Selpercatinib

Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). ( 2.4 , 7.1 ) Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. ( 2.6 , 7.1 ) Strong and Moderate CYP3A Inducers: Avoid coadministration. ( 7.1 ) CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 ) Certain P-gp and BCRP Substrates: Avoid coadministration.

If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 )

7.1 Effects of Other Drugs on RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) [see Dosage and Administration ( 2.4 )] .

Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.4 )] .

Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

7.2 Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.

7.3 Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.2 )] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

8.1 Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. 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 Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss.

At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).