Adult Dosing

• 400 mg PO taken twice daily on an empty stomach until disease progression or unacceptable toxicity. Swallow the capsules whole.
• Do not open, break, or chew the capsules.
• Administer on an empty stomach, at least one hour before or two hours after a meal or snack
• If a patient vomits or misses a dose, instruct the patient to take the next dose at its scheduled time.
• concomitant use with strong CYP3A inhibitor or UGT inhibitor:
• If originally taking pexidartinib 600 mg/day PO or 800 mg/day PO, reduce the dose to 200 mg PO twice daily
• if originally taking pexidartinib 400 mg/day PO, reduce dose to 200 mg PO once daily.

Pediatric Dosing

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

[Outline]

• Adult Dosing
• Pediatric Dosing

• Adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

• None

Renal Dose Adjustment

• Renal impairment: 200 mg PO in the morning and 400 mg PO in the evening for patients with mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min estimated by Cockcroft-Gault using actual body weight) is 200 mg PO in the morning and 400 mg PO in the evening.

Hepatic Dose Adjustment

• 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)

Geriatric Dosing

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

• Mild to severe renal impairment.
• Can cause serious and potentially fatal liver injury and is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).
• 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
• Pregnancy: may cause embryo-fetal harm, potential risk to a fetus.
• Lactation: Because of the potential for serious adverse reactions in the breastfed child, not to breastfeed during treatment and for at least one week after the final dose.
• Females and Males of Reproductive Potential :
• Verify pregnancy status in females of reproductive potential prior to the initiation of pexidartinib hydrochloride.
• Advise females of reproductive potential to use effective contraception during treatment with pexidartinib hydrochloride 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 hydrochloride and for 1 week after the final dose.
• Based on findings from animal studies, pexidartinib hydrochloride may impair both male and female fertilit

Interaction

• Strong CYP3A Inhibitors: Concomitant use increases pexidartinib plasma concentrations.which may increase the incidence and severity advrse reaction. Reduce the dose, if concomitant use, including grapefruit or grapefruit juice cannot be avoided.
• Strong CYP3A Inducers: Concomitant use decreases pexidartinib plasma concentrations, may decrease the efficacy. Avoid concomitant use, including St John's wort.
• UGT Inhibitors: May increase pexidartinib plasma concentrations. Avoid concurrent use. If concurrent use cannot be avoided, then reduce the dose.
• PPI: May decrease levels and effectivenes. Aavoid concurrent use. As alternative, administer pexidartinib 2 hr before or after taking an antacid or 2 or more hr before or 10 hr after taking an H2 antagonist.

Pregnancy Category:X

Breastfeeding: 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, not to breastfeed during treatment and for at least one week after the final dose.

• CNS: Dysgeusia, ageusia
• CV: Hypertension, face edema, localized edema, edema peripheral, peripheral swelling.
• DERM: Hair color changes,alopecia, rash, maculo-papular rash, rash pruritic, urticaria, erythema, dermatitis acneiform, dermatitis allergic, hyperpigmentation, hypopigmentation, depigmentation
• EYE: Blurred vision, photophobia, diplopia, reduced visual acuity
• GI: Hepatotoxicity, dry mouth, stomatitis, mouth ulceration, vomiting, constipation, cholangitis, liver disorder
• HEMAT: lymphocytopenia,
• NEURO: Neuropathy peripheral, paresthesia, hypoesthesia, burning sensation, cognitive disorders (memory impairment, amnesia, confusional state, disturbance in attention, attention deficit/hyperactivity disorder)
• PSYC: Anxiety, depressive disorders
• GEN: Fatigue, asthenia, malaise, pyrexia

• 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.
• Absorption: Increases drug exposure by 100% with high-fat meals and delays absorption by 2.5 hrs.
• Distribution: Extensively distributed to extravascular tissues.
• Protein Binding: >99%.
• Metabolism/Excretion: Primarily metabolized by CYP3A4 isoenzyme and through glucuronidation (via UGT1A4). Major inactive metabolite formed via glucuronidation. 65% excreted via feces (44% as unchanged drug), 27% excreted in urine as metabolites.
• Half-life: 26.6 hrs.

US Trade Name(s)

• Turalio

US Availability

Turalio

• CAPS: 200 mg

[Outline]

Hematology/Oncology

Antineoplastics

Kinase Inhibitors