Hepatotoxicity risk factors and acetaminophen dose adjustment, do prescribers give this issue adequate consideration? A French university hospital study

  • Astrid Bacle
  • Charlotte Pronier
  • Helene Gilardi
  • Elisabeth Polard
  • Sophie Potin
  • Lucie-Marie ScailteuxEmail author
Pharmacoepidemiology and Prescription



The hepatotoxicity of acetaminophen is recognised worldwide. Unfavourable prognoses relating to overdose include liver transplantation and/or death. Several hepatotoxicity risk factors (HRFs) should motivate the adjustment of acetaminophen daily intake (to < 4 g/day): advanced age, weight < 50 kg, malnutrition, chronic alcoholism, chronic hepatitis B and C and HIV infection, severe chronic renal failure and hepatocellular insufficiency.


Over a 7-day period in Rennes University Hospital in December 2017, using DxCare® software, with an odds ratio estimation, we analysed all acetaminophen prescriptions, to assess to what extent the presence of HRFs altered the prescribers’ choice of acetaminophen dose (< 4 g/day versus 4 g/day).


Among 1842 patients, considering only the first acetaminophen prescription, 73.7% were on 4 g/day. Almost half this population had at least 1 HRF. Whereas around 80% of the prescriptions in the < 4 g/day group were for patients with at least 1 HFR, only 53% of the prescriptions in the 4 g/day group concerned patients without HFRs (p < 0.001). Age > 75 and low weight were associated with the prescriber’s choice of dose. Neither chronic alcoholism nor hepatocellular insufficiency influenced the acetaminophen doses prescribed.


Considering the widespread use of acetaminophen and its favourable safety profile compared with other analgesic drugs, it appears urgent to remind prescribers of the maximum daily dose recommendations for acetaminophen for patients with HRFs, especially those with chronic alcoholism and hepatocellular insufficiency.


Hepatotoxicity Acetaminophen Dose adjustment Risk factor 



Administrative, technical or material support was provided by Rennes Hospital University. We thank Jean-Paul Sinteff (Medical Information Departement, CHU Rennes) for the DxCare® software data extraction, and Adrien Turban, Anne-Sophie Michel, Justine Geffroy and Stephanie Ollivier for their help in the data collection.

Authors’ contribution

LMS and AB had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. SP, EP, LMS and AB were part of the study concept and design. All authors were a part in the acquisition, analysis or interpretation of data. Drafting of the manuscript was done by LMS. All authors took part in the critical revision of the manuscript for important intellectual content. LMS was a part in the statistical analysis.

