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


Ortland, Imke; Mirjalili, Mahtabalsadat; Kullak-Ublick, Gerd A; Peymani, Payam (2021). Drug-induced liver injury in Switzerland: an analysis of drug-related hepatic disorders in the WHO pharmacovigilance database VigiBase™ from 2010 to 2020. Swiss Medical Weekly, 151:w20503.

Abstract

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

Methods
This was a retrospective study analyzing the ICSRs (individual case safety reports) of the global pharmacovigilance database VigiBaseTM. We explored all ICSRs submitted in Switzerland within the last 10 years (July 1st, 2010 until June 30th, 2020). For data extraction, the Standardised MedDRA Query (SMQ) “narrow drug-related hepatic disorders – severe events only” was applied. Descriptive analyses regarding the ICSRs, drug-reaction pairs, and adverse drug reactions were performed for summarizing the data, including a special focus on checkpoint inhibitors. For comparing the hepatic adverse drug reactions of pembrolizumab, nivolumab, and ipilimumab, the reporting odds ratios (ROR) were calculated in a disproportionality analysis.

Results
In total, 2’042 individual case safety reports (ICSR) could be investigated, comprising 10’646 drugs and 6’436 adverse drug reactions. Gender was equally distributed between male and female, patients were on average 57 years old, and 86.4% of ICSRs were classified as serious. The mortality rate was high with fatal adverse reactions in over 10% of cases. On average, patients used 5 drugs including 2 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 thus these results should be interpreted with caution due to the possible influence of co-medication or co-morbidity. An average of 3 adverse drug reactions per ICSR was reported, most frequently including hepatocellular injury, cholestatic liver injury as well as liver injury. Hepatic failure and acute hepatic failure were reported less frequently but demonstrated a poor prognosis with a mortality rate of 44.2% and 32.9%, respectively. For checkpoint inhibitors, hepatitis was the most frequently reported hepatic adverse drug reaction. In comparison with nivolumab and ipilimumab, pembrolizumab indicated a significantly higher ROR for hepatitis (2.41, p = 0.016) but also a lower ROR for autoimmune hepatitis (0.11, p = 0.009).

Conclusions
Our findings highlight the importance for health-care providers in Switzerland to pay special attention to possible drug-induced liver injuries due to 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 of different checkpoint inhibitors.

Abstract

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

Methods
This was a retrospective study analyzing the ICSRs (individual case safety reports) of the global pharmacovigilance database VigiBaseTM. We explored all ICSRs submitted in Switzerland within the last 10 years (July 1st, 2010 until June 30th, 2020). For data extraction, the Standardised MedDRA Query (SMQ) “narrow drug-related hepatic disorders – severe events only” was applied. Descriptive analyses regarding the ICSRs, drug-reaction pairs, and adverse drug reactions were performed for summarizing the data, including a special focus on checkpoint inhibitors. For comparing the hepatic adverse drug reactions of pembrolizumab, nivolumab, and ipilimumab, the reporting odds ratios (ROR) were calculated in a disproportionality analysis.

Results
In total, 2’042 individual case safety reports (ICSR) could be investigated, comprising 10’646 drugs and 6’436 adverse drug reactions. Gender was equally distributed between male and female, patients were on average 57 years old, and 86.4% of ICSRs were classified as serious. The mortality rate was high with fatal adverse reactions in over 10% of cases. On average, patients used 5 drugs including 2 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 thus these results should be interpreted with caution due to the possible influence of co-medication or co-morbidity. An average of 3 adverse drug reactions per ICSR was reported, most frequently including hepatocellular injury, cholestatic liver injury as well as liver injury. Hepatic failure and acute hepatic failure were reported less frequently but demonstrated a poor prognosis with a mortality rate of 44.2% and 32.9%, respectively. For checkpoint inhibitors, hepatitis was the most frequently reported hepatic adverse drug reaction. In comparison with nivolumab and ipilimumab, pembrolizumab indicated a significantly higher ROR for hepatitis (2.41, p = 0.016) but also a lower ROR for autoimmune hepatitis (0.11, p = 0.009).

Conclusions
Our findings highlight the importance for health-care providers in Switzerland to pay special attention to possible drug-induced liver injuries due to 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 of different checkpoint inhibitors.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > General Medicine
Uncontrolled Keywords:General Medicine DILI Drug Induced Liver Injury
Language:English
Date:12 May 2021
Deposited On:31 Jan 2022 18:52
Last Modified:26 Jun 2024 01:51
Publisher:SMW supporting association
ISSN:1424-3997
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.4414/smw.2021.20503
PubMed ID:34000058
  • Content: Published Version
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)