Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019
DOI:
https://doi.org/10.1590/s2175-97902023e21471Keywords:
COVID-19, Hepatotoxicity, Pharmacovigilance, Drug-drug interactionAbstract
Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.
Downloads
References
Abdel Galil SM. Hydroxychloroquine-induced toxic hepatitis in a patient with systemic lupus erythematosus: a case report. Lupus. 2015;24(6):638-640. doi:10.1177/0961203314561667.
» https://doi.org/10.1177/0961203314561667
Almenoff JS, Pattishall EN, Gibbs TG, DuMouchel W, Evans SJ, Yuen N. Novel statistical tools for monitoring the safety of marketed drugs. Clin Pharmacol Ther. 2007;82(2):157-66. doi: 10.1038/sj.clpt.6100258.
» https://doi.org/10.1038/sj.clpt.6100258
Bull-Otterson L, Gray EB, Budnitz DS, Strosnider HM, Schieber LZ, Courtney J, et al. Hydroxychloroquine and chloroquine prescribing patterns by provider specialty following initial reports of potential benefit for COVID-19 Treatment - United States, January-June 2020. MMWR. Morb Mortal Wkly Rep. 2020;69(35):1210-1215. https://doi.org/10.15585/mmwr.mm6935a4
» https://doi.org/10.15585/mmwr.mm6935a4
Campbell J. Important Safety Update - ACTEMRA (tocilizumab). A new important identified risk: Hepatoxicity. Internet Document: [3 pages], 7 May 2019. Available from: URL: https://medsafe.govt.nz/safety/DHCPLetters/ActemraMay2019.pdf
» https://medsafe.govt.nz/safety/DHCPLetters/ActemraMay2019.pdf
Carvalho T, Krammer F, Iwasaki A. The first 12 months of COVID-19: a timeline of immunological insights. Nat Rev Immunol. 2021;21(4):245-256. https://doi.org/10.1038/s41577-021-00522-1
» https://doi.org/10.1038/s41577-021-00522-1
Dias P, Penedones A, Alves C, Ribeiro CF, Marques FB. The role of disproportionality analysis of pharmacovigilance databases in safety regulatory actions: a systematic review. Curr Drug Saf. 2015;10(3):234-50. doi: 10.2174/15748863106 66150729112903.
» https://doi.org/10.2174/15748863106 66150729112903
European medicines agency conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring adressed to member states for remdesivir available for compassionate use (2020) European medicines agency conditions of use, conditions for distribution and patients targeted and conditions for safety monitoring adressed to member states for remdesivir available for compassionate use (2020) https://www.ema.europa.eu/en/documents/other/conditions-use-conditions-distribution-patients-targeted-conditions-safety-monitoring-adressed_en-2.pdf Accessed October 9, 2020.
European Medicines Agency. Summary on compassionate use; Remdesivir Gilead. https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf Published April 3, 2020. Accessed October 9, 2020.
» https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf
Faillie JL. Case-non-case studies: Principle, methods, bias and interpretation. Therapie. 2019;74(2):225-232. doi:org/10.1016/j.therap.2019.01.006.
» https://doi.org/10.1016/j.therap.2019.01.006
Falcão MB, Pamplona de Góes Cavalcanti L, Filgueiras Filho NM, Antunes de Brito CA. Case report: hepatotoxicity associated with the use of hydroxychloroquine in a patient with COVID-19. Am J Trop Med Hyg. 2020;102(6):1214-1216. doi:10.4269/ajtmh.20-0276.
» https://doi.org/10.4269/ajtmh.20-0276
Food And Drug Administration. FDA Adverse Event Reporting System (FAERS) Public Dashboard. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard Accessed August, 2020
Gatti M, Fusaroli M, Caraceni P, Poluzzi E, De Ponti F, Raschi E. Serious adverse events with tocilizumab: pharmacovigilance as an aid to prioritize monitoring in COVID-19 [published online ahead of print, July 8, 2020]. Br J Clin Pharmacol. 2021;87(3):1533-1440. doi: 10.1111/bcp.14459.
» https://doi.org/10.1111/bcp.14459
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A. Compassionate use of remdesivir for patients with severe covid-19 [published online ahead of print June 11, 2020]. N Engl J Med. 2020;382(24):2327-2336. doi:10.1056/NEJMoa2007016.
» https://doi.org/10.1056/NEJMoa2007016
Gulati A, Pomeranz C, Qamar Z, Thomas S, Frisch D, George G, et al. A comprehensive review of manifestations of novel coronaviruses in the context of deadly COVID-19 global pandemic. Am J Med Sci. 2020;360(1):5-34. doi:10.1016/j.amjms.2020.05.006
» https://doi.org/10.1016/j.amjms.2020.05.006
Health Canada. Important Safety Information on ACTEMRA (tocilizumab) - Risk of Hepatotoxicity. Internet Document: 21 May 2019. Available from: URL: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/69991a-eng.php
» https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/69991a-eng.php
Hepatotoxicity with tocilizumab: Canadian and NZ warnings. React Wkly. 2019;1755:2.
