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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: February 10, 2018.



Rivaroxaban is a recently developed oral anticoagulant and direct factor Xa inhibitor which is used in the prevention of stroke and venous embolism in patients with chronic atrial fibrillation, as well as treatment and prevention of deep venous thromboses and pulmonary embolism. Rivaroxaban has been associated with a low rate of serum enzyme elevations during treatment and with rare instances of clinically apparent liver injury with jaundice.


Rivaroxaban (riv" a rox' a ban) is a selective inhibitor of factor Xa, the rate controlling last step in the generation of thrombin, the final intermediate in blood coagulation. Inhibiting thrombin prevents the conversion of fibrinogen to fibrin and subsequent cross linking of fibrin monomers, platelet activation and amplification of coagulation. Rivaroxaban has been shown to be as effective as warfarin in preventing stroke and systemic embolization in patients with atrial fibrillation, and to decrease the risk of deep vein thrombosis and pulmonary embolism in patients undergoing surgery. Rivaroxaban is orally available and provides a reliable anticoagulant effect for which monitoring of INR is not needed. Rivaroxaban was approved for use in the United States in 2011 and indications are for prevention of stroke and embolism in patients with chronic atrial fibrillation not related to valvular heart disease, as well as prevention and treatment of deep vein thrombosis and pulmonary embolism. Rivaroxaban is available in tablets of 10, 15 and 20 mg under the brand name Xarelto, and the recommended dose in adults is 10 to 20 mg once daily depending upon indication and renal function. Rivaroxaban, like other anticoagulants, is associated with bleeding adverse events (5% to 6%, major in ~1%), but these are no more frequent than with low molecular weight heparins or warfarin. Side effects not directly attributable to the anticoagulant activity of rivaroxaban are not common, but can include nausea, abdominal discomfort, back pain, anorexia, fever, and skin rash.


Chronic therapy with rivaroxaban is associated with moderate ALT elevations (greater than 3 times the upper limit of normal) in 1.5% to 3% of patients, an overall rate which is slightly lower than with low molecular weight heparins and similar to the rates with warfarin. During the large, prelicensure clinical trials of rivaroxaban, several instances of ALT elevations with jaundice occurred, but few details were provided and it was not clear whether the liver injury was clinically apparent. The cases were evidently mild and self-limited, resolving completely once therapy was stopped. Since its licensure and more wide scale use, rivaroxaban has been linked to many instances of acute liver injury with jaundice. The clinical features of these cases varied widely. Most cases had an onset within 1 to 8 weeks of starting rivaroxaban and presented with jaundice, fatigue and a hepatocellular pattern of serum enzyme elevations. In some individuals, a cholestatic or mixed pattern was found. Immunoallergic features and autoimmune markers were atypical but at least one case occurred with skin rash and fever suggestive of DRESS syndrome. One case of acute hepatic necrosis and death attributed to rivaroxaban has been reported, but ischemic hepatitis due to severe heart failure was a more likely cause of the acute liver failure. All other reported cases of rivaroxaban induced liver injury recovered upon stopping rivaroxaban, usually quite promptly, within 2 to 4 weeks.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of liver injury during rivaroxaban therapy is unknown, but is likely to be idiosyncratic and perhaps immunologic. Rivaroxaban is metabolized in the liver largely by CYP 3A4 and is susceptible to drug-drug interactions; inhibitors of CYP 3A4 (such as clarithromycin and itraconazole) can lead to increased levels, while inducers of CYP 3A4 (such as rifampin and phenytoin) can cause decreased and potential subtherapeutic drug levels.

Outcome and Management

Liver injury attributed to rivaroxaban varies from mild serum ALT elevations to liver injury with jaundice, but is usually mild to moderate in severity and self-limited, resolving within a few weeks of stopping. Convincing examples of acute liver failure, chronic hepatitis or vanishing bile duct syndrome due to rivaroxaban have not been reported in the published literature. Recurrence of liver injury with rechallenge has not been described, but should be expected to occur. There is no evidence or reason to suspect that there is cross sensitivity to hepatic injury among the different anticoagulants even with the other direct factor X inhibitors such as apixaban and edoxaban which appear to have a lower rate of hepatotoxicity.

Drug Class: Antithrombotic Agents, Anticoagulants

Other Drugs in the Subclass, Anticoagulants, Factor Xa Antagonists: Apixaban, Betrixaban, Edoxaban, Fondaparinux



Rivaroxaban – Xarelto®


Antithrombotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Rivaroxaban Chemical Structure


References updated: 10 February 2018

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    (67 year old man developed ALT elevations 6 months after starting rivaroxaban [peak ALT 391 U/L, Alk P 120 U/L, bilirubin 1.3 mg/dL], which fell into the normal range within 2 months of switching to apixaban; ultrasound suggested fatty liver which also resolved with stopping).
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    (71 year old man developed jaundice one month after starting rivaroxaban [bilirubin 3.5 rising to 13.2 mg/dL, ALT 141 U/L, Alk P 257 U/L], improving once rivaroxaban was stopped with normal values one month later).
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    (74 year old woman developed jaundice 1 month after knee arthroplasty and 14 day course of rivaroxaban [bilirubin 7.5 mg/dL, ALT 506 U/L, Alk P 332 U/L] with complete resolution in follow up one year later; no mention of antibiotic administration during surgery).
  • Christopoulou EC, Filippatos TD, Elisaf MS. Non-hemorrhage-related adverse effects of rivaroxaban. Arch Med Sci Atheroscler Dis 2017; 2: e108-e112. [PMC free article: PMC5777473] [PubMed: 29379891]
    (Review of non-hematologic adverse events from rivaroxaban including hepatobiliary effects with summaries of 28 cases in the literature).
  • Licata A, Puccia F, Lombardo V, Serruto A, Minissale MG, Morreale I, Giannitrapani L, Soresi M, Montalto G, Almasio PL. Rivaroxaban-induced hepatotoxicity: review of the literature and report of new cases. Eur J Gastroenterol Hepatol 2018; 30: 226-32. [PubMed: 29120909]
    (Review of 26 cases of suspected rivaroxaban induced liver injury from the literature and description of 2 new cases of elderly patients developing hepatocellular injury 7-8 weeks after starting rivaroxaban [bilirubin 21.8 mg/dL and not given, ALT 35 and 9 times ULN, Alk P 2 times and within ULN], both resolving rapidly within a month of stopping).


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