Drug Interaction Report

MONITOR: Lindane penetrates human skin and has the potential to cause central nervous system toxicity. Seizures have been reported after excessive use or oral ingestion of lindane. There may be a theoretical risk of increased seizure potential when lindane is used with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), and/or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, theophylline). These agents are often individually epileptogenic and may have additive effects when combined.

MANAGEMENT: Caution is advised if lindane is used with any substance that can reduce the seizure threshold, particularly in the very young or the elderly and in patients with epilepsy, a history of seizures, or other risk factors for seizures (e.g., head trauma, brain tumor, metabolic disorders, alcohol and drug withdrawal, CNS infections). Lindane should be used according to recommended dosage and directions for application.

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.