Abstract
Background/Aim: Recent research has increasingly demonstrated an association between proton pump inhibitors (PPIs) and serious adverse events. This study aimed to evaluate the association between PPI and rhabdomyolysis (RM), examining its time-to-onset profiles using the Japanese Adverse Drug Event Report (JADER) database. Patients and Methods: Data spanning from April 2004 to March 2022 were used. The association between PPIs and RM was evaluated using the reporting odds ratio (ROR), adjusted for sex and age. Subsequent analyses were conducted after excluding cases involving concomitant use of statins or fibrates. Furthermore, the onset time of RM and Weibull distribution parameters were calculated to evaluate the expression profile of RM, and the outcomes were examined. Results: RM was associated with the use of esomeprazole, omeprazole, and rabeprazole, even in the absence of concomitant statin or fibrate use. The median time to RM onset varied among PPIs, ranging from 6.5 to 127 d. The Weibull distribution parameters indicated that the hazard types of nearly all orally administered PPIs were classified as early failure or close to random failure. Regarding outcomes, cases of death were reported for all PPIs except vonoprazan. Conclusion: The findings suggest the need for vigilant monitoring of RM during PPI administration, particularly in the early stages, considering the varying onset times.
- Rhabdomyolysis
- proton pump inhibitors
- disproportionality analysis
- adverse event profiles
- Weibull distribution
- Japanese Adverse Drug Event Report database
Drug-induced myopathies can arise through various mechanisms, including direct myotoxicity associated with substances like corticosteroids, alcohol, cocaine, colchicine, statins, and antimalarials. Additionally, immunologically induced inflammatory myopathy can occur with statins, penicillamine, interferon-alfa/interferon-beta, TNF-alpha blockers, immune checkpoint inhibitors, and monoclonal antibodies. Another mechanism involves indirect skeletal muscle tissue injury resulting from multifactorial etiologies, such as drug-induced comas leading to ischemic muscle compression or drug-induced hypokalemia (1, 2). The clinical manifestations of drug-induced myopathies can vary widely, ranging from asymptomatic or mild myalgias with or without muscle weakness to chronic myopathy with severe weakness and in rare cases, it may progress to more severe conditions like rhabdomyolysis (RM) (1, 3). RM is characterized by muscle necrosis and the release of cell degradation products and intracellular elements into the bloodstream and extracellular space (3, 4). The incidence of acute kidney injury, the most significant consequence of RM, varies from 13% to over 50%, depending on the cause, clinical context, and histological findings at the time of diagnosis (4).
Proton pump inhibitors (PPIs) are frequently prescribed medications for the management of gastric acid-related conditions, such as gastroesophageal reflux disease, Helicobacter pylori-induced gastric ulcers, duodenal ulcers, erosive esophagitis, and Zollinger–Ellison syndrome (5, 6). In addition to the common adverse events (AEs) listed in package inserts, recent studies have provided growing evidence of the association between PPIs and severe AEs, including kidney injury (7, 8), bone fractures (9), and Clostridium difficile-associated diarrhea (10).
In addition to the previously mentioned AEs, RM is also identified as a severe AE linked to the use of PPIs (11-13). Currently, mild myalgias are categorized as rare AEs for the overall PPI class, but the development of RM is not recognized as a known consequence of PPI usage (14). Notably, not all package inserts for each PPI available in Japan include RM as a listed AE, raising uncertainty about whether this AE is a class effect of PPIs. Moreover, there is limited information on the time to onset of RM in patients undergoing PPI treatment. Therefore, this study aimed to evaluate the association between PPIs and RM and the time-to-onset profiles of PPIs using the Japanese Adverse Drug Event Report (JADER) database.
