Adverse events associated with oseltamivir and baloxavir marboxil in against influenza virus therapy: A pharmacovigilance study using the FAERS database

Abstract

Background: Influenza virus is a widespread pathogen that poses significant health risks to humans. Oseltamivir and Baloxavir Marboxil are commonly utilized medications for both treating and preventing influenza infections. Despite their widespread use, there remains a need to thoroughly investigate their safety profiles and potential adverse reactions.

Objective: This study aims to comprehensively analyze the adverse events associated with oseltamivir and baloxavir marboxil in real-world clinical settings, with the goal of assessing their safety and potential risks in the management of influenza virus infections.

Methods: We conducted a retrospective analysis utilizing data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, spanning from the first quarter of 2004 to the third quarter of 2023. The analysis encompassed examination of drug utilization patterns, types of adverse events reported, patient demographics, and other pertinent factors.

Results: From the first quarter of 2004 to the third quarter of 2023, FAERS collected over 17,035,521 adverse event reports (AE reports). Among these reports, there were 38,384 reports associated with oseltamivir, and 3,364 reports associated with baloxavir marboxil. Oseltamivir and Baloxavir Marboxil were primarily used for the treatment of influenza virus infections, accounting for 62.43% and 67.49% of their total usage, respectively. The main adverse reactions reported for oseltamivir were vomiting (case reports = 1402) followed by confusional state (case reports = 353), while for baloxavir marboxil, adverse reactions mainly centered around off-label use (case reports = 378) and intentional product use issues (case reports = 278). In terms of systemic adverse reactions, oseltamivir primarily affected psychiatric disorders (n = 45), whereas baloxavir marboxil mainly impacted the gastrointestinal system (n = 7). Additionally, regarding adverse reactions in pregnant women, the occurrence of normal newborns was a significant signal for oseltamivir, suggesting a certain level of safety during maternal use. Conversely, reports of adverse reactions such as respiratory arrest were documented for baloxavir marboxil, while no such reports were associated with oseltamivir.

Conclusion: This study provides a comprehensive analysis of the adverse reactions observed with the clinical use of oseltamivir and baloxavir marboxil, revealing the safety and risks associated with these two drugs in the treatment and prevention of influenza virus infections. Firstly, although both drugs are used for influenza treatment, they exhibit different types of adverse reactions. Oseltamivir predominantly affects the psychiatric system, while baloxavir marboxil primarily impacts the gastrointestinal system. Additionally, oseltamivir demonstrates a certain level of safety for use in pregnant women, while reports of adverse reactions such as respiratory arrest are associated with baloxavir marboxil. Despite the clinical significance of this study, limitations exist due to the voluntary nature of data reporting, which may lead to reporting biases and incomplete information. Future research could employ more rigorous prospective study designs, integrating clinical trials and epidemiological studies, to more accurately assess the safety risks of oseltamivir and baloxavir marboxil.

Fig 1. Number of adverse events reported per quarter after marketing for oseltamivir and baloxavir marboxil.

The blue line represents the report of oseltamivir, and the red line represents the report of Baloxavir Marboxil. The x-axis shows the timeline of drug use, and the y-axis shows the number of reports per quarter.

Fig 2. The number of individual adverse reaction reports for oseltamivir and baloxavir marboxil in different systems.

A: oseltamivir; B: Baloxavir Marboxil.

Fig 3. Comparison of four system organ classes safety signals between oseltamivir and baloxavir marboxil.

A: psychiatric disorders;B: ’pregnancy, puerperium and perinatal conditions; C:investigations;D: congenital, familial and genetic disorders Fig 3A-3D respectively shows the mining results of adverse event signals of oseltamivir and Baloxavir Marboxil in four system organ classes. The x- axis is log2ROR, and the y- axis is the square root of the χ2 value. All points in the Fig represent the mined adverse reaction signals, and the size of points represents the number of reported adverse reactions. ROR and PRR methods were used to determine the location of each adverse event in the Fig. When the position of the point in the graph is higher and further, both algorithms prove that the signal of the adverse event is strong.

Fig 4. Comparison of four system organ classes safety signals between oseltamivir and baloxavir marboxil.

A: nervous system disorders; B: infections and infestations; C: respiratory, thoracic and mediastinal disorders; D: gastrointestinal disorders Fig 4A-4D respectively shows the mining results of adverse event signals of oseltamivir and Baloxavir Marboxil in four system organ classes. The x- axis is log2ROR, and the y- axis is the square root of the χ2 value. All points in the Fig represent the mined adverse reaction signals, and the size of points represents the number of reported adverse reactions. ROR and PRR methods were used to determine the location of each adverse event in the Fig. When the position of the point in the graph is higher and further, both algorithms prove that the signal of the adverse event is strong.

Fig 5. Comparison of four system organ classes safety signals between oseltamivir and baloxavir marboxil.

Note:A: skin and subcutaneous tissue disorders; B: general disorders and administration site conditions; C: cardiac disorders; D: eye disorders Fig 5A-5D respectively shows the mining results of adverse event signals of oseltamivir and Baloxavir Marboxil in four system organ classes. The x- axis is log2ROR, and the y- axis is the square root of the χ2 value. All points in the Fig represent the mined adverse reaction signals, and the size of points represents the number of reported adverse reactions. ROR and PRR methods were used to determine the location of each adverse event in the Fig. When the position of the point in the graph is higher and further, both algorithms prove that the signal of the adverse event is strong.

Fig 6. Comparison of four system organ classes safety signals between oseltamivir and baloxavir marboxil.

Note: A: hepatobiliary disorders; B: renal and urinary disorders; C: injury, poisoning and procedural complications; D: gastrointestinal disorders Fig 6A-6D respectively shows the mining results of adverse event signals of oseltamivir and Baloxavir Marboxil in four system organ classes. The x- axis is log2ROR, and the y- axis is the square root of the χ2 value. All points in the Fig represent the mined adverse reaction signals, and the size of points represents the number of reported adverse reactions. ROR and PRR methods were used to determine the location of each adverse event in the Fig. When the position of the point in the graph is higher and further, both algorithms prove that the signal of the adverse event is strong.

Fig 7. Information component and its 95% credibility interval over time for oseltamivir and baloxavir marboxil -associated adverse events in investigations.

The blue line represents the reports of oseltamivir while the red line represents the reports of Baloxavir Marboxil; IC, information component; CI, credibility interval. The error bars show the 95% credibility interval (CI) of the information component (IC), when the IC curve is in a steady upward trend and the 95% CI narrowed, the signal is sTable and the association is strong. Shrinkage of CI of IC over time with increasing data means that confidence interval gets smaller. Once the value 0 is not included in the CI, a signal is flagged.