Proc, 2018, 93(2): 240-6.[16] Altebainawi A F, Alfaraj L A, Alharbi A A, et al. Association between proton pump inhibitors and rhabdomyolysis risk: a post-marketing surveillance using FDA adverse event reporting system (FAERS) database [J]. Ther Adv Drug Saf, 2023, 14: 20420986231154075.[17] Wu B, Hu Q, Tian F, et al. A pharmacovigilance study of association between proton pump inhibitor and dementia event based on FDA adverse event reporting system data [J]. Sci Rep, 2021, 11(1): 10709.[18] Shanika L G T, Reynolds A, Pattison S, et al. Proton pump inhibitor use: systematic review of global trends and practices [J]. Eur J Clin Pharmacol, 2023, 79(9): 1159-72.[19] Jeong S H, Jang J H, Lee Y B. Exploring Differences in Pharmacometrics of Rabeprazole between Genders via Population Pharmacokinetic-Pharmacodynamic Modeling [J]. Biomedicines, 2023, 11(11).[20] Helgadottir H, Bj¨ornsson E S. The Impact of Sex on the Response to Proton Pump Inhibitor Treatment [J]. Pharmaceuticals (Basel), 2023, 16(12).[21] Cui G, Waldum H L. Physiological and clinical significance of enterochromaffin- like cell activation in the regulation of gastric acid secretion [J]. World J Gastroenterol, 2007, 13(4): 493- 6.[22] Waldum H L, Qvigstad G, Fossmark R, et al. Rebound acid hypersecretion from a physiological, pathophysiological and clinical viewpoint [J]. Scand J Gastroenterol, 2010, 45(4): 389-94.[23] Helgad´ ottir H, Metz D C, Lund S H, et al. Study of Gender Differences in Proton Pump Inhibitor Dose Requirements for GERD: A Double-Blind Randomized Trial [J]. J Clin Gastroenterol, 2017, 51(6): 486-93.[24] Gao W, Huang Y, Lu S, et al. The clinicopathological characteristics of gastric polyps and the relationship between fundic gland polyps, Helicobacter pylori infection, and proton pump inhibitors [J]. Ann Palliat Med, 2021, 10(2): 2108-14.[25] H´ alfd´ anarson´O, Potteg˚ ard A, Bj¨ornsson E S, et al. Proton-pump inhibitors among adults: 9 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. a nationwide drug-utilization study [J]. Therap Adv Gastroenterol, 2018, 11: 1756284818777943.[26] Maes M L, Fixen D R, Linnebur S A. Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence [J]. Ther Adv Drug Saf, 2017, 8(9): 273-97.[27] Lazarus B, Chen Y, Wilson F P, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease [J]. JAMA Intern Med, 2016, 176(2): 238-46.[28] Klatte D C F, Gasparini A, Xu H, et al. Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease [J]. Gastroenterology, 2017, 153(3): 702-10.[29] Sierra F, Suarez M, Rey M, et al. Systematic review: Proton pump inhibitor-associated acute interstitial nephritis [J]. Aliment Pharmacol Ther, 2007, 26(4): 545-53.[30] Krishnan N, Perazella M A. Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment [J]. Iran J Kidney Dis, 2015, 9(1): 3-13.[31] Muriithi A K, Leung N, Valeri A M, et al. Biopsy-proven acute interstitial nephritis, 1993-2011: a case series [J]. Am J Kidney Dis, 2014, 64(4): 558-66.[32] Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury [J]. Kidney Int, 2017, 91(6): 1482-94.[33] Chawla L S, Eggers P W, Star R A, et al. Acute kidney injury and chronic kidney disease as interconnected syndromes [J]. N Engl J Med, 2014, 371(1): 58-66.[34] William J H, Danziger J. Proton-pump inhibitor- induced hypomagnesemia: Current research and proposed mechanisms [J]. World J Nephrol, 2016, 5(2): 152-7.