International Journal of Clinical Pharmacy

, Volume 40, Issue 4, pp 911–920 | Cite as

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

  • Jun-Hong Ye
  • Yunn-Fang HoEmail author
  • Angela W.-F. On
  • Wen-Wen Chen
  • Yen-Ming Huang
  • Wei-I. Huang
  • Yun-Wen Tang
Research Article


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.


Adverse 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.


  1. 1.
    Manasse HR Jr. Medication use in an imperfect world: drug misadventuring as an issue of public policy, part 1. Am J Hosp Pharm. 1989;46(5):929–44.PubMedGoogle Scholar
  2. 2.
    Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG, et al. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. N Engl J Med. 1991;324(6):370–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med. 1995;155(18):1949–56.CrossRefPubMedGoogle Scholar
  4. 4.
    Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9.CrossRefPubMedGoogle Scholar
  5. 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
  6. 6.
    Vlahović-Palčevski V, Mentzer D. Postmarketing surveillance. Handb Exp Pharmacol. 2011;205:339–51.CrossRefPubMedGoogle Scholar
  7. 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. 8.
    Andrews EB, Moore N, editors. Mann’s pharmacovigilance. 3rd ed. Chichester: Wiley; 2014.Google Scholar
  9. 9.
    Taiwan National Adverse Drug Reactions Reporting System.
  10. 10.
    On AW-F, Chih LH, Liu C, Lin KH, Huang YW, Tai HY, et al. A unique drug-injury relief system in Taiwan: comparing drug-injury compensation in different countries. J Pharm Health Serv Res. 2012;3(1):3–9.CrossRefGoogle Scholar
  11. 11.
    Björnsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol. 2015;89(3):327–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Licata A. Adverse drug reactions and organ damage: the liver. Eur J Intern Med. 2016;28:9–16.CrossRefPubMedGoogle Scholar
  13. 13.
    Lewis JH. The art and science of diagnosing and managing drug-induced liver injury in 2015 and beyond. Clin Gastroenterol Hepatol. 2015;13(12):2173-89.e8.CrossRefPubMedGoogle Scholar
  14. 14.
    Senior JR. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf. 2014;37(Suppl 1):S9–17.CrossRefPubMedGoogle Scholar
  15. 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
  16. 16.
    Temple R. Hy’s Law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15(4):241–3.CrossRefPubMedGoogle Scholar
  17. 17.
    Shen X, Yuan Z, Mei J, Zhang Z, Guo J, Wu Z, et al. Anti-tuberculosis drug-induced liver injury in Shanghai: validation of Hy’s Law. Drug Saf. 2014;37(1):43–51.CrossRefPubMedGoogle Scholar
  18. 18.
    Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58(1):388–96.CrossRefPubMedGoogle Scholar
  19. 19.
    Cordarone® (amiodarone HCl) tablets package insert (Cordarone, revised March 27, 2015).
  20. 20.
    US Food and Drug Administration. Medication guide: amiodarone HCl. Washington, DC: US Food and Drug Administration, 2004.
  21. 21.
    Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis. 2006;38(1):33–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Nasser M, Larsen TR, Waanbah B, Sidiqi I, McCullough PA. Hyperacute drug-induced hepatitis with intravenous amiodarone: case report and review of the literature. Drug Healthc Patient Saf. 2013;5:191–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hussain N, Bhattacharyya A, Prueksaritanond S. Amiodarone-induced cirrhosis of liver: what predicts mortality? ISRN Cardiol. 2013;2013:617943.PubMedPubMedCentralGoogle Scholar
  24. 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
  25. 25.
    Lu J, Jones AD, Harkema JR, Roth RA, Ganey PE. Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: role of tumor necrosis factor-alpha. Toxicol Sci. 2012;125(1):126–33.CrossRefPubMedGoogle Scholar
  26. 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. 27.
    Medical Dictionary for Regulatory Activities (MedDRA®).
  28. 28.
    WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment, 2013. Oslo, Norway: Institute of Public Health, 2012.
