Drug Interactions between givosiran and Methadone Diskets

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of methadone. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of methadone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 8 study subjects stabilized on methadone maintenance treatment, ingestion of regular strength grapefruit juice (200 mL one-half hour before and 200 mL simultaneously with the daily methadone dose) for five days resulted in an approximately 17% mean increase in methadone peak plasma concentration (Cmax) and systemic exposure (AUC) and a 14% mean decrease in apparent clearance for both the R(+) and S(-) enantiomers. Grapefruit juice did not affect the time to peak level (Tmax), terminal half-life, or apparent volume of distribution of methadone. No signs or symptoms of methadone toxicity or changes in intensity of withdrawal symptoms were reported in the study. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In addition, high dosages (particularly above 200 mg/day) and high serum levels of methadone have been associated with QT interval prolongation and torsade de pointes arrhythmia.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with methadone. Any history of alcohol or illicit drug use should be considered when prescribing methadone, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. In addition, patients treated with oral methadone should preferably avoid or limit the consumption of grapefruit juice, particularly during the induction of maintenance treatment. Given the interindividual variability in the pharmacokinetics of methadone, a significant interaction with grapefruit juice in certain patients cannot be ruled out. 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.