[35] Perazella M A. Proton pump inhibitors and hypomagnesemia: a rare but serious complication [J]. Kidney Int, 2013, 83(4): 553-6.[36] Gardner J D, Perdomo C, Sloan S, et al. Integrated acidity and rabeprazole pharmacology [J]. Aliment Pharmacol Ther, 2002, 16(3): 455-64.[37] Shin J M, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors [J]. J Neurogastroenterol Motil, 2013, 19(1): 25-35.[38] Kim G H. Proton Pump Inhibitor-Related Gastric Mucosal Changes [J]. Gut Liver, 2021, 15(5): 646-52.[39] Tran-Duy A, Spaetgens B, Hoes A W, et al. Use of Proton Pump Inhibitors and Risks of Fundic Gland Polyps and Gastric Cancer: Systematic Review and Meta-analysis [J]. Clin Gastroenterol Hepatol, 2016, 14(12): 1706-19.e5.[40] Tandon V R, Chandail V, Khajuria V, et al. Gastrointestinal bleed induced by a fixed dose combination of rabeprazole and diclofenac sodium [J]. Indian J Pharmacol, 2014, 46(5): 555-6.[41] Hongo M, Fujimoto K. Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan [J]. J Gastroenterol, 2010, 45(6): 618-24.[42] Rindi G, Fiocca R, Morocutti A, et al. Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa [J]. Eur J Gastroenterol Hepatol, 2005, 17(5): 559-66.[43] Nikaido M, Kumagai K, Ota Y. A hemorrhagic duodenal polyp disappeared with gastric polyps after discontinuation of proton pump inhibitor [J]. Gastrointest Endosc, 2022, 96(2): 381-2.[44] Tanaka M, Kataoka H, Yagi T. Proton-pump inhibitor- induced fundic gland polyps with hematemesis [J]. Clin J Gastroenterol, 2019, 12(2): 193-5.[45] Kinoshita Y, Ishimura N, Ishihara S. Advantages and Disadvantages of Long-term Proton Pump Inhibitor Use [J]. J Neurogastroenterol Motil, 2018, 24(2): 182-96.[46] Trifan A, Stanciu C, Girleanu I, et al. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis [J]. World J Gastroenterol, 2017, 23(35): 6500-15.[47] Bavbek S, Kepil ¨Ozdemir S, Bonadonna P, et al. Hypersensitivity reactions to proton pump inhibitors. An EAACI position paper [J]. Allergy, 2024, 79(3): 552-64.[48] Salloum A, Nasr D, Maalouf D. Dermatologic adverse reactions to proton-pump inhibitors: A synthetized review [J]. J Cosmet Dermatol, 2021, 20(4): 1073-9.[49] Gupta S, Gupta S, Mahendra A, et al. Multiple widespread fixed drug eruption caused by rabeprazole [J]. J Postgrad Med, 2020, 66(2): 105-7.[50] Chen C B, Abe R, Pan R Y, et al. An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity [J]. J Immunol Res, 2018, 2018: 6431694.[51] Robinson L B, Ruffner M A. Proton Pump Inhibitors in Allergy: Benefits and Risks [J]. J Allergy Clin Immunol Pract, 2022, 10(12): 3117-23.[52] Choudhury A, Jena A, Jearth V, et al. Vitamin B12 deficiency and use of proton pump inhibitors: a systematic review and meta-analysis [J]. Expert Rev Gastroenterol Hepatol, 2023, 17(5): 479-87.[53] Gommers L M M, Hoenderop J G J, De Baaij J H F. Mechanisms of proton pump inhibitor-induced hypomagnesemia [J]. Acta Physiol (Oxf), 2022, 235(4): e13846.[54] Falhammar H, Lindh J D, Calissendorff J, et al. Associations of proton pump inhibitors and hospitalization due to hyponatremia: A population-based case-control study [J]. Eur J Intern Med, 2019, 59: 65-9.[55] Issa I, Skov J, Falhammar H, et al. Time-dependent association between omeprazole and esomeprazole and hospitalization due to hyponatremia [J]. Eur J Clin Pharmacol, 2023, 79(1): 71- 7.