Drug Interactions between amoxicillin / clarithromycin / vonoprazan and venetoclax

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of venetoclax, which is primarily metabolized by 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. 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), the concomitant use of potent CYP450 3A4 inhibitors is contraindicated during the initiation and dosage ramp-up phase of venetoclax. The manufacturer also advises against use of potent CYP450 3A4 inhibitors once the dosage ramp-up phase is completed and the steady daily dose phase of venetoclax therapy begins. However, if concomitant therapy with a potent CYP450 3A4 inhibitor other than posaconazole is considered necessary, the daily dose of venetoclax should be reduced to 100 mg or less. If a dose had already been modified for venetoclax-related adverse reactions/toxicities in accordance with product labeling, some authorities suggest the dose should be further reduced by 75%. If concomitant use with posaconazole is required during the steady daily dose phase of therapy, the manufacturer advises the venetoclax dosage be reduced to 70 mg.

In patients with acute myeloid leukemia (AML), the dose of venetoclax should be reduced when coadministered with potent CYP450 3A4 inhibitors. This adjustment applies throughout both the initiation and dosage ramp-up phases, as well as the ongoing steady daily dose phase of therapy. During the initiation and ramp-up phases, the recommended schedule from the manufacturer is 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, and 100 mg on day 4. Following completion of the ramp-up phase, a maintenance dose of 100 mg or less per day is advised for the steady daily dose phase. Some authorities suggest reducing the dose by at least 75% if adjustments have already been made due to venetoclax-related adverse reactions or toxicities. However, in cases where concurrent use with posaconazole is necessary, certain authorities propose a similar initiation and ramp-up phase dosing regimen of venetoclax from days 1 to 3 , followed by 70 mg on day 4, and continuing into the steady daily dose phase of therapy.

All patients, regardless of indication, should be closely monitored for signs and symptoms of venetoclax-induced adverse effects/toxicities. In addition, the dosage used prior to initiating the potent CYP450 3A4 inhibitor may be resumed 2 to 3 days after discontinuation of the inhibitor.

MONITOR: Coadministration with 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) inhibitor 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 AUC of venetoclax by between 2- to 4.9-fold, 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: Caution is advised when venetoclax is used with inhibitors of CYP450 3A4. Close clinical and laboratory monitoring for the development of tumor lysis syndrome and myelosuppression is recommended following the addition of a CYP450 3A4 inhibitor. If signs or symptoms of venetoclax-related adverse effects develop, the dosage should be modified as per the manufacturer's recommendations.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.