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

Abstract

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.

A new framework for advancing in drug‐induced liver injury research. The Prospective European DILI Registry

“…It constituted 8.6% of the cases induced by single prescription drugs, compared with only 0.9% in the DILIN study (4). Atorvastatin and simvastatin hepatotoxicity have been reported to be of similar frequency (26,34), but atorvastatin appears to cause DILI more frequently than simvastatin in more recent studies (35,36). Another discrepancy between causes of DILI in the US and Europe was the low frequency of azithromycin in the current study with only 2 cases (0.8%) vs. 2% in the DILIN study (4).…”

“…7 Atorvastatin and simvastatin hepatotoxicity have been reported to be of similar frequency, 26,34 but atorvastatin appears to cause DILI more frequently than simvastatin in more recent studies. 35,36 Another discrepancy between causes of DILI in the United…”

Acute Methotrexate Toxicity under Low Dose Therapy

“…Based on the documented ALT and AP values of the patient three days after the administration of MTX, an R value of 3.3 was calculated, which is indicative of a mixed pattern liver injury. Drug-induced liver injuries are most frequently reported as adverse drug reactions (ADRs) with paracetamol, esomeprazole, amoxicillin/clavulanic acid and atorvastatin [58].…”

Acute Methotrexate Toxicity under Low Dose Therapy: A Case of Synergistic Pharmacokinetic and Pharmacodynamic Interactions

“…Based on the documented ALT and AP values of the patient three days after the administration of MTX, an R value of 3.3 was calculated, which is indicative of a mixed pattern liver injury. Drug-induced liver injuries are most frequently reported as adverse drug reactions (ADRs) with paracetamol, esomeprazole, amoxicillin/clavulanic acid and atorvastatin [65].…”