Oseltamivir Treatment for Influenza Linked to Fulminant Hepatitis, Liver Damage

A recent analysis of US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data is calling attention to the hepatic toxicity of oseltamivir treatment for influenza and the potential use of baloxavir marboxil as a safer alternative in patients with liver diseases.¹

The study was conducted using real-world data to investigate the post-market safety profiles of both medications, outlining notable adverse event (AE) categories to provide clinicians with insight into preferred treatment options for influenza from a safety perspective.¹

“To our knowledge, we are the first study where the AEs of oseltamivir and baloxavir marboxil were comprehensively evaluated and compared using a vast real-world AE reporting database,” Wei Zhuang, post-doctorate researcher at Xiamen University in China, and colleagues wrote.¹

According to the US Centers for Disease Control and Prevention (CDC), the effects of flu vary but generally pose a substantial health burden, resulting in an estimated 9.3 million - 41 million illnesses, 100,000 - 710,000 hospitalizations, and 4,900 - 51,000 deaths annually between 2010 and 2023.² Although it is preventable with annual vaccination, for those who are infected and at an increased risk of influenza-related complications, antiviral treatment is recommended.³ However, real-world data comparing the safety of these medications are limited.

To investigate post-market safety profiles and real-world safety data of 2 FDA-approved influenza antiviral treatments, oseltamivir and baloxavir marboxil, investigators sourced data from the FAERS from the first quarter of 2004 through the fourth quarter of 2022. However, investigators noted adverse reaction data for baloxavir marboxil were only available from the first quarter of 2018 to the fourth quarter of 2022.¹

After duplicate records were removed, investigators included analyses involving ≥ 3 reports and recorded AEs using preferred terms from the Medical Dictionary for Drug Regulatory Activities. This study utilized hierarchical term sets of preferred terms and System Organ Class (SOC) terms for categorization and standardization.¹

The final analysis included 15,104 oseltamivir cases and 1594 baloxavir marboxil cases. Within the 2753 different types of AE reports for oseltamivir, totaling 43,675 reports, 242 AEs displayed significant safety signals. In the 536 different types of AE reports for baloxavir marboxil, comprising 3315 reports, 55 AEs exhibited significant safety signals.¹

Investigators performed differential analyses of SOC signal strength for age groups < 18 years vs ≥18–64 years and age groups > 64 years vs ≥18–64 years for both medication groups. For oseltamivir, in the age group < 18 years compared to ≥ 18–64 years, a significant safety signal was observed in nervous system disorders, whereas in the age group > 64 years compared to ≥ 18–64 years, more significant safety signals were observed in renal and urinary disorders, metabolism and nutrition disorders, and cardiac disorders. For baloxavir marboxil, in the age group < 18 years compared to ≥ 18–64 years, a more significant safety signal was observed in general disorders and administration site reactions, whereas in the age group > 64 years compared to ≥ 18–64 years, more significant safety signals were observed in metabolism and nutrition disorders, cardiac disorders, musculoskeletal and connective tissue disorders, and blood and lymphatic system disorders.¹

Additional differential analyses of SOC signal strength were conducted for male and female subgroups receiving oseltamivir and baloxavir marboxil. Across both treatment groups, the number of reports and reporting odds ratios were similar between males and females, although the significance of certain safety signals varied.¹

Investigators noted oseltamivir had 221 specific AEs, whereas baloxavir marboxil had 34. Wain analysis revealed 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains.¹

Significant AEs for oseltamivir included appendicolith (reporting odds ratio [ROR], 459.53; 95% CI, 340.88 - 619.47); acne infantile (ROR, 368.65; 95% CI, 118.89 - 1143.09); acute macular neuroretinopathy (ROR, 294.92; 95% CI, 97.88 - 888.64); proctitis (ROR, 245.74; 95% CI, 101.47 - 595.31); and Purpura senile (ROR, 154.02; 95% CI, 81.96 - 289.43). Designated adverse events (DMEs) associated with oseltamivir included fulminant hepatitis (ROR, 12.12; 95% CI, 8.30-17.72); ventricular fibrillation (ROR, 7.68; 95% CI, 6.01-9.83); and toxic epidermal necrolysis (ROR, 7.21; 95% CI, 5.74-9.05).¹

Significant AEs for baloxavir marboxil included melena (ROR, 21.34; 95% CI, 14.15–32.18); cystitis hemorrhagic (ROR, 20.22; 95% CI, 7.57-54.00); ileus paralytic (ROR, 18.57; 95% CI, 5.98–57.71), and hemorrhagic diathesis (ROR, 16.86; 95% CI, 5.43–52.40). DMEs associated with baloxavir marboxil included rhabdomyolysis (ROR, 15.50; 95% CI, 10.53 - 22.80).¹

Investigators pointed out multiple limitations to these findings, including the inability to confirm any causal relationships, the potential influence of lost data, disease complications, comorbidities, and drug interactions on safety signal data, the large difference in sample size between the drugs, and the fact that the FAERS database only accounts for reported cases rather than all cases.¹

“This study offers crucial safety insights for guiding drug selection in seasonal influenza therapy. Key findings highlight the need for vigilant monitoring of fulminant hepatitis during oseltamivir treatment, especially in patients with liver-related diseases,” investigators concluded.¹ “Baloxavir marboxil, with lower hepatic toxicity, emerges as a promising alternative for patients with liver diseases."

References:

1. ^{Li Y, Wang X, Liao Y, et al. Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system. BMC Infect Dis. 2024;24(1):446. doi:10.1186/s12879-024-09339-4}
2. ^{US Centers for Disease Control and Prevention. Disease Burden of Flu. Influenza (Flu). February 28, 2024. Accessed May 16, 2024. https://www.cdc.gov/flu/about/burden/index.html}
3. ^{US Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Influenza (Flu). December 8, 2023. Accessed May 16, 2024. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm}