Pexidartinib (Monograph)

Brand name: Turalio
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jul 10, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for pexidartinib hydrochloride to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of pexidartinib hydrochloride and consists of the following: communication plan, elements to assure safe use, and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Warning

Serious and potentially fatal liver injury may occur.
Monitor liver function prior to initiation of the drug and periodically during therapy. Withhold therapy, reduce dosage, or permanently discontinue based on severity of hepatotoxicity.
Available only through a restricted program called the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), c-Kit proto-oncogene proteins (c-Kit), and fms-like tyrosine kinase-3 (Flt-3).

Uses for Pexidartinib

Tenosynovial Giant Cell Tumor

Treatment of adult patients with symptomatic tenosynovial giant cell tumor (also referred to as giant cell tumor of the tendon sheath [GCT-TS] or pigmented villonodular synovitis [PVNS]) associated with severe morbidity or functional limitations that is not amenable to improvement with surgery.

Designated an orphan drug by FDA for the treatment of this condition.

Pexidartinib Dosage and Administration

General

Pretreatment Screening

Obtain liver function tests (i.e., AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase [GGT]) prior to initiating pexidartinib. Do not initiate pexidartinib in patients with preexisting elevations in AST, ALT, alkaline phosphatase, active liver or biliary tract disease, or total or direct bilirubin greater than the upper limit of normal (ULN).
Verify pregnancy status in females of reproductive potential prior to the initiation of pexidartinib.

Patient Monitoring

Monitor liver function tests weekly during the first 8 weeks of therapy, every 2 weeks for the next month, and then every 3 months thereafter.

REMS

Because pexidartinib may cause serious and potentially fatal liver injury, the drug is only available through a restricted program under a REMS.
Contact the manufacturer or visit [Web] for additional information.

Administration

Oral Administration

Administer orally with a low-fat meal (approximately 11-14 grams of fat). Administration with a high-fat meal (approximately 55-65 grams of total fat) may increase the risk of adverse reactions.

Swallow pexidartinib capsules whole; do not open, break, or chew the capsules.

If a dose of pexidartinib is missed or vomited, take the prescribed dose at the next scheduled time; do not take an additional dose to replace the missed dose.

Dosage

Dosage of pexidartinib hydrochloride is expressed in terms of pexidartinib.

Adults

Tenosynovial Giant Cell Tumor

Oral

250 mg orally twice daily with a low-fat meal (approximately 11-14 grams of fat). Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

If adverse reactions occur during pexidartinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of pexidartinib should be reduced as described in Table 1.

Table 1: Recommended Dosage Reduction for Pexidartinib Toxicity1
Dose Reduction Level	Dosage Reduction after Recovery from Toxicity (Initial Dosage = 250 mg twice daily with low-fat meal)
First	Resume at 125 mg in the morning and 250 mg in the evening (for a total daily dosage of 375 mg)
Second	Resume at 125 mg twice daily (for a total daily dosage of 250 mg)
Third	Permanently discontinue drug

The following table indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for certain adverse effects according to severity.

Confirm alkaline phosphatase elevations as liver isoenzyme fraction.

Table 2. Dosage Modification for Pexidartinib Toxicity1
Adverse Reaction and Severity	Modification
Hepatotoxicity
ALT and/or AST concentrations >3–5 times the ULN	Withhold therapy and monitor liver function tests weekly
	If AST and ALT improve to ≤3 times the ULN within 4 weeks, resume at reduced dosage (see Table 1); permanently discontinue drug if elevated AST and/or ALT concentrations persist for ≥4 weeks
ALT and/or AST concentrations >5–10 times the ULN	Withhold therapy and monitor liver function tests twice weekly
	If AST and ALT improve to ≤3 times the ULN within 4 weeks, resume at reduced dosage (see Table 1); permanently discontinue drug if elevated AST and/or ALT concentrations persist for ≥4 weeks
ALT and/or AST concentrations >10 times the ULN	Permanently discontinue drug and monitor liver function tests twice weekly until AST or ALT improves to ≤5 times the ULN, then monitor weekly until AST or ALT improves to ≤3 times the ULN
Alkaline phosphatase concentrations >2 times the ULN with gamma-glutamyl transferase (GGT) concentrations >2 times the ULN	Permanently discontinue drug and monitor liver function tests twice weekly until alkaline phosphatase concentrations improve to ≤5 times the ULN, and then monitor weekly until alkaline phosphatase concentrations improve to ≤2 times the ULN
Total bilirubin concentrations exceeding the ULN to <2 times the ULN	Withhold therapy and monitor liver function tests twice weekly
	If alternate etiology is confirmed and total bilirubin concentration improves to less than the ULN within 4 weeks, resume at reduced dosage (see Table 1)
	If total bilirubin concentration does not improve to less than the ULN within 4 weeks, permanently discontinue drug
Direct bilirubin concentrations exceeding the ULN to <1.5 times the ULN	Withhold therapy and monitor liver function tests twice weekly
	If alternate etiology is confirmed and direct bilirubin concentration improves to less than the ULN within 4 weeks, resume at reduced dosage (see Table 1)
	If direct bilirubin concentration does not improve to less than the ULN within 4 weeks, permanently discontinue drug
Total bilirubin concentrations ≥2 times the ULN	Permanently discontinue drug and monitor liver function tests twice weekly until total bilirubin concentration improves to the ULN or less
Direct bilirubin concentrations ≥1.5 times the ULN	Permanently discontinue drug and monitor liver function tests twice weekly until direct bilirubin concentration improves to the ULN or less
Other Toxicity
Severe or intolerable	Withhold therapy until toxicity improves or resolves; resume at reduced dosage (see Table 1)

