Drug Interaction Report

GENERALLY AVOID: Macimorelin can cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a dedicated thorough QT study consisting of 60 healthy subjects, a mean baseline- and placebo-adjusted change in QTcF of 9.6 msec was observed 4 hours following administration of a supratherapeutic dose of macimorelin 2 mg/kg (4 times the recommended dose), which occurred after the mean maximum macimorelin plasma concentration (0.5 hour). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels: 0.5 mg/kg; 1 mg/kg (2 times the recommended dose); and 2 mg/kg (4 times the recommended dose). All three doses levels produced a similar magnitude of QTcF prolongation as reported in the thorough QT study, suggesting an absence of dose-dependent changes. The mechanism for the observed QTcF prolongation is unknown. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of macimorelin with other drugs that can prolong the QT interval should generally be avoided. A sufficient washout period following discontinuation of these drugs is recommended prior to macimorelin administration. Patients treated with any medication that can cause QT prolongation should be advised to seek prompt 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: 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.

ADJUST DOSING INTERVAL: Food reduces the oral bioavailability of macimorelin. According to the product labeling, administration with a liquid meal decreased macimorelin peak plasma concentration (Cmax) and systemic exposure (AUC) by 55% and 49%, respectively, compared to administration under fasting conditions (i.e., for at least 8 hours).

MANAGEMENT: Macimorelin should be administered after fasting for at least 8 hours.