[56] El-Alali E, Al Jaber E. Association of proton pump inhibitor use and significant hyponatremia-a US population-based case-control study [J]. Proc (Bayl Univ Med Cent), 2022, 35(4): 434-6.[57] Laheij R 10 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. J, Sturkenboom M C, Hassing R J, et al. Risk of community-acquired pneumonia and use of gastric acid- suppressive drugs [J]. Jama, 2004, 292(16): 1955-60.[58] Filion K B, Chateau D, Targownik L E, et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis [J]. Gut, 2014, 63(4): 552-8.[59] Bartal C, Sagy I, Barski L. Drug-induced eosinophilic pneumonia: A review of 196 case reports [J]. Medicine (Baltimore), 2018, 97(4): e9688.[60] Hwang K W, Woo O H, Yong H S, et al. Reversible lansoprazole-induced interstitial lung disease showing improvement after drug cessation [J]. Korean J Radiol, 2008, 9(2): 175-8.[61] Krishnan M, Fernando H, Mohammed H H, et al. Proton Pump Inhibitor Induced Hypomagnesemia Causing Seizures: A Rare Adverse Effect of a Commonly Used Medication [J]. Cureus, 2024, 16(7): e64044.[62] Miyanaga R, Hisahara S, Ohhashi I, et al. Hyperemesis- induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors [J]. Intern Med, 2020, 59(21): 2783-7.[63] Alfonzo C A, Bobo W V, Almond M D. Not a usual suspect; rabeprazole therapy presenting as a severe neuropsychiatric illness: case report [J]. Int J Psychiatry Med, 2003, 33(3): 311-5.[64] Chen H L, Lei W Y, Wang J H, et al. Proton pump inhibitor use and the risk for Parkinson’s disease: A nationwide population-based study in Taiwan [J]. Medicine (Baltimore), 2023, 102(19): e33711.[65] Hong J T, Jung H K, Lee K J, et al. Potential risk of proton pump inhibitors for Parkinson’s disease: A nationwide nested case-control study [J]. PLoS One, 2023, 18(12): e0295981.[66] Almarza Novoa E, Kasbekar S, Thrasher A J, et al. Leukocyte adhesion deficiency-I: A comprehensive review of all published cases [J]. J Allergy Clin Immunol Pract, 2018, 6(4): 1418-20.e10.[67] Yoshida N, Yoshikawa T, Tanaka Y, et al. A new mechanism for anti-inflammatory actions of proton pump inhibitors–inhibitory effects on neutrophil-endothelial cell interactions [J]. Aliment Pharmacol Ther, 2000, 14 Suppl 1: 74-81.[68] Fowler J F, Eubank T A, Garey K W. Proton pump inhibitor effect on macrophage and neutrophil function: a systematic review [J]. Front Immunol, 2024, 15: 1477993. Figure and Table legends Figure 1. The flow diagram of the study. FAERS, the FDA Adverse Event Reporting System; DEMO, demographic and administrative details; DRUG, drug information; REAC, drug reactions; AEs, adverse events; PS, primary suspect. Figure 2. Descriptive characteristics of AE reports on rabeprazole. Figure 3. Time to onset of rabeprazole -associated AEs. A and B: Overall characteristics of time to onset for rabeprazole -associated AEs; C: Subgroup analysis of time to onset for rabeprazole -associated AEs by gender; D: Subgroup analysis of time to onset for rabeprazole -associated AEs by age group; E: Subgroup analysis of time to onset for rabeprazole -associated AEs by outcome; F: Subgroup analysis of time to onset for rabeprazole -associated AEs by SOCs. AEs, adverse events; SOC, system organ class. Figure 4. Signal mining at the SOC level. A: Distribution of rabeprazole -associated AEs across SOCs; B: Signal detection was performed across SOCs. SOC, system organ class; ROR, reporting odds ratios; CI: confidence interval; PRR, proportional reporting ratios; χ2, chi-squared; EBGM: empirical Bayesian geometric mean; EBGM05: the lower limit of 95% CI of EBGM; IC, information component; IC025, the lower limit of 95% CI of the IC. Figure 5. Gender-stratified analysis of significant rabeprazole-associated AEs. SOC, System Organ Class; PT, preferred term; ROR: reporting odds ratios; CI, confidence interval. Figure 6. Severity-stratified analysis of significant rabeprazole-associated AEs. SOC, System Organ Class; PT, preferred term; ROR: reporting odds ratios; CI, confidence interval. Severity-Stratified Figure 7. Fatality-stratified analysis of significant rabeprazole-associated AEs. AEs, adverse events; SOC, System Organ Class; PT, preferred term; ROR: reporting odds ratios; CI, confidence interval. Severity-Stratified Table 1. 122 AEs signals of rabeprazole classified by SOC Table 2. Signals of renal and urinary disorders 11 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. Table 3. Signals of gastrointestinal disorders Table 4. Signals of skin and subcutaneous tissue disorders Table 5. Signals of metabolism and nutrition disorders Table 6. Signals of respiratory, thoracic and mediastinal disorders Table 7. Signals of nervous system disorders Supplementary material Supplementary Table 1. The algorithm formulas and thresholds of disproportional analyses Supplementary Table 2. The algorithm formulas and thresholds of subgroup analysis Supplementary Table 3. 122 AEs signals of rabeprazole classified by PT FAERS database 2004Q1~2025Q2 Total Case = 23,168,942 DEMO (n =19,344,796) DRUG (n = 71,245,893) REAC (n = 57,725,545) Reports of Rabeprazole as the PS (n = 3,696) AEs of Rabeprazole as the PS (n = 9,811) Descriptive analysis Time to onset analysisDisproportionality analysis Subgroup analysis Exclude Duplication records (n = 3,824,146) Screening via Rabeprazole 12 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. 100 85 95 103 74 68 34 127 117 4 166 230 199 145 900 229 179 177 166 240 198 60 0 100 200 300 400 500 600 700 800 900 1000 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Case Number Reporter Physician 23.3%--863 reports Lawyer 21.9%--810 reports Consumer 16.7%--616 reports Pharmacist 6.5%--239 reports Other Health-professional 27.7%--1022 reports Missing 146 (4%) 1607 477 429 332 234 94 68 55 44 25 23 19 16 13 10Greece South Korea India Germany Netherlands Brazil Spain the United Kingdom Italy Australia Canada China France Japan the United States 0 200 400 600 800 1000 1200 1400 1600 1800 Case Number Gender Female 45.7%--1690 reports Male 28.7%--1059 reports Missing 25.6%--947 reports Non-Serious 40.1%--1481 reports Serious Disability 1.2%--46 reports Life-Threatening 1.5%--54 reports Death 6.4%--236 reports Hospitalization 18.9%--697 reports Other 32.0%--1481 reports Outcome Age Group 85 3.9%--145 reports Missing 38.9%--1439 reports A B C D E F13 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. 581 64 31 21 12 14 35 126 65.7% 7.2% 3.5% 2.4% 1.4% 1.6% 4% 14.3% 0-30 31-60 61-90 91-120 121-150 151-180 181-360 >360 70% 60% 50% 40% 30% 20% 10% 0 100 200 300 400 500 600 Time to event onset (days) Number of Case Percentage 0.00 0.25 0.50 0.75 1.00 0 60 120 180 240 300 360 Time to event (days) Cumulative percent Overall: 12.0 [IQR 5.0-75.0] 884 240 188 162 152 135 126 - 0 60 120 180 240 300 360 Time to event (days) Number at risk
