Summary

Quetiapine and fluconazole have a clinically significant drug interaction that can increase the risk of cardiac arrhythmias and QT interval prolongation. This interaction occurs through fluconazole's inhibition of CYP3A4 enzymes, leading to increased quetiapine plasma concentrations and enhanced cardiac effects.

Introduction

Quetiapine is an atypical antipsychotic medication primarily used to treat schizophrenia, bipolar disorder, and major depressive disorder as adjunctive therapy. It belongs to the dibenzothiazepine class and works by blocking dopamine and serotonin receptors. Fluconazole is a triazole antifungal medication commonly prescribed for treating candidiasis, cryptococcal infections, and other fungal infections. It works by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

The interaction between quetiapine and fluconazole occurs primarily through cytochrome P450 enzyme inhibition. Fluconazole is a potent inhibitor of CYP3A4 and moderate inhibitor of CYP2C19, enzymes responsible for quetiapine metabolism. When fluconazole inhibits these enzymes, it reduces quetiapine clearance, leading to increased plasma concentrations and prolonged half-life. Additionally, both medications independently carry risks for QT interval prolongation, and their combination can have additive effects on cardiac conduction, potentially increasing the risk of torsades de pointes and other serious arrhythmias.

Risks and Symptoms

The primary clinical risks of combining quetiapine and fluconazole include significantly increased quetiapine plasma levels, which can lead to enhanced sedation, orthostatic hypotension, and extrapyramidal symptoms. Most concerning is the increased risk of QT interval prolongation and potentially life-threatening cardiac arrhythmias, including torsades de pointes. Patients may experience excessive drowsiness, dizziness, confusion, and increased fall risk. The interaction is particularly dangerous in elderly patients, those with pre-existing cardiac conditions, electrolyte imbalances, or concurrent use of other QT-prolonging medications. Overdose-like symptoms may occur even at therapeutic doses of quetiapine when combined with fluconazole.

Management and Precautions

When this combination cannot be avoided, close monitoring is essential. Obtain baseline and follow-up ECGs to monitor QT intervals, and check electrolyte levels (potassium, magnesium, calcium) before and during treatment. Consider reducing quetiapine dose by 50% or more when initiating fluconazole, and titrate based on clinical response and tolerability. Monitor patients closely for signs of quetiapine toxicity, including excessive sedation, orthostatic hypotension, and cardiac symptoms. If possible, consider alternative antifungal agents with less CYP3A4 inhibition, such as terbinafine for appropriate indications. Educate patients about potential symptoms and advise them to report dizziness, palpitations, or fainting immediately. Regular clinical assessments should include vital signs, mental status, and cardiac monitoring throughout concurrent therapy.

Quetiapine interactions with food and lifestyle

Quetiapine should not be taken with alcohol as it can increase the risk of drowsiness, dizziness, and impaired coordination. Grapefruit juice may increase quetiapine levels in the blood and should be avoided. Patients should be cautious when driving or operating machinery due to potential sedation effects. Smoking may decrease quetiapine effectiveness, and patients should discuss smoking cessation with their healthcare provider.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.