Summary

Terbinafine can significantly increase sirolimus blood levels by inhibiting CYP3A4 metabolism, potentially leading to enhanced immunosuppression and increased risk of adverse effects. This interaction requires careful monitoring and possible dose adjustments of sirolimus.

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. Terbinafine (Lamisil) is an allylamine antifungal agent commonly prescribed for treating dermatophyte infections of the skin and nails. Both medications are metabolized through the cytochrome P450 system, creating potential for clinically significant drug interactions.

Mechanism of Interaction

The interaction between sirolimus and terbinafine occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Terbinafine acts as a moderate CYP3A4 inhibitor, reducing the hepatic metabolism of sirolimus, which is a CYP3A4 substrate. This inhibition leads to decreased clearance of sirolimus, resulting in elevated plasma concentrations and prolonged half-life of the immunosuppressant. The interaction may also involve inhibition of P-glycoprotein transport, further contributing to increased sirolimus exposure.

Risks and Symptoms

The primary clinical risk of this interaction is sirolimus toxicity due to elevated blood levels. Increased sirolimus concentrations can lead to enhanced immunosuppression, increasing susceptibility to infections and malignancies. Other potential adverse effects include nephrotoxicity, hepatotoxicity, hyperlipidemia, thrombocytopenia, and delayed wound healing. In transplant patients, while the risk of rejection may decrease due to higher immunosuppression, the overall risk-benefit ratio shifts unfavorably due to increased toxicity potential. The interaction significance is considered moderate to major, requiring clinical intervention.

Management and Precautions

Management of this interaction requires proactive monitoring and potential dose adjustments. Key strategies include: frequent monitoring of sirolimus trough levels (initially weekly, then bi-weekly until stable), consideration of empiric sirolimus dose reduction by 25-50% when initiating terbinafine, close monitoring for signs of immunosuppression and infection, regular assessment of renal function and complete blood counts, and evaluation of alternative antifungal agents with less CYP3A4 inhibition potential (such as fluconazole at lower doses). Healthcare providers should maintain close communication between transplant teams and prescribing physicians. Patients should be educated about 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.

Terbinafine interactions with food and lifestyle

Terbinafine should be taken with food to improve absorption and reduce gastrointestinal side effects. Alcohol consumption should be avoided or limited during terbinafine treatment due to the potential for increased risk of liver toxicity, as both terbinafine and alcohol can affect liver function. Patients should also avoid excessive caffeine intake, as terbinafine can reduce caffeine metabolism, potentially leading to increased caffeine effects such as jitteriness, insomnia, and rapid heartbeat.