Median time to event (days): p = 0.00054 0.00 0.25 0.50 0.75 1.00 0 60 120 180 240 300 360 Time to event (days) Cumulative percent Female: 10.0 [IQR 4.0-51.0] Male: 15.0 [IQR 6.0-118.0] 523 122 96 83 77 67 61 341 110 85 74 70 63 60 -- 0 60 120 180 240 300 360 Time to event (days) Number at risk
Median time to event (days): p = 0.0081 0.00 0.25 0.50 0.75 1.00 0 60 120 180 240 300 360 Time to event (days) Cumulative percent 85: 7.0 [IQR 2.0-32.5] 6 2 1 1 1 1 0 474 102 78 64 61 51 46 286 97 74 63 58 55 53 39 7 7 6 6 6 6 ---- 0 60 120 180 240 300 360 Time to event (days) Number at risk
Median time to event (days): p < 0.0001 0.00 0.25 0.50 0.75 1.00 0 60 120 180 240 300 360 Time to event (days) Cumulative percent Serious: 9.0 [IQR 4.0-19.0] Non-Serious: 34.0 [IQR 7.0-254.0] 494 72 64 55 53 49 45 390 168 124 107 99 86 81 -- 0 60 120 180 240 300 360 Time to event (days) Number at risk Median time to event (days): p < 0.0001 0.00 0.25 0.50 0.75 1.00 0 60 120 180 240 300 360 Time to event (days) Cumulative percent Gastrointestinal disorders: 14.0 [IQR 4.0-211.0] General disorders and administration site conditions: 14.5 [IQR 4.0-124.5] Nervous system disorders: 53.0 [IQR 4.0-337.0] Renal and urinary disorders: 70.5 [IQR 14.2-268.2] Skin and subcutaneous tissue disorders: 8.0 [IQR 3.0-13.0] 190 68 58 50 46 39 33 192 67 52 42 41 37 34 113 55 45 38 35 31 27 46 25 18 14 13 10 9 308 17 13 10 8 6 6 ----- 0 60 120 180 240 300 360 Time to event (days) Number at risk
Median time to event (days): A B C D E F14 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. 1395 1338 1188 891 689 545 486 468 426 334 302 289 249 199 178 163 130 108 94 87 52 50 47 35 29 28 11Congenital, familial and genetic disorders Surgical and medical procedures Pregnancy, puerperium and perinatal conditions Social circumstances Reproductive system and breast disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) Product issues Immune system disorders Vascular disorders Hepatobiliary disorders Blood and lymphatic system disorders Cardiac disorders Infections and infestations Psychiatric disorders Injury, poisoning and procedural complications Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Investigations Nervous system disorders Skin and subcutaneous tissue disorders General disorders and administration site conditions Gastrointestinal disorders Renal and urinary disorders 0 200 400 600 800 1000 1200 1400 Number of AE reports A B SOCs Renal and urinary disorders Reports Endocrine disorders ROR (95%CI) Metabolism and nutrition disorders PRR (χ2) Hepatobiliary disorders EBGM (EBGM05) Skin and subcutaneous tissue disorders IC (IC025) Gastrointestinal disorders Blood and lymphatic system disorders Immune system disorders Ear and labyrinth disorders Respiratory, thoracic and mediastinal disorders Cardiac disorders Musculoskeletal and connective tissue disorders Investigations Nervous system disorders Vascular disorders Social circumstances Pregnancy, puerperium and perinatal conditions Product issues General disorders and administration site conditions Infections and infestations Psychiatric disorders Reproductive system and breast disorders Eye disorders Congenital, familial and genetic disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) Injury, poisoning and procedural complications