pexidartinib (Rx)

Brand and Other Names:Turalio
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 200mg

Tenosynovial Giant Cell Tumor

Indicated for adults with tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery

400 mg PO BID on an empty stomach until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction schedule

  • First reduction: 200 mg in AM and 400 mg in PM
  • Second reduction: 200 mg BID
  • Permanently discontinue if unable to tolerate 200 mg BID
  • >3-5x ULN
    • Withhold and monitor liver tests weekly
    • If AST and ALT are ≤3x ULN within 4 weeks, resume at reduced dose
    • If AST or ALT is not ≤3x ULN in 4 weeks, permanently discontinue
  • >5-10x ULN
    • Withhold and monitor liver tests twice weekly
    • If AST and ALT are ≤3x ULN within 4 weeks, resume at reduced dose
    • If AST or ALT are not ≤3x ULN in 4 weeks, permanently discontinue
  • >10 ULN
    • Permanently discontinue
    • Monitor liver tests twice weekly until AST or ALT ≤5x ULN, then weekly until ≤