Top-ranking drugs out of 3312 drug-induced liver injury cases evaluated by the Roussel Uclaf Causality Assessment Method

ABSTRACT

Introduction: A list presenting a valid ranking of drugs most commonly implicated is hardly to be found.

Areas covered: Published cases of drug-induced liver injury (DILI) with verified causality using RUCAM (Roussel Uclaf Causality Assessment Method) were used for a ranking of drugs most commonly implicated in causing DILI.

Expert opinion: RUCAM-based DILI cases were retrieved from 15 reports published by six international databases of DILI registries and three large medical centers, which provided 3312 cases. Overall 48 drugs with the highest number of DILI cases were listed. Among the top 10 ranking drugs implicated in causing DILI were, in decreasing order: amoxicillin-clavulanate, flucloxacilllin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin, and anabolic steroids as bodybuilding agents. For these 10 drugs, respective DILI case numbers were highest for Amoxicillin-clavulanate (n=333) and lowest for anabolic steroids (n=26). The author classifies the databases of national DILI registries and large medical centers as best sources of drugs implicated in DILI. Presently discouraged is the use of the LiverTox website because many cases were derived from published cases of poor quality and could previously not be classified as DILI, calling for the inclusion of DILI cases with established causality by the updated RUCAM.

KEYWORDS:

• Drug-induced liver injury
• herb-induced liver injury
• Roussel Uclaf Causality Assessment Method
• alternative causes
• DILI registries
• clinical DILI centers

Acknowledgement

The author dedicates this article to Gaby Danan as an outstanding scientist, appreciating his pioneering work to establish RUCAM that is now used worldwide to falicitate causality assessment in suspected DILI and HILI cases.

Article highlights

• Among the top-ranking drugs implicated in causing DILI, in first place is amoxicillin-clavulanate, followed by flucloxacilllin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin, and finally anabolic steroids.

• High causality ranking was ascertained by using published DILI cases, which initially had been assessed for causality by RUCAM.

• These DILI cases have been retrieved from 15 reports presented by the databases of three medical centers located in different countries and six national DILI registries from various countries.

• The three centers and six registries provided highly qualified DILI cases and are considered as best sources for future studies related to DILI.

• Studies published 2 years ago tried to establish a valid top-ranking of drugs causing DILI, based on cases of the US NIH LiverTox database. However, in a large number of these cases, the diagnosis of DILI could not be verified.

• DILI is best diagnosed by a liver-specific CAM such as RUCAM, the worldwide most commonly applied diagnostic algorithm for causality assessment of DILI.

• Physicians, regulators, and administrators responsible for data quality of the NIH LiverTox are encouraged to include in their database the newly established drug listing and other RUCAM-based DILI cases.

• In addition, their RUCAM section requires an urgent actualization regarding the updated RUCAM version and RUCAM use, combined with the recommendation using the updated RUCAM more frequently as done in other countries worldwide.

• The author concludes that DILI is a fascinating clinical issue, requiring more attention and more stringent causality assessment, best achieved by RUCAM.

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Declaration of interest

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.