Dordaviprone

7 DRUG INTERACTIONS • CYP3A4 Inhibitors: Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO as recommended. ( 2.5 , 7.1 ) • CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. ( 7.1 ) • Drugs Known to Prolong QTc Interval: Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product. ( 5.2 , 7.2 , 12.2 )

7.1 Effect of Other Drugs on MODEYSO Table 6 describes drug interactions where concomitant use of another drug affects MODEYSO. Table 6: Effect of Other Drugs on MODEYSO Strong and Moderate CYP3A4 Inhibitors Prevention or Management • Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. • If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the MODEYSO dose as recommended [see Dosage and Administration ( 2.5 )] . Mechanism and Clinical Effects • Dordaviprone is a CYP3A4 substrate.

• Strong and moderate CYP3A4 inhibitors increase dordaviprone exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of MODEYSO‑related adverse reactions [see Warnings and Precautions ( 5.2 )] . Strong or Moderate CYP3A4 Inducers Prevention or Management • Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO . Mechanism and Clinical Effects • Dordaviprone is a CYP3A4 substrate. • Strong and moderate CYP3A4 inducers decrease dordaviprone exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the anti-tumor activity of MODEYSO.

7.2 Drugs Known to Prolong QTc Interval Table 7 describes drug interactions associated with QTc interval prolongation when used concomitantly with MODEYSO. Table 7: Products that Prolong QTc Interval Products that Prolong QTc Interval Prevention or Management • Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. • If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )] . Clinical Impact • MODEYSO causes concentration dependent QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] .

• Concomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias [see Warnings and Precautions ( 5.2 )] .

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , MODEYSO can cause fetal harm when administered to a pregnant woman. There are no available data on MODEYSO use in pregnant women to inform a drug‑associated risk. In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended 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 an embryo-fetal development study, dordaviprone was administered orally to pregnant rats during the period of organogenesis from gestation day 7 to 17 at doses of 25, 62.5, and 125 mg/kg/day. Dordaviprone caused maternal mortality, pre-implantation loss, and embryo-fetal toxicity of absent eye and small renal papillae at the 125 mg/kg/day dose (≥2 times the human recommended doses based on body surface area).

In an embryo-fetal development study, dordaviprone was administered orally to pregnant rabbits during the period of organogenesis from gestation days 7 to 19 at doses of 10, 25, 62.5, and 100 mg/kg/day. Dordaviprone caused maternal mortality, embryo‑fetal mortality, lower fetal weights, and structural malformations of the face, limbs, vessels, brain, and heart at doses of ≥10 mg/kg/day (≥0.4 times the human exposure at the highest recommended dose based on C max ).