PEXIDARTINIB Drug Interactions: What You Need to Know

INTERACTIONS 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 (&gt;ULN) or active liver or biliary tract disease, avoid coadministration of TURALIO with other products known to cause hepatotoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>, 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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.

None. None. ( 4 )

AND PRECAUTIONS Embryo-Fetal Toxicity : May cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use an effective non-hormonal method of contraception. ( 5.3 , 7.3 , 8.1 , 8.3 )

Potential Risks

Associated with a High-Fat Meal : May increase incidence and severity of adverse reactions, including hepatotoxicity. Avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat). ( 2.1 , 5.4 )

5.1 Hepatotoxicity TURALIO can cause serious and potentially fatal liver injury and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. Hepatotoxicity, including liver failure and life-threatening vanishing bile duct syndrome (VBDS), ductopenia, and symptomatic cholestasis (including severe pruritus) can occur in patients treated with TURALIO and can occur despite monitoring and prompt drug cessation. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury can also occur in the absence of increased transaminases. Of the first 609 patients who received TURALIO under the REMS program, 32 (5.3%) developed a liver injury event of concern (LIEC), defined as any serious liver-related outcome or any liver abnormality that triggers drug discontinuation per the US Prescribing Information [ see Dosage and Administration (2.2) ].

These

32 patients developed liver toxicity within 71 days of the first dose of TURALIO; ten required hospitalization, and two developed VBDS. Sixteen of the 32 patients had not fully recovered at the time of the analysis, including 6 patients followed for at least 6 months after discontinuation.

Among

768 patients who received TURALIO in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient with advanced cancer and ongoing liver toxicity died and one patient with a confirmed case of VBDS required a liver transplant. In ENLIVEN, 3 of 61 (5%) patients who received TURALIO developed signs of serious liver injury, defined as ALT or AST ≥3 × ULN with total bilirubin ≥2 × ULN. In these patients, peak ALT ranged from 6 to 9 × ULN, peak total bilirubin ranged from 2.5 to 15 × ULN, and alkaline phosphatase (ALP) was ≥2 × ULN. ALT, AST, and total bilirubin improved to <2 × ULN in these three patients 1 to 7 months after discontinuing TURALIO. Avoid TURALIO in patients with pre-existing increased serum transaminases; total bilirubin or direct bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP, and gamma-glutamyl transferase (GGT) prior to initiation of TURALIO, weekly for the first 8 weeks, every 2 weeks for the next month and every 3 months thereafter. Withhold and dose reduce, or permanently discontinue TURALIO based on the severity of the hepatotoxicity [see Dosage and Administration (2.2) ] . Refer patients to a hepatologist if liver tests do not return to normal. Rechallenge with a reduced dose of TURALIO may result in a recurrence of increased serum transaminases, bilirubin, ALP., or other signs of liver injury. Monitor liver tests weekly for the first month after rechallenge.

5.2 TURALIO REMS Program TURALIO is only available through a restricted program under a REMS, because of the risk of hepatotoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Notable requirements of the TURALIO REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training. Patients must complete and sign an enrollment form for inclusion in a patient registry. Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive TURALIO. Further information is available at www.TURALIOREMS.com or 1-833-887-2546.

5.3 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, TURALIO may cause fetal harm when administered to a pregnant woman. Oral administration of pexidartinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at exposures approximately equal to the human exposure at the recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception, since TURALIO can render hormonal contraceptives ineffective, during treatment with TURALIO and for 1 month after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TURALIO and for 1 week after the final dose <span class="opacity-50 text-xs">[see Drug Interactions (7.3) , Use in Specific Populations (8.1 , 8.3) ]</span> .

5.4 Potential Risks Associated with a High-Fat Meal Taking TURALIO with a high-fat meal increases pexidartinib concentrations, which may increase the incidence and severity of adverse reactions, including hepatotoxicity <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2 , 12.3) ]</span>. Instruct patients to take TURALIO with a low-fat meal (approximately 11 to 14 grams of total fat) and to avoid taking TURALIO with a high-fat meal (approximately 55 to 65 grams of total fat). Consider referring patients to a dietician as deemed necessary <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) , Warnings and Precautions (5.1) , Drug Interactions (7.2) ]</span>.