gms | German Medical Science

Background: Liver impairment, liver cirrhosis and hepatic insufficiency are terms used to describe liver disease in Summaries of Product Characteristics (SmPCs) and Prescribing Information (PI) as an important medical condition that can cause alterations in drug disposition, susceptibility to drug toxicities and with that increase the risk of adverse drug reactions [1], [2]. Since alterations in liver function are a common health disorder worldwide, many drugs require monitoring, dose adjustment or relative and absolute contraindications on the subject of liver disease. European SmPCs and American PI should therefore be comprehensible to prescribers regarding their liver-associated contraindications to ensure safe prescribing. Various studies pointed out inconsistencies and information deficits in liver-related prescribing recommendations [1], [2], [3]. Still unclear is, which terms used in SmPCs/PI describing absolute contraindications on liver-related conditions are best suited to ensure safe prescribing in clinical practice. The objective of this study was to analyze liver-related contraindications in SmPCs/PI of representative, commonly prescribed drugs in major drug markets (Germany (DE), Switzerland (CH), United Kingdom (UK), and United States (US)) in the context of consistency and clinical comprehensibility for prescribers as well as usability in clinical decision support systems (CDSS) via standardized codes. Our intention was to point out common but unclear terms as a basis and an incentive for editing or clarification that leads to standardized definitions of contraindications in future SmPC/PI guidelines, so as to enhance safe medication prescribing and to facilitate the integration of this information in CDSS.

Materials and Methods: 280 SmPCs/PI of commonly prescribed drugs of the inpatient and outpatient sector, available on the German, Swiss, British and American drug market were analyzed regarding liver-related absolute contraindications found in section 4.3 “contraindications” in SmPCs and “contraindications” in US PI. Liver-related terms and wordings used for absolute contraindications were tabulated and assigned to categories in respect of their definition. All terms belonging to one category were then evaluated for unambiguity and clarity with an assessment system of three grades of explicitness (Grade I: explicit; Grade II: understandable, but still room for interpretation; Grade III: unclear wording). Further all terms of one category were assessed regarding their codability based on the evaluation system published by Then et al. [4]. In our analysis this was comprised of four categories: Simple codability, complex codability, not codable and partially codable.

Results: 228 out of 280 SmPCs/PI contained liver-related contraindications. The categories with the most SmPCs/PI, that contained their associated expressions, were “hepatic impairment” (n = 108, 47%), “liver disease” (n = 57, 25%), and “liver insufficiency” (n = 52, 23%), whereas the fewest SmPCs/PI were found with expressions for the categories “albumin” (n = 4, 2%), “ascites” (n = 5, 2%), and “hepatitis” (n = 8, 4%). This ranking overall was largely consistent for all drug markets for the amount of SmPCs/PI that were most often assigned with the respective categories of “hepatic impairment”, “liver disease”, “liver insufficiency” and “liver cirrhosis”. Further, our study findings show that out of the 280 SmPCs/PI containing liver-related contraindications, 75% (n = 171) of SmPCs/PI contained unclear wording as indicated by Grade III of clarity in our assessment system. Only 42% (n = 96) of SmPCs/PI included terms with explicit wording as indicated by Grade I in our assessment system. When evaluating the codability of SmPCs/PI assigned to the respective categories, 95% (n = 217) of SmPCs/PI contained not codable expressions. Only 21% (n = 47) and 18% (n = 41) of SmPCs/PI included expressions that could be transferred to simple codes and complex codes, respectively.

Conclusion: Liver-related contraindications still require improvement in the explicitness of used terms and wording to improve clarity, codability and therefore safety of drug prescription. Including more precise statements in SmPCs/PI utilizing laboratory parameters (such as albumin) or scores (e.g., the Child-Pugh score) to objectify the severity of liver disease may increase unambiguousness for prescribers and usability for CDSS.

Parts of these results have been previously published [5].

The work on information deficits in liver-related contraindications performed within the overarching use case of the German Medical Informatics Initiative “POLAR_MI – POLypharmacy, Drug interActions, Risks” – is supported by the Federal Ministry of Education and Research (BMBF) (Funding numbers 01ZZ1910C and 01ZZ1910O).