Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Original article

Vol. 151 No. 1920 (2021)

Drug-induced liver injury in Switzerland: an analysis of drug-related hepatic disorders in the WHO pharmacovigilance database VigiBase™ from 2010 to 2020

DOI
https://doi.org/10.4414/smw.2021.20503
Cite this as:
Swiss Med Wkly. 2021;151:w20503
Published
12.05.2021

Summary

AIMS OF THE STUDY

Our aim was to explore drug-induced liver injury (DILI) in Switzerland using the real-world data of the global pharmacovigilance database VigiBase™, with a special focus on the new drug class of checkpoint inhibitors. This is the first study investigating drug-related hepatic disorders in Switzerland in a global pharmacovigilance database.

METHODS

This was a retrospective study analysing the ICSRs (individual case safety reports) of the global pharmacovigilance database VigiBase™. We explored all ICSRs submitted in Switzerland within the last 10 years (1 July 2010 to 30 June 2020). For data extraction, the standardised MedDRA query (SMQ) “narrow drug-related hepatic disorders – severe events only” was applied. The ICSRs, drug-reaction pairs and adverse drug reactions were analysed descriptively, including a special focus on checkpoint inhibitors. For comparing the hepatic adverse drug reactions of pembrolizumab, nivolumab and ipilimumab, the reporting odds ratios (RORs) were calculated in a disproportionality analysis.

RESULTS

In total, 2042 ICSRs could be investigated, comprising 10,646 drugs and 6436 adverse drug reactions. Gender was equally distributed between male and female. Patients were on average 57 years old. The mortality rate was high, with fatal adverse reactions in over 10% of cases. On average, patients used five drugs including two suspected drugs. Paracetamol, amoxicillin/clavulanic acid, esomeprazole and atorvastatin ranked among the most frequently suspected drugs for severe drug-related hepatic disorders. However, Vigibase™ data are not appropriate for judging causality and these results should be interpreted with caution owing to the possible influences of comedication or comorbidity. An average of three adverse drug reactions per ICSR were reported, most frequently including hepatocellular injury, cholestatic liver injury, and liver injury. For checkpoint inhibitors, hepatitis was the most frequently reported hepatic adverse drug reaction. In comparison with nivolumab and ipilimumab, pembrolizumab had a significantly higher ROR for hepatitis (2.41, p = 0.016), but also a lower ROR for autoimmune hepatitis (0.11, p = 0.009).

CONCLUSION

Our findings highlight the importance for healthcare providers in Switzerland to pay special attention to possible drug-induced liver injuries because of their high mortality rate. The analysis of real-world data confirms the previous assumption that hepatitis is the most frequent hepatic adverse event for checkpoint inhibitors. Further clinical studies are warranted to directly compare hepatic adverse drug reactions to different checkpoint inhibitors.

References

  1. Lee WM. Drug-induced acute liver failure. Clin Liver Dis. 2013;17(4):575–86, viii. doi:.https://doi.org/10.1016/j.cld.2013.07.001
  2. Larrey D Pageaux GP. Drug-induced acute liver failure. Eur J Gastroenterol Hepatol. 2005;17(2):141–3. doi:.https://doi.org/10.1097/00042737-200502000-00002
  3. Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB DILIN Network. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147(1):96–108.e4. doi:.https://doi.org/10.1053/j.gastro.2014.03.045
  4. Kullak-Ublick GA Andrade RJ Merz M End P Benesic A Gerbes AL Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017;66(6):1154–64. doi:.https://doi.org/10.1136/gutjnl-2016-313369
  5. Hoofnagle JH Björnsson ES. Drug-Induced Liver Injury - Types and Phenotypes. N Engl J Med. 2019;381(3):264–73. doi:.https://doi.org/10.1056/NEJMra1816149
  6. Ferrajolo C Capuano A Verhamme KM Schuemie M Rossi F Stricker BH Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol. 2010;70(5):721–8. doi:.https://doi.org/10.1111/j.1365-2125.2010.03754.x
  7. Suzuki A Andrade RJ Bjornsson E Lucena MI Lee WM Yuen NA Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work. Drug Saf. 2010;33(6):503–22. doi:.https://doi.org/10.2165/11535340-000000000-00000
  8. Liakoni E Rätz Bravo AE Krähenbühl S. Hepatotoxicity of New Oral Anticoagulants (NOACs). Drug Saf. 2015;38(8):711–20. doi:.https://doi.org/10.1007/s40264-015-0317-5
  9. Postow MA Sidlow R Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378(2):158–68. doi:.https://doi.org/10.1056/NEJMra1703481
  10. VigiBase [cited 2020 Nov 24]. Available from: https://www.who-umc.org/.
  11. Standardised MedDRA Queries (SMQs) [cited 2020 Nov 24]. Available from: https://www.meddra.org.
  12. Rothman KJ Lanes S Sacks ST. The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiol Drug Saf. 2004;13(8):519–23. doi:.https://doi.org/10.1002/pds.1001
  13. Chalasani N Fontana RJ Bonkovsky HL Watkins PB Davern T Serrano J Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135(6):1924–34, 1934.e1–4. doi:.https://doi.org/10.1053/j.gastro.2008.09.011
  14. Suzuki A Yuen NA Ilic K Miller RT Reese MJ Brown HR Comedications alter drug-induced liver injury reporting frequency: Data mining in the WHO VigiBase™. Regul Toxicol Pharmacol. 2015;72(3):481–90. doi:.https://doi.org/10.1016/j.yrtph.2015.05.004
  15. Swiss drug information [cited 2020 Nov 27]. Available from: https://www.swissmedicinfo.ch.
  16. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012- [cited 2020 Nov 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547852/.
  17. Helsana Arzneimittel-Report Ausgabe. 2020 [cited 2021 Jan 26]. Available from: https:// www.helsana.ch.
  18. Rovegno M Vera M Ruiz A Benítez C. Current concepts in acute liver failure. Ann Hepatol. 2019;18(4):543–52. doi:.https://doi.org/10.1016/j.aohep.2019.04.008
  19. Wolchok JD Chiarion-Sileni V Gonzalez R Rutkowski P Grob JJ Cowey CL Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):1345–56. doi:.https://doi.org/10.1056/NEJMoa1709684
  20. Schachter J Ribas A Long GV Arance A Grob JJ Mortier L Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62. doi:.https://doi.org/10.1016/S0140-6736(17)31601-X
  21. Hofmann L Forschner A Loquai C Goldinger SM Zimmer L Ugurel S Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–209. doi:.https://doi.org/10.1016/j.ejca.2016.02.025
  22. Xu C Chen YP Du XJ Liu JQ Huang CL Chen L Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ. 2018;363:k4226. doi:.https://doi.org/10.1136/bmj.k4226