Risk Evaluation for Acute Kidney Injury Induced by the Concomitant Use of Valacyclovir, Analgesics, and Renin–Angiotensin System Inhibitors: The Detection of Signals of Drug–Drug Interactions

Abstract

Background: Drug-related acute kidney disease is a common side effect of valacyclovir (VACV) treatment. Although analgesics are frequently administered concomitantly with VACV to treat the pain of herpes zoster, the differences between nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in relation to VACV-related acute kidney injury (AKI) are unclear. The risk for AKI with concomitant use of VACV and renin–angiotensin system (RAS) inhibitors that can cause AKI via a similar mechanism to NSAIDs is also unknown. We therefore evaluated the association between concomitant use of these drugs and VACV-related AKI, which was characterized according to the Japanese Adverse Drug Event Report (JADER) database. Methods: We analyzed data from the JADER database, which is a spontaneous reporting system. The reporting odds ratio was used to evaluate the signals of AKI. Results: A high proportion of VACV-related AKI cases occurred in summer. There was an increase in AKI signal in cases with concomitant use of VACV and NSAIDs, while no increase was detected in cases with concomitant use of VACV and acetaminophen. AKI events in cases with concomitant use of VACV and NSAIDs were more frequent in older and female patients and those with hypertension. Additionally, a signal increase for VACV-related AKI was observed with concomitant use of RAS inhibitors, with or without NSAIDs. Conclusions: We identified a seasonal variation in VACV-related AKI. Additionally, our findings indicate that acetaminophen might represent a safer analgesic than NSAIDs with respect to VACV-related AKI. We also identified candidate risk factors for AKI with concomitant use of NSAIDs, such as older age, female sex, and hypertension. Although further studies are warranted, our findings highlight the need to consider concomitant drug use and seasonal factors that lead to urinary output loss so that VACV-related AKI can be avoided.

Time until onset of acute kidney injury by combination therapy with “Triple Whammy” drugs obtained from Japanese Adverse Drug Event Report database

“…There are several limitations to the ADE reporting databases [ 9 , 10 , 17 ]. First, ADE reporting databases only contain information about patients who have experienced ADEs.…”

“…First, ADE reporting databases only contain information about patients who have experienced ADEs. Therefore, the incidence of ADEs for a target drug cannot be determined [ 9 , 17 ]. Second, because the database is based on spontaneous reports, reporting bias may exist.…”

“…Clinical studies that accurately assess the severity and risk of AKI using certain criteria are needed in the future. Third, analysis of the confounding factors was difficult due to the lack of disease information (e.g., chronic kidney, pulmonary, heart, and hepatic disease, cancer, and diabetes), clinical laboratory values (e.g., serum creatinine and hemoglobin levels), and lifestyle [ 9 , 17 ]. In addition, some age, sex, and prescription information were missing and cases with missing information were excluded from the analyses.…”

“…23.1, was used for this analysis. AKI events were identified using PTs related to AKI [ 9 , 10 ] in the Standardized MedDRA Query for “acute renal failure.” The PTs used for identification of AKI events are shown in S1 Table . The outcomes of ADEs were reported as “Recovered”, “Remission”, “Unrecovered”, “Death”, and “With sequelae”.…”

Evaluation of Potential Complications of Interstitial Lung Disease Associated With Antiandrogens Using Data From Databases Reporting Spontaneous Adverse Effects

“…Antiandrogen drugs, such as enzalutamide, apalutamide, bicalutamide, flutamide, chlormadinone acetate, and abiraterone acetate, were included in the analysis, and so were patients' age and sex. The timing of adverse drug events in patients reporting adverse reactions was determined using a log-rank test with EZR (Easy R), freely available statistical software (Inaba et al, 2019).…”