Drug Interaction Report

MONITOR: Coadministration with potent CYP450 3A4 inducers may decrease the plasma concentration and therapeutic effects of momelotinib. The proposed mechanism is increased metabolism of momelotinib via the CYP450 3A4 isoenzyme. However, momelotinib is metabolized by multiple pathways and so the clinical significance is unclear. In a phase I study, coadministration of multiple doses of rifampin (600 mg once daily) following a single dose of momelotinib (200 mg) reduced the Cmax and AUC of momelotinib by 29% and 46%, respectively, when compared with a single dose of momelotinib (200 mg) plus a single dose of rifampin (600 mg). No data are available for use with other, less potent inducers.

MANAGEMENT: Caution and monitoring for decreased momelotinib efficacy may be required when used concomitantly with potent CYP450 3A4 inducers. An alternative agent with less potential for induction should be considered if possible.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.