Trends in reporting drug-associated liver injuries in Taiwan: a focus on amiodarone
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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.
KeywordsAdverse drug reactions Amiodarone Hepatotoxicity MedDRA-coded database Pharmacovigilance Taiwan
The authors thank Dr. Fu-Chang Hu, M.S., Sc.D., for the helpful statistical discussions.
The study was supported by a research grant from the National Science Council (NSC 102-2320-B-002-005), Taiwan, R.O.C.
Conflicts of interest
The authors have no conflicts of interest to declare.
- 5.Middleton RK. Adverse drug reactions. In: Allen LV, editor. Remington: the science and practice of pharmacy, vol. 2. 21st ed. London: Pharmaceutical Press; 2013. p. 2013–22.Google Scholar
- 7.Bahri P, Arlett P. Regulatory pharmacovigilance in the European Union. In: Andrews EB, Moore N, editors. Mann’s pharmacovigilance. 3rd ed. Chichester: Wiley; 2014. p. 173–84.Google Scholar
- 8.Andrews EB, Moore N, editors. Mann’s pharmacovigilance. 3rd ed. Chichester: Wiley; 2014.Google Scholar
- 9.Taiwan National Adverse Drug Reactions Reporting System. http://adr.fda.gov.tw.
- 15.Watkins PB, Desai M, Berkowitz SD, Peters G, Horsmans Y, Larrey D, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf. 2011;34(3):243–52.CrossRefPubMedGoogle Scholar
- 19.Cordarone® (amiodarone HCl) tablets package insert (Cordarone, revised March 27, 2015). http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018972s047lbl.pdf.
- 20.US Food and Drug Administration. Medication guide: amiodarone HCl. Washington, DC: US Food and Drug Administration, 2004. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018972s038s039lbl.pdf.
- 24.Serviddio G, Bellanti F, Giudetti AM, Gnoni GV, Capitanio N, Tamborra R, Romano AD, Quinto M, Blonda M, Vendemiale G, Altomare E. Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration. Free Radic Biol Med. 2011;51(12):2234–42.CrossRefPubMedGoogle Scholar
- 26.Chao P-H, Huang C-Y, Chen W-W. An analysis on 2015 post-marketing spontaneous reports of adverse drug reactions. Drug Saf Newsl. 2016;53:10–8 (in Chinese).Google Scholar
- 27.Medical Dictionary for Regulatory Activities (MedDRA®). http://www.meddra.org/about-meddra/organisation/msso.
- 28.WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment, 2013. Oslo, Norway: Institute of Public Health, 2012. http://www.whocc.no/filearchive/publications/1_2013guidelines.pdf.
- 29.International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Introductory Guide for Standardised MedDRA Queries (SMQs) Version 18.0. https://www.meddra.org/software-packages, 2015.
- 31.European Commission in consultation with the European Medicines Agency. Volume 9. Pharmacovigilance: medicinal products for human use and veterinary medicinal products. http://ec.europa.eu/DocsRoom/document/2809/attachments/l/translations/en/renditions/pdf. Accessed 27 June 2018.
- 33.Thomson Reuters Healthcare. Micromedex computerized clinical information system. Micromedex website, 2015. micromedex.com. Accessed 5 Aug 2015.Google Scholar
- 34.Guo T, Gelperin K, Senior J. A tool to help you decide (detect potentially serious liver injury). US Food and Drug Association, 2008. http://www.fda.gov/downloads/Drugs/ScienceResearch/%20ResearchAreas/ucm076777.pdf.
- 40.Drug-induced livery injury: premarketing clinical evaluation. Guidance for industry. US Food and Drug Administration, 2009. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory.
- 43.Zimmerman HJ. Drugs used in cardiovascular disease. In: Zimmerman HJ, editor. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999. p. 639–71.Google Scholar
- 47.Farrell GC. Drug-induced steatohepatitis. In: Farrell GD, editor. Drug-induced liver disease. Edinburge: Churchill Livingstone; 1994. p. 431–8.Google Scholar