title: Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.
abstract: Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%.
  
  
  
  This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis.
  
  
  
  We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00).
  
  
  
  Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Donati
authors.affiliation: Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Conforti
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, 50139, Florence, Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Lenti
authors.affiliation: Department of Experimental Medicine, Second University of Neaples, via de Crecchio 7, 80138, Neaples, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capuano
authors.affiliation: Hospital Statistic Unit, University Hospital of Verona, p.le Aristide Stefani, 1, 37126, Verona, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Bortolami
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Motola
authors.affiliation: Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Moretti
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, 50139, Florence, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Vannacci
authors.affiliation: Department of Experimental Medicine, Second University of Neaples, via de Crecchio 7, 80138, Neaples, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Rafaniello
authors.affiliation: Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Vaccheri
authors.affiliation: Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Arzenton
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, 50139, Florence, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bonaiuti
authors.affiliation: Department of Experimental Medicine, Second University of Neaples, via de Crecchio 7, 80138, Neaples, Italy.
authors.forename: Liberata
authors.initials: L
authors.lastname: Sportiello
authors.affiliation: Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Leone
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000009:adverse effects; D007558:Italy / Q000453:epidemiology; D007660:Ketoprofen / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012306:Risk; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013449:Sulfonamides; D007660:Ketoprofen; C012655:nimesulide; D007052:Ibuprofen
keywords: DILI; NSAIDs; case-control study; liver injury; nimesulide