Hepatotoxicity of newer antiseizure medications in children: an overview and disproportionality analysis of VigiBase

ABSTRACT

Background

We aimed to characterize newer antiseizure medications (ASMs)-induced hepatotoxicity in children and identify signals of disproportionate reporting of hepatotoxicity-related adverse drug events (ADEs).

Research Design and Methods

Case reports reported to VigiBase were accessed using Empirica™ Signal software. To summarize characteristics of the retrieved cases, descriptive statistics were used. A disproportionality analysis was conducted using the Multi-item Gamma Poisson Shrinker algorithm, which calculates Empirical Bayesian Geometric Mean value and its lower and upper 95% confidence limits (EB05 and EB95, respectively). EB05 > 2, N > 0 was considered a signal.

Results

Based on 870 analyzed cases, a higher proportion of cases was reported in girls than in boys and in patients aged 2–11 years than in other age groups. Most cases were serious. In 25 cases, hepatotoxicity resulted in death. A high proportion of patients (n = 275, 31.61%) experienced hypersensitivity reactions, mostly due to lamotrigine. The disproportionality analysis yielded 17 signals concerning felbamate, lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and topiramate. Four signals were for severe liver injury and concerned felbamate, lamotrigine, levetiracetam, and topiramate. Gender-biased reporting frequency was detected for four ASM-ADE combinations.

Conclusion

Our results should serve to raise clinicians’ awareness about the potential association between several newer ASMs and drug-induced liver injury in children.

KEYWORDS:

• Antiseizure medications
• drug-induced liver injury
• hypersensitivity
• pediatric
• pharmacovigilance

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Data availability statement

The data that support the findings of this study are not the property of the authors and thus cannot be shared. The data may be available on request from Uppsala Monitoring Centre.

Ethics approval

Ethical approval was not required for this study as it was conducted using anonymized health-related data.

Author contributions

All the authors have substantially contributed to the conception and design of the study, interpreting the results, and have been involved in writing the article and revision of its intellectual content. All the authors are accountable for the contents of the article and share responsibility for the accuracy and integrity of the published work. Study conception and planning: S Petrović, M Kovačević, S Vezmar Kovačević, B Miljković. Acquisition and analysis of data: S Petrović. Interpretation of data: S Petrović, M Kovačević, S Vezmar Kovačević, B Miljković. Drafting of the manuscript: S Petrović. Critical revision of the manuscript for important intellectual content: M Kovačević, S Vezmar Kovačević, B Miljković. All the authors approved the final version of the manuscript.

Acknowledgments

The information within VigiBase comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. The results and conclusions of this study do not represent the opinion of the Uppsala Monitoring Centre or the World Health Organization.

Additional information

Funding

This research was funded by the Ministry of Science, Technological Development and Innovation, Republic of Serbia through Grant Agreement with University of Belgrade-Faculty of Pharmacy No: [451-03-65/2024-03/ 200161 and 451-03-66/2024-03/ 200161].