title: Rivaroxaban postmarketing risk of liver injury.
abstract: OBJECTIVE
  Rivaroxaban is an oral direct factor Xa inhibitor that has been marketed worldwide since 2008 for the primary and secondary prevention and treatment of thromboembolic disorders. Although liver injury was observed in premarketing trials of rivaroxaban, there are no published postmarketing cases of liver injury associated with rivaroxaban.
  
  
  METHODS
  Report of 14 cases of liver injury associated with rivaroxaban, including two with liver biopsy, and search queries in three large international pharmacovigilance databases for comparable cases.
  
  
  RESULTS
  Formal causality assessment classified rivaroxaban as the "highly probable", "probable", and "possible" cause in 4, 7, and 3 patients, respectively. Search results from three large international pharmacovigilance databases revealed a considerable number of additional hepatic adverse events where rivaroxaban was reported as a suspected cause.
  
  
  CONCLUSIONS
  We interpret the presented information as a relevant safety signal that should be followed by pharmacoepidemiological studies in order to reliably estimate absolute and relative risks of liver injury associated with rivaroxaban in support of rational risk-benefit assessment. Meanwhile, incident symptoms and signs of liver disease in patients treated with rivaroxaban should be considered as a potential adverse drug reaction, and if no other likely cause can be identified rivaroxaban should be stopped as soon as possible.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. Electronic address: stefan.russmann@usz.ch.
authors.forename: Stefan
authors.initials: S
authors.lastname: Russmann
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: David F
authors.initials: DF
authors.lastname: Niedrig
authors.affiliation: Department of Surgery, Regional Hospital Lucerne-Sursee, Sursee, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Budmiger
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Institute of Pathology, Regional Hospital Lucerne, Lucerne, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hürlimann
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D065427:Factor Xa Inhibitors / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects*; D011358:Product Surveillance, Postmarketing; D012306:Risk; D000069552:Rivaroxaban; D013876:Thiophenes / Q000009:adverse effects*
chemical_list: D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban
keywords: Adverse drug reactions; Anticoagulants; Drug safety; Drug-induced liver injury; Factor Xa inhibitors; Hepatotoxicity; Pharmacovigilance; Postmarketing; Rivaroxaban