Summary

Diltiazem significantly increases 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 primarily used to prevent organ transplant rejection and treat certain autoimmune conditions. It belongs to the mTOR inhibitor class of drugs. Diltiazem is a calcium channel blocker commonly prescribed for hypertension, angina, and certain heart rhythm disorders. Both medications are metabolized through the cytochrome P450 system, which creates the potential for significant drug interactions.

Mechanism of Interaction

The interaction between sirolimus and diltiazem occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Diltiazem is a moderate to strong CYP3A4 inhibitor, while sirolimus is extensively metabolized by this same enzyme pathway. When diltiazem inhibits CYP3A4, it reduces the metabolism and clearance of sirolimus, leading to increased sirolimus plasma concentrations. This pharmacokinetic interaction can result in sirolimus levels that are 2-3 times higher than expected, significantly prolonging the drug's half-life and enhancing its immunosuppressive effects.

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 the risk of infections and malignancies. Other potential adverse effects include nephrotoxicity, hepatotoxicity, hyperlipidemia, delayed wound healing, and increased risk of thrombotic microangiopathy. In transplant patients, while higher sirolimus levels may provide better immunosuppression, they also increase the risk of serious complications. The interaction is considered clinically significant and requires active management to prevent adverse outcomes.

Management and Precautions

When sirolimus and diltiazem must be used together, close monitoring and dose adjustments are essential. Key management strategies include: frequent monitoring of sirolimus trough levels (initially weekly, then every 2 weeks until stable), reducing sirolimus dose by 25-50% when initiating diltiazem, monitoring for signs of sirolimus toxicity including infection, delayed wound healing, and laboratory abnormalities, regular assessment of kidney and liver function, and lipid profile monitoring. Consider alternative antihypertensive agents that don't significantly inhibit CYP3A4 if clinically appropriate. Any dose adjustments should be made gradually with careful monitoring of therapeutic response and adverse effects.

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.

Diltiazem interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking diltiazem as they can significantly increase blood levels of the medication, potentially leading to dangerous drops in blood pressure and heart rate. Alcohol consumption should be limited or avoided as it can enhance the blood pressure-lowering effects of diltiazem and increase the risk of dizziness, fainting, and falls. Patients should also be cautious when standing up quickly or engaging in activities requiring alertness, as diltiazem can cause dizziness and lightheadedness, especially when starting treatment or increasing the dose.