Anticoagulants: interactions with dabigatran, rivaroxaban and apixaban

Use these 3 tables to minimise the risk of metabolic, drug–drug, and food/alcohol or antacid interactions with the newer anticoagulants.

Practice points

  • The newer anticoagulants differ in their uptake, metabolism and excretion (see Table 1) and hepatic or renal impairment which may increase the potential for drug interactions.
  • Some interactions have been formally studied, others are theoretical and clinical experience is limited.
  • There are known and important drug interactions between the newer oral anticoagulants and medicines that are CYP3A4 or P-glyocoprotein inhibitors or inducers (see Table 2).
  • Some medicines are contraindicated with the newer oral anticoagulants – avoid concomitant use (see Table 2).
  • Avoid, when possible, concomitant use of medicines that are recommended to be used with caution with one of the newer oral anticoagulants (Table 2). Consider an alternative medicine, particularly in patients with renal and/or hepatic impairment or seek specialist advice.
  • Medicines that interfere with platelet function, e.g. antiplatelets such as aspirin or clopidogrel and fish oils or medicines that cause injury to gastrointestinal mucosa, e.g. aspirin or other NSAIDs, may increase the risk of bleeding (see Table 2).
  • Food, alcohol and antacids affect newer anticoagulants in different ways (see Table 3).
  • Unlike warfarin, the newer oral anticoagulants currently have no validated and readily available test to confirm under- or over- anticoagulation or to monitor the effects of drug interactions.
  • Monitor patients taking anticoagulants closely for signs and symptoms of bleeding and thromboembolism (see Anticoagulant Safety Checklist).
  • Remind patients to check with their doctor or pharmacist before starting, stopping or changing doses of any medicines (including prescription, over-the-counter or complementary medicines).
  • Report any suspected drug interactions to the TGA

Table 1: Metabolism of newer oral anticoagulants and use in hepatic impairment1-3,7

Drug metabolism and excretion
80% excreted renally unchanged.
Dabigatran etexilate is converted to dabigatran after absorption.
Dabigatran etexilate (but not the active dabigatran) is a substrate of P-glycoprotein.
Dabigatran is NOT a substrate of CYP450 enzymes.
1/3 excreted renally unchanged.
2/3 is metabolised in the liver by CYP3A4 and CYP2J2 and also by CYP independent mechanisms.
Substrate of P-glycoprotein.
27% excreted renally unchanged.
73% metabolised to inactive metabolites mainly by CYP3A4.
Substrate of P-glycoprotein.
Contraindicated in patients with
  • Hepatic impairment or liver disease expected to have any impact on survival, OR
  • Elevated liver enzymes > 2 × upper limit of normal (ULN)


  • Significant hepatic disease (including moderate and severe hepatic impairment, i.e. Child-Pugh B and C) which is associated with coagulopathy leading to a clinically relevant bleeding risk

  • Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including severe hepatic impairment (Child-Pugh C)
Use with caution in patients with
(No dose adjustment required)

  • Cirrhosis with moderate hepatic impairment, if it is not associated with coagulopathy
  • Mild or moderate hepatic impairment,
  • Elevated liver enzymes ALT/AST > 2 × ULN or total bilirubin ≥ 1.5 × ULN
Monitoring Perform liver function tests before starting therapy, repeat when a condition may impact on hepatic function.

See Dose adjustments for use of newer oral anticoagulant in renal impairment.

Table 2: Drug–drug interactions with the newer oral anticoagulants1-8

Rivaroxaban (Xarelto) and
Apixaban (Eliquis)
Recommended action
Increase plasma levels of oral anticoagulant and increase bleeding risk
Contraindicated with potent P-glycoprotein inhibitors

Includes: systemic azole antifungalsA (e.g. itraconazole and ketoconazole), cyclosporin, dronedarone, tacrolimus, simultaneous initiation with verapamil
Contraindicated with potent CYP3A4 and/or P-glycoprotein inhibitors

Includes: systemic azole antifungals (e.g. itraconazole and ketoconazole, posaconazole and voriconazole, but not fluconazole),
HIV-protease inhibitors (e.g. ritonavir, saquinavir)
Avoid concomitant use
Increase plasma levels of oral anticoagulant and increase bleeding risk
Other P-glycoprotein inhibitors should be used with caution

Includes: amiodarone, clarithromycin, erythromycin,  fluconazole, HIV protease inhibitors (e.g. ritonavir, saquinavir,  nelfinavir), quinidine, ticagrelor, verapamil (verapamil should be given 2 hours after dabigatran for the first 3 days)
Less potent CYP3A4 and/or P-glycoprotein inhibitors should be used with caution

Includes: amiodarone, cyclosporin, clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, quinidine, tacrolimus, verapamil

Ideally avoid concomitant use.

Consider an alternative therapy, particularly in the presence or renal and/or hepatic impairment.

The presence of renal or hepatic impairment may increase the risk of bleeding or make even weak inhibitors significant.

If there is no alternative therapy, seek specialist advice.

During concomitant use, monitor patients closely for altered response (bleeding or loss of anticoagulant effect) and seek specialist advice.

Routinely ask patients about and encourage them to report signs and symptoms of thromboembolic events or bleeding (see Anticoagulant Safety Checklist

Reduce plasma levels of oral anticoagulant and increase thromboembolic risk
Caution with potent P-glycoprotein and CYP3A4 inducers
Includes: carbamazepine, phenobarbitone, phenytoin, rifampicin, St John’s wort
Pharmacodynamic  interactions that increase bleeding risk

Other medicines to be used with caution:

  • aspirin, NSAIDs (including selective COX-2 inhibitors), antiplatelet medicines (e.g. clopidogrel, prasugrel and ticagrelor)
  • fish oils
  • thrombolytics (e.g. alteplase, reteplase and tenecteplase) for the treatment of acute stroke
  • selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors (SNRIs).

A. Posaconazole and voriconazole are also contraindicated by some experts.7

Note: This is not an exhaustive interaction list and clinical experience with drug interactions is limited.

Table 3: Gastric absorption, food and alcohol interactions1-3,5-7

No interaction with food

Should be taken with a full glass of water while sitting upright

Can take with food to minimise dyspepsia
15 mg and 20 mg doses should be taken with food No interaction with food
Antacids and proton pump inhibitorsB No interaction with rantidine or pantoprazoleB,C No interaction with ranitidine, aluminium or magnesium containing antacids or omeprazoleB No data on antacids or proton pump inhibitors
AlcoholD Recommend no more than 1–2 drinks per day
B. This data may apply to other antacids or proton pump inhibitors, but only the medicines listed have been studied

C. This study utilised a dose of 40 mg twice daily pantoprazole.

D. Alcohol should be restricted to no more than 1–2 standard drinks per day. Heavy alcohol consumption also contributes to poor adherence, falls, alcohol-induced gastritis and poor diet.

  1. Boehringer Ingelheim Pty Limited. Pradaxa (dabigatran etexilate) Product Information. 11 June 2013.
  2. Bayer Australia Limited. Xarelto (rivaroxaban) Product Information. 27 June 2013.
  3. Bristol-Myers Squibb Australia Pty Ltd. Eliquis Product Information. 29 April 2013.
  4. US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. (accessed 10 July 2013).
  5. Australian medicines handbook. Adelaide:Australian Medicines Handbook Pty Ltd, 2012
  6. Baxter K (ed). Stockley's drug interactions [online]. London: Pharmaceutical Press, 2012.
  7. Heidbuchel H, et al. European Hearth Rhythm Association Practical Guide on the use of the new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625–51. [full text]
  8. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012;119:3016–23.