What are the potential drug interactions with Apixaban (apixaban) and how can they be managed?

From the Guidelines

Apixaban should not be combined with strong dual inhibitors of CYP3A4 and P-glycoprotein (P-gp) such as ketoconazole, itraconazole, ritonavir, or clarithromycin, as these can significantly increase apixaban blood levels and bleeding risk. When considering the management of apixaban, it is crucial to understand its pharmacokinetic characteristics, including its metabolism by CYP3A4 and its status as a substrate for P-gp transport proteins 1. The most recent and highest quality study on this topic, published in 2024, emphasizes the importance of avoiding strong CYP3A4 and P-gp inducers, such as rifampin, carbamazepine, phenytoin, and St. John's wort, as they can reduce apixaban effectiveness 1. Key points to consider in managing apixaban interactions include:

• Avoiding concomitant use with strong dual inhibitors of CYP3A4 and P-gp
• Reducing the dose of apixaban by 50% if it must be used with strong CYP3A4 inhibitors, for patients on a regimen of 5-10 mg twice daily
• Avoiding use with strong CYP3A4 and P-gp inducers
• Considering alternative medications or staggering administration times to minimize interactions
• Regular monitoring for signs of bleeding, especially when apixaban is used with NSAIDs or antiplatelet agents like aspirin These strategies are supported by studies detailing the effects of various inhibitors and inducers on apixaban plasma concentrations and the associated risks of bleeding or reduced efficacy 1. For example, a retrospective study examining the safety of clarithromycin versus azithromycin in patients taking direct oral anticoagulants (DOACs), including apixaban, found that clarithromycin use was associated with a higher incidence of hospitalization for major bleeding 1. In clinical practice, the management of apixaban interactions requires careful consideration of the patient's individual risk factors, the specific medications involved, and the potential consequences of drug interactions on apixaban's efficacy and safety profile.

From the FDA Drug Label

Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events. For patients receiving apixaban 5 mg or 10 mg twice daily, the dose of apixaban should be decreased by 50% when coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) Avoid concomitant use of apixaban tablets with combined P-gp and strong CYP3A4 Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding

The following drugs should be avoided or have their dose adjusted when used with apixaban:

• Combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) - decrease apixaban dose by 50% for patients receiving 5 mg or 10 mg twice daily, avoid coadministration for patients receiving 2.5 mg twice daily
• Combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) - avoid concomitant use
• Antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use - increases the risk of bleeding, use with caution 2 No specific food interactions are mentioned in the drug label. However, it is recommended to avoid concomitant use of certain drugs that may increase the risk of bleeding or affect apixaban exposure 2

From the Research

Potential Drug Interactions with Apixaban

The following are potential drug interactions with apixaban that should be avoided or managed with caution:

• Strong inducers and inhibitors of cytochrome P450 3A4 (CYP3A4), such as cobicistat, rifampicin, and clarithromycin, as they may cause variations in the blood level of apixaban 3, 4, 5
• P-glycoprotein (P-gp) inhibitors, such as amiodarone and diltiazem, as they may increase the concentration of apixaban 5, 6
• Statins, such as atorvastatin, rosuvastatin, and simvastatin, as they may interact with apixaban when co-administered with P-gp inhibitors 6
• Aspirin, as it may increase the risk of gastrointestinal hemorrhage when co-administered with apixaban 4

Management of Drug Interactions

To manage drug interactions with apixaban:

• Avoid concomitant use of strong CYP3A4 inducers and inhibitors, and P-gp inhibitors, if possible 3, 4, 5
• Monitor patients closely for signs of bleeding or thrombosis when apixaban is co-administered with interacting drugs 4, 6
• Consider using alternative medications or adjusting the dose of apixaban when interacting drugs are necessary 6
• Use the apixaban anti-Xa assay or comparative heparin anti-Xa assay to determine if patients require dose reduction to decrease adverse events 6

Food Interactions

• Food does not have a clinically meaningful impact on the bioavailability of apixaban, and no specific dietary restrictions are recommended 7