Surgical and medical procedures 1395 52 426 178 891 1338 199 130 50 486 249 468 545 689 163 35 29 108 1188 289 302 47 87 11 94 334 28 8.63 ( 8.15 - 9.13 ) 2.07 ( 1.58 - 2.72 ) 2.06 ( 1.87 - 2.27 ) 1.98 ( 1.71 - 2.3 ) 1.74 ( 1.63 - 1.87 ) 1.7 ( 1.61 - 1.8 ) 1.2 ( 1.05 - 1.39 ) 1.2 ( 1.01 - 1.42 ) 1.18 ( 0.89 - 1.56 ) 1.05 ( 0.96 - 1.16 ) 0.98 ( 0.86 - 1.11 ) 0.92 ( 0.83 - 1 ) 0.9 ( 0.83 - 0.98 ) 0.82 ( 0.76 - 0.89 ) 0.78 ( 0.67 - 0.91 ) 0.76 ( 0.54 - 1.06 ) 0.69 ( 0.48 - 1 ) 0.66 ( 0.55 - 0.8 ) 0.65 ( 0.61 - 0.69 ) 0.55 ( 0.49 - 0.61 ) 0.54 ( 0.48 - 0.6 ) 0.54 ( 0.41 - 0.72 ) 0.44 ( 0.36 - 0.54 ) 0.37 ( 0.21 - 0.68 ) 0.36 ( 0.3 - 0.45 ) 0.3 ( 0.27 - 0.33 ) 0.21 ( 0.14 - 0.3 ) 7.54 ( 8059.3 ) 2.06 ( 28.58 ) 2.01 ( 220.89 ) 1.97 ( 85.17 ) 1.68 ( 256.19 ) 1.61 ( 334.99 ) 1.2 ( 6.76 ) 1.19 ( 4.08 ) 1.18 ( 1.36 ) 1.05 ( 1.32 ) 0.98 ( 0.15 ) 0.92 ( 3.48 ) 0.91 ( 5.41 ) 0.83 ( 24.94 ) 0.78 ( 10.05 ) 0.76 ( 2.71 ) 0.7 ( 3.89 ) 0.67 ( 18.32 ) 0.69 ( 193.59 ) 0.56 ( 106.39 ) 0.55 ( 116.3 ) 0.55 ( 17.97 ) 0.44 ( 61.53 ) 0.38 ( 11.47 ) 0.37 ( 103.82 ) 0.32 ( 526.29 ) 0.21 ( 84.86 ) 7.53 ( 7.12 ) 2.06 ( 1.57 ) 2.01 ( 1.82 ) 1.97 ( 1.69 ) 1.67 ( 1.56 ) 1.61 ( 1.52 ) 1.2 ( 1.04 ) 1.19 ( 1 ) 1.18 ( 0.89 ) 1.05 ( 0.96 ) 0.98 ( 0.86 ) 0.92 ( 0.84 ) 0.91 ( 0.83 ) 0.83 ( 0.77 ) 0.78 ( 0.67 ) 0.76 ( 0.54 ) 0.7 ( 0.48 ) 0.67 ( 0.55 ) 0.69 ( 0.65 ) 0.56 ( 0.5 ) 0.55 ( 0.49 ) 0.55 ( 0.41 ) 0.44 ( 0.36 ) 0.38 ( 0.21 ) 0.37 ( 0.3 ) 0.32 ( 0.29 ) 0.21 ( 0.14 ) 2.91 ( 2.82 ) 1.05 ( 0.62 ) 1.01 ( 0.86 ) 0.97 ( 0.75 ) 0.74 ( 0.64 ) 0.68 ( 0.6 ) 0.26 ( 0.06 ) 0.25 ( 0 ) 0.24 ( -0.17 ) 0.07 ( -0.06 ) -0.04 ( -0.22 ) -0.12 ( -0.26 ) -0.14 ( -0.27 ) -0.26 ( -0.38 ) -0.35 ( -0.58 ) -0.4 ( -0.87 ) -0.52 ( -1.04 ) -0.59 ( -0.86 ) -0.53 ( -0.61 ) -0.84 ( -1.01 ) -0.86 ( -1.02 ) -0.87 ( -1.28 ) -1.17 ( -1.47 ) -1.41 ( -2.17 ) -1.44 ( -1.72 ) -1.63 ( -1.78 ) -2.26 ( -2.75 ) 0 2 4 6 8 10 ROR (95% CI)15 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. SOC Cardiac disorders PT Gastrointestinal disorders Female/Male ROR(95% CI) General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Tachycardia Dyspepsia Abdominal pain Vomiting Drug ineffective Chest pain Swelling face Drug interaction Feeling abnormal Hepatic function abnormal Anaphylactic reaction Product use in unapproved indication Weight increased Blood pressure increased Hyponatraemia Hypomagnesaemia Hypocalcaemia Arthritis Headache Insomnia Acute kidney injury Interstitial lung disease Rash Angioedema 7 / 14 56 / 16 55 / 19 54 / 14 151 / 50 26 / 27 18 / 3 17 / 36 15 / 2 16 / 19 17 / 2 15 / 2 18 / 1 11 / 17 48 / 15 36 / 44 27 / 35 13 / 1 69 / 22 12 / 18 17 / 29 21 / 27 86 / 31 10 / 15 0.3(0.12-0.75) 2.13(1.22-3.72) 1.76(1.04-2.97) 2.35(1.3-4.24) 1.85(1.34-2.56) 0.58(0.34-1) 3.64(1.07-12.37) 0.28(0.16-0.51) 4.55(1.04-19.92) 0.51(0.26-0.99) 5.16(1.19-22.35) 4.55(1.04-19.92) 10.93(1.46-81.94) 0.39(0.18-0.83) 1.95(1.09-3.48) 0.49(0.32-0.77) 0.46(0.28-0.77) 7.89(1.03-60.33) 1.91(1.18-3.09) 0.4(0.19-0.84) 0.35(0.19-0.64) 0.47(0.26-0.83) 1.69(1.12-2.56) 0.4(0.18-0.9) 0.01 0.1 1 10 100 ROR (95% CI)16 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. SOC Cardiac disorders PT Endocrine disorders Serious/Non-Serious Gastrointestinal disorders ROR(95% CI) General disorders and administration site conditions Hepatobiliary disorders Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders Product