Concomitant Use with Moderate or Strong CYP3A Inhibitors or UGT Inhibitors

Oral

Avoid concomitant use of pexidartinib and moderate or strong CYP3A inhibitors or UGT inhibitors. If concomitant use cannot be avoided, reduce the dosage of pexidartinib as described in Table 3. If the moderate or strong CYP3A inhibitor or UGT inhibitor is discontinued, return the pexidartinib dosage (after 3 elimination half-lives of the CYP3A or UGT inhibitor) to the dosage used prior to initiation of the CYP3A or UGT inhibitor.

Table 3. Recommended Dosage Reduction for Concomitant Use with Moderate or Strong CYP3A Inhibitors or UGT Inhibitors1
Total Daily Dose	Modified Total Daily Dose for Concomitant Use with Moderate or Strong CYP3A Inhibitors or UGT Inhibitors	Dosing Schedule for Modified Total Daily Dose for Use with Moderate or Strong CYP3A Inhibitors or UGT Inhibitors Administer with Low-fat Meal
500 mg	250 mg	125 mg twice daily
375 mg	250 mg	125 mg twice daily
250 mg	125 mg	125 mg once daily

Special Populations

Hepatic Impairment

Moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN, not due to Gilbert syndrome, with any AST concentration): Reduce dosage to 125 mg twice daily with a low-fat meal.

Severe hepatic impairment (total bilirubin 3–10 times the ULN with any AST concentration): Pharmacokinetics not studied.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): Reduce dosage to 125 mg in the morning and 250 mg in the evening with a low-fat meal.

Geriatric Patients

Manufacturer makes no specific dosage recommendations for geriatric patients.

Cautions for Pexidartinib

Contraindications

None.

Warnings/Precautions

Warnings

Hepatotoxicity

Risk of serious and potentially fatal liver injury (see Boxed Warning.). Hepatotoxicity with ductopenia and cholestasis reported. Unknown whether liver injury occurs in the absence of elevated serum aminotransferase concentrations.

Because of this risk, pexidartinib is only available through a restricted program under a REMS. Requirements of the REMS program may be accessed at [Web] or calling 833-887-2546.

Avoid pexidartinib in patients with preexisting elevated AST or ALT concentrations; total bilirubin or direct bilirubin greater than ULN; or active liver or biliary tract disease, including increased alkaline phosphatase. Administration of pexidartinib with a high-fat meal increases exposure to the drug by 100% and may increase the risk of hepatotoxicity.

Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase (GGT) prior to initiation of pexidartinib, weekly for the first 8 weeks, every 2 weeks for the next month, and then every 3 months thereafter. Based on the severity of hepatotoxicity, temporary interruption of therapy, dosage reduction, or permanent discontinuance of the drug may be necessary.

Recurrence of elevated serum aminotransferases, bilirubin, or alkaline phosphatase may occur following resumption of pexidartinib therapy at a reduced dosage. Monitor liver function tests weekly for the initial month after rechallenge.

Other Warnings and Precautions

Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, pexidartinib may cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Apprise pregnant females of potential risk to a fetus. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with pexidartinib and for 1 month after discontinuing treatment; nonhormonal contraceptives should be used because concomitant use of pexidartinib and hormonal contraceptives may result in decreased systemic exposure to the hormonal contraceptive and reduced efficacy.

Males with female partners of reproductive potential should also use effective contraception during treatment with pexidartinib and for 1 week after discontinuing treatment.

Potential Risks Associated with a High-fat Meal

Administration with a high-fat meal may increase incidence and severity of adverse reactions including hepatotoxicity. Take pexidartinib with a low-fat meal (approximately 11-14 grams of total fat). Refer patients to a dietitian as necessary.

Specific Populations

Pregnancy

May cause fetal harm based on animal data and its mechanism of action.

Available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of pexidartinib.

