Summary

Itraconazole significantly increases apixaban blood levels by inhibiting CYP3A4 metabolism, leading to elevated bleeding risk. This major drug interaction requires careful monitoring and potential dose adjustments when these medications are used together.

Introduction

Apixaban (brand name Eliquis) is a direct oral anticoagulant (DOAC) belonging to the factor Xa inhibitor class, primarily used to prevent stroke in atrial fibrillation and treat venous thromboembolism. Itraconazole is a triazole antifungal medication used to treat various fungal infections, including aspergillosis, blastomycosis, and histoplasmosis. Both medications are metabolized through the cytochrome P450 system, creating potential for significant drug interactions.

Mechanism of Interaction

The interaction occurs through itraconazole's potent inhibition of CYP3A4 and P-glycoprotein (P-gp), both crucial pathways for apixaban metabolism and elimination. Itraconazole blocks these enzymes, reducing apixaban clearance and significantly increasing plasma concentrations. Studies show that itraconazole can increase apixaban AUC (area under the curve) by approximately 60% and maximum concentration by 40%, leading to enhanced anticoagulant effects and prolonged drug exposure.

Risks and Symptoms

The primary clinical risk is significantly increased bleeding, including major hemorrhage events such as gastrointestinal bleeding, intracranial hemorrhage, and other serious bleeding complications. Patients may experience prolonged bleeding times, easy bruising, and delayed wound healing. The interaction is classified as major due to the substantial increase in apixaban exposure and the serious nature of potential bleeding complications. Elderly patients and those with renal impairment face particularly elevated risks.

Management and Precautions

When concurrent use is necessary, consider reducing apixaban dose by 50% and implement enhanced monitoring for bleeding signs and symptoms. Regular assessment of hemoglobin, hematocrit, and coagulation parameters is recommended. Patients should be educated about bleeding precautions and instructed to report unusual bruising, prolonged bleeding, or signs of internal bleeding immediately. Alternative antifungal agents with less CYP3A4 inhibition potential should be considered when possible. If itraconazole is discontinued, apixaban dosing may need readjustment after allowing adequate washout time.

Apixaban interactions with food and lifestyle

Apixaban does not have any clinically significant food interactions and can be taken with or without food. However, patients should limit alcohol consumption while taking apixaban, as excessive alcohol use may increase the risk of bleeding. Additionally, patients should avoid activities with high risk of injury or trauma that could lead to bleeding, and should inform healthcare providers before any surgical or dental procedures. Grapefruit juice does not significantly affect apixaban levels, unlike some other medications.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.