issues Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Arrhythmia Inappropriate antidiuretic hormone secretion Diarrhoea Nausea Gastric polyps Abdominal pain Gastrooesophageal reflux disease Abdominal pain upper Enterocolitis haemorrhagic Dyspepsia Colitis microscopic Flatulence Drug ineffective Drug interaction Therapeutic product effect decreased Condition aggravated Inflammation Hepatic function abnormal Off label use Weight decreased Hypomagnesaemia Hypocalcaemia Hypokalaemia Myalgia Headache Dysgeusia Tremor Loss of consciousness Product substitution issue Depression Renal failure Chronic kidney disease Acute kidney injury Tubulointerstitial nephritis Dyspnoea Interstitial lung disease Asthma Wheezing Oropharyngeal pain Pruritus Drug eruption Urticaria Erythema multiforme Erythema Angioedema Dermatitis allergic Rash erythematous Rash pruritic Stevens-johnson syndrome 4 / 9 14 / 2 60 / 66 50 / 50 36 / 10 34 / 41 34 / 54 28 / 35 24 / 3 19 / 56 18 / 2 12 / 17 71 / 158 46 / 13 12 / 17 11 / 30 5 / 10 28 / 7 21 / 3 12 / 20 86 / 2 66 / 2 45 / 4 17 / 22 33 / 59 8 / 13 7 / 14 6 / 15 28 / 39 8 / 16 453 / 17 264 / 220 188 / 20 69 / 16 53 / 20 38 / 10 25 / 4 15 / 1 5 / 11 101 / 27 93 / 2 61 / 15 55 / 4 36 / 8 23 / 3 23 / 1 23 / 2 22 / 1 14 / 2 0.28(0.09-0.92) 4.47(1.02-19.69) 0.58(0.4-0.82) 0.63(0.43-0.94) 2.3(1.14-4.65) 0.53(0.33-0.83) 0.4(0.26-0.61) 0.51(0.31-0.84) 5.12(1.54-17.01) 0.21(0.13-0.36) 5.75(1.33-24.81) 0.45(0.21-0.94) 0.28(0.21-0.37) 2.27(1.22-4.2) 0.45(0.21-0.94) 0.23(0.12-0.46) 0.32(0.11-0.93) 2.56(1.12-5.86) 4.48(1.33-15.02) 0.38(0.19-0.78) 27.81(6.84-113.05) 21.27(5.21-86.88) 7.22(2.59-20.09) 0.49(0.26-0.93) 0.35(0.23-0.54) 0.39(0.16-0.95) 0.32(0.13-0.79) 0.25(0.1-0.66) 0.46(0.28-0.74) 0.32(0.14-0.74) 18.3(11.26-29.75) 0.75(0.63-0.91) 6.16(3.88-9.78) 2.77(1.61-4.78) 1.7(1.01-2.84) 2.43(1.21-4.89) 4(1.39-11.5) 9.59(1.27-72.61) 0.29(0.1-0.83) 2.41(1.57-3.69) 30.11(7.41-122.25) 2.61(1.48-4.6) 8.84(3.2-24.42) 2.88(1.34-6.2) 4.9(1.47-16.35) 14.72(1.99-109.05) 7.36(1.73-31.23) 14.08(1.9-104.49) 4.47(1.02-19.69) 0.01 0.1 1 10 100 ROR (95% CI) SOC General disorders and administration site conditions PT Immune system disorders Fatal/Non-Fatal Renal and urinary disorders ROR(95% CI) Death Drug hypersensitivity Renal failure Chronic kidney disease Acute kidney injury 21 / 14 4 / 28 160 / 310 65 / 419 32 / 176 32.21(16.27-63.77) 2.95(1.03-8.44) 15.77(12.62-19.71) 3.55(2.68-4.69) 3.94(2.67-5.81) 0.01 0.1 1 10 100 ROR (95%) Hosted file Table 1.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database Hosted file Table 2.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database 17 Posted on 22 Oct 2025 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.176112205.50850773/v1 — This is a preprint and has not been peer-reviewed. Data may be preliminary. Hosted file Table 3.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database Hosted file Table 4.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database Hosted file Table 5.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database Hosted file Table 6.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database Hosted file Table 7.docx available at https://authorea.com/users/898443/articles/1348811-a-comprehensive- safety-profile-of-rabeprazole-insights-from-a-real-world-pharmacovigilance-study-of-the- fda-adverse-event-reporting-system-faers-database 18