Summary

Lurasidone and ketoconazole have a significant drug interaction that can lead to dangerously elevated lurasidone levels. This interaction is considered contraindicated due to the risk of serious adverse effects including cardiac arrhythmias 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. Ketoconazole is a potent antifungal medication from the azole class, used to treat serious fungal infections. It is known as a strong inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, which is responsible for metabolizing many medications including lurasidone.

Mechanism of Interaction

The interaction between lurasidone and ketoconazole occurs through inhibition of the CYP3A4 enzyme pathway. Lurasidone is extensively metabolized by CYP3A4, and ketoconazole is a potent CYP3A4 inhibitor. When ketoconazole blocks this enzyme, it significantly reduces lurasidone's metabolism, leading to dramatically increased plasma concentrations of lurasidone. Studies have shown that ketoconazole can increase lurasidone exposure by approximately 9-fold, creating a risk for dose-dependent adverse effects.

Risks and Symptoms

The primary risks of this interaction include significantly elevated lurasidone plasma levels, which can lead to serious adverse effects. These may include prolonged QT interval and potential cardiac arrhythmias, increased risk of extrapyramidal symptoms (such as dystonia, akathisia, and tardive dyskinesia), severe sedation and cognitive impairment, orthostatic hypotension, and metabolic side effects. Due to the magnitude of this interaction and the potential for life-threatening complications, the combination is considered contraindicated by regulatory agencies and clinical guidelines.

Management and Precautions

The concurrent use of lurasidone and ketoconazole should be avoided. If antifungal treatment is necessary in patients taking lurasidone, alternative antifungal agents with less CYP3A4 inhibition should be considered, such as fluconazole (though dose adjustments may still be needed) or topical antifungals when appropriate. If ketoconazole must be used, lurasidone should be discontinued and alternative antipsychotic therapy considered. Healthcare providers should review all medications for potential CYP3A4 interactions before prescribing lurasidone, and patients should be counseled to inform all healthcare providers about their lurasidone therapy before starting any new medications.

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.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.