Drug Interactions between Tazverik and venetoclax

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of venetoclax. Relative to fasting conditions, venetoclax systemic exposure (AUC) increased by approximately 3.4-fold when administered with a low-fat meal (approximately 512 kilocalories, 25% calories from fat) and by 5.1- to 5.3-fold when administered with a high-fat meal (approximately 753 kilocalories, 55% calories from fat).

GENERALLY AVOID: Grapefruit, grapefruit juice, Seville oranges, and starfruit may increase the plasma concentrations of venetoclax, which is primarily 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 potent CYP450 3A4 inhibitors. In a study of 11 previously treated non-Hodgkin lymphoma patients, when the potent CYP450 3A4 inhibitor, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor ketoconazole (400 mg daily for 7 days) was coadministered with venetoclax (50 mg single dose), venetoclax peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.3-fold and 6.4-fold, respectively. Physiologically based pharmacokinetic modeling estimates that the moderate CYP450 3A4 inhibitors diltiazem and erythromycin may increase the Cmax and AUC of venetoclax by between 1.4- to 2- fold and 2- to 4.9-fold, respectively, while the weak CYP450 3A4 inhibitors fluoxetine and fluvoxamine appear to have no significant effect on its Cmax or AUC. 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. Increased venetoclax exposure may potentiate the risk of tumor lysis syndrome, particularly at initiation of therapy and during the dosage ramp-up phase, as well as other adverse effects such as diarrhea, nausea, vomiting, neutropenia, anemia, and thrombocytopenia.

MANAGEMENT: Venetoclax should be administered with a meal and water at approximately the same time each day. Patients should avoid consumption of grapefruit products, Seville oranges, and starfruit during treatment with venetoclax.

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.