Rivaroxaban with Itraconazole Interaction Details

Brand Names Associated with Rivaroxaban

Brand Names Associated with Itraconazole

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 14, 2023

Interaction Effect

Increased rivaroxaban exposure

Interaction Summary

The concomitant use of itraconazole (a strong inhibitor of CYP3A4 and P-gp) and rivaroxaban may result in increased rivaroxaban exposure and increase the risk of bleeding. Although no formal drug-interaction studies have been done with itraconazole, coadministration of ketoconazole (also a strong inhibitor of CYP3A4 and P-gp) and rivaroxaban resulted in statistically significant and potentially clinically significant increases in rivaroxaban AUC and Cmax and decreased rivaroxaban clearance. Concomitant use of fluconazole (a moderate CYP3A4 inhibitor and a potential breast cancer resistance protein (BCRP) inhibitor) and rivaroxaban also resulted in increases in rivaroxaban AUC and Cmax and decreased rivaroxaban clearance, although these changes were not considered clinically significant. Avoid concomitant use of rivaroxaban and itraconazole during and for 2 weeks after itraconazole therapy  since clinically relevant interactions similar to ketoconazole and rivaroxaban may occur . Monitor closely if coadministration is necessary .

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Avoid the concomitant use of rivaroxaban during and for 2 weeks after itraconazole therapy as coadministration may cause increased rivaroxaban exposure and an increased risk of bleeding . Monitor closely if coadministration is necessary .

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism and P-gp-mediated efflux transport of rivaroxaban by itraconazole

Literature Reports

A) In a study evaluating data from the Food and Drug Administration Adverse Event Reporting System (FAERS), adverse events associated with direct oral anticoagulants (DOACs) used concomitantly with CYP3A4 inhibitors (including macrolide antibiotics and azole antimycotics) were pooled to identify signals of hemorrhages. From 2010 to 2021, 1128 cases of bleeding associated with coadministration of CYP3A4 inhibitors and DOACs were identified, including cases with rivaroxaban (529 events), apixaban (315 events), dabigatran (296 events), and edoxaban (19 events); no cases were reported with betrixaban. Patients were a median age of 73 years (range, 61 to 81 years). Hemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals and considered significant when the lower limit of 95% CI was greater than 1 and the number of interaction group was 3 or more. Subgroup analyses and logistic regression were conducted by adjusting associated factors in hemorrhagic events. The hemorrhagic signal was significant for rivaroxaban when coadministered with itraconazole compared with rivaroxaban treatment alone (ROR, 3.58; 95% CI, 1.3 to 9.85) .

B) Although no formal drug-interaction studies have been performed with itraconazole, during a randomized open-label, 2-way crossover study, coadministration of ketoconazole (a strong inhibitor of CYP3A4 and P-glycoprotein) and rivaroxaban resulted in statistically significant increases in rivaroxaban AUC and Cmax. Healthy subjects (n=12) received a single dose of rivaroxaban 10 mg alone or in combination with ketoconazole 200 mg daily. Coadministration of ketoconazole 200 mg daily increased rivaroxaban mean AUC by 82% (90% CI, 59% to 108%) and increased rivaroxaban mean Cmax by 53% (90% CI, 27% to 85%). In addition, coadministration of ketoconazole significantly decreased the plasma clearance of rivaroxaban by a mean of 45% (90% CI, -52% to -37%). In an additional nonrandomized, open-label study, healthy subjects (n=20) received rivaroxaban 10 mg daily for 5 days, followed by combination rivaroxaban 10 mg and ketoconazole 400 mg daily for an additional 5 days. Concurrent administration of ketoconazole 400 mg resulted in statistically significant and potentially clinically significant increases in rivaroxaban mean AUC (158%; 90% CI, 136% to 182%) and increased rivaroxaban Cmax (72%; 90% CI, 61% to 83%). Similar to the crossover study, coadministration of ketoconazole also decreased rivaroxaban mean plasma clearance by 61% (90% CI, -65% to -58%) and decreased rivaroxaban clearance by active renal secretion by a mean of 44% (90% CI, -50% to -32%) .

C) Although no formal drug-interaction studies have been performed with itraconazole, during an open-label, 2-way crossover study, coadministration of fluconazole (a moderate CYP3A4 inhibitor and a potential breast cancer resistance protein (BCRP) inhibitor) and rivaroxaban resulted in increases in rivaroxaban AUC and Cmax. Healthy subjects (n=13) received a single dose of rivaroxaban 20 mg alone or fluconazole 400 mg daily for 6 days, with a single dose of rivaroxaban 20 mg on study day 5. Concomitant use of fluconazole and rivaroxaban increased rivaroxaban mean AUC by 42% (90% CI, 29% to 56%) and increased rivaroxaban mean Cmax by 28% (90% CI, 12% to 47%). In addition, coadministration of fluconazole decreased rivaroxaban plasma clearance by 29% (90% CI, -36% to -22%) and decreased rivaroxaban clearance by active renal secretion by 22% (90% CI, -29% to -14%) .

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.

Itraconazole Overview

• Itraconazole capsules (Sporanox, Tolsura) are used to treat fungal infections in the lungs that can spread throughout the body. Itraconazole capsules (Sporanox) are also used to treat fungal infections of the fingernails and toenails. Itraconazole oral solution (liquid) is used to treat yeast infections of the mouth and throat or of the esophagus (tube that connects the throat to the stomach). Itraconazole is in a class of antifungals called triazoles. It works by slowing the growth of fungi that cause infection.

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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:

• 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.