pexidartinib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

**REMS Drug**

Pronunciation:
pex-i-dar-ti-nib


Trade Name(s)

  • Turalio

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

Symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

Action

Acts as a tyrosine kinase inhibitor that selectively inhibits the colony-stimulating factor 1 receptor, which slows proliferation of tumor cells in the synovium.

Therapeutic Effect(s):

Reduction in tumor size and improvement in joint movement.

Pharmacokinetics

Absorption: High-fat food ↑ drug exposure by 100% and delays absorption.

Distribution: Extensively distributed to extravascular tissues.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized by the CYP3A4 isoenzyme and through glucuronidation (via UGT1A4); inactive metabolite formed via glucuronidation. 65% excreted via feces (44% as unchanged drug), 27% excreted in urine as metabolites.

Half-life: 26.6 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown2.5 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • Pre-existing liver enzyme elevations or active liver or biliary tract disease;
  • Severe hepatic impairment;
  • OB:  Pregnancy;
  • Lactation:  Lactation.

Use Cautiously in:

  • Renal impairment (↓ dose);
  • Moderate hepatic impairment (↓ dose);
  • Rep:  Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: hypertension, peripheral edema

Derm: hair color changes, pruritus, rash, alopecia, skin pigmentation changes

EENT: eye edema, blurred vision, diplopia, photophobia

F and E: hypophosphatemia

GI: constipation, vomiting, dry mouth, HEPATOTOXICITY, stomatitis

GU: ↓ fertility

Hemat: anemia, lymphocytopenia, thrombocytopenia, NEUTROPENIA

Metabolic: ↓ appetite, hypercholesterolemia

Neuro: dysgeusia, fatigue, peripheral neuropathy, amnesia, amnesia, attention disturbances, confusion, memory impairment

Misc: fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Hepatotoxic drugs  can ↑ risk of hepatotoxicity; avoid concurrent use.
  •  Strong CYP3A inhibitors, including  itraconazole, and  moderate CYP3A inhibitors, including  fluconazole, may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use cannot be avoided, ↓ pexidartinib dose.
  •  Strong CYP3A inducers  may ↓ levels and effectiveness; avoid concurrent use.
  •  UGT inhibitors  may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use cannot be avoided, ↓ pexidartinib dose.
  •  Proton pump inhibitors  may ↓ levels and effectiveness; avoid concurrent use; as alternative, administer pexidartinib 2 hr before or after taking an antacid or ≥2 hr before or 10 hr after taking an H2  antagonist.
  • May ↓ levels and effectiveness of  CYP3A substrates, including  hormonal contraceptives ; avoid concurrent use with hormonal contraceptives; avoid concurrent use with other CYP3A substrates; if concurrent use unavoidable, ↑ dose of CYP3A substrate.

Drug-Natural Products:

 St. John's wort  may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

  • Grapefruit or grapefruit juice may ↑ levels and risk of toxicity; if concurrent use cannot be avoided, ↓ pexidartinib dose.
  • High-fat meals ↑ levels and risk of toxicity; avoid concurrent use; take each dose with low-fat meal.

Route/Dosage

PO (Adults): 250 mg twice daily until disease progression or unacceptable toxicity.  Concurrent use of strong or moderate CYP3A inhibitors or UGT inhibitors: If originally taking pexidartinib 500 mg/day or 375 mg/day, ↓ dose to 125 mg twice daily; if originally taking pexidartinib 250 mg/day, ↓ dose to 125 mg once daily.

Renal Impairment 
PO (Adults): CCr 15–89 mL/min: 125 mg every morning and 250 mg every evening until disease progression or unacceptable toxicity.

Hepatic Impairment 
PO (Adults): Moderate hepatic impairment (total bilirubin 1.51–3 times upper limit of normal [ULN] not due to Gilbert's syndrome): 125 mg twice daily until disease progression or unacceptable toxicity.

Availability

Capsules: 125 mg

Assessment

  • Monitor for signs and symptoms of liver toxicity (yellowing of your skin and whites of eyes, dark urine, loss of appetite, right upper abdominal pain or tenderness, feeling overly tired, nausea, vomiting, fever, rash, itching) during therapy.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

  • Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT), before starting therapy, weekly for first 8 wk, every 2 wk for next mo and every 3 mo thereafter.  If AST and ALT >3–5 times ULN,  hold dose and monitor liver tests weekly. If AST and ALT ≤3 times ULN within 4 wk, resume at reduced dose. If AST or ALT >3 times ULN in 4 wk, permanently discontinue therapy.  If AST and ALT >5–10 times ULN,  hold dose and monitor liver tests twice weekly. If AST and ALT ≤3 times ULN within 4 wk, resume at reduced dose. If AST or ALT >3 times ULN in 4 wk, permanently discontinue therapy.  If AST and ALT >10 times ULN,  permanently discontinue therapy. Monitor liver tests twice weekly until AST or ALT ≤5 times ULN, then weekly until ≤3 times ULN.  If ALP and GGT >2 times ULN,  discontinue therapy permanently. Monitor liver tests twice weekly, until ALP ≤5 times ULN, then weekly until ≤2 times ULN.  If total bilirubin ↑ >ULN to <2 times ULN or direct bilirubin >ULN and <1.5 times ULN,  hold dose and monitor liver tests twice weekly. If an alternate cause for ↑ bilirubin is confirmed and bilirubin <ULN within 4 wk, resume at reduced dose. If bilirubin is >ULN in 4 wk, permanently discontinue therapy.  If total bilirubin ≥2 times ULN or direct bilirubin >1.5 times ULN,  discontinue therapy permanently. Monitor liver tests twice weekly until bilirubin ≤ULN. Rechallenge with a reduced dose of pexidartinib may result in a recurrence of ↑ AST, ALT, bilirubin, or ALP. Monitor liver tests weekly for 1st mo after rechallenge.
  • May cause ↑ LDH and cholesterol and ↓ serum phosphate.
  • May cause ↓ neutrophils, lymphocytes, hemoglobin, and platelets.

Implementation

  •  REMS: Pexidartinib is only available through a restricted program:  Turalio  REMS. Prescribers must enroll and complete training. Patient must sign enrollment form for inclusion in a patient registry. Pharmacies must be certified and only dispense to authorized patients. Information is available at www.turalioREMS.com or 1-833-887-2546.
  • Dose reduction schedule: First dose reduction,  375 mg daily taken as 125 mg in morning and 250 mg in evening.  Second dose reduction,  250 mg daily taken as 125 mg twice daily.  If patient unable to tolerate 125 mg twice daily,  discontinue pexidartinib permanently.
  • PO Administer twice daily with a low-fat meal (11–14 g of total fat). DNC:  Swallow capsules whole; do not open, break, or chew. 
    • If antacids or H2  antagonists are needed, administer pexidartinib 2 hr before or 2 hr after antacids. Administer pexidartinib at least 2 hr before or 10 hr after H2 antagonists.

Patient/Family Teaching

  • Instruct patient to take pexidartinib with a low-fat meal, as directed. If a dose is missed or patient vomits after dose, omit dose and take next dose at scheduled time. Advise patient to read  Medication Guide  before starting therapy and with each Rx refill in case of changes.
  •  REMS: Inform patient of the  Turalio  REMS program and requirements.
  • Caution patient to avoid grapefruit juice during therapy.
  • Advise patient to take pexidartinib 2 hr before or 2 hr after antacids and at least 2 hr before or 10 hr after H2 antagonists.
  • Advise patient to notify health care professional immediately if signs and symptoms of liver toxicity occur.
  • Inform patient that pexidartinib may cause a change in hair color and a loss of taste or changes in the way things taste.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, herbal products, especially St. John's wort.
  • Rep:  May cause fetal harm. Advise females of reproductive potential to use effective nonhormonal contraception during and for 1 mo after last dose and to avoid breastfeeding during and for 1 wk after last dose. Advise males with female partners of reproductive potential to use effective nonhormonal contraception during and for 1 wk after last dose of pexidartinib. May impair male and female fertility.
  • Emphasize the need for regular lab tests to monitor for side effects.

Evaluation/Desired Outcomes

Reduction in tumor size and improvement in joint movement.