Patients and Methods
Study data. The JADER data spanning from the first quarter of 2004 to the second quarter of 2022 were downloaded from the Pharmaceuticals and Medical Devices Agency website (15). The data encompassed four types of information: patient demographics (DEMO), drug treatments (DRUG), AEs (REAC), and medical history and primary disease information (HIST). The DEMO table contained basic patient details like reporting year, sex, and age, with age described in decades (e.g., 10s, 20s, etc.). For this study, reports with incomplete, unclear, or ambiguous age categories (e.g., adult, child, aged, and newborn) were excluded. Only reports with age stratification (<10s, 10s, 20s, 30s, 40s, 50s, 60, 70s, 80s, and ≥90s) were utilized. The DRUG table included details about the drug name, route of administration, start and end dates of administration, and its association with AEs. The REAC table provided information on AEs, including their names, onset dates, and outcomes. In this study, DEMO, DRUG, and REAC tables were used for analysis.
Drug of interest. The drugs of interest included esomeprazole, lansoprazole, omeprazole, rabeprazole, and vonoprazan. Drugs intended for H. pylori eradication, including combined drugs, were excluded. Within the DRUG table, each drug’s causality was categorized using codes indicating its association with adverse drug reactions, such as “suspected drug”, “concomitant drug”, or “interacting drug”. In this study, only “suspected drug” was used for the analysis.
Definition of RM. RM was defined based on the preferred term “rhabdomyolysis” (PT 10039020) in the Medical Dictionary for Regulatory Activities (MedDRA/J ver. 25.1).
Disproportionality analysis. The association between PPIs and RM was evaluated using the reporting odds ratio (ROR) (16-18). Signal scores were determined through the case/non-case method (19, 20).
To account for covariates and enable adjustment via logistic regression analysis (21-23), the adjusted ROR (aROR) was calculated following established methodologies (24, 25). Only reports containing complete information on sex and age were considered for aROR calculation. Additional analyses were conducted, excluding reports involving concomitant use of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) or fibrates (clofibrate, fenofibrate, bezafibrate, and pemafibrate) for further assessment.
An association was defined when the lower limit of the 95% confidence interval (CI) of the aROR was >1, and the p-value was <0.05.
Time to onset of RM. The calculation of the onset time of RM involved determining the number of days from the initiation of the administration of the drug of interest to the onset of RM, using time information from the DRUG and REAC tables. Therefore, only reports containing available time-to-onset data were analyzed. The median days (interquartile range: IQR; no. d) for the onset of RM were calculated based on the administration routes.
Outcomes after RM onset. There are six outcome descriptors in the REAC table of the JADER: “recovery”, “remission”, “with sequelae”, “not recovered”, “death”, and “unclear”.
Weibull distribution. Furthermore, the Weibull parameters from the Weibull distribution were used to evaluate the AE profile (26-28). The Weibull distribution is expressed using the scale parameter α, representing the scale of the distribution function, and the shape parameter β, indicating the change in hazard without a reference population over time. The shape parameter β value categorizes failure into three groups: a β value with a 95%CI <1 indicates an initial increase in hazard followed by a decrease (early failure type); a β value close to or equal to 1, with a 95%CI of 1, indicates a constant hazard throughout the exposure period (random failure type); and a β value with a 95% CI >1 signifies an increasing hazard over time (wear-out failure type).
All statistical analyses and data visualization were conducted using JMP Pro ver. 13.2.1 (SAS Institute, Cary, NC, USA). Significance was considered for p-values <0.05, and an aROR with the lower limit of the 95%CI >1 was deemed significant.
Results
Data analyzed. In total, 777,555 reports were extracted from the JADER database. Following the exclusion of records with missing, unknown, or inadequate data, only reports involving suspected drugs were considered. Finally, 618,338 reports were analyzed, including 5,962 RM reports.
Association between PPI use and RM. Table I shows the analysis of the association between PPIs and RM. Esomeprazole, omeprazole, and rabeprazole were associated with RM (Table I). Even after excluding users of concomitant statins or fibrates, the aROR values exhibited no significant change, and the association between each drug and RM remained consistent (Table I).
