Pexidartinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Turalio: 200 mg

Pharmacology

Mechanism of Action

Pexidartinib is a tyrosine kinase inhibitor with selective and strong inhibitory activity against the colony-stimulating factor 1 receptor (CSF1R); pexidartinib also inhibits KIT and FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (Tap 2019). Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium. Pexidartinib inhibits proliferation of a CSF1R dependent cell line

Pharmacokinetics/Pharmacodynamics

Distribution

V_z/F: 187 L

Metabolism

Oxidation via CYP3A4 and glucuronidation via UGT1A4 (glucuronidation forms inactive N-glucuronide metabolite)

Excretion

Feces (65%; 44% as unchanged drug); Urine (27% as metabolites); Clearance: 5.1 L/hour

Time to Peak

2.5 hours

Half-Life Elimination

26.6 hours

Protein Binding

>99%; to albumin and alpha-1 acid glycoprotein

Use in Specific Populations

Special Populations: Renal Function Impairment

Mild, moderate, and severe impairment (CrCl 15 to 89 mL/minute) increased pexidartinib exposure by ~30%, compared to normal renal function (CrCl ≥90 mL/minute).

Use: Labeled Indications

Tenosynovial giant cell tumor: Treatment of symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery in adults.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Tenosynovial giant cell tumor: Oral: 400 mg twice daily until disease progression or unacceptable toxicity (Tap 2019).

Dosage adjustment for concomitant CYP3A inhibitors or UGT inhibitors: Avoid concomitant use of pexidartinib with strong CYP3A inhibitors or UGT inhibitors. If concomitant use with a strong CYP3A inhibitor or UGT inhibitor cannot be avoided, reduce the pexidartinib dose (from 400 mg twice daily to 200 mg twice daily, or from 600 mg/day [200 mg in the morning and 400 mg in the evening] to 200 mg twice daily, or from 200 mg twice daily to 200 mg once daily). If concomitant use of a strong CYP3A inhibitor or UGT inhibitor is discontinued, increase the pexidartinib dose to the dose that was used prior to initiating the inhibitor after 3 plasma half-lives of the strong CYP3A inhibitor or UGT inhibitor have elapsed.

Missed dose: If a dose is missed or vomited, administer the next dose at its scheduled time.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended pexidartinib dosage reduction levels:

Initial (usual dose): 400 mg twice daily (total of 800 mg/day).

First dose reduction level: 200 mg in the morning and 400 mg in the evening (total of 600 mg/day).

Second dose reduction level: 200 mg twice daily (total of 400 mg/day).

Permanently discontinue if unable to tolerate 200 mg twice daily.

Severe or intolerable adverse reactions or lab abnormalities (other than hepatic): Withhold pexidartinib until improvement or resolution. Resume pexidartinib at a reduced dose upon improvement or resolution.

Administration

Oral: Administer on an empty stomach, ≥1 hour before or 2 hours after a meal or snack. Swallow capsules whole; do not open, break or chew.

Acid-reducing agents: Administer pexidartinib 2 hours before or 2 hours after locally-acting antacids; administer pexidartinib ≥2 hours before or 10 hours after a H₂-receptor antagonist. Avoid concomitant administration of pexidartinib with proton pump inhibitors.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep container(s) closed; do not remove desiccant from bottles.

Drug Interactions

Antacids: May decrease the serum concentration of Pexidartinib. Management: Administer pexidartinib 2 hours before or after antacids. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Pexidartinib. Exceptions: St John's Wort. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Pexidartinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Pexidartinib. Exceptions: Grapefruit Juice. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Pexidartinib. Management: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Pexidartinib. Avoid combination

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Pexidartinib. Management: Administer pexidartinib 2 hours before or 10 hours after histamine H2 receptor antagonists. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Proton Pump Inhibitors: May decrease the serum concentration of Pexidartinib. Management: If acid-reduction is needed, consider administering an antacid 2 hours before or after pexidartinib, or administer pexidartinib 2 hours before or 10 hours after an H2 receptor antagonist. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of Pexidartinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

UGT1A4 Inhibitors: May increase the serum concentration of Pexidartinib. Management: Avoid use of UGT1A4 inhibitors and pexidartinib. If combined use is required, reduce the pexidartinib dose. If receving pexidartinib 800 mg or 600 mg daily, reduce to 200 mg twice daily. If receiving 400 mg/day, reduce to 200 mg/day. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (20%), hypertension (15%)

Central nervous system: Fatigue (64%)

Dermatologic: Hair discoloration (67%), skin rash (28%), pruritus (18%)

Endocrine & metabolic: Increased lactate dehydrogenase (92%), increased serum cholesterol (44%), decreased serum phosphate (25%)

Gastrointestinal: Dysgeusia (26%), vomiting (20%), decreased appetite (16%), constipation (12%)

