Rivaroxaban with Nirmatrelvir Interaction Details
Brand Names Associated with Rivaroxaban
- Rivaroxaban
- Xarelto®
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 14, 2023
Interaction Effect
Increased rivaroxaban exposure
Interaction Summary
Avoid concomitant use of nirmatrelvir/ritonavir and rivaroxaban as coadministration may cause increased rivaroxaban exposure and an increased risk of bleeding. In drug interaction studies, coadministration of ritonavir (a strong inhibitor of CYP3A4 and P-glycoprotein) and rivaroxaban led to significant increases in mean AUC and Cmax of rivaroxaban , as well as decreased rivaroxaban clearance . Withhold rivaroxaban during nirmatrelvir/ritonavir treatment and for 2 to 3 days (or longer in certain cases) after discontinuation if possible, and consider the use of another anticoagulant (such as low molecular weight heparin) in patients at high risk of thrombosis or low-dose aspirin in patients at low risk of thrombosis. Consider treatment with an alternative COVID-19 treatment if temporarily withholding rivaroxaban is not clinically reasonable .
Severity
Major
Onset
Unspecified
Evidence
Established
How To Manage Interaction
Avoid concomitant use of nirmatrelvir/ritonavir and rivaroxaban as coadministration may cause increased rivaroxaban exposure and an increased risk of bleeding. Withhold rivaroxaban during nirmatrelvir/ritonavir treatment and for 2 to 3 days (or longer in certain cases such as advanced patient age) after discontinuation if possible, and consider the use of another anticoagulant (such as low molecular weight heparin) in patients at high risk of thrombosis or low-dose aspirin in patients at low risk of thrombosis. Consider treatment with an alternative COVID-19 treatment if temporarily withholding rivaroxaban is not clinically reasonable .
Mechanism Of Interaction
Inhibition of CYP3A4-mediated metabolism and P-glycoprotein-mediated efflux transport of rivaroxaban by ritonavir
Literature Reports
A) In a physiologically-based pharmacokinetic (PBPK) modeling study (N=100), simulated coadministration of ritonavir with rivaroxaban was estimated to increase rivaroxaban AUC in general population subjects (range, 20 to 65 years) by 1.91-fold with normal renal function or 2-fold with moderate renal impairment (CrCl, 30 to 49 mL/min) and in geriatric patients (range, 65 to 85 years) by 2.08-fold with normal renal function or 2.12-fold with moderate renal impairment compared with rivaroxaban use alone. Rivaroxaban AUC was estimated to normalize on day 4 after discontinuation of ritonavir. Risk of major bleeding was also estimated to increase with coadministration of ritonavir and rivaroxaban compared with rivaroxaban alone in patients normal renal function (5.9% vs 3.34%) or moderate renal impairment (11.39% vs 4.51%) and geriatric patients with normal renal function (14.44% vs 4.88%) or moderate renal impairment (24.03% vs 6.11%). The simulated ritonavir dosage was 100 mg twice daily for 5 days (consistent with nirmatrelvir/ritonavir dosing for COVID-19) and rivaroxaban was 15 or 20 mg daily, dependent on renal function; nirmatrelvir was not incorporated into the simulation due to low drug interaction potential. A prospective simulation of reduced-dose rivaroxaban 10 mg compared with full-dose rivaroxaban given on day 1 of ritonavir treatment and continued for 3 days post ritonavir discontinuation demonstrated maintenance of an acceptable rivaroxaban AUC and decreased bleeding risk by approximately half for all 4 cohorts. Ritonavir causes mechanism-based inactivation of CYP3A4, which is the predominant enzyme involved in rivaroxaban metabolism; other potential mechanisms may include CYP2J2, or transporters including OAT3 or P-gp .
B) During a nonrandomized, open-label study, coadministration of ritonavir and rivaroxaban resulted in a statistically significant and potentially clinically significant increase in rivaroxaban AUC and Cmax. Subjects (n=16) received a single dose of rivaroxaban 10 mg on study day 1 and were scheduled to receive ritonavir 600 mg twice daily on study days 3 through 7, followed by ritonavir 600 mg twice daily in combination with rivaroxaban 10 mg on study day 8. All subjects valid for analysis (n=12) received both doses of rivaroxaban and at least 1 dose of ritonavir. Steady state ritonavir coadministration significantly increased rivaroxaban mean AUC by 153% (90% CI, 134% to 174%) and substantially increased rivaroxaban mean Cmax by 55% (90% CI, 41% to 69%) compared with rivaroxaban alone. In addition, concomitant administration of ritonavir significantly decreased the plasma clearance of rivaroxaban by 60% (90% CI, -63% to -57%) and the rivaroxaban clearance by active renal secretion by 82% (90% CI, -86% to -76%) .
C) In drug interaction studies, following the concomitant administration of ritonavir and rivaroxaban, the mean AUC and Cmax of rivaroxaban increased by 150% and 60%, respectively. Increases in pharmacodynamic effects were also observed .
Rivaroxaban Overview
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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.
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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:
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.