Association between Concomitant Use of Acyclovir or Valacyclovir with NSAIDs and an Increased Risk of Acute Kidney Injury: Data Mining of FDA Adverse Event Reporting System

Abstract

Whereas nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of acute or chronic conditions where pain and inflammation are present. Due to the current use profile of NSAIDs, either as prescription or OTC drugs, NSAIDs are likely to be used concomitantly with acyclovir or valacyclovir in clinical practice such as rheumatoid arthritis and herpes zoster virus infection, while the study on the safety of such combinations was hardly reported.It is known that both oral acyclovir (or valacyclovir) and NSAIDs have the potential to affect kidney function, and in rare instances these drugs may cause more severe renal conditions such as acute kidney injury (AKI).3,4) Our previous research has revealed that the concomitant use of loxoprofen (a non-selective NSAID) and valacyclovir might lead to an increase in reports of AKI.5) However, it is not known whether the combination therapy of other NSAIDs with acyclovir or valacyclovir is associated with increased risk of AKI, and we also need to know the differences of drug interactions between acyclovir and valacyclovir.In the present study, we examined the United States Food and Drug Administration (FDA) database to determine the frequency of AKI adverse events in patients taking both acyclovir or valacyclovir and an NSAID, and the differences of drug interactions between acyclovir and valacyclovir. METHODSWe used the public release of the FDA's Adverse Event Reporting System (AERS) database 6) which covers the period from January 2004 to June 2012. The AERS contains reports of adverse drug events spontaneously submitted by physicians, pharmacists, other health care professionals, manufacturers, and consumers from the U.S. and other countries. From the first quarter (Q1) of 2004 through the second quarter (Q2) of 2012, tables including demographic information-DEMO file; drug information-DRUG file and adverse events coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology-REAC file for the reported drugs were considered. A unique ISR number allows linking all information from different tables. As the AERS database has some duplicate reports, we removed the older ones from duplicate reports by sorting case identification numbers. 7)

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

“…Therefore, AKI risk evaluation for analgesics in concomitant use with VACV is needed. In previous studies, Yue et al (2014), Yue et al (2018) found that concomitant use of VACV and NSAIDs might increase AKI risk. However, the risk of AKI with concomitant use of acetaminophen remains unclear.…”

“…Analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently administered alongside VACV to treat pain related to herpes zoster. However, some NSAIDs have been shown to be associated with increased risk of VACV-related AKI in the FDA spontaneous reporting system (Yue et al, 2014; Yue et al, 2018). Acetaminophen, an analgesic, is generally regarded as safer than NSAIDs with regard to kidney function (Griffin et al, 2000).…”

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2

“…The combination of NSAIDs with methotrexate could result in serious toxicity, including an increased risk of nephrotoxicity [ 48 , 49 ]. An increased risk of acute kidney injury was also observed with the concomitant use of NSAIDs with acyclovir or valacyclovir (a prodrug of acyclovir) [ 20 , 50 ].…”

Evaluation of the Expression Time of Ganciclovir-Induced Adverse Events Using JADER and FAERS

“…JADER has been utilized in many retrospective studies, [1][2][3] playing a major role in the safety evaluation of drugs in clinical practice sites in Japan. 4) The U.S. Food and Drug Administration (FDA) opened the FDA's Adverse Event Reporting System (FAERS) to the public, which is also a spontaneous adverse event report database similar to JADER. 5,6) This system was started in 1996, and data from more than 7 million reports have been collected from the U.S. and other countries.…”

“…Detecting adverse event signals by data mining of the adverse reaction reports accumulated in these databases will enable the clarification of the incidence of adverse drug events. 4) The aim of this study was to evaluate the expression time of ganciclovir-induced adverse events by data mining of the adverse reaction reports, JADER, and FAERS. For this purpose, the number of reported cases of the main adverse reactions (cytopenia, leukopenia, thrombocytopenia, liver damage, and acute renal failure) of ganciclovir in JADER and FAERS were surveyed, and the incidence of these adverse reactions due to ganciclovir and their expression time were evaluated.…”