Summary

Amiodarone significantly increases everolimus blood levels through CYP3A4 enzyme inhibition, potentially leading to enhanced toxicity and adverse effects. This interaction requires careful monitoring and possible dose adjustments of everolimus when used concurrently with amiodarone.

Introduction

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor used as an immunosuppressant in organ transplant recipients and as an anticancer agent in certain malignancies. It belongs to the class of drugs known as sirolimus analogs. Amiodarone is a class III antiarrhythmic medication primarily used to treat and prevent various types of cardiac arrhythmias, including atrial fibrillation and ventricular tachycardia. Both medications are commonly prescribed in clinical practice, making their potential interaction clinically relevant.

Mechanism of Interaction

The interaction between everolimus and amiodarone occurs primarily through the inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Everolimus is extensively metabolized by CYP3A4, while amiodarone is a potent inhibitor of this enzyme. When amiodarone inhibits CYP3A4, it significantly reduces the metabolism of everolimus, leading to increased plasma concentrations and prolonged elimination half-life. Additionally, amiodarone may also inhibit P-glycoprotein, a drug efflux pump that affects everolimus transport, further contributing to elevated everolimus levels.

Risks and Symptoms

The primary clinical risk of this interaction is everolimus toxicity due to elevated drug concentrations. Increased everolimus levels can lead to enhanced immunosuppression, increasing the risk of infections and malignancies in transplant patients. Other significant adverse effects include severe mucositis, pneumonitis, delayed wound healing, hyperlipidemia, proteinuria, and hematologic toxicities such as anemia and thrombocytopenia. In cancer patients, the risk of severe side effects may compromise treatment efficacy and patient safety. The interaction is considered clinically significant and requires proactive management.

Management and Precautions

When concurrent use of everolimus and amiodarone is necessary, several management strategies should be implemented. First, consider reducing the everolimus dose by approximately 50% when initiating amiodarone therapy. Monitor everolimus trough levels more frequently, targeting the lower end of the therapeutic range. Conduct regular clinical assessments for signs of everolimus toxicity, including complete blood counts, liver function tests, lipid profiles, and urinalysis. Monitor for signs of infection, delayed wound healing, and respiratory symptoms. If possible, consider alternative antiarrhythmic agents with less CYP3A4 inhibition potential. Always consult with a clinical pharmacist or specialist when managing this interaction, and adjust doses based on therapeutic drug monitoring and clinical response.

Everolimus interactions with food and lifestyle

Everolimus should be taken consistently either with food or without food, but not alternating between the two, as food can significantly affect absorption and blood levels. Grapefruit and grapefruit juice should be avoided as they can increase everolimus blood levels and potentially lead to increased side effects. St. John's wort should be avoided as it can decrease everolimus effectiveness by reducing blood levels. Live vaccines should be avoided during everolimus treatment due to immunosuppressive effects.

Amiodarone interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided as they can significantly increase amiodarone blood levels and risk of toxicity. Alcohol consumption should be limited or avoided as it may increase the risk of liver toxicity when combined with amiodarone. Patients should maintain consistent dietary habits and avoid excessive sun exposure, as amiodarone can cause photosensitivity reactions and skin discoloration with prolonged sun exposure.