Summary

Itraconazole significantly increases venetoclax blood levels through CYP3A4 enzyme inhibition, potentially leading to severe toxicity. This interaction requires careful dose adjustments or alternative antifungal therapy to ensure patient safety.

Introduction

Itraconazole is a triazole antifungal medication used to treat various fungal infections, including aspergillosis, candidiasis, and dermatophyte infections. It works by inhibiting fungal cytochrome P450 enzymes essential for ergosterol synthesis. Venetoclax is a selective BCL-2 inhibitor approved for treating certain blood cancers, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). It works by blocking the BCL-2 protein, which helps cancer cells survive, thereby promoting cancer cell death.

Mechanism of Interaction

The interaction between itraconazole and venetoclax occurs through cytochrome P450 3A4 (CYP3A4) enzyme inhibition. Itraconazole is a potent CYP3A4 inhibitor, while venetoclax is primarily metabolized by this enzyme system. When itraconazole inhibits CYP3A4, it significantly reduces venetoclax metabolism, leading to increased plasma concentrations and prolonged elimination half-life. This pharmacokinetic interaction can result in venetoclax levels that are 3-5 times higher than normal, substantially increasing the risk of dose-related adverse effects.

Risks and Symptoms

The primary risk of this interaction is venetoclax toxicity due to elevated drug concentrations. Key clinical risks include severe neutropenia, thrombocytopenia, and anemia, which can lead to life-threatening infections, bleeding complications, and the need for blood transfusions. Tumor lysis syndrome (TLS) risk may also be increased, particularly during venetoclax initiation or dose escalation. Other potential adverse effects include gastrointestinal toxicity, fatigue, and increased susceptibility to opportunistic infections. The interaction is considered clinically significant and requires immediate attention to prevent serious complications.

Management and Precautions

When itraconazole and venetoclax must be used together, venetoclax dose reduction is essential. Reduce venetoclax dose by approximately 75% when co-administered with strong CYP3A4 inhibitors like itraconazole. Monitor complete blood counts more frequently, typically weekly during the first month and then as clinically indicated. Consider alternative antifungal agents with less CYP3A4 inhibition potential, such as fluconazole (with appropriate dose adjustments) or echinocandins like caspofungin. If itraconazole is discontinued, gradually resume the original venetoclax dose after a washout period of 2-3 days. Patients should be counseled about signs of infection, bleeding, and other toxicity symptoms requiring immediate medical attention.

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.

Venetoclax interactions with food and lifestyle

Venetoclax should be taken with food to improve absorption and reduce gastrointestinal side effects. Grapefruit and grapefruit juice should be avoided as they can significantly increase venetoclax blood levels and toxicity risk. Seville oranges (bitter oranges) should also be avoided for the same reason. Patients should maintain adequate hydration, especially during the initial treatment period when tumor lysis syndrome risk is highest. St. John's wort should be avoided as it may decrease venetoclax effectiveness.