Association of rhabdomyolysis with proton pump inhibitor treatment with and without concomitant use of statins or fibrates.
Time to onset of RM. Figure 1 displays box plots illustrating the onset times of RM. The median day (IQR) for RM onset for the intravenous administration route (only omeprazole was calculable) was 2 [1-6] d. Conversely, for the oral administration route, the smallest value for RM onset was 6.5 [2-25] d for esomeprazole, while the largest value was 127 [17.5-196] d for omeprazole (Figure 1).
Box plot illustrating the onset time of rhabdomyolysis after the administration of proton pump inhibitors. Lines within the boxes represent the median, the boxes depict the interquartile range, and the whiskers indicate the minimum and maximum values.
Weibull distribution analysis. Table II shows the results of the Weibull distribution analysis for PPIs. For the oral administration route, esomeprazole, lansoprazole, and rabeprazole were indicated to have an early failure-type profile, whereas others exhibited a random failure-type profile (Table II).
Weibull parameters for rhabdomyolysis as an adverse event of treatment with proton pump inhibitor.
Outcomes after RM onset. Table III displays the number and percentage of the six outcomes following the onset RM. Omeprazole was the most frequently reported drug, observed in both oral and intravenous routes. Across oral route medications, the reported numbers were nearly equal for all PPIs, with recovery and remission accounting for more than 80% of the cases. It is important to note that deaths were reported for all drugs except vonoprazan, albeit in small numbers.
The number and percentage of rhabdomyolysis outcomes by route of proton pump inhibitor administration.
Discussion
Our findings suggest an association of certain PPIs, such as esomeprazole, omeprazole, and rabeprazole, with RM even when concomitant use of statins or fibrates is excluded. The median onset day for RM via intravenous administration was 2 [1-6] d for omeprazole, whereas for the oral administration route, the smallest median ranged from 6.5 [2-25] d for esomeprazole to 127 [17.5-196] d for omeprazole, the highest median observed. The Weibull distribution analysis revealed early failure-type profiles for esomeprazole, lansoprazole, and rabeprazole, while others exhibited random failure-type profiles. Regarding outcomes post-RM onset, almost all cases were favorable; however, although the numbers were small, deaths were reported for all drugs, except vonoprazan.
While the precise mechanism of RM following PPI use remains uncertain, various hypotheses have been proposed, including the potential development of electrolyte imbalances or autoimmune antibodies as a result of long-term PPI use (29, 30). In particular, two mechanisms have been under consideration. First, it has been suggested that PPIs bind to H+/K+-ATPase in gastric parietal cells. As H+/K+-ATPase regulates intracellular pH, this interaction could enhance susceptibility to cellular degradation, thereby increasing the risk of RM (31). Another hypothesis revolves around the potential of PPIs to induce autoimmune disorders in patients with familial myopathy, subsequently leading to autoimmune muscle diseases like polymyositis or myasthenia gravis (32, 33).
In Japan, RM is listed in the package inserts for esomeprazole, omeprazole, and rabeprazole, but not for lansoprazole or vonoprazan. Therefore, our findings indicate that each package insert appropriately reflects the observed association between the respective drug and RM. In contrast, a disproportionality analysis using the FDA Adverse Event Reporting System (FAERS), the largest spontaneous reporting database, demonstrated an association between RM and all PPIs, including pantoprazole (34). However, this study using the JADER differs from previous reports concerning lansoprazole and vonoprazan. Further studies are needed to clarify whether the occurrence of RM following PPI use represents a class effect of PPIs, including understanding its underlying mechanism.
