Summary

Sirolimus and voriconazole have a significant drug interaction that can lead to dangerously elevated sirolimus levels. This interaction occurs through voriconazole's potent inhibition of CYP3A4, the primary enzyme responsible for sirolimus metabolism, potentially resulting in serious toxicity.

Introduction

Sirolimus (Rapamune) is an immunosuppressive medication belonging to the mTOR inhibitor class, primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. Voriconazole (Vfend) is a triazole antifungal agent used to treat serious fungal infections, including invasive aspergillosis and candidemia. Both medications are metabolized through the cytochrome P450 system, making them susceptible to significant drug interactions.

Mechanism of Interaction

The interaction between sirolimus and voriconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Voriconazole is a potent CYP3A4 inhibitor that significantly reduces the metabolism of sirolimus, which is primarily metabolized by this same enzyme pathway. When voriconazole blocks CYP3A4, sirolimus clearance decreases dramatically, leading to substantially elevated plasma concentrations that can persist for extended periods due to sirolimus's long half-life.

Risks and Symptoms

The primary risk of this interaction is sirolimus toxicity due to elevated drug levels, which can manifest as severe immunosuppression, increased infection risk, delayed wound healing, hyperlipidemia, thrombocytopenia, and nephrotoxicity. Studies have shown that voriconazole can increase sirolimus levels by 10-fold or more, creating a high risk for serious adverse events. The interaction is considered clinically significant and may require dose modifications or alternative therapy selection to prevent toxicity.

Management and Precautions

When this combination cannot be avoided, sirolimus doses should be significantly reduced (often by 80-90%) and frequent therapeutic drug monitoring is essential. Sirolimus trough levels should be checked within 3-5 days of starting voriconazole and monitored closely throughout concurrent therapy. Consider alternative antifungal agents with less CYP3A4 inhibition when possible. If voriconazole is discontinued, sirolimus levels may remain elevated for several days, requiring continued monitoring and gradual dose adjustments. Healthcare providers should maintain close communication and consider consultation with clinical pharmacists or transplant specialists.

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.

Voriconazole interactions with food and lifestyle

Voriconazole should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food significantly reduces absorption and bioavailability. High-fat meals can decrease voriconazole absorption by up to 22%. Patients should avoid grapefruit and grapefruit juice during treatment, as these can increase voriconazole blood levels and risk of toxicity. Alcohol consumption should be avoided or limited, as both voriconazole and alcohol are metabolized by the liver and concurrent use may increase the risk of liver toxicity. Patients should also avoid prolonged sun exposure and use adequate sun protection, as voriconazole can cause photosensitivity reactions and increase risk of skin cancer with long-term use.