DRUG INTERACTIONS- summary

 Use with Hepatotoxic Products: Avoid coadministration of TURALIO with other products known to cause hepatotoxicity.  

 Strong CYP3A Inhibitors: Reduce the dose of TURALIO if concomitant use of strong CYP3A inhibitors cannot be avoided. 

 Strong CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers. 

UGT Inhibitors: Reduce the dose of TURALIO if concomitant use of UGT inhibitors cannot be avoided. 

Acid Reducing Agents: Avoid concomitant use of proton pump inhibitors. Use histamine-2 receptor antagonists or antacids if needed. 

 DRUG INTERACTIONS

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

2. Effect of Other Drugs on TURALIO-clinical impact

Concomitant use of a strong CYP3A inhibitor increases pexidartinib plasma concentrations, which may increase the incidence and severity of adverse reactions of TURALIO.

Management

 Reduce TURALIO dosage if concomitant use of strong CYP3A inhibitors, including grapefruit or grapefruit juice, cannot be avoided.

Strong CYP3A Inducers 

 Concomitant use of a strong CYP3A inducer decreases pexidartinib plasma concentrations, which may decrease the efficacy of TURALIO.

Management

 Avoid concomitant use of strong CYP3A inducers, including St John’s wort. UGT Inhibitors

 UGT inhibitors

Concomitant use of a UGT inhibitors increases pexidartinib plasma concentrations , 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  

Acid-Reducing Agents 

 Concomitant use of a PPI decreases pexidartinib plasma concentrations  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 H2-receptor antagonists.

Pat inform-                                                                                                                Advise patients of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury and to report immediately any signs or symptoms of severe liver injury to their healthcare provider

ADVERSE REACTIONS

 Most common adverse reactions (>20%) were increased lactate dehydrogenase, increased aspartate aminotransferase, hair color changes, fatigue, increased alanine aminotransferase, decreased neutrophils, increased cholesterol, increased alkaline phosphatase, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased phosphate.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hepatotoxicity

Advise patients of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury and to report immediately any signs or symptoms of severe liver injury to their healthcare providerTURALIO REMS Program

 TURALIO is available only through a restricted program called TURALIO REMS Program and patients are required to be part of the patient registry 

 TURALIO is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

Embryo-Fetal Toxicity

 Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy 

Use in Specific Populations 

 Advise females of reproductive potential to use effective contraception during treatment with TURALIO and for one month after the final dose

 Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for one week after the final dose

Lactation

Advise females not to breastfeed during treatment with TURALIO and for one week after the final dose.

Infertility

Advise females and males of reproductive potential that TURALIO may impair fertility [s

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter products and supplements.

Administration

Instruct patients to take TURALIO on an empty stomach (at least 1 hour before or 2 hours after a meal or snack).

Instruct patients to swallow capsules whole (do not open, break, or chew)

Manufactured for: Daiichi Sankyo, Inc. Basking Ridge, NJ 07920 TURALIO™ is a trademark of Daiichi Sankyo Company, Limited. ©2019, Daiichi Sankyo, Inc. USPI-TUR-0819-r001

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Pexidartinib is a small molecule tyrosine kinase inhibitor that targets colony stimulating factor 1 receptor (CSF1R), KIT proto-oncogene receptor tyrosine kinase (KIT), and FMS-like tyrosine kinase 3 (FLT3) harboring an internal tandem duplication (ITD) mutation.

2. Pharmacodynamics

Exposure-Response Relationships                                                                          There is an exposure response relationship between pexidartinib steady state exposure and serum transaminase levels (ALT and AST) with a higher risk of increased serum transaminases at higher exposure. Additionally, increased transaminases occurred more frequently with higher pexidartinib doses (200 to 1200 mg per day).

Cardiac Electrophysiology

At two times the mean maximum exposure of the 400 mg twice daily dose, TURALIO does not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics

The pharmacokinetics of TURALIO was evaluated following single doses in healthy subjects and following multiple doses in patients as summarized 

Steady state exposure [Mean (SD)]a Cmax 8625 (2746) ng/mL AUC0-12h 77465 (24975) ng•h/mL

Dose proportionality Pexidartinib exposure (Cmax and AUC0-INF) increased linearly over the single oral dose range of 200 to 2400 mg (0.5 to 6 times the recommended dose).

Time to steady stateb Approximately 7 days

Accumulation ratio (AUC) [Median]

 Absorption Tmax [Median] 2.5 hours

Effect of food

Administration with high fat mealc ? Increased pexidartinib Cmax and AUC0-INF by 100% .  Delayed Tmax by 2.5 hours

Distribution

In vitro plasma protein binding  Greater than 99%                                                     Human serum albumin: 99.9%                                                                                          ? a-1 acid glycoprotein: 89.9%                                                                                Apparent volume of distribution (Vz/F) [Mean (CV%)]d ? 187 L (27%)

Elimination

Apparent clearance [Mean (CV%)]d ? 5.1 L/h (36%) t1/2 [Mean (SD)] ? 26.6 (6.5) hours 

Metabolism

Primary pathway ? Oxidation: CYP3A4                                                              Glucuronidation: UGT1A4 N-glucuronide metabolite                                                            Major inactive metabolite formed by UGT1A4 ? Approximately 10% higher exposure than pexidartinib after a single dose

Excretion

 Feces: 65% (44% as unchanged)                                                                                       Urine: 27% as metabolites (=10% as N-glucuronide)

a Pexidartinib 400 mg twice daily b Estimated based on half life c The high fat meal comprised 800 to 1000 calories with fat being 50% of total caloric content; approximately 150 calories from protein, 250 calories from carbohydrates, and 500-600 calories from fat. 

