Drug Interactions between cimetidine and revumenib

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).

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.