Kujawski SA, Wong KK, Collins JP, Epstein L, Killerby ME, Midgley CM, et al.. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat Med. 2020;26:861-868. https://doi.org/10.1038/s41591-020-0877-5
» https://doi.org/10.1038/s41591-020-0877-5
Lescure FX, Bouadma L, Nguyen D, Parisey M, Wicky PH, Behillil S. Clinical and virological data of the first cases of COVID-19 in Europe: a case series [published online ahead of print March 27, 2020]. Lancet Infect Dis. 2020. doi:10.1016/S1473-3099(20)30200-0.
» https://doi.org/10.1016/S1473-3099(20)30200-0
Li J, Fan JG. Characteristics and mechanism of liver injury in 2019 coronavirus disease. J Clin Transl Hepatol. 2020;8(1):13-17.
Lin WT, Hung SH, Lai CC, Wang CY, Chen CH. The effect of tocilizumab on COVID-19 patient mortality: A systematic review and meta-analysis of randomized controlled trials. Int Immunopharmacol. 2021;96:107602. doi: 10.1016/j.intimp.2021.107602. Epub ahead of print. PMID: 33812260; PMCID: PMC7988468.
» https://doi.org/10.1016/j.intimp.2021.107602
LiverTox: Hydroxychloroquine. Clinical and research information on drug-induced liver injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2012. https://www.ncbi.nlm.nih.gov/books/NBK548738/ Updated March 25, 2018. Accessed October 9, 2020.
» https://www.ncbi.nlm.nih.gov/books/NBK548738/
Marjot T, Webb GJ, Barritt AS, Moon AM, Stamataki Z, Wong VW, et al. COVID-19 and liver disease: mechanistic and clinical perspectives. Nat Rev Gastroenterol Hepatol. 2021;18(5):348-364. https://doi.org/10.1038/s41575-021-00426-4
» https://doi.org/10.1038/s41575-021-00426-4
McCarthy CP, Murphy S, Jones-O’Connor M, Olshan DS, Khambhati JR, Rehman S, et al. Early clinical and sociodemographic experience with patients hospitalized with COVID-19 at a large American healthcare system. EClinicalMedicine. [published online ahead of print August 19, 2020]. 2020;26:100504. doi.org/10.1016/j.eclinm.2020.100504
» https://doi.org/10.1016/j.eclinm.2020.100504
Melo JRR, Duarte EC, Moraes MV, Fleck K, Silva ASN, Arrais PSD. Reações adversas a medicamentos em pacientes com COVID-19 no Brasil: análise das notificações espontâneas do sistema de farmacovigilância brasileiro. Cadernos de Saúde Pública. 2021;37(1):e00245820. Epub January 22, 2021.https://doi.org/10.1590/0102-311x00245820
» https://doi.org/10.1590/0102-311x00245820
Michel C, Scosyrev E, Petrin M, Schmouder R. Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles? Clin Drug Investig. 2017;37(5):415-422. doi: 10.1007/s40261-017-0503-6.
» https://doi.org/10.1007/s40261-017-0503-6
Montastruc F, Thuriot S, Durrieu G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin Gastroenterol Hepatol. 2020;18(12):2835-2836. doi:10.1016/j.cgh.2020.07.050
» https://doi.org/10.1016/j.cgh.2020.07.050
Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Karem QA, et al. Repurposed antiviral drugs for Covid-19 - Interim WHO solidarity trial results. N Engl J Med . 2021;11:384 (6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2. PMID: 33264556; PMCID: PMC7727327.
» https://doi.org/10.1056/NEJMoa2023184
Santos-Pinto CDB, Miranda ES, Osorio-de-Castro CGS. “Kit-covid” and the popular pharmacy program in Brazil. Cad Saude Publica. 2021;22:37 (2):e00348020. English, Portuguese. doi: 10.1590/0102-311X00348020. PMID: 33624699.
» https://doi.org/10.1590/0102-311X00348020
Serviddio G, Villani R, Stallone G, Scioscia G, Foschino-Barbaro MP, Lacedonia D. (2020). Tocilizumab and liver injury in patients with COVID-19. Ther Adv Gastroenterol. 2020;13:1756284820959183. https://doi.org/10.1177/1756284820959183
» https://doi.org/10.1177/1756284820959183
Siemieniuk RA, Bartoszko JJ, Zeraatkar D, Kum E, Qasim A, Martinez JPD, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ [Internet]. 2020;370:2980.
Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis. 2004;38(2):S90-S97.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial [published online ahead of print April 19, 2020]. Lancet. 2020;395(10236):1569-1578. doi:10.1016/S0140-6736(20)31022-9.
» https://doi.org/10.1016/S0140-6736(20)31022-9
Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 2020;40(5):998‐1004. doi:10.1111/liv.14435.
» https://doi.org/10.1111/liv.14435
Yadav DK, Singh A, Zhang Q, Bai X, Zhang W, Yadav RK, et al. Involvement of liver in COVID-19: systematic review and meta-analysis. Gut. 2021;70(4):807-809.
Zhao D, Yao F, Wang L, Zheng L, Gao Y, Ye J, et al. A comparative study on the clinical features of COVID‐19 pneumonia to other pneumonias [published online ahead of print March 12, 2020]. Clin Infect Dis . 2020;71(15)756-761. doi:10.1093/cid/ciaa247.
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on line journal has open and free access.