Lactation

Not known whether pexidartinib or its metabolites are distributed into human milk. Effects of the drug on breast-fed infants or on the production of milk are also unknown.

Females should not breast-feed while receiving the drug and for at least one week after the last dose.

Females and Males of Reproductive Potential

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

Advise females of reproductive potential to use effective nonhormonal contraception during treatment with pexidartinib and for 1 month after the final dose.

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

May impair male and female fertility based on animal studies.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Experience in patients ≥65 years of age is insufficient to determine whether geriatric patients respond differently than younger individuals.

Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤ULN with AST >ULN or total bilirubin >1 up to 1.5 times ULN with any AST concentration): No clinically significant effect on pharmacokinetics of pexidartinib; no dosage adjustment necessary.

Moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN, not due to Gilbert syndrome, with any AST concentration): AUC of pexidartinib increased by 43% compared to patients with normal hepatic function; reduce dosage of pexidartinib to 125 mg twice daily with a low-fat meal.

Severe (total bilirubin greater than 3–10 times ULN and any AST concentration) hepatic impairment: Not studied.

Renal Impairment

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): AUC of pexidartinib increased by approximately 30% compared to patients with normal renal function; reduce dosage of pexidartinib to 125 mg in the morning and 250 mg in the evening with a low-fat meal.

Race and Gender

No clinically significant differences in pharmacokinetics based on race or gender.

Common Adverse Effects

Adverse effects occurring in >20% of patients: Increased lactate dehydrogenase concentrations, increased AST/ALT concentrations, hair color changes, fatigue, decreased neutrophils, increased cholesterol, increased alkaline phosphatase concentrations, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, decreased phosphate.

Drug Interactions

Primarily metabolized by CYP3A4 and glucuronidation by uridine diphosphate-glucuronosyltransferase to the major inactive N-glucuronide metabolite. In vitro, likely to inhibit CYP2B6 and induce CYP2B6 at clinically relevant concentrations.

At clinically relevant concentrations, likely to inhibit UGT1A1. Inhibitor of multidrug and toxin extrusion (MATE) 1, MATE2-K, organic anion transporter protein (OATP) 1B1, OATP1B3 and OATP2B1. In vitro, not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), OAT1, OAT3, organic cation transporter (OCT) 1, OCT2, OATP1B1, OATP1B3, OATP2B1, or bile salt export pump (BSEP).

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate or Strong CYP3A Inhibitors: Concomitant use may increase concentrations of pexidartinib and increase risk and severity of adverse reactions. Avoid concomitant use, including grapefruit and grapefruit products. If concomitant use cannot be avoided, reduce dosage of pexidartinib as described in Table 3. If the moderate or strong CYP3A inhibitor is discontinued, return the pexidartinib dosage (after 3 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the CYP3A inhibitor.

CYP3A Inducers: Concomitant use with moderate or strong CYP3A inducers may decrease concentrations of pexidartinib and reduce efficacy of the drug. Avoid concomitant use of pexidartinib and strong CYP3A inducers, including St. John's wort (Hypericum perforatum).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Concomitant use of pexidartinib and substrates of CYP3A may decrease systemic exposure to the CYP3A substrate and reduce efficacy of the substrate drug. Avoid concomitant use of pexidartinib with hormonal contraceptives and other CYP3A substrates, where minimal concentration changes may lead to serious therapeutic failures. If concomitant use cannot be avoided, consult manufacturer's labeling of the CYP3A substrate drug for dosage modification recommendations.

Substrates of Other CYP Isoenzymes: Effect of pexidartinib on CYP2C8 substrates is not expected to be clinically relevant.

Drugs Affected by Uridine Diphosphate-glucuronosyltransferase

Concomitant use with uridine diphosphate-glucuronosyltransferase (UGT) inhibitors may increase concentrations of pexidartinib and increase the risk and severity of adverse reactions.

Avoid concomitant use of pexidartinib and UGT inhibitors. If concomitant use cannot be avoided, reduce the dosage of pexidartinib as described in Table 3. If the UGT inhibitor is discontinued, return the pexidartinib dosage (after 3 elimination half-lives of the UGT inhibitor) to dosage used prior to initiation of the UGT inhibitor.

Drugs Affecting Gastric Acidity

Concomitant use of pexidartinib with proton-pump inhibitors decreases pexidartinib concentrations and reduces efficacy of the drug. Effect of H₂-receptor antagonists and locally-acting antacids on pexidartinib pharmacokinetics has not been studied.

Avoid concomitant use of pexidartinib and proton-pump inhibitors. Manufacturer recommends locally-acting antacids or H₂-receptor antagonists as an alternative.

High-fat Meal

Concomitant use of pexidartinib with a high-fat meal (approximately 55-65 grams of fat) increases pexidartinib concentrations and increases incidence and severity of adverse reactions.

Avoid administration of pexidartinib with a high-fat meal.

Specific Drugs

Drug	Interaction	Comments
Antifungals, azoles (e.g., fluconazole, itraconazole)	Fluconazole: Increased AUC and peak plasma concentrations of pexidartinib by 67% and 41%, respectively Itraconazole: Increased AUC and peak plasma concentrations of pexidartinib by 70% and 48%, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of pexidartinib according to Table 3
Digoxin	Increased AUC and peak plasma concentrations of digoxin by 9% and 30%, respectively
Efavirenz	Decreased AUC and peak plasma concentrations of pexidartinib by 38% and 27%, respectively
Grapefruit or grapefruit juice	Potential increased AUC and peak plasma concentrations	Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of pexidartinib according to Table 3
Hormonal contraceptives	Potential decreased systemic exposure to the hormonal contraceptive and reduced efficacy of the hormonal contraceptive	Use nonhormonal contraceptive
Midazolam	Decreased midazolam AUC and peak plasma concentrations by 59% and 28%, respectively	Avoid concomitant use; if concomitant use cannot be avoided, consult manufacturer's labeling for dosage modifications
Probenecid	Increased AUC and peak plasma concentrations of pexidartinib by 60% and 5%, respectively	Avoid concomitant use; if concomitant use cannot be avoided, reduce dosage of pexidartinib according to Table 3
Proton-pump inhibitors (e.g., esomeprazole, omeprazole)	Esomeprazole: Decreased AUC and peak plasma concentrations of pexidartinib by 50% and 55% Omeprazole: Decreased AUC and peak plasma concentrations by 17% and 37%, respectively	Avoid concomitant use; use H₂-receptor antagonist or locally-acting antacid
Rifampin	Decreased AUC and peak plasma concentrations of pexidartinib by 65% and 33%, respectively	Avoid concomitant use

Pexidartinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC of pexidartinib are dose proportional over a single oral dose range of 200–2400 mg administered on an empty stomach.

Peak plasma concentrations attained in a median of 2.5 hours following oral administration.

Time to steady state approximately 7 days.

Food

Peak plasma concentrations and AUC increased by 100% when administered with high-fat meal; peak plasma concentrations and AUC increased by 56% and 59%, respectively, when administered with a low-fat meal.

Special Populations

Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin >1 up to 1.5 times ULN with any AST concentration): No clinically significant effect on pharmacokinetics of pexidartinib.

Severe (total bilirubin greater than 3–10 times ULN and any AST concentration) hepatic impairment: Not studied.

Mild to severe renal impairment (Cl_cr 15–89 mL/minute): AUC of pexidartinib increased by approximately 30% compared to patients with normal renal function.

Distribution

Extent

Not known whether pexidartinib or its metabolites distribute into human milk.

Plasma Protein Binding

Human serum albumin: 99.9%.

α-1 acid glycoprotein: 89.9%.

Elimination

Metabolism

Oxidation by CYP3A4 and glucuronidation by UGT1A4.

Elimination Route

Eliminated in feces (65% [44% unchanged drug]) and 27% in urine (≥10% as N-glucuronide).

Half-life

26.6 hours.

Stability

Storage

Oral

Capsules

20–25ºC; excursions permitted to 15–30ºC. Keep container closed and do not discard desiccant.

Actions

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), c-Kit proto-oncogene proteins (c-Kit), and fms-like tyrosine kinase-3 (Flt-3).
In vitro, inhibits proliferation of cell lines dependent on CSF-1R and ligand-induced autophosphorylation of CSF-1R.
In vivo, inhibits proliferation of a CSF-1R-dependent cell line.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instruct patients to take pexidartinib hydrochloride with a low-fat meal (approximately 11-14 grams of total fat) and avoid taking with a high-fat meal (approximately 55-65 grams of total fat). Instruct patients to swallow capsules whole (do not open, break, or chew).
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.
Advise patients of the risk of photosensitivity and to avoid prolonged sun exposure and use sunscreen and protective clothing during pexidartinib treatment.
Pexidartinib hydrochloride is available only through a restricted program called the Turalio REMS Program and patients are required to be part of the patient registry.
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. Advise females of reproductive potential to use effective contraception during treatment with pexidartinib hydrochloride 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.
Advise females not to breast-feed during treatment with pexidartinib hydrochloride and for one week after the final dose.
Advise females and males of reproductive potential that pexidartinib hydrochloride may impair fertility.
Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pexidartinib hydrochloride is only available through a restricted program called the Turalio REMS Program. Clinicians should consult the Turalio REMS website at [Web] or call 833-887-2546.

Pexidartinib hydrochloride can only be obtained through a designated specialty pharmacy.