Drug Interaction Report

MONITOR CLOSELY: Coadministration with inducers of CYP450 3A4 may increase the peak activity and/or decrease the duration of action of levomethadyl acetate, which is primarily metabolized by the isoenzyme. Induction of CYP450 3A4 also results in increased formation of the active metabolites, nor-LAAM and dinor-LAAM. High plasma levels of these metabolites may increase the risk of QT interval prolongation and serious ventricular arrhythmias such as torsade de pointes.

MANAGEMENT: Close monitoring is recommended if levomethadyl acetate is used with CYP450 3A4 inducers, particularly potent ones like carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, primidone (partially metabolized to phenobarbital), rifamycins, and St. John's wort. The dose or dosing interval may require adjustment if an interaction is suspected. A 12-lead ECG should be performed before initiating levomethadyl acetate therapy, 12 to 14 days after initiating therapy, and periodically thereafter. Patients should be advised to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

GENERALLY AVOID: The concurrent use of levomethadyl acetate and alcohol may result in additive CNS and respiratory depression, hypotension, sedation, or coma. Grapefruit juice may increase the plasma concentrations of orally administered drugs which are substrates of the CYP450 3A4 isoenzyme, such as levomethadyl acetate. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Patients who are known to abuse alcohol should be warned of the risk of potentially fatal overdose if these substances are taken concurrently. Patients who regularly consume grapefruits and grapefruit juice should be monitored for adverse effects and altered plasma concentrations of levomethadyl acetate. A 12-lead ECG should be performed before initiating therapy, 12 to 14 days after initiating therapy, and periodically thereafter. Patients should be advised to immediately seek medical attention if they experience palpitations, dizziness, lightheadedness, fainting, or seizures. Grapefruits and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact.