Summary

Everolimus and clarithromycin have a significant drug interaction due to clarithromycin's potent inhibition of CYP3A4, the primary enzyme responsible for everolimus metabolism. This interaction can lead to substantially increased everolimus blood levels and increased risk of toxicity.

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 and requires careful monitoring due to its narrow therapeutic window. Clarithromycin is a macrolide antibiotic commonly prescribed for respiratory tract infections, skin infections, and as part of Helicobacter pylori eradication therapy. It is known to be a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, which makes it prone to significant drug interactions with medications metabolized by this pathway.

Mechanism of Interaction

The interaction between everolimus and clarithromycin occurs through inhibition of the CYP3A4 enzyme system. Everolimus is extensively metabolized by CYP3A4 in the liver and intestinal wall, with this pathway accounting for the majority of its elimination from the body. Clarithromycin is a potent competitive inhibitor of CYP3A4, significantly reducing the enzyme's ability to metabolize everolimus. This inhibition leads to decreased clearance of everolimus, resulting in increased plasma concentrations and prolonged half-life. The interaction can increase everolimus exposure by 3-fold or more, depending on the dose and duration of clarithromycin therapy.

Risks and Symptoms

The primary risk of this drug interaction is everolimus toxicity due to significantly elevated blood levels. Common signs of everolimus toxicity include severe immunosuppression leading to increased infection risk, delayed wound healing, mouth ulcers (stomatitis), pneumonitis, hyperlipidemia, proteinuria, and thrombocytopenia. In transplant patients, excessive immunosuppression may paradoxically increase the risk of rejection due to poor tolerability requiring dose reductions. Cancer patients may experience enhanced anticancer effects but also increased adverse reactions including severe mucositis, fatigue, and metabolic disturbances. The interaction is considered clinically significant and requires immediate attention when these medications are used concurrently.

Management and Precautions

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.

Clarithromycin interactions with food and lifestyle

Clarithromycin can be taken with or without food. However, taking clarithromycin with food may help reduce stomach upset and gastrointestinal side effects. Grapefruit juice should be avoided as it may increase clarithromycin blood levels and potentially increase the risk of side effects. Alcohol does not have a direct interaction with clarithromycin, but it's generally recommended to limit alcohol consumption while taking antibiotics to support immune system function and recovery.