Summary

Posaconazole significantly increases sirolimus blood levels through CYP3A4 enzyme inhibition, potentially leading to sirolimus toxicity. This major drug interaction requires careful monitoring and dose adjustments when both medications are used concurrently.

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. Posaconazole (Noxafil) is a triazole antifungal medication used to treat and prevent serious fungal infections, particularly in immunocompromised patients. Both medications are commonly prescribed in transplant recipients, making their interaction clinically significant.

Mechanism of Interaction

The interaction occurs through posaconazole's potent inhibition of the CYP3A4 enzyme system in the liver and intestines. Sirolimus is extensively metabolized by CYP3A4, and when posaconazole blocks this enzyme, sirolimus clearance is significantly reduced. This results in substantially elevated sirolimus blood concentrations, with studies showing increases of 8-9 fold in sirolimus levels when co-administered with posaconazole. The interaction is dose-dependent and occurs with all formulations of posaconazole.

Risks and Symptoms

The primary risk is sirolimus toxicity due to elevated drug levels, which can manifest as bone marrow suppression (thrombocytopenia, leukopenia, anemia), nephrotoxicity, hepatotoxicity, delayed wound healing, increased infection risk, and hyperlipidemia. Severe cases may lead to life-threatening complications including severe immunosuppression and organ dysfunction. The interaction is classified as major clinical significance, requiring immediate attention and management when both drugs are prescribed together.

Management and Precautions

When concurrent use is necessary, sirolimus doses should be significantly reduced (often by 80-90%) before starting posaconazole. Frequent monitoring of sirolimus trough levels is essential, with levels checked 3-5 days after any dose change. Target therapeutic ranges should be maintained while watching for signs of toxicity. Complete blood counts, liver function tests, and renal function should be monitored regularly. Consider alternative antifungal agents with less CYP3A4 inhibition if clinically appropriate. Always consult with a clinical pharmacist or transplant specialist for dose adjustments and monitoring protocols.

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.

Posaconazole interactions with food and lifestyle

Posaconazole should be taken with food or a nutritional supplement to enhance absorption, as food significantly increases bioavailability. The delayed-release tablet formulation should be taken with food, while the oral suspension should be taken with a full meal or liquid nutritional supplement. Avoid taking posaconazole on an empty stomach as this can result in significantly reduced drug levels and potential treatment failure. Patients should also avoid antacids, proton pump inhibitors, and H2-receptor antagonists when possible, as these medications can reduce posaconazole absorption by increasing gastric pH.