Summary

Lurasidone and fluconazole have a significant drug interaction due to fluconazole's inhibition of CYP3A4, the primary enzyme responsible for lurasidone metabolism. This interaction can lead to substantially increased lurasidone levels, potentially causing serious adverse effects including QT prolongation and extrapyramidal symptoms.

Introduction

Lurasidone (brand name Latuda) is an atypical antipsychotic medication primarily used to treat schizophrenia and bipolar depression. It belongs to the benzisothiazol class of antipsychotics and works by modulating dopamine and serotonin receptors in the brain. Fluconazole (brand name Diflucan) is a triazole antifungal medication commonly prescribed to treat various fungal infections, including candidiasis and cryptococcal 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 lurasidone and fluconazole occurs through cytochrome P450 enzyme inhibition. Lurasidone is primarily metabolized by the CYP3A4 enzyme system, with approximately 80% of the drug undergoing hepatic metabolism via this pathway. Fluconazole is a potent inhibitor of CYP3A4, as well as CYP2C9 and CYP2C19 enzymes. When fluconazole inhibits CYP3A4, it significantly reduces lurasidone's clearance from the body, leading to increased plasma concentrations and prolonged half-life. This pharmacokinetic interaction can result in lurasidone levels that are 7-9 times higher than normal, dramatically increasing the risk of dose-related adverse effects.

Risks and Symptoms

The primary clinical risks of this interaction include significantly elevated lurasidone plasma concentrations, which can lead to serious adverse effects. Key risks include QT interval prolongation, which may result in potentially fatal cardiac arrhythmias such as torsades de pointes. Patients may also experience increased extrapyramidal symptoms including dystonia, akathisia, parkinsonism, and tardive dyskinesia. Other concerning effects include severe sedation, orthostatic hypotension, metabolic disturbances, and increased risk of neuroleptic malignant syndrome. The interaction is considered clinically significant and may require dose adjustments or alternative therapy selection to ensure patient safety.

Management and Precautions

Lurasidone interactions with food and lifestyle

Lurasidone should be taken with food (at least 350 calories) to ensure proper absorption and effectiveness. Taking lurasidone on an empty stomach can significantly reduce drug absorption by approximately 50%. Patients should avoid grapefruit and grapefruit juice while taking lurasidone, as grapefruit can increase lurasidone blood levels and potentially increase the risk of side effects. Alcohol should be avoided or limited while taking lurasidone, as it may increase drowsiness, dizziness, and impair judgment and motor skills.

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.