Compliance with ethical standards

All data was collected in accordance with the French legislation on retrospective clinical studies, in accordance with the precepts established by the Helsinki declaration.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W (2017) 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila) 55:1072–1252. CrossRefGoogle Scholar
  2. 2.
    Guerlais M et al (2018) Abstracts of the Annual Meeting of French Society of Pharmacology and Therapeutics, and INSERM Clinical Research Centers (CIC) Meeting, 12-14 June 2018, Toulouse, France “Misuse of analgesics in the context of self-medication: resutls of a large cross-sectional survey from the DANTE study (une Décennie d’ANTalgiques en France) (CO-041). Fundam Clin Pharmacol 32:16.
  3. 3.
    Bernal W, Auzinger G, Dhawan A, Wendon J (2010) Acute liver failure. Lancet 376:190–201CrossRefGoogle Scholar
  4. 4.
    Hawton K, Bergen H, Simkin S, Dodd S, Pocock P, Bernal W, Gunnell D, Kapur N (2013) Long term effect of reduced pack sizes of paracetamol on poisoning deaths and liver transplant activity in England and Wales: interrupted time series analyses. BMJ 346:f403CrossRefGoogle Scholar
  5. 5.
    Gulmez SE, Larrey D, Pageaux G-P, Bernuau J, Bissoli F, Horsmans Y, Thorburn D, McCormick PA, Stricker B, Toussi M, Lignot-Maleyran S, Micon S, Hamoud F, Lassalle R, Jové J, Blin P, Moore N (2015) Liver transplant associated with paracetamol overdose: results from the seven-country SALT study. Br J Clin Pharmacol 80:599–606CrossRefGoogle Scholar
  6. 6.
    Vale JA, Proudfoot AT (1995) Paracetamol (acetaminophen) poisoning. Lancet 346:547–552CrossRefGoogle Scholar
  7. 7.
    Bateman DN (2015) Paracetamol poisoning: beyond the nomogram. Br J Clin Pharmacol 80:45–50CrossRefGoogle Scholar
  8. 8.
    Rumack BH, Bateman DN (2012) Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol (Phila) 50:91–98CrossRefGoogle Scholar
  9. 9.
    Lee WM (2017) Acetaminophen (APAP) hepatotoxicity-Isn’t it time for APAP to go away? J Hepatol 67:1324–1331CrossRefGoogle Scholar
  10. 10.
    Twycross R, Pace V, Mihalyo M, Wilcock A (2013) Acetaminophen (paracetamol). J Pain Symptom Manag 46:747–755CrossRefGoogle Scholar
  11. 11.
    Caparrotta TM, Antoine DJ, Dear JW (2018) Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature. Eur J Clin Pharmacol 74:147–160CrossRefGoogle Scholar
  12. 12.
    (2018) What dose of paracetamol for older people? Drug Ther Bull 56:69–72.
  13. 13.
    Schena FP (2011) Management of patients with chronic kidney disease. Intern Emerg Med 6(Suppl 1):77–83CrossRefGoogle Scholar
  14. 14.
    Blantz RC (1996) Acetaminophen: acute and chronic effects on renal function. Am J Kidney Dis 28:S3–S6CrossRefGoogle Scholar
  15. 15.
    Larrey D (2006) Is there a risk to prescribe paracetamol at therapeutic doses in patients with acute or chronic liver disease? Gastroenterol Clin Biol 30:753–755CrossRefGoogle Scholar
  16. 16.
    Bunchorntavakul C, Reddy KR (2013) Acetaminophen-related hepatotoxicity. Clin Liver Dis 17:587–607 viiiCrossRefGoogle Scholar
  17. 17.
    Kurtovic J, Riordan SM (2003) Paracetamol-induced hepatotoxicity at recommended dosage. J Intern Med 253:240–243CrossRefGoogle Scholar
  18. 18.
    Eriksson LS, Broomé U, Kalin M, Lindholm M (1992) Hepatotoxicity due to repeated intake of low doses of paracetamol. J Intern Med 231:567–570CrossRefGoogle Scholar
  19. 19.
    Krähenbuhl S, Brauchli Y, Kummer O et al (2007) Acute liver failure in two patients with regular alcohol consumption ingesting paracetamol at therapeutic dosage. Digestion 75:232–237CrossRefGoogle Scholar
  20. 20.
    Forget P, Wittebole X, Laterre P-F (2009) Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of risk factors: a report of two cases. Br J Anaesth 103:899–900CrossRefGoogle Scholar
  21. 21.
    Claridge LC, Eksteen B, Smith A, Shah T, Holt AP (2010) Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults. BMJ 341:c6764CrossRefGoogle Scholar
  22. 22.
    Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC (2006) Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 296:87–93CrossRefGoogle Scholar
  23. 23.
    Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC (2014) A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol 15:39CrossRefGoogle Scholar
  24. 24.
    Agence Nationale d’Accréditation et d’Évaluation en Santé (ANAES) (2000) Evaluation et prise en charge thérapeutique de la douleur chez les personnes âgées ayant des troubles de la communication verbale -
  25. 25.
    Haute Autorité de Santé (2007) Surveillance des malades atteints de cirrhose non compliquée et prévention primaire des complications - Recommandations -
  26. 26.
    Agence française de sécurité sanitaire des produits de santé (AFSSAPS) (2011) Prise en charge des douleurs de l’adulte modérées à intenses. In: Recommandations après le retrait des associations dextropropoxyphène/paracétamol et dextropropoxyphène/paracétamol/caféineGoogle Scholar