  29. 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., 2015.
  30. 30.
    Iasella CJ, Johnson HJ, Dunn MA. Adverse drug reactions: type A (intrinsic) or type B (idiosyncratic). Clin Liver Dis. 2017;21(1):73–87.CrossRefPubMedGoogle Scholar
  31. 31.
    European Commission in consultation with the European Medicines Agency. Volume 9. Pharmacovigilance: medicinal products for human use and veterinary medicinal products. Accessed 27 June 2018.
  32. 32.
    Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ, et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950–66.CrossRefPubMedGoogle Scholar
  33. 33.
    Thomson Reuters Healthcare. Micromedex computerized clinical information system. Micromedex website, 2015. Accessed 5 Aug 2015.Google Scholar
  34. 34.
    Guo T, Gelperin K, Senior J. A tool to help you decide (detect potentially serious liver injury). US Food and Drug Association, 2008.
  35. 35.
    Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol. 2015;63(2):503–14.CrossRefPubMedGoogle Scholar
  36. 36.
    Björnsson ES. Epidemiology and risk factors for idiosyncratic drug-induced liver injury. Semin Liver Dis. 2014;34(2):115–22.CrossRefPubMedGoogle Scholar
  37. 37.
    Robles-Díaz M, Medina-Caliz I, Stephens C, Andrade RJ, Lucena MI. Biomarkers in DILI: one more step forward. Front Pharmacol. 2016;7:267.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Greene N, Fisk L, Naven RT, Note RR, Patel ML, Pelletier DJ. Developing structure-activity relationships for the prediction of hepatotoxicity. Chem Res Toxicol. 2010;23(7):1215–22.CrossRefPubMedGoogle Scholar
  39. 39.
    Chen M, Vijay V, Shi Q, Liu Z, Fang H, Tong W. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today. 2011;16(15–16):697–703.CrossRefPubMedGoogle Scholar
  40. 40.
    Drug-induced livery injury: premarketing clinical evaluation. Guidance for industry. US Food and Drug Administration, 2009.
  41. 41.
    Regev A, Björnsson ES. Drug-induced liver injury: morbidity, mortality, and Hy’s law. Gastroenterology. 2014;147(1):20–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Lewis JH, Ranard RC, Caruso A, Jackson LK, Mullick F, Ishak KG, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology. 1989;9(5):679–85.CrossRefPubMedGoogle Scholar
  43. 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
  44. 44.
    Rizzioli E, Incasa E, Gamberini S, Savelli S, Zangirolami A, Tampieri M. Acute toxic hepatitis after amiodarone intravenous loading. Am J Emerg Med. 2007;25(9):1082.e1-4.CrossRefPubMedGoogle Scholar
  45. 45.
    Verhovez A, Elia F, Riva A, Ferrari G, Aprà F. Acute liver injury after intravenous amiodarone: a case report. Am J Emerg Med. 2011;29(7):843.e5-6.CrossRefPubMedGoogle Scholar
  46. 46.
    Pirovino M, Müller O, Zysset T, Honegger U. Amiodarone-induced hepatic phospholipidosis: correlation of morphological and biochemical findings in an animal model. Hepatology. 1988;8(3):591–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Farrell GC. Drug-induced steatohepatitis. In: Farrell GD, editor. Drug-induced liver disease. Edinburge: Churchill Livingstone; 1994. p. 431–8.Google Scholar
  48. 48.
    Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.CrossRefPubMedGoogle Scholar
  49. 49.
    Thiessard F, Roux E, Miremont-Salamé G, Fourrier-Réglat A, Haramburu F, Tubert-Bitter P, et al. Trends in spontaneous adverse drug reaction reports to the French pharmacovigilance system (1986–2001). Drug Saf. 2005;28(8):731–40.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Jun-Hong Ye
    • 1
    • 2
  • Yunn-Fang Ho
    • 1
    • 3
    Email author
  • Angela W.-F. On
    • 1
    • 4
  • Wen-Wen Chen
    • 4
  • Yen-Ming Huang
    • 1
  • Wei-I. Huang
    • 4
  • Yun-Wen Tang
    • 2
  1. 1.Graduate Institute of Clinical Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.National Taiwan University HospitalTaipeiTaiwan
  3. 3.School of Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  4. 4.Taiwan National ADR Reporting CenterTaiwan Drug Relief FoundationTaipeiTaiwan

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