After a single oral dose of pexidartinib 400 mg e After a single oral dose of radiolabeled pexidartinib 400 mg

Specific Populations -                                                                                                   No clinically meaningful differences in the pharmacokinetics of pexidartinib were observed based on age (18 to 84 years), sex, race (White and Black), or mild hepatic impairment (total bilirubin = ULN with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST).

Patients with Renal Impairment-                                                                                      Mild (CLcr 60 to 89 mL/min), moderate (CLcr 30 to 59 mL/min) and severe (CLcr 15 to 29 mL/min) renal impairment increased pexidartinib exposure (AUC) by approximately 30%, relative to that in patients with normal renal function (CLcr =90 mL/min).

Patients with Hepatic Impairment-                                                                                       The pharmacokinetics of pexidartinib has not been adequately characterized in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST) or studied in patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST).

Drug Interaction Studies

Clinical Studies Effect of Strong CYP3A Inducers on Pexidartinib: Coadministration of rifampicin (a strong CYP3A inducer) decreased pexidartinib Cmax by 33% and AUC by 65% [see Drug Interactions (7.2)].

The effect of coadministration with a moderate CYP3A inducer on pexidartinib pharmacokinetics is not known.

Effect of Strong CYP3A Inhibitors on Pexidartinib: Coadministration of itraconazole (a strong CYP3A inhibitor) increased pexidartinib Cmax by 48% and AUC by 70% [see Drug Interactions (7.2)].

The effect of coadministration with a moderate CYP3A inhibitor on pexidartinib pharmacokinetics is not known. Reference ID: 4471832 15

Effect of UGT Inhibitors on Pexidartinib: Coadministration of probenecid (a UGT inhibitor) increased pexidartinib Cmax by 5% and AUC by 60% [see Drug Interactions (7.2)].

Effect of Acid-Reducing Agents on Pexidartinib: Coadministration of esomeprazole (a proton pump inhibitor) decreased pexidartinib Cmax by 55% and AUC by 50% [see Drug Interactions (7.2)].

The effects of H2-receptor antagonists and locally-acting antacids on pexidartinib pharmacokinetics have not been studied.

Effect of Pexidartinib on CYP2C19 Substrates: Coadministration of a single oral dose of TURALIO 1800 mg decreased omeprazole (CYP2C19 substrate) Cmax by 37% and AUC by 17% compared to omeprazole alone.

Effect of Pexidartinib on P-gp Substrates: Coadministration of a single oral dose of TURALIO 1800 mg increased digoxin (P-gp substrate) Cmax by 30% and AUC by 9% compared to digoxin alone

. Effect of Pexidartinib on CYP2C8 Substrates: Based on modeling and simulation, pexidartinib is predicted to have negligible interaction potential with CYP2C8 substrates at clinically relevant concentrations.

In Vitro Studies Effects of Pexidartinib on CYP Enzymes: Pexidartinib is likely to inhibit CYP2B6, 2C9, and 3A4 and induce CYP3A and 2B6 at clinically relevant concentrations.

Effect of Pexidartinib on UGT: Pexidartinib is likely to inhibit UGT1A1 at clinically relevant concentrations. Pexidartinib as a Substrate for Transporters: Pexidartinib is not a substrate for Pgp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, OATP2B1, and BSEP.

Effect of Pexidartinib on Transporters: Pexidartinib inhibits the transport activities of MATE1, MATE2-K, OATP1B1, OATP1B3 and OATP2B1.

 USE IN SPECIFIC POPULATIONS

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.

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.

2 Lactation Risk Summary

There are no data on the presence of pexidartinib or its metabolites in either human or animal milk or its effects on a breastfed child or on milk production.

Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with TURALIO and for at least one week after the final dose. 

3. Females and Males of Reproductive Potential Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to the initiation of TURALIO 

Contraception -                                                                                                          TURALIO may cause embryo-fetal harm when administered to a pregnant woman

 Females -Advise females of reproductive potential to use effective contraception during treatment with TURALIO and for 1 month after the final dose

Males -Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TURALIO and for 1 week after the final dose.

Infertility -Based on findings from animal studies, TURALIO may impair both male and female fertility ].

4. Pediatric Use

The safety and effectiveness of TURALIO in pediatric patients have not been established.

.5. Geriatric Use

Clinical studies of TURALIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

6. Renal Impairment

Reduce the dose when administering TURALIO to patients with mild to severe renal impairment (CLcr 15 to 89 mL/min, estimated by Cockcroft-Gault [C-G])

7. Hepatic Impairment

No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST)

The recommended dose of TURALIO has not been established for patients with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) to severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment .

 OVERDOSAGE

Due to the high plasma protein binding, TURALIO is not expected to be dialyzable

.