istration (2.4, 2.5) and Clinical Pharmacology (12.3)].
Co-administration of ketoconazole increased venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold.
Moderate CYP3A Inhibitors and P-gp Inhibitors
Avoid concomitant use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil) or P-gp inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine, ticagrelor) with VENCLEXTA. Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor patients more closely for signs of VENCLEXTA toxicities [see Dosage and Administration (2.4, 2.5) and Clinical Pharmacology (12.3)].
Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as they contain inhibitors of CYP3A.
Co-administration of a single dose of rifampin, a P-gp inhibitor, increased venetoclax Cmax by 106% and AUC∞ by 78%.
CYP3A Inducers
Avoid concomitant use of VENCLEXTA with strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). Consider alternative treatments with less CYP3A induction [see Clinical Pharmacology (12.3)].
Co-administration of multiple doses of rifampin, a strong CYP3A inducer, decreased venetoclax Cmax by 42% and AUC∞ by 71%.
7.2 Effects of VENCLEXTA on Other DrugsWarfarin
In a drug-drug interaction study in healthy subjects, administration of a single dose of venetoclax with warfarin resulted in an 18% to 28% increase in Cmax and AUC∞ of R-warfarin and S-warfarin. Because venetoclax was not dosed to steady state, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving warfarin.
P-gp substrates
In vitro data suggest venetoclax has inhibition potential on P-gp substrates at therapeutic dose levels in the gut. Therefore, co-administration of narrow therapeutic index P-gp substrates (e.g., digoxin, everolimus, and sirolimus) with VENCLEXTA should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before VENCLEXTA.
8 USE IN SPECIFIC POPULATIONS
8.1 PregnancyRisk Summary
There are no available human data on the use of VENCLEXTA in pregnant women. Based on toxicity observed in mice, VENCLEXTA may cause fetal harm when administered to pregnant women. In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure based on AUC at the recommended human dose of 400 mg daily. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient should be apprised of the potential risk to a fetus.
The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal data
In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and decreas |
