Drug Interaction Report

MONITOR: Coadministration of metyrosine in combination with haloperidol, phenothiazines, or other dopamine antagonists may increase the risk of extrapyramidal disorders. Extrapyramidal effects have been reported during metyrosine therapy. The mechanism is inhibition of catecholamine synthesis by metyrosine. In addition, sedative effects of both drugs may be increased.

MANAGEMENT: When concurrent use is required, patients should be monitored for extrapyramidal symptoms and instructed to notify their physician if they experience symptoms such as bradykinesia, hypertonia, rigidity, restlessness, and dysphagia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of lumateperone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit but has been reported for other CYP450 3A4 inhibitors. In a drug interaction study, the strong CYP450 3A4 inhibitor itraconazole increased lumateperone peak plasma concentration (Cmax) and systemic exposure (AUC) approximately 3.5- and 4-fold, respectively, while diltiazem (a moderate CYP450 3A4 inhibitor) increased lumateperone Cmax and AUC approximately 2- and 2.5-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

When administered with a high-fat meal, lumateperone Cmax decreased by 33% while its AUC increased by 9% and its median time to peak plasma concentration (Tmax) was delayed by about 1 hour.

MANAGEMENT: Lumateperone should be administered with food. Coadministration of grapefruit or grapefruit juice with lumateperone should be avoided.

MONITOR: Metyrosine, when coadministered with other CNS depressants including alcoholic beverages, may lead to excessive somnolence and other forms of nervous system depression.

MANAGEMENT: The patient should be informed to use caution if these agents are coadministered, especially if performing hazardous tasks such as driving or operating machinery.