Summary

Fluconazole significantly increases sirolimus blood levels by inhibiting CYP3A4 metabolism, potentially leading to sirolimus toxicity. This major drug interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Sirolimus (Rapamune) is an immunosuppressive medication primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. It belongs to the mTOR inhibitor class of drugs. Fluconazole (Diflucan) is an antifungal medication from the triazole class, commonly prescribed to treat various fungal infections including candidiasis and cryptococcal infections. Both medications are frequently used in transplant patients, making their interaction clinically significant.

Mechanism of Interaction

The interaction between sirolimus and fluconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Sirolimus is extensively metabolized by CYP3A4 in the liver and intestines. Fluconazole is a potent inhibitor of CYP3A4, which significantly reduces the metabolism of sirolimus. This results in increased sirolimus plasma concentrations, prolonged half-life, and enhanced pharmacological effects. The interaction is dose-dependent, with higher fluconazole doses causing more pronounced effects on sirolimus levels.

Risks and Symptoms

The primary risk of this interaction is sirolimus toxicity due to elevated blood levels. Clinical manifestations may include increased immunosuppression leading to higher infection risk, delayed wound healing, bone marrow suppression, hyperlipidemia, proteinuria, and potential nephrotoxicity. Patients may experience symptoms such as fatigue, mouth ulcers, skin rash, or signs of infection. The interaction can also increase the risk of sirolimus-related adverse effects including pneumonitis, lymphoma, and skin cancer. Therapeutic drug monitoring becomes critical to prevent both toxicity and transplant rejection.

Management and Precautions

When concurrent use is necessary, sirolimus doses should be reduced by approximately 33-50% and therapeutic drug monitoring should be intensified. Sirolimus trough levels should be checked within 3-5 days of starting fluconazole and weekly thereafter until stable. Target therapeutic ranges may need adjustment based on clinical response. Consider alternative antifungal agents with less CYP3A4 inhibition if clinically appropriate, such as micafungin or anidulafungin. Monitor for signs of sirolimus toxicity including complete blood count, liver function tests, lipid profile, and renal function. Patients should be counseled on infection prevention and advised to report any unusual symptoms promptly.

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.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.