Encorafenib

7 DRUG INTERACTIONS • Strong or moderate CYP3A4 inhibitors: Avoid coadministration. If unavoidable, reduce BRAFTOVI dosage. ( 2.6 , 7.1 ) • Strong CYP3A4 inducers: Avoid coadministration. ( 7.1 ) • Sensitive CYP3A4 substrates: Avoid coadministration with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. ( 7.2 ) • Transporters: Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. ( 7.2 , 12.3 )

7.1 Effect of Other Drugs on BRAFTOVI Strong or Moderate CYP3A4 Inhibitors Coadministration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increases encorafenib plasma concentrations [see Clinical Pharmacology (12.3) ] and may increase encorafenib adverse reactions. Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose [see Dosage and Administration (2.6) ] . Strong CYP3A4 Inducers Coadministration of BRAFTOVI with a strong CYP3A4 inducer may decrease encorafenib plasma concentrations [see Clinical Pharmacology (12.3) ] and may decrease encorafenib efficacy.

Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.

7.2 Effect of BRAFTOVI on Other Drugs Sensitive CYP3A4 Substrates BRAFTOVI is a strong CYP3A4 inducer at steady-state. Concomitant use of BRAFTOVI may decrease the plasma concentrations of CYP3A4 substrates (including hormonal contraceptives), [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of these substrates. Avoid the coadministration of BRAFTOVI with CYP3A4 substrates for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.

OATP1B1, OATP1B3, or BCRP Substrates Coadministration of BRAFTOVI with OATP1B1, OATP1B3, or BCRP substrates can result in increased concentrations of the substrates, and may increase toxicity of these agents. When used in combination, monitor patients closely for signs and symptoms of increased exposure and consider adjusting the dose of these substrates [see Clinical Pharmacology (12.3) ].

7.3 Drugs That Prolong the QT Interval BRAFTOVI is associated with dose-dependent QTc interval prolongation [see Warnings and Precautions (5.7) , Clinical Pharmacology (12.2) ] . Avoid coadministration of BRAFTOVI with drugs known to prolong the QT/QTc interval.

8.1 Pregnancy Risk Summary Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available clinical data on the use of BRAFTOVI during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses (see Data ) .

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily).

In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.