Summary

Verapamil 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 when these medications are used together.

Introduction

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor used as an immunosuppressant in organ transplant recipients and as an anticancer agent for certain malignancies. It belongs to the class of drugs known as sirolimus analogs. Verapamil is a calcium channel blocker primarily used to treat hypertension, angina, and certain cardiac arrhythmias. It works by blocking calcium channels in the heart and blood vessels, reducing cardiac contractility and causing vasodilation.

Mechanism of Interaction

The interaction between everolimus and verapamil occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Everolimus is extensively metabolized by CYP3A4, while verapamil acts as a moderate to strong inhibitor of this enzyme. When verapamil inhibits CYP3A4, it reduces the metabolism of everolimus, leading to increased plasma concentrations and prolonged elimination half-life. Additionally, verapamil may inhibit P-glycoprotein, a drug efflux pump that also affects everolimus disposition, 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. Common adverse effects that may be intensified include stomatitis, pneumonitis, delayed wound healing, hyperlipidemia, hyperglycemia, and hematologic toxicities such as anemia and thrombocytopenia. In cancer patients, the risk of severe side effects may compromise treatment tolerability and require dose modifications or treatment discontinuation.

Management and Precautions

When everolimus and verapamil must be used concurrently, close monitoring is essential. Everolimus blood levels should be measured more frequently, with dose adjustments made based on therapeutic drug monitoring results. Consider reducing the everolimus dose by 50% when initiating verapamil therapy, then titrate based on clinical response and drug levels. Monitor patients closely for signs of everolimus toxicity, including complete blood counts, liver function tests, lipid profiles, and glucose levels. If possible, consider alternative antihypertensive agents that do not significantly inhibit CYP3A4, such as amlodipine or ACE inhibitors. Healthcare providers should educate patients about potential signs of toxicity and the importance of adherence to monitoring schedules.

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.

Verapamil interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking verapamil as they can significantly increase blood levels of the medication, potentially leading to dangerous drops in blood pressure and heart rate. Alcohol consumption should be limited or avoided as it can enhance verapamil's blood pressure-lowering effects and increase the risk of dizziness, fainting, and falls. High-fiber foods or fiber supplements may reduce verapamil absorption when taken at the same time, so it's recommended to separate their administration by at least 2 hours.