Summary

Diltiazem significantly increases everolimus blood levels by inhibiting the CYP3A4 enzyme responsible for everolimus metabolism. This interaction can lead to enhanced everolimus toxicity and requires careful monitoring and potential dose adjustments.

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. Diltiazem is a calcium channel blocker primarily used to treat hypertension, angina, and certain arrhythmias. It works by blocking calcium channels in the heart and blood vessels, leading to vasodilation and reduced cardiac workload.

Mechanism of Interaction

The interaction between everolimus and diltiazem occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Everolimus is extensively metabolized by CYP3A4 in the liver and intestines. Diltiazem is a moderate inhibitor of CYP3A4, which significantly reduces the clearance of everolimus from the body. This results in increased everolimus plasma concentrations and prolonged exposure, potentially leading to enhanced therapeutic effects and increased risk of adverse reactions.

Risks and Symptoms

The primary clinical risk of this interaction is everolimus toxicity due to elevated drug levels. Common manifestations include increased immunosuppression leading to higher infection risk, delayed wound healing, mouth ulcers (stomatitis), pneumonitis, hyperlipidemia, and hematologic toxicity such as anemia, thrombocytopenia, and leukopenia. In transplant patients, while increased immunosuppression may reduce rejection risk, it significantly elevates the risk of opportunistic infections and malignancies. The interaction is considered clinically significant and requires active management.

Management and Precautions

When everolimus and diltiazem must be used together, close monitoring is essential. Everolimus blood levels should be measured more frequently, with dose reductions typically required (often 50% or more). Complete blood counts, liver function tests, and lipid profiles should be monitored regularly. Patients should be assessed for signs of infection, mouth sores, breathing difficulties, and other everolimus-related side effects. Alternative antihypertensive agents that don't significantly inhibit CYP3A4, such as amlodipine or ACE inhibitors, should be considered when possible. Any dose adjustments should be made gradually with appropriate monitoring intervals.

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.

Diltiazem interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking diltiazem 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 the blood pressure-lowering effects of diltiazem and increase the risk of dizziness, fainting, and falls. Patients should also be cautious when standing up quickly or engaging in activities requiring alertness, as diltiazem can cause dizziness and lightheadedness, especially when starting treatment or increasing the dose.