Summary

Everolimus and erythromycin have a significant drug interaction due to erythromycin's strong inhibition of CYP3A4, the primary enzyme responsible for everolimus metabolism. This interaction can lead to substantially increased everolimus blood levels, potentially causing serious adverse effects including immunosuppression, infections, and organ 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 including renal cell carcinoma and neuroendocrine tumors. It belongs to the class of drugs known as sirolimus analogs. Erythromycin is a macrolide antibiotic commonly prescribed for bacterial infections including respiratory tract infections, skin infections, and sexually transmitted diseases. It works by inhibiting bacterial protein synthesis and is known to be a potent inhibitor of the cytochrome P450 3A4 enzyme system.

Mechanism of Interaction

The interaction between everolimus and erythromycin occurs through competitive inhibition of the CYP3A4 enzyme system. Everolimus is extensively metabolized by CYP3A4 in the liver and intestines, with this pathway accounting for the majority of its elimination from the body. Erythromycin is a strong CYP3A4 inhibitor that significantly reduces the enzyme's activity, leading to decreased everolimus clearance and substantially increased plasma concentrations. This pharmacokinetic interaction can result in everolimus levels that are 3-5 times higher than normal, dramatically increasing the risk of dose-related adverse effects.

Risks and Symptoms

The primary risks of this drug interaction include severe immunosuppression leading to increased susceptibility to infections and malignancies, nephrotoxicity, hepatotoxicity, pulmonary toxicity including pneumonitis, delayed wound healing, and metabolic complications such as hyperglycemia and hyperlipidemia. Patients may experience symptoms such as fever, fatigue, mouth ulcers, delayed healing, respiratory symptoms, and laboratory abnormalities including elevated liver enzymes and creatinine levels. The interaction is considered clinically significant and can be life-threatening if not properly managed, particularly in immunocompromised patients such as transplant recipients.

Management and Precautions

Concurrent use of everolimus and erythromycin should generally be avoided when possible. If erythromycin treatment is absolutely necessary, consider alternative antibiotics such as azithromycin (which has less CYP3A4 inhibition) or non-macrolide antibiotics. If co-administration cannot be avoided, everolimus dosing should be significantly reduced (typically by 50-75%) and therapeutic drug monitoring should be implemented with frequent measurement of everolimus trough levels. Patients require close monitoring for signs of everolimus toxicity including complete blood counts, liver function tests, kidney function, and clinical assessment for infections or other adverse effects. The everolimus dose should be adjusted based on therapeutic drug monitoring results 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.

Erythromycin interactions with food and lifestyle

Erythromycin should be taken on an empty stomach (1 hour before or 2 hours after meals) for optimal absorption, as food can significantly reduce the drug's bioavailability. However, if gastrointestinal upset occurs, it may be taken with food to minimize stomach irritation, though this may reduce effectiveness. Alcohol consumption should be avoided or limited while taking erythromycin, as it may increase the risk of gastrointestinal side effects and potentially reduce the antibiotic's effectiveness. Patients should also avoid taking erythromycin with dairy products or calcium-fortified foods within 2 hours of dosing, as calcium can interfere with absorption.