Hematologic & oncologic: Decreased neutrophils (44%; grade ≥3: 3%), lymphocytopenia (38%; grade ≥3: 2%), decreased hemoglobin (30%), thrombocytopenia (15%)

Hepatic: Increased serum aspartate aminotransferase (61%), increased serum alanine aminotransferase (31%), increased serum alkaline phosphatase (31%)

Ophthalmic: Swelling of eye (30%)

1% to 10%:

Central nervous system: Neuropathy (10%), cognitive dysfunction

Dermatologic: Alopecia, dyschromia

Gastrointestinal: Cholangitis, oral mucosa ulcer, stomatitis, xerostomia

Hepatic: Hepatotoxicity (5% to <10%), increased serum bilirubin (3%), hepatic disease

Ophthalmic: Blurred vision, decreased visual acuity, diplopia, photophobia

Miscellaneous: Fever

Frequency not defined:

Central nervous system: Dizziness

Endocrine & metabolic: Increased gamma-glutamyl transferase

Gastrointestinal: Abdominal pain, nausea

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: [US Boxed Warning]: Pexidartinib can cause serious and potentially fatal liver injury. Monitor liver function prior to pexidartinib initiation and during treatment. Based on the severity, hepatotoxicity may require treatment interruption, dose reduction, and/or permanent discontinuation. Hepatotoxicity with ductopenia and cholestasis has occurred, including rare irreversible cases of cholestatic liver injury (which were fatal or required liver transplantation). The occurrence of pexidartinib-related cholestatic hepatoxicity cannot be predicted, and the mechanism of hepatotoxicity is unknown. It is not known if liver injury occurs in the absence of transaminase elevations. A small percentage of patients in a clinical study who received pexidartinib developed signs of serious liver injury (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 was ≥2 × ULN. ALT, AST and total bilirubin improved to <2 × ULN at 1 to 7 months after discontinuing pexidartinib. Avoid pexidartinib in patients with preexisting increased serum transaminases, total bilirubin or direct bilirubin (> ULN), or active liver or biliary tract disease (including increased alkaline phosphatase). Monitor liver function tests (including AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase [GGT]) prior to pexidartinib initiation, weekly for the first 8 weeks, every 2 weeks for the next month, and then every 3 months thereafter. Hepatotoxicity may require treatment interruption, dose reduction, and/or permanent discontinuation (based on the severity). Rechallenge with a reduced pexidartinib dose may result in a recurrence of increased transaminases, bilirubin, or alkaline phosphatase; following rechallenge, monitor liver function tests weekly for the first month. Administer pexidartinib on an empty stomach (1 hour before or 2 hours after a meal or snack), as administration with food increases exposure by 100% and may increase the risk of hepatotoxicity. Avoid concurrent administration of other hepatotoxic medications in patients with elevated transaminases, elevated total or direct bilirubin (> ULN), or active liver or biliary tract disease.

Disease-related concerns:

• Renal impairment: Dose reduction recommended in patients with renal impairment.

Concurrent drug therapy issues:

• Acid-reducing agents: Avoid concomitant administration of pexidartinib with proton pump inhibitors. A locally-acting antacid or a histamine 2 (H₂)-receptor antagonist may be alternatively utilized. Administer pexidartinib 2 hours before or 2 hours after local antacids. Administer pexidartinib ≥2 hours before or 10 hours after a H₂-receptor antagonist.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions

• REMS program: [US Boxed Warning]: Pexidartinib is available only through a restricted program called the TURALIO Risk Evaluation and Mitigation Strategy (REMS) Program. Information is available at www.turalioREMS.com or 1-833-887-2546.

Monitoring Parameters

Monitor liver function tests (including AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase [GGT]) prior to pexidartinib initiation, weekly for the first 8 weeks, every 2 weeks for the next month and then every 3 months thereafter; following rechallenge, monitor liver function tests weekly for the first month. Monitor renal function. Evaluate pregnancy status prior to treatment initiation (in females of reproductive potential). Monitor for signs/symptoms of liver injury. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to pexidartinib may cause fetal harm.

Evaluate pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment and for 1 month after the last pexidartinib dose. Males with a female partner of reproductive potential should use effective contraception during treatment and for 1 week after the last pexidartinib dose.

Patient Education

What is this drug used for?

• It is used to treat a type of cancer called tenosynovial giant cell tumor (TGCT).

Frequently reported side effects of this drug

• Hair discoloration
• Change in taste
• Vomiting
• Constipation
• Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe headache
• Dizziness
• Passing out
• Vision changes
• Low phosphate like vision changes, confusion, mood changes, muscle pain, muscle weakness, shortness of breath, difficulty breathing, or difficulty swallowing
• Swelling of arms or legs
• Swelling in or around the eyes
• Burning or numbness feeling
• Infection
• Bruising
• Bleeding
• Severe loss of strength and energy
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.