Tazemetostat

Strong or Moderate Cytochrome P450 (CYP)3A Inhibitors : Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. Reduce the dose of TAZVERIK if coadministration of strong or moderate CYP3A inhibitors cannot be avoided. ( 2.3 , 7.1 ) Strong or Moderate CYP3A Inducers : Avoid coadministration with TAZVERIK. ( 7.1 )

7.1 Effect of Other Drugs on TAZVERIK Strong or Moderate CYP3A Inhibitors Coadministration of TAZVERIK with a strong or moderate CYP3A inhibitor increases tazemetostat plasma concentrations [see Clinical Pharmacology ( 12.3 )], which may increase the frequency or severity of adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. If coadministration of strong or moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose [see Dosage and Administration ( 2.4 )].

Strong or Moderate CYP3A Inducers Coadministration of TAZVERIK with a strong CYP3A inducer decreases tazemetostat plasma concentrations [see Clinical Pharmacology ( 12.3 )] , and coadministration of TAZVERIK with a moderate CYP3A inducer may also decrease tazemetostat plasma concentrations. The decrease in tazemetostat plasma concentration may decrease the efficacy of TAZVERIK. Avoid coadministration of moderate or strong CYP3A inducers with TAZVERIK.

7.2 Effect of TAZVERIK on Other Drugs CYP3A Substrates Coadministration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates [see Use in Specific Populations ( 8.3 ), Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , TAZVERIK can cause fetal harm when administered to pregnant women. There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk. Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure [AUC 0-45h ] at the 800 mg twice daily dose (see Data ) . Advise pregnant women 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 pregnant rats, once daily oral administration of tazemetostat during the period of organogenesis from gestation day (GD) 7 through 17 resulted in no maternal adverse effects at doses up to 100 mg/kg/day (approximately 6 times the adult human exposure at 800 mg twice daily). Skeletal malformations and variations occurred in fetuses at doses of ≥50 mg/kg (approximately 2 times the adult human exposure at the 800 mg twice daily dose).

At 200 mg/kg (approximately 14 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss, missing digits, fused vertebrae, domed heads and fused bones of the skull, and reduced fetal body weights. In pregnant rabbits, no adverse maternal effects were observed after once daily oral administration of 400 mg/kg/day tazemetostat (approximately 7 times the adult human exposure at the 800 mg twice daily dose) from GD 7 through 19.

Skeletal variations were present at doses ≥100 mg/kg/day (approximately 1.5 times the adult human exposure at the 800 mg twice daily dose), with skeletal malformations at ≥200 mg/kg/day (approximately 5.6 times the adult human exposure at the 800 mg twice daily dose). At 400 mg/kg (approximately 7 times the adult human exposure at the 800 mg twice daily dose), major findings included increased post implantation loss and cleft palate and snout.