Given that statins and fibrates are commonly implicated in RM development (1, 35), we explored the impact of concomitant statin use in patients receiving PPI. Some statins serve as substrates for CYP3A4, the enzyme responsible for PPI sulfoxidation (36, 37). Additionally, CYP2C19, exhibiting genetic polymorphism in approximately 20% of East Asians, is accountable for the primary metabolic pathway of PPIs, involving 5-hydroxylation, except for vonoprazan. Therefore, the concomitant use of both drugs is anticipated to raise the likelihood of RM. Nevertheless, the effect of concomitant statin usage on the association between PPIs and this AE appeared to be limited. Similar findings have been observed in analyses of other spontaneous AE databases, including the FAERS and the Italian National Network of Pharmacovigilance database (14, 34). This is likely attributed to the distinct mechanisms underlying PPI-induced RM compared to that caused by statins, coupled with the lower incidence of PPI-induced RM in comparison to that induced by statins.
In this study, the time-to-onset of RM varied across PPIs. The largest median value with IQR was 127 [17.5-196] d for omeprazole, while the smallest value was 6.5 [2-25] d for oral esomeprazole (Figure 1). This variability could be attributed to differences in the involvement of CYP2C19 in the metabolism of each drug. Since esomeprazole consists only of the S (-) form, the contribution of CYP2C19 is limited, with CYP3A4 playing a predominant role in metabolism. On the contrary, omeprazole, a racemic form, may have a more complex metabolism due to the presence of the R (-) form and the varying contribution of CYP2C19 and CYP3A4 among individuals, especially in East Asians.
There is limited available information on the time-to-onset profile of RM related to PPIs. In this study, the analyses of median onset time and Weibull distribution for the intravenous administration route, although focused on a single drug, revealed a median of 2 [1-6] d characterized by a random failure type. For the oral administration route, the onset time varied from 6.5 [2-25] d to 127 [17.5-196] d, displaying early failure/random failure types (tending toward early failure) (Figure 1). This suggests that healthcare providers should closely monitor patients throughout the course of intravenous administration, particularly in the early stages following oral administration initiation, for the occurrence of RM.
Regarding the outcomes following the oral administration of RM, “Recovery” and “Remission” constituted more than 80%-90% for each orally administered drug, while “Death” ranged from 3.4% to 9.7% for each drug, excluding vonoprazan (Table III). This aligns with general reports indicating that approximately 5% of RM patients experience worse outcomes (38), consistent with previous findings. In contrast, though the results primarily involving omeprazole, the occurrence of “Death” was approximately 17% for patients treated intravenously (Table III). The primary contributing factor to this difference may be the patient’s condition. As highlighted earlier, RM following intravenous PPI administration unfolds within a confined and brief timeframe, underscoring the importance of vigilant monitoring during this period.
While using a spontaneous reporting system has several advantages in detecting potential drug–AE associations, including access to information regarding AE onset times, its inherent characteristics introduce potential limitations that might impact the interpretation of our findings. First, it remains uncertain whether the reported AEs can be definitively attributed to the administration of a specific medication. Second, RM can be influenced by various concomitant drugs, other than statins and fibrates. Although the PPIs examined in this study were designated as “suspected drugs”, the impact of concomitant drugs known to induce myopathy, such as corticosteroids, colchicine, penicillamine, and other anticancer drugs, was not considered (1, 2). Third, not every AE associated with a drug may be reported (i.e., reporting bias). Finally, the exclusion of some data was necessary due to the missing information that rendered the calculation of onset times impossible.
Conclusion
Our results suggest that the time-to-onset profiles of RM due to PPI differ depending on the drug and administration route. Considering the potential fatality associated with RM during PPI administration, healthcare providers should exercise careful monitoring, especially during intravenous administration and the early stages of oral administration. This vigilance is crucial considering the different onset times associated with different PPIs.
Footnotes
Authors’ Contributions
K. Ohyama and Y. Hori conceived of and designed the study. K. Ohyama, M. Iida, and S. Akiyama analyzed the data. K. Ohyama and H. Yamazaki drafted the manuscript. All Authors critically reviewed and approved the final version of the manuscript.
Funding
This research received no specific grants from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received January 12, 2024.
- Revision received February 14, 2024.
- Accepted February 15, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
