Drug information of pexidartinib
Mechanism of effect
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
Oxidation via CYP3A4 and glucuronidation via UGT1A4 (glucuronidation forms inactive N-glucuronide metabolite
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.
Tenosynovial giant cell tumor: Oral: 400 mg twice daily until disease progression or unacceptable toxicity (Tap 2019).
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.
Dosage adjustment for concomitant therapy:Significant drug
interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Missed dose: If a dose is missed or vomited, administer the next dose at its scheduled time.
There are no contraindications listed in the manufacturer's labeling
- Abdominal or stomach pain or tenderness
- clay colored stools
- dark urine
- decreased appetite
- itching or skin rash
- loss of appetite
- nausea and vomiting
- swelling of the feet or lower legs
- unusual tiredness or weakness
- yellow eyes or skin
- Blurred vision
- burning, tingling, numbness or pain in the hands, arms, feet, or legs
- change or loss of taste
- difficulty having a bowel movement (stool)
- hair color changes
- pounding in the ears
- sensation of pins and needles
- slow or fast heartbeat
- stabbing pain
- swelling of the eyes
InteractionsLansoprazole , Medroxyprogesterone , Carbamazepine , Quinine , Perindopril , Binimetinib , Butabarbital , Dexlansoprazole , trabectedine , trametinib , Duvelisib , Dapsone , Deferasirox , Deflazacort , Clarithromycin , Clozapine , Daclatasvir , Acetaminophen and benzhydrocodone , Doravirine , Cobimetinib , ELBASVIR/GRAZOPREVIR , Clofazimine , codeine , Axitinib , dasabuvir , brigatinib , Dabrafenib , elagolix , Valdecoxib , atovaquone/proguanil , Larotrectinib , Dacomitinib , Oxaprozin , gilteritinib , Triphasic , oleandomycin , bedaquiline , Gefitinib , Remdesivir , ambrisentan , voxelotor , Daclizumab , Fidaxomicin , Netupitant , chenodiol , calaspargase , Capmatinib
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 up to 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.
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.
Points of recommendation
(Treatment of symptomatic tenosynovial giant cell tumor (TGCT
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to pexidartinib may cause fetal harm.