Sevabertinib

Strong CYP3A Inhibitors: Avoid concomitant use with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dosage. ( 2.4 , 7.1 ). Moderate CYP3A Inhibitors: Monitor patients for increased HYRNUO-associated adverse reactions ( 2.3 , 7.1 ) Strong and Moderate CYP3A Inducers: Avoid concomitant use with strong or moderate CYP3A inducers. ( 7.1 ) Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates where minimal increases in concentration may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information of the CYP3A substrate.

( 7.2 ) Certain P-gp Substrates: Refer to the Prescribing Information for P-gp substrates where minimal increases in concentration may lead to serious adverse reactions ( 7.2 )

7.1 Effect of Other Drugs on HYRNUO Table 6 describes drug interactions where concomitant use of another drug affects HYRNUO. Table 6: Drug Interactions that Affect HYRNUO Strong and Moderate CYP3A Inhibitors Prevention or management Strong CYP3A Inhibitors : Avoid concomitant use of HYRNUO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce HYRNUO dosage [see Dosage and Administration (2.4) ] . Moderate CYP3A Inhibitors : Monitor patients for increased HYRNUO-associated adverse reactions [see Dosage and Administration (2.3) ] . Mechanism and Clinical Effect Sevabertinib is a CYP3A substrate.

Concomitant use with a strong or moderate CYP3A inhibitor may increase sevabertinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of HYRNUO-associated adverse reactions. Strong and Moderate CYP3A Inducers Prevention or management Avoid concomitant use of HYRNUO with strong or moderate CYP3A inducers. Mechanism and Clinical Effect Sevabertinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inducer may decrease sevabertinib plasma concentrations [see Clinical Pharmacology (12.3) ], which may decrease the effectiveness of HYRNUO.

7.2 Effects of HYRNUO on Other Drugs Table 7 describes drug interactions where concomitant use of HYRNUO affects another drug. Table 7: HYRNUO Drug Interactions that Affect Other Drugs Certain CYP3A Substrates Prevention or management Avoid concomitant use of HYRNUO with CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information of the CYP3A substrate. Mechanism and Clinical Effect Sevabertinib is a weak to moderate CYP3A inhibitor.

Sevabertinib increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. Certain P-gp Substrates Prevention or management Refer to the Prescribing Information for P-gp substrates where minimal increases in the concentration may lead to serious adverse reactions. Mechanism and Clinical Effect Sevabertinib is a P-gp inhibitor. Sevabertinib increases exposure of P-gp substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates. CYP1A1 Substrates Prevention or management Refer to the Prescribing Information of CYP1A1 substrates.

Mechanism and Clinical Impact Sevabertinib is an inhibitor of CYP1A1 in vitro. Sevabertinib may increase exposure of CYP1A1 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , HYRNUO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of HYRNUO in pregnant women to inform a drug-associated risk. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily.

Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality (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 embryo-fetal development studies, sevabertinib was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses ranging from 1.5 to 11 mg/kg/day.

Sevabertinib treatment resulted in maternal toxicity (reduced body weight and body weight gain) and a reduction in fetal weights at ≥6 mg/kg/day (≥0.18 times the human exposure based on AUC at the clinical dose). Additional Nonclinical Data A literature-based assessment of the effects on reproduction in mouse models with disrupted or depleted HER2 / EGFR demonstrated that HER2/EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. In a human-induced pluripotent stem cell-based assay, sevabertinib reduced cardiomyocyte and hepatocyte differentiation markers.