Ziftomenib

Strong or Moderate CYP3A4 Inhibitors: Monitor more frequently for adverse reactions. ( 7.1 ) Strong or Moderate CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) Proton Pump Inhibitors: Avoid concomitant use. ( 2.4 , 7.1 ) H2 Receptor Antagonists and Antacids: Avoid concomitant use. If concomitant use cannot be avoided, modify KOMZIFTI administration time. ( 2.4 , 7.1 ) Drugs that Prolong the QTc Interval: Avoid concomitant use. If concomitant use is unavoidable, monitor patients more frequently for QTc interval prolongations. ( 5.2 , 7.1 )

7.1 Effect of Other Drugs on KOMZIFTI Strong or Moderate CYP3A4 Inhibitors Monitor patients more frequently for KOMZIFTI-associated adverse reactions. Ziftomenib is primarily metabolized by CYP3A. Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inhibitors increases ziftomenib exposure [see Clinical Pharmacology ( 12.3 )], which may increase the risk of adverse reactions such as QT prolongation. Strong or Moderate CYP3A4 Inducers Avoid concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers. Ziftomenib is primarily metabolized by CYP3A.

Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers may decrease ziftomenib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of KOMZIFTI. Gastric Acid Reducing Agents Concomitant administration of ziftomenib with proton pump inhibitors (PPIs) decreases ziftomenib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of KOMZIFTI. Avoid concomitant use of KOMZIFTI with PPIs. Avoid concomitant use of KOMZIFTI with H2 receptor antagonists (H2RAs) or locally acting antacids. If concomitant use cannot be avoided, modify KOMZIFTI administration time [see Dosage and Administration ( 2.4 )] .

Drugs that Prolong the QT Interval Avoid concomitant use of KOMZIFTI with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions ( 5.2 )] . Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms [see Dosage and Administration ( 2.5 )] . Ziftomenib causes QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] .

Concomitant use of KOMZIFTI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsades de pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions ( 5.2 )] .

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , KOMZIFTI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on KOMZIFTI use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at maternal exposures approximately 0.3 times the human exposure (AUC) at the 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 Ziftomenib was administered orally twice daily to pregnant mice at doses of 6, 20, and 60 mg/kg/day during organogenesis (gestation days 6-15).

Decreased fetal body weight, embryo-fetal lethality, fetal external and skeletal malformations and variations (cleft palate, fused cervical arches, absent lumbar vertebrae fused and/or misaligned costal cartilage, absent or short rib, supernumerary site in the suture bone or split palatine of the skull, and/or fused, unossified, and/or incompletely ossified sternebrae) were noted at all doses. At the dose of 6 mg/kg/day in mice, the maternal exposure was approximately 0.3 times the human exposure at the recommended dose of 600 mg once daily.