  27. 27.
    Arques-Armoiry E, Cabelguenne D, Stamm C, Janoly-Dumenil A, Grosset-Grange I, Vantard N, Maire P, Charpiat B (2010) Most frequent drug-related events detected by pharmacists during prescription analysis in a university hospital. Rev Med Interne 31:804–811CrossRefGoogle Scholar
  28. 28.
    Zhou L, Maviglia SM, Mahoney LM, Chang F, Orav EJ, Plasek J, Boulware LJ, Lou H, Bates DW, Rocha RA (2012) Supratherapeutic dosing of acetaminophen among hospitalized patients. Arch Intern Med 172:1721–1728CrossRefGoogle Scholar
  29. 29.
    Charpiat B, Henry A, Leboucher G, Tod M, Allenet B (2012) Overdosed prescription of paracetamol (acetaminophen) in a teaching hospital. Ann Pharm Fr 70:213–218CrossRefGoogle Scholar
  30. 30.
    Viguier F, Roessle C, Zerhouni L, Rouleau A, Benmelouka C, Chevallier A, Chast F, Conort O (2016) Clinical pharmacist influence at hospital to prevent overdosed prescription of acetaminophen. Ann Pharm Fr 74:482–488CrossRefGoogle Scholar
  31. 31.
    Pace J-B, Nave V, Moulis M, Bourdelin M, Coursier S, Jean-Bart É, Leroy B, Bonnefous JL, Bontemps H, Coutet J, Eyssette C, Pont E (2017) Prescription of acetaminophen in five French hospitals: what are the practices? Therapie 72:579–586CrossRefGoogle Scholar
  32. 32.
    Wynne HA, Cope LH, Herd B et al (1990) The association of age and frailty with paracetamol conjugation in man. Age Ageing 19:419–424CrossRefGoogle Scholar
  33. 33.
    Mitchell SJ, Hilmer SN, Murnion BP, Matthews S (2011) Hepatotoxicity of therapeutic short-course paracetamol in hospital inpatients: impact of ageing and frailty. J Clin Pharm Ther 36:327–335CrossRefGoogle Scholar
  34. 34.
    Liukas A, Kuusniemi K, Aantaa R, Virolainen P, Niemi M, Neuvonen PJ, Olkkola KT (2011) Pharmacokinetics of intravenous paracetamol in elderly patients. Clin Pharmacokinet 50:121–129CrossRefGoogle Scholar
  35. 35.
    Yan J, Li S, Li S (2014) The role of the liver in sepsis. Int Rev Immunol 33:498–510CrossRefGoogle Scholar
  36. 36.
    Koehne de Gonzalez AK, Lefkowitch JH (2017) Heart disease and the liver: Pathologic Evaluation. Gastroenterol Clin North Am 46:421–435CrossRefGoogle Scholar
  37. 37.
    Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) (2018) Thésaurus des interactions médicamenteuses - mise à jour mars 2018Google Scholar
  38. 38.
    Leise MD, Poterucha JJ, Talwalkar JA (2014) Drug-induced liver injury. Mayo Clin Proc 89:95–106CrossRefGoogle Scholar
  39. 39.
    Fisher K, Vuppalanchi R, Saxena R (2015) Drug-induced liver injury. Arch Pathol Lab Med 139:876–887CrossRefGoogle Scholar
  40. 40.
    Hawkins LC, Edwards JN, Dargan PI (2007) Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature. Drug Saf 30:465–479CrossRefGoogle Scholar
  41. 41.
    Krenzelok EP (2009) The FDA Acetaminophen Advisory Committee meeting - what is the future of acetaminophen in the United States? The perspective of a committee member. Clin Toxicol (Phila) 47:784–789CrossRefGoogle Scholar
  42. 42.
    Federal Drug Agency (FDA) Prescription drug products containing acetaminophen: actions to reduce liver injury from unintentional overdose. Notice Document. Accessed 10 Sep 2018
  43. 43.
    Federal Drug Agency (FDA) FDA Drug Safety Communication:[1-13-2011] prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure Accessed 10 Sep 2018
  44. 44.
    Paracétamol : l’ANSM lance une consultation publique pour sensibiliser les patients et les professionnels de santé au risque de toxicité pour le foie en cas de mésusage - Point d’Information - ANSM : Agence nationale de sécurité du médicament et des produits de santé. Accessed 10 Sep 2018
  45. 45.
    Résumé des caractéristiques du produit - Paracétamol Teva 1g, comprimé. Accessed 10 Sept 2018
  46. 46.
    Résumé des caractéristiques du produit - Paracétamol Codéine EG 500 mg/ 30 mg, comprimé effervescent sécable. Accessed 10 Sept 2018
  47. 47.
    Résumé des caractéristiques du produit - Paracétamol Zydus 500 mg, gélule. Accessed 10 Sept 2018
  48. 48.
    Résumé des caractéristiques du produit - Paracétamol AHCL 1g, comprimé effervescent. (page consultée le 17/01/2019). Accessed 17 Jan 2019
  49. 49.
    Résumé des caractéristiques du produit - Doliprane 100 mg, comprimé. (page consultée le 17/01/2019). Accessed 17 Jan 2019

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmacy DepartmentCHU RennesRennesFrance
  2. 2.Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085RennesFrance
  3. 3.Virology DepartmentCHU PontchaillouRennesFrance
  4. 4.Pharmacovigilance and Pharmacoepidemiology Centre, Pharmacology DepartmentCHU RennesRennesFrance
  5. 5.Univ Rennes, REPERES ([Pharmacoepidemiology and Heath Services Research]) - EA 7449RennesFrance

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