Time-to-onset Analysis of Rhabdomyolysis due to Different Proton Pump Inhibitors Using a Pharmacovigilance Database

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.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 pro...