Drug Interactions between galantamine and revumenib

ADJUST DOSING INTERVAL: The administration of galantamine with food and adequate fluid intake may reduce the impact of nausea, vomiting, diarrhea, anorexia, and weight loss that are commonly associated with acetylcholinesterase inhibitors (AChEIs). According to product labeling, the administration of food with various galantamine formulations (e.g., liquid, immediate-release tablets, modified/extended-release capsules) has no significant effect on the systemic absorption (AUC) of galantamine. While the presence of food has been shown to delay the rate of absorption (Tmax) and reduce peak concentration (Cmax), these changes are unlikely to be clinically significant. For example, when galantamine modified release was given after food, Tmax increased by approximately 30 minutes. Similarly, in 24 healthy elderly subjects, the presence of food with galantamine immediate release tablets (12 mg twice a day) delayed the Tmax by 1.5 hours and decreased the Cmax by about 25% without affecting the AUC.

MONITOR: Grapefruit and grapefruit juice may increase the plasma concentrations of galantamine, which is partially metabolized by the CYP450 3A4 isoenzyme. 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 juice, but has been reported with both moderate and potent CYP450 3A4 inhibitors. When study subjects (n=16) received the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 4 days) with galantamine (4 mg twice daily for 8 days), the systemic exposure (AUC) of galantamine increased by 30%. However, when study subjects (n=16) received the moderate CYP450 3A4 inhibitor erythromycin (500 mg 4 times daily for 4 days) with galantamine (4 mg twice daily for 6 days), the AUC of galantamine only increased by 10%. In general, the effects of grapefruit products are concentration-, dose-, and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit (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. While the clinical significance of this interaction is unknown, increased exposure to galantamine may lead to AChEI related adverse effects such as vagotonic effects on the heart rate (e.g., bradycardia and heart block), neurologic side effects (e.g., seizure activity), respiratory distress, bladder outflow obstruction, dizziness or syncope, nausea, vomiting and/or diarrhea.

MANAGEMENT: According to product labeling, galantamine should be administered with food and adequate fluid intake to reduce the impact of cholinergic-related gastrointestinal adverse effects (e.g., nausea, vomiting, diarrhea, anorexia, and weight loss). Caution and closer monitoring for AChEI related adverse effects may advisable if galantamine is used in combination with grapefruit and/or grapefruit juice. Modified and/or extended-release formulations must also be swallowed whole and not crushed, chewed, or divided.

ADJUST DOSING INTERVAL: In pharmacokinetic studies, revumenib was administered while fasting or with a low fat meal. Revumenib has not been studied with meals of higher fat content and the impact on its pharmacokinetic parameters is unknown.

MONITOR: Grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges may increase the plasma concentrations of revumenib. 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. In pharmacokinetic studies in patients with relapsed or refractory acute leukemia, revumenib area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) increased 2-fold following concomitant use with the potent CYP450 3A4 inhibitors posaconazole, itraconazole, and voriconazole, and 2.5-fold following concomitant use with the potent CYP450 3A4 inhibitor cobicistat. However, clinically significant differences in revumenib pharmacokinetics were not observed when used concomitantly with the moderate CYP450 3A4 inhibitors fluconazole and isavuconazole. 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. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability. Increased exposure to revumenib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Due to the potential impact of high fat content meals on revumenib absorption and exposure, it is recommended that revumenib be administered while fasting or with a low fat meal (approximately 400-500 calories, with 25% of calories from fat). In addition, if grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, or Seville oranges are consumed during treatment with revumenib, assess patient tolerability and monitor for serious adverse effects (e.g., QT prolongation and torsade de pointes arrhythmia, differentiation syndrome, neutropenia, thrombocytopenia).