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, specifically CYP3A4, which creates the potential for significant drug interactions.

Mechanism of Interaction

The interaction between sirolimus and diltiazem occurs through competitive inhibition of the CYP3A4 enzyme system. Diltiazem is a moderate to strong CYP3A4 inhibitor that reduces the hepatic metabolism of sirolimus. Since sirolimus has a narrow therapeutic index and relies heavily on CYP3A4 for elimination, concurrent use with diltiazem can result in 2-3 fold increases in sirolimus blood concentrations. This pharmacokinetic interaction also affects P-glycoprotein transport, further contributing to elevated sirolimus levels.

Risks and Symptoms

The primary clinical risk of this interaction is sirolimus toxicity due to elevated drug levels. Increased sirolimus concentrations can lead to enhanced immunosuppression, increasing susceptibility to infections and malignancies. Other significant risks include nephrotoxicity, hepatotoxicity, delayed wound healing, hyperlipidemia, and bone marrow suppression. Patients may experience symptoms such as mouth ulcers, diarrhea, thrombocytopenia, and elevated serum creatinine. The interaction is considered clinically significant and requires active management.

Management and Precautions

When concurrent use is necessary, sirolimus doses should typically be reduced by 33-50% with frequent therapeutic drug monitoring. Sirolimus trough levels should be checked within 3-5 days of starting diltiazem and weekly thereafter until stable levels are achieved. Target therapeutic ranges should be maintained according to the specific indication. Consider alternative calcium channel blockers with less CYP3A4 inhibition potential, such as amlodipine or nifedipine, if clinically appropriate. Monitor for signs of sirolimus toxicity including complete blood counts, liver function tests, and renal function. Patients should be counseled about infection precautions 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.

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.