Summary

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

Introduction

Itraconazole is a triazole antifungal medication commonly prescribed for systemic fungal infections, including aspergillosis, histoplasmosis, and onychomycosis. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase. Cyclosporine is a calcineurin inhibitor immunosuppressant primarily used to prevent organ transplant rejection and treat certain autoimmune conditions like severe rheumatoid arthritis and psoriasis. Both medications are metabolized through the cytochrome P450 system, making them susceptible to significant drug interactions.

Mechanism of Interaction

The interaction between itraconazole and cyclosporine occurs through competitive inhibition of the CYP3A4 enzyme system. Itraconazole is a potent inhibitor of CYP3A4, the primary enzyme responsible for cyclosporine metabolism. When itraconazole blocks this metabolic pathway, cyclosporine clearance is significantly reduced, leading to elevated plasma concentrations. Studies have shown that itraconazole can increase cyclosporine levels by 50-100% or more, with the effect persisting for several days after itraconazole discontinuation due to its long half-life and irreversible enzyme binding.

Risks and Symptoms

The primary clinical risk of this interaction is cyclosporine toxicity, which can manifest as nephrotoxicity (kidney damage), hepatotoxicity (liver damage), neurotoxicity (tremors, seizures, confusion), and hypertension. Elevated cyclosporine levels increase the risk of acute and chronic kidney injury, which may be irreversible in severe cases. Additional risks include increased susceptibility to infections due to over-immunosuppression, development of malignancies, and cardiovascular complications. The interaction is considered major in clinical significance, requiring immediate attention and intervention when both drugs are prescribed together.

Management and Precautions

Management of this interaction requires proactive cyclosporine dose reduction (typically 25-50%) when initiating itraconazole therapy, with frequent therapeutic drug monitoring of cyclosporine trough levels. Monitor cyclosporine levels within 2-3 days of starting itraconazole and adjust doses accordingly to maintain target therapeutic ranges. Close monitoring of kidney function (serum creatinine, BUN), liver enzymes, blood pressure, and neurological status is essential. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole (though it also interacts) or echinocandins like caspofungin. When discontinuing itraconazole, gradually increase cyclosporine doses back to baseline while monitoring levels, as the interaction effect may persist for 1-2 weeks.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.

Cyclosporine interactions with food and lifestyle

Cyclosporine has several important food and lifestyle interactions that patients should be aware of: **Grapefruit and Grapefruit Juice:** Avoid grapefruit and grapefruit juice while taking cyclosporine. Grapefruit contains compounds that inhibit CYP3A4 enzymes, which can significantly increase cyclosporine blood levels and potentially lead to toxicity. This interaction is well-documented and patients are specifically warned to avoid grapefruit products. **High-Fat Meals:** Taking cyclosporine with high-fat meals can increase the absorption of the medication, potentially leading to higher blood levels. While this doesn't require complete avoidance, patients should maintain consistent dietary habits and take cyclosporine at the same time each day relative to meals. **St. John's Wort:** This herbal supplement should be avoided as it can significantly decrease cyclosporine blood levels by inducing CYP3A4 enzymes, potentially leading to organ rejection in transplant patients or treatment failure. **Alcohol:** While moderate alcohol consumption may not be completely contraindicated, patients should discuss alcohol use with their healthcare provider as cyclosporine can affect liver function, and alcohol may compound these effects. **Sun Exposure:** Patients taking cyclosporine have an increased risk of skin cancer and should limit sun exposure, use sunscreen with high SPF, and wear protective clothing when outdoors.