Pexidartinib

Use with Hepatotoxic Products : Avoid coadministration of TURALIO with other products known to cause hepatotoxicity. ( 7.1 ) Moderate or Strong CYP3A Inhibitors : Reduce the dose of TURALIO if concomitant use of moderate or strong CYP3A inhibitors cannot be avoided. ( 2.3 , 7.2 ) Strong CYP3A Inducers : Avoid concomitant use of strong CYP3A inducers. ( 7.2 ) UGT Inhibitors : Reduce the dose of TURALIO if concomitant use of UGT inhibitors cannot be avoided. ( 2.3 , 7.2 ) Acid-Reducing Agents : Avoid concomitant use of proton pump inhibitors. Use histamine-2 receptor antagonists or antacids if needed. ( 2.4 , 7.2 ) High-Fat Meal : Avoid taking TURALIO with a high-fat meal.

( 2.1 , 5.4 , 7.2 ). CYP3A Substrates : Avoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious therapeutic failure. ( 7.3 )

7.1 Use with Hepatotoxic Products TURALIO can cause hepatotoxicity. In patients with increased serum transaminases, total bilirubin, or direct bilirubin (>ULN) or active liver or biliary tract disease, avoid coadministration of TURALIO with other products known to cause hepatotoxicity [see Warnings and Precautions (5.1) ] .

7.2 Effect of Other Drugs or Food on TURALIO Table 7: Effect of Other Drugs or Food on TURALIO Moderate or Strong CYP3A Inhibitors Clinical Impact Concomitant use of a moderate or strong CYP3A inhibitor may increase pexidartinib concentrations [see Clinical Pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of TURALIO. Management Reduce TURALIO dosage if concomitant use of moderate or strong CYP3A inhibitors, including grapefruit or grapefruit juice, cannot be avoided [see Dosage and Administration (2.3) ].

Strong CYP3A Inducers Clinical Impact Concomitant use of a strong CYP3A inducer decreases pexidartinib concentrations [see Clinical Pharmacology (12.3) ] , which may decrease the efficacy of TURALIO. Management Avoid concomitant use of strong CYP3A inducers, including St John's wort. UGT Inhibitors Clinical Impact Concomitant use of a UGT inhibitor increases pexidartinib concentrations [see Clinical Pharmacology (12.3) ], which may increase the incidence and severity of adverse reactions of TURALIO. Management Reduce TURALIO dosage if concomitant use of UGT inhibitors cannot be avoided [see Dosage and Administration (2.3) ].

Acid-Reducing Agents Clinical Impact Concomitant use of a PPI decreases pexidartinib concentrations [see Clinical Pharmacology (12.3) ], which may decrease the efficacy of TURALIO. Management Avoid concomitant use of PPIs with TURALIO. As an alternative to PPIs, use locally-acting antacids or H 2 -receptor antagonists [see Dosage and Administration (2.4) ] . High-Fat Meal Clinical Impact Taking TURALIO with a high-fat meal increased pexidartinib concentrations [see Clinical Pharmacology (12.3) ] , which may increase the incidence and severity of TURALIO adverse reactions, including hepatotoxicity [see Warnings and Precautions (5.1 , 5.4) ].

Management Take TURALIO with a low-fat meal (approximately 11 to 14 grams of total fat) . Avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat) [see Dosage and Administration (2.1) ] .

7.3 Effect of TURALIO on Other Drugs Table 8: Effect of TURALIO on Other Drugs CYP3A Substrates Clinical Impact TURALIO is a moderate CYP3A inducer. Concomitant use of TURALIO decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of these substrates . Management Avoid coadministration of TURALIO with hormonal contraceptives [see Warnings and Precautions (5.3) , Use in Specific Populations (8.3) ]. Avoid concomitant use of TURALIO with other CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures.

If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , TURALIO may cause embryo-fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of TURALIO. Oral administration of pexidartinib to pregnant animals during the period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal exposures that were approximately equal to the human exposure 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 Embryo-fetal development studies investigating the administration of pexidartinib during the period of organogenesis were conducted in rats and rabbits.

In rats, pexidartinib resulted in increased post-implantation loss and fetal malformations including localized fetal edema, absence of kidney and ureter, abnormalities of the reproductive tract, and developmental variations including misshapen kidney, decreased skeletal ossification and higher mean litter proportions of slightly or moderately malaligned sternebrae at doses of 40 mg/kg (approximately equal to the human exposure at the recommended dose).

In rabbits, administration of pexidartinib resulted in increased post-implantation loss, abortion, and fetal malformations including absence of kidney or ureter, rudimentary, misshapen or malpositioned kidney, rib abnormalities, and skeletal variations of accessory skull bones at doses of 60 mg/kg (approximately equal to the human exposure at the recommended dose).