Drug Interaction Report

MONITOR: Coadministration with tazemetostat may decrease the plasma concentrations of drugs that are primarily metabolized by the CYP450 3A4 isoenzyme. The proposed mechanism is increased clearance due to induction of CYP450 3A4 by tazemetostat. According to the product labeling, coadministration of tazemetostat (800 mg twice daily) with the sensitive CYP450 3A4 substrate midazolam in patients led to reduction in the systemic exposure (AUC 0 to 12 hours) and peak plasma concentration (Cmax) of midazolam by 40% and 21%, respectively. The interaction may be more significant for sensitive CYP450 3A4 substrates.

MANAGEMENT: Caution is advised when tazemetostat is used concomitantly with drugs that undergo metabolism by CYP450 3A4. Dose adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever tazemetostat is added to or withdrawn from therapy.

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.

GENERALLY AVOID: Acute ethanol ingestion may potentiate the CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: Patients should be advised to avoid alcohol during benzodiazepine therapy.