Drug Interaction Report

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of venetoclax, which is a substrate of the isoenzyme. 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. Likewise, concomitant use of the P-gp and potent CYP450 3A4 inhibitor posaconazole (300 mg) with venetoclax 50 mg or 100 mg daily for 7 days increased the venetoclax Cmax by 1.61-fold and 1.86-fold, respectively, and AUC by 1.9-fold and 2.44-fold, respectively, compared with venetoclax (400 mg daily) alone. Clinical data exploring the use of venetoclax with less potent CYP450 3A4 inhibitors are not available. However, 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. 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: In patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), concomitant use of moderate CYP450 3A4 inhibitors with venetoclax at its steady daily dosage (after the dosage ramp-up phase) should generally be avoided. Some authorities advise that the concomitant use of moderate CYP450 3A4 inhibitors with venetoclax should also be avoided at initiation and during the dose titration phase in patients with CLL/SLL. However, if coadministration is required, the manufacturer recommends the venetoclax dosage be reduced by at least 50% of the original dose for patients with CLL/SLL as well as patients with acute myeloid leukemia (AML). All patients, regardless of indication, should be monitored closely for signs and symptoms of venetoclax-related adverse effects/toxicities. In addition, the dosage used prior to initiating the moderate CYP450 3A4 inhibitor may be resumed 2 to 3 days after discontinuation of the inhibitor.

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.