Enzalutamide

7 DRUG INTERACTIONS • Strong CYP2C8 Inhibitors: Avoid strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI. ( 2.3 , 7.1 ) • Strong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI. ( 2.3 , 7.1 ) • Avoid coadministration with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. In cases where active metabolites are formed, there may be increased exposure to the active metabolites. ( 7.2 )

7.1 Effect of Other Drugs on XTANDI Strong CYP2C8 Inhibitors The coadministration of XTANDI with gemfibrozil (a strong CYP2C8 inhibitor) increases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may increase the incidence and severity of adverse reactions of XTANDI. Avoid the coadministration of XTANDI with strong CYP2C8 inhibitors. If the coadministration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of XTANDI [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )].

Strong CYP3A4 Inducers The coadministration of XTANDI with rifampin (a strong CYP3A4 inducer and a moderate CYP2C8 inducer) decreases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may decrease the efficacy of XTANDI. Avoid the coadministration of XTANDI with strong CYP3A4 inducers. If the coadministration of XTANDI with a strong CYP3A4 inducer cannot be avoided, increase the dosage of XTANDI [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )].

7.2 Effect of XTANDI on Other Drugs Certain CYP3A4, CYP2C9, or CYP2C19 Substrates XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. The coadministration of XTANDI decreases the concentrations of certain CYP3A4, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of these substrates. Avoid the coadministration of XTANDI with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. If the coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information.

In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

7.3 Laboratory Test Interference XTANDI can interfere with certain digoxin immunoassays (e.g., Chemiluminescent Microparticle Immunoassays), resulting in falsely elevated digoxin plasma concentration results. Notify the laboratory conducting the digoxin plasma concentration assay to use an appropriate method in patients receiving XTANDI and digoxin [see Warnings and Precautions ( 5.8 )] .

8.1 Pregnancy Risk Summary The safety and efficacy of XTANDI have not been established in females. Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy. There are no human data on the use of XTANDI in pregnant females. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data).

Data Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients.

Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a C max that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration.