Trends in reporting drug-associated liver injuries in Taiwan: a focus on amiodarone

Abstract

Background A pharmacovigilance database of real-world adverse drug reaction (ADR) reports is helpful for characterising adverse events and identifying new signals after drug approval. Objective This study aimed to analyse trends of ADR reporting in relation to liver injury and to delineate critical factors for suspected drug-related hepatotoxicity with a focus on reports associated with amiodarone. Setting The 2000-2014 Taiwan pharmacovigilance database. Method Relevant Standardized Medical Dictionary for Regulatory Activities queries were used to identify reports associated with liver injury. Information on ADR, patient characteristics, and the verbatim pertaining to amiodarone prescriptions, liver injury, comedications, and comorbidities were extracted and evaluated. Group comparisons between Hy's Law cases and Temple's Corollary cases of suspected amiodarone-related hepatotoxicity were performed. Main outcome measure Number and nature of drug-related liver injuries, particularly those associated with amiodarone. Results Of the 98,777 ADR reports over a 15-year period, 4261 (4.3%) were related to liver injury. Sixty-eight reports contained amiodarone prescriptions, but only 49 (1.1%) were eligible for further analysis. Hepatotoxic cases associated with amiodarone mostly occurred within 1 week, exhibited a hepatocellular pattern, and were more common among elderly individuals. Among 23 discernible cases, four (17.4%) recovered fully from liver injury. The critical Hy's Law cases were associated with shorter height, lower body surface area, and higher average daily doses. Conclusion This study substantiates the importance of ADR reporting. Data pertaining to drug-associated liver injury and factors associated with suspected amiodarone-related hepatotoxicity warrants continual attention in pharmacovigilance for those at risk, especially the elderly.

The Advantages and Challenges of Using Real‐World Data for Patient Care

“…Nonetheless, solid evidence for elusive intangible drug covariates associated with either therapeutic or toxic effects are often not readily available upon regulatory approval. It is valuable to perform studies with RWD from real settings, as demonstrated in Table 1 , to supplement awaited determinants of drug effects for clinical decision making. By health record (electronic and paper) review, nephrotoxic polypharmacy exhibited a significant association with contrast medium–induced nephropathy among inpatients undergoing contrast‐enhanced computed tomography.…”

“…By health record (electronic and paper) review, nephrotoxic polypharmacy exhibited a significant association with contrast medium–induced nephropathy among inpatients undergoing contrast‐enhanced computed tomography. Through investigations of health records and postmarketing surveillance data, drug dispositions (interacting drugs, amiodarone cumulative dose, and adjusted average daily dose) and host factors (shorter height and smaller body surface area) were reported to be important predictors of amiodarone‐related liver injury. Studies of health claims helped identify the inverse associations between dose intensity (bisphosphonates or statins) and the likelihood of unintended risk (esophageal cancer or poststroke epilepsy).…”

“…Second, the health claims (e.g., Taiwan National Health Insurance Research Database; US Surveillance, Epidemiology, and End Results; and UK General Practice Research Database) as an important source of secondary data are usually population based, longitudinally collected, and structurally constructed. The huge sizes of such data facilitate efficient data analyses and make certain subgroup evaluations possible . Unfortunately, health claims have inherent limitations, such as discrepancy between claims data and real‐life behaviors (e.g., true adherence), inadequate clinical information (e.g., proximity of surrogates to actual disease status), uncertainty in causality, lack of laboratory and body image data, and potentially inconsistent data quality between tertiary and primary care practices.…”

“…Methodic study flow (e.g., appropriate inclusion and exclusion criteria), objective outcome measures, and serial sensitivity analyses are surely required . Third, postmarket spontaneous reporting of ADRs has the merit of identifying effectively new or rare signals . However, the aforementioned limitations of health claims are also applicable to studies using ADR registries.…”

“…The paradigm of drug discovery and development has gradually been shifted from a linear process to an integrated (circular or cyclic) approach by linking reciprocally earlier stages of discovery to later stages of clinical development and postlicensure practice evidence . Likewise, drug‐associated intangible factors relevant to clinical therapeutics could also be collectively uncovered from the beginning of drug discovery to preclinical assessment, various phases of clinical trials, and RWD data from healthcare services (e.g., health records, administrative health claims, and disease registry), and postmarketing surveillance (e.g., ADR reporting).…”