Summary

The combination of quetiapine and fluconazole represents a significant drug interaction that can increase the risk of QT interval prolongation and potentially life-threatening cardiac arrhythmias. This interaction occurs primarily through fluconazole's inhibition of CYP3A4 enzymes, leading to increased quetiapine plasma concentrations.

Introduction

Quetiapine (brand name Seroquel) 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 of antipsychotics and works by blocking dopamine and serotonin receptors. Fluconazole (brand name Diflucan) is a triazole antifungal medication commonly prescribed for treating various fungal infections, including candidiasis, cryptococcal meningitis, and other systemic 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 through pharmacokinetic mechanisms involving cytochrome P450 enzyme inhibition. Fluconazole is a potent inhibitor of CYP3A4 and moderate inhibitor of CYP2C9 and CYP2C19 enzymes. Quetiapine is primarily metabolized by CYP3A4, with approximately 73% of the drug undergoing hepatic metabolism through this pathway. When fluconazole inhibits CYP3A4, it significantly reduces quetiapine's clearance, leading to increased plasma concentrations and prolonged half-life. This pharmacokinetic interaction can result in enhanced quetiapine effects, including increased risk of QT interval prolongation, sedation, and other adverse effects associated with elevated antipsychotic levels.

Risks and Symptoms

The primary clinical risk of combining quetiapine and fluconazole is the increased potential for QT interval prolongation, which can lead to torsades de pointes, a potentially fatal ventricular arrhythmia. Studies have shown that quetiapine can prolong the QT interval in a dose-dependent manner, and this risk is significantly amplified when combined with CYP3A4 inhibitors like fluconazole. Additional risks include enhanced sedation, orthostatic hypotension, extrapyramidal symptoms, and metabolic effects such as hyperglycemia and weight gain. Patients with pre-existing cardiac conditions, electrolyte imbalances (particularly hypokalemia or hypomagnesemia), or those taking other QT-prolonging medications are at particularly high risk. The interaction is considered clinically significant and requires careful monitoring or alternative treatment considerations.

Management and Precautions

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.