Summary

Sirolimus and itraconazole have a significant drug interaction that can lead to dangerously elevated sirolimus levels. This interaction occurs because itraconazole strongly inhibits CYP3A4, the primary enzyme responsible for sirolimus metabolism, potentially resulting in serious toxicity.

Introduction

Sirolimus (brand name Rapamune) is an immunosuppressive medication belonging to the mTOR inhibitor class, primarily used to prevent organ transplant rejection and treat certain rare diseases. Itraconazole is a triazole antifungal medication used to treat various fungal infections, including aspergillosis, histoplasmosis, and onychomycosis. Both medications are metabolized through the cytochrome P450 system, which creates the potential for significant drug interactions when used together.

Mechanism of Interaction

The interaction between sirolimus and itraconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Sirolimus is extensively metabolized by CYP3A4 in the liver and intestinal wall, with this pathway accounting for the majority of its clearance from the body. Itraconazole is a potent CYP3A4 inhibitor that significantly reduces the enzyme's activity. When administered concurrently, itraconazole blocks the metabolism of sirolimus, leading to decreased clearance and substantially increased plasma concentrations of sirolimus. This can result in sirolimus levels that are 3-5 times higher than expected, creating a high risk for dose-related toxicity.

Risks and Symptoms

The primary risk of this drug interaction is sirolimus toxicity due to elevated blood levels. Clinical manifestations may include severe immunosuppression leading to increased infection risk, delayed wound healing, mouth ulcers, hyperlipidemia, thrombocytopenia, anemia, and nephrotoxicity. In transplant patients, while over-immunosuppression increases infection risk, the interaction paradoxically may also lead to unpredictable immunosuppression levels that could compromise transplant protection. Additional risks include increased likelihood of sirolimus-related side effects such as pneumonitis, lymphedema, and impaired glucose tolerance. The interaction is considered clinically significant and requires careful management to prevent serious adverse outcomes.

Management and Precautions

When sirolimus and itraconazole must be used together, close monitoring and dose adjustments are essential. Sirolimus doses should typically be reduced by 50-75% when initiating itraconazole therapy. Frequent monitoring of sirolimus trough levels is crucial, with levels checked within 3-5 days of starting, stopping, or changing itraconazole doses. Target sirolimus levels should be maintained within the therapeutic range appropriate for the patient's indication. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole (though this also requires monitoring) or echinocandins when clinically appropriate. If itraconazole is discontinued, sirolimus doses may need to be increased back toward baseline levels, with continued monitoring to ensure therapeutic levels are maintained. Healthcare providers should educate patients about signs of sirolimus toxicity and the importance of adherence to monitoring schedules.

Sirolimus interactions with food and lifestyle

Sirolimus should be taken consistently either with or without food, as food can significantly affect absorption. High-fat meals can increase sirolimus blood levels by up to 35%, while taking it on an empty stomach may reduce absorption. Patients should avoid grapefruit and grapefruit juice, as they contain compounds that inhibit CYP3A4 enzymes and can significantly increase sirolimus blood levels, potentially leading to toxicity. St. John's wort should be avoided as it can decrease sirolimus levels by inducing CYP3A4 metabolism, potentially reducing the drug's effectiveness. Patients should limit sun exposure and use sunscreen, as sirolimus increases photosensitivity and skin cancer risk. Live vaccines should be avoided due to sirolimus's immunosuppressive effects.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.