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Pexidartinib Hydrochloride

Class: Antineoplastic Agents
Chemical Name: 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine
Molecular Formula: C20H15ClF3N5
CAS Number: 1029044-16-3
Brands: Turalio

Medically reviewed by Drugs.com. Last updated on Aug 19, 2019.

Warning

Warning: Hepatotoxicity1

See full prescribing information for complete boxed warning.1

  • Pexidartinib hydrochloride can cause serious and potentially fatal liver injury.1

  • Monitor liver tests prior to initiation of pexidartinib hydrochloride and at specified intervals during treatment. Withhold and dose reduce or permanently discontinue pexidartinib hydrochloride based on severity of hepatotoxicity.1

  • Pexidartinib hydrochloride is available only through a restricted program called the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program.1

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for pexidartinib hydrochloride to ensure that the benefits outweigh the risk. 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/.

Introduction

Pexidartinib hydrochloride, a kinase inhibitor, is an antineoplastic agent.1

Uses for Pexidartinib Hydrochloride

Pexidartinib hydrochloride has the following uses:

Pexidartinib hydrochloride is indicated for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.1

Pexidartinib Hydrochloride Dosage and Administration

General

Pexidartinib hydrochloride is available in the following dosage form(s) and strength(s):

Capsules: 200 mg1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Important Administration Instructions: Administer pexidartinib hydrochloride on an empty stomach, at least 1 hour before or 2 hours after a meal or snack.1

  • Recommended Dosage: 400 mg orally twice daily.1

Cautions for Pexidartinib Hydrochloride

Contraindications

None.1

Warnings/Precautions

Hepatotoxicity

Pexidartinib hydrochloride can cause serious and potentially fatal liver injury and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). 1

Hepatotoxicity with ductopenia and cholestasis occurred in patients treated with pexidartinib hydrochloride. Across 768 patients who received pexidartinib hydrochloride in clinical trials, there were two irreversible cases of cholestatic liver injury. One patient died with advanced cancer and ongoing liver toxicity and one patient required a liver transplant. The mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted. It is unknown whether liver injury occurs in the absence of increased aminotransferases.1

In ENLIVEN, 3 of 61 (5%) patients who received pexidartinib hydrochloride developed signs of serious liver injury, defined as ALT or AST ≥3 times the ULN with total bilirubin ≥2 times the ULN. In these patients, peak ALT ranged from 6 to 9 times the ULN, peak total bilirubin ranged from 2.5 to 15 times the ULN, and alkaline phosphatase (ALP) was ≥2 times the ULN. ALT, AST and total bilirubin improved to <2 times the ULN in these patients 1 to 7 months after discontinuing pexidartinib hydrochloride. 1

Avoid pexidartinib hydrochloride in patients with pre-existing increased serum aminotransferases; total bilirubin or direct bilirubin (>ULN); or active liver or biliary tract disease, including increased ALP. Taking pexidartinib hydrochloride with food increases drug exposure by 100% and may increase the risk of hepatotoxicity. Administer pexidartinib hydrochloride on an empty stomach, either 1 hour before or 2 hours after a meal or snack. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyl transferase (GGT), prior to initiation of pexidartinib hydrochloride, 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 pexidartinib hydrochloride based on the severity of the hepatotoxicity. Rechallenge with a reduced dose of pexidartinib hydrochloride may result in a recurrence of increased serum aminotransferases, bilirubin, or ALP. Monitor liver tests weekly for the first month after rechallenge.1

Turalio REMS Program

Pexidartinib hydrochloride is only available through a restricted program under a REMS, because of the risk of hepatotoxicity.1

Notable requirements of the Turalio REMS Program include the following: 1

  • Prescribers must be certified with the program by enrolling and completing training.1

  • Patients must complete and sign an enrollment form for inclusion in a patient registry. 1

  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive pexidartinib hydrochloride.1

Further information is available at www.turalioREMS.com or 1-833-887-2546.1

Embryo-fetal Toxicity

Based on animal studies and its mechanism of action, pexidartinib hydrochloride 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 of 800 mg based on area under the curve (AUC).1

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with pexidartinib hydrochloride and for 1 month after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pexidartinib hydrochloride and for 1 week after the final dose.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and its mechanism of action, pexidartinib hydrochloride 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 pexidartinib hydrochloride. 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 of 800 mg. Advise pregnant women of the potential risk to a fetus.1

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.1

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 of 800 mg). 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 of 800 mg).1

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 pexidartinib hydrochloride and for at least one week after the final dose.1

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to the initiation of pexidartinib hydrochloride.1

Pexidartinib hydrochloride may cause embryo-fetal harm when administered to a pregnant woman.1

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

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

Based on findings from animal studies, pexidartinib hydrochloride may impair both male and female fertility. 1

Pediatric Use

The safety and effectiveness of pexidartinib hydrochloride in pediatric patients have not been established.1

Geriatric Use

Clinical studies of pexidartinib hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.1

Renal Impairment

Reduce the dose when administering pexidartinib hydrochloride to patients with mild to severe renal impairment (CLcr 15 to 89 mL/min, estimated by Cockcroft-Gault [C-G]). 1

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). 1

The recommended dose of pexidartinib hydrochloride 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. 1

Common Adverse Effects

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.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Use with Hepatotoxic Products: Avoid coadministration of pexidartinib hydrochloride with other products known to cause hepatotoxicity.1

  • Strong CYP3A Inhibitors: Reduce the dose of pexidartinib hydrochloride if concomitant use of strong CYP3A inhibitors cannot be avoided.1

  • Strong CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers.1

  • UGT Inhibitors: Reduce the dose of pexidartinib hydrochloride if concomitant use of UGT inhibitors cannot be avoided.1

  • Acid Reducing Agents: Avoid concomitant use of proton pump inhibitors. Use histamine-2 receptor antagonists or antacids if needed.1

Actions

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. Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium. In vitro, pexidartinib inhibited proliferation of cell lines dependent on CSF1R and ligand-induced autophosphorylation of CSF1R. Pexidartinib also inhibited the proliferation of a CSF1R dependent cell line in vivo.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

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 provider.1

Turalio REMS Program

Pexidartinib hydrochloride is available only through a restricted program called Turalio REMS Program and patients are required to be part of the patient registry.1

Pexidartinib hydrochloride 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.1

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.1

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

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

Lactation

Advise females not to breastfeed during treatment with pexidartinib hydrochloride and for one week after the final dose. 1

Infertility

Advise females and males of reproductive potential that pexidartinib hydrochloride may impair fertility. 1

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter products and supplements.1

Administration

Instruct patients to take pexidartinib hydrochloride 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).1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg (of pexidartinib)

Turalio

Daiichi Sankyo Inc.

AHFS Drug Information. © Copyright 2020, Selected Revisions August 19, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Daiichi Sankyo Inc. Turalio (pexidartinib) ORAL prescribing information. 2019 Aug. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24c5a6f1-b640-4d14-b44b-dd293ed002b1