Taletrectinib adipate

Strong and Moderate CYP3A inhibitors : Avoid concomitant use. ( 7.1 ) Strong and Moderate CYP3A inducers: Avoid concomitant use. ( 7.1 ) Gastric Acid Reducing Agents: Avoid concomitant use with proton pump inhibitors (PPIs) and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer IBTROZI 2 hours before or 2 hours after taking a locally acting antacid. ( 7.1 ) Drugs That Prolong the QTc Interval: Avoid concomitant use. ( 7.2 )

7.1 Effects of Other Drugs on IBTROZI Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Taletrectinib is a CYP3A substrate. Concomitant use of IBTROZI with a strong or moderate CYP3A inhibitor increases taletrectinib exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of IBTROZI adverse reactions. Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of IBTROZI with a strong or moderate CYP3A inducer decreases taletrectinib exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of IBTROZI.

Gastric Acid Reducing Agents Avoid concomitant use with proton pump inhibitors (PPI) and H2 receptor antagonists. Administer locally acting antacids at least 2 hours before or 2 hours after taking IBTROZI [see Clinical Pharmacology ( 12.3 )]. Concomitant use of a proton pump inhibitor decreases taletrectinib exposure [see Clinical Pharmacology ( 12.3 )], which may reduce the effectiveness of IBTROZI. 7.2. Drugs That Prolong the QTc Interval Avoid concomitant use of IBTROZI with other drug(s) with a known potential to prolong the QTc interval, such as antiarrhythmic drugs.

If concomitant use cannot be avoided, adjust the frequency of monitoring as recommended [see Warnings and Precautions ( 5.3 ), Clinical Pharmacology ( 12.2 )]. Withhold IBTROZI if the QTc interval is >500 msec or the change from baseline is >60 msec [see Dosage and Administration ( 2.4 )]. IBTROZI causes QTc interval prolongation [see Warnings and Precautions ( 5.3 ), Clinical Pharmacology ( 12.2 )] . Concomitant use of IBTROZI with other drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.

8.1 Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , IBTROZI can cause fetal harm when administered to a pregnant woman. Limited data from case reports with IBTROZI used in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

In animal reproduction studies, oral administration of taletrectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal mortalities and structural abnormalities at exposures that were below or equal to the human exposure based on 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 Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data In an embryo-fetal development study, taletrectinib was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses of 10, 30, and 100 mg/kg/day. Taletrectinib caused fetal abnormalities including abnormal ossification of the pelvis at 100 mg/kg/day (1.3 times the human exposure based on AUC at the recommended dose).

In an embryo-fetal development study, taletrectinib was administered orally to pregnant rabbits during the period of organogenesis from gestation day 6 to 19 at doses of 15, 30, and 90 mg/kg/day. Maternal lethality and increased total pregnancy loss were observed at doses ≥15 mg/kg/day (≥0.04 times the human exposure based on AUC at the recommended dose). Fetal malformations, including undeveloped or no development of eyes, nose, and mouth, ventricular malformations, thoracic vascular malformations, and skull malformations were observed at 30 mg/kg/day (0.1 times the human exposure based on AUC at the recommended dose).