Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate or potent CYP450 3A4 inhibitors may significantly increase the plasma concentrations of tazemetostat, which is primarily metabolized by the isoenzyme. According to the product labeling, coadministration of tazemetostat (400 mg twice daily) with the moderate CYP450 3A4 inhibitor fluconazole increased the tazemetostat steady state exposure (AUC 0 to 8 hours) by 3.1-fold and peak plasma concentration by 2.3-fold. Clinically, this interaction may result in an increased risk of the frequency or severity of adverse reactions due to tazemetostat such as secondary malignancies, hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

MANAGEMENT: Concomitant use of tazemetostat with moderate or potent CYP450 3A4 inhibitors should generally be avoided. Alternative therapeutic agents with less inhibitory potential should be considered whenever possible. If coadministration with a moderate CYP450 3A4 inhibitor is required and no other alternatives are possible, the dose of tazemetostat should be reduced as per manufacturer recommendations. After the inhibitor has been discontinued for 3 elimination half-lives, the tazemetostat dose that was taken prior to initiating the inhibitor may be resumed. Patients should be advised to notify their health care professional if they experience signs or symptoms of possible tazemetostat-related adverse effects including secondary malignancies, hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during tazemetostat therapy may significantly increase the plasma concentrations of tazemetostat. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of tazemetostat by certain compounds in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). According to the product labeling, coadministration of tazemetostat (400 mg twice daily) with the moderate CYP450 3A4 inhibitor fluconazole increased the tazemetostat steady state exposure (AUC 0 to 8 hours) by 3.1-fold and peak plasma concentration by 2.3-fold. 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. 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. Clinically, this interaction may result in an increased risk of the frequency or severity of adverse reactions due to tazemetostat such as hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

MANAGEMENT: The manufacturer advises that patients treated with tazemetostat should avoid consumption of grapefruit or grapefruit juice.