Rivaroxaban with Amiodarone Interaction Details

Brand Names Associated with Rivaroxaban

Brand Names Associated with Amiodarone

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 27, 2024

Interaction Effect

Increased rivaroxaban exposure and increased risk of bleeding

Interaction Summary

Concurrent use of rivaroxaban with a dual P-gp and CYP3A4 inhibitor, including amiodarone, may increase the risk of bleeding[1], and may result in rivaroxaban plasma concentrations greater than 50 mcg/L even 24 to 48 hours after the last rivaroxaban dose. Consider measuring rivaroxaban concentrations prior to elective surgery [2]. Elderly patients and those with declining renal function may be at increased risk of elevated rivaroxaban exposure with concomitant use of amiodarone; this interaction may persist for weeks or even months following discontinuation of amiodarone [3]. A subgroup analysis of the ROCKET AF trial found that concomitant use of amiodarone and rivaroxaban was not associated with increased mortality or embolic or bleeding outcomes compared with rivaroxaban without amiodarone [4].

Severity

Moderate

Onset

Unspecified

Evidence

Probable

How To Manage Interaction

Concurrent use of rivaroxaban with a dual P-gp and CYP3A4 inhibitor, including amiodarone, may increase the risk of bleeding[1] and may result in rivaroxaban plasma concentrations greater than 50 mcg/L even 24 to 48 hours after the last rivaroxaban dose. Consider measuring rivaroxaban concentrations prior to elective surgery [2]. Elderly patients and those with declining renal function may be at increased risk of elevated rivaroxaban exposure with concomitant use of amiodarone; this interaction may persist for weeks or even months following discontinuation of amiodarone [3].

Mechanism Of Interaction

Inhibition of CYP3A4-mediated rivaroxaban metabolism; inhibition of P-gp-mediated efflux transport of rivaroxaban

Literature Reports

A) In a case report, an 88-year-old woman presented with an INR of 2.6 from a routine blood test after 7 weeks of concomitant therapy with amiodarone and rivaroxaban 20 mg daily for paroxysmal atrial fibrillation; amiodarone was discontinued for adverse events 3 weeks prior to presentation. At presentation, rivaroxaban levels were supratherapeutic (over 800 mcg/L). Additionally, her renal function had decreased from an estimated GFR of greater than 60 mL/min when starting rivaroxaban to approximately 50 mL/min. After rivaroxaban was discontinued, the INR reduced to 1.2 and rivaroxaban levels decreased to below detection within 3 days. Warfarin was initiated after INR normalization [3].

B) Treatment with a combined P-gp and moderate CYP3A4 inhibitor significantly increased risk of bleeding in patients taking apixaban or rivaroxaban for atrial fibrillation in a retrospective observational analysis (N=426). Bleeding, defined as the composite of major, clinically relevant non-major, and minor bleeding, occurred in 26.4% of the interacting agent group vs 18.4% in the propensity-matched control group (HR, 1.8; 95% CI, 1.19 to 2.73). Interacting agents consisted of diltiazem (68.1%), amiodarone (26.8%), verapamil (5.7%), dronedarone (2.3%), and multiple agents (2.8%); no patients received concomitant erythromycin. No significant differences in bleeding rates were identified when individual drug interactions were evaluated, and the impact of renal dysfunction, specific inhibitor, or specific anticoagulant were not evaluated [1].

C) Patients taking amiodarone concomitantly with rivaroxaban (N=66) had a significantly increased risk (OR, 1.97; 95% CI, 1.04 to 3.72) of having a residual rivaroxaban plasma concentration greater than 50 mcg/L 24 to 48 hours after the last rivaroxaban dose; these elevated levels may not be appropriate for patients scheduled for surgery [2].

D) The concomitant use of amiodarone and rivaroxaban (n=1144) was not associated with increased mortality or embolic or bleeding outcomes compared with rivaroxaban without amiodarone in the ROCKET AF trial [4].

References

1 ) Hanigan S, Das J, Pogue K, et al: The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding. J Thromb Thrombolysis 2020; 49(4):636-643.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

2 ) Kaserer A, Schedler A, Jetter A, et al: Risk factors for higher-than-expected residual rivaroxaban plasma concentrations in real-life patients. Thromb Haemost 2018; 118(5):808-817.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

3 ) Skov K, Falskov B, Jensen EA, et al: Supratheraputic rivaroxaban levels: a persistent drug-drug interaction after discontinuation of amiodarone. Basic Clin Pharmacol Toxicol 2020; 127(4):351-353.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

4 ) Shah R & Patel MR: Primary and key secondary results from the ROCKET AF trial, and their implications on clinical practice. Ther Adv Cardiovasc Dis 2017; 11(3):105-120.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

Rivaroxaban Overview

• Rivaroxaban is used to treat deep vein thrombosis (DVT; a blood clot, usually in the leg) and pulmonary embolism (PE; a blood clot in the lung) in adults. Rivaroxaban is also used to prevent DVT and PE from happening again after initial treatment is completed in adults. It is also used to help prevent strokes or serious blood clots in adults who have atrial fibrillation (a condition in which the heart beats irregularly, increasing the chance of clots forming in the body, and possibly causing strokes) that is not caused by heart valve disease. Rivaroxaban is also used to prevent DVT and PE in adults who are having hip replacement or knee replacement surgery or in people who are hospitalized for serious illnesses and are at risk of developing a clot due to decreased ability to move around or other risk factors. It is also used along with aspirin to lower the risk of a heart attack, stroke, or death in adults with coronary artery disease (narrowing of the blood vessels that supply blood to the heart) or peripheral arterial disease (poor circulation in the blood vessels that supply blood to the arms and legs). Rivaroxaban is also used to treat and prevent DVT and PE from happening again in children and certain infants who have received at least 5 days of initial anticoagulation (blood thinner) treatment. It is also used to prevent DVT and PE after heart surgery in children 2 years of age or older who have congenital heart disease (abnormality in the heart that develops before birth). Rivaroxaban is in a class of medications called factor Xa inhibitors. It works by blocking the action of a certain natural substance that helps blood clots to form.

Amiodarone Overview

• Amiodarone is used to treat and prevent certain types of serious, life-threatening ventricular arrhythmias (a certain type of abnormal heart rhythm when other medications did not help or could not be tolerated. Amiodarone is in a class of medications called antiarrhythmics. It works by relaxing overactive heart muscles.

Return To Our Drug Interaction Homepage

Feedback, Question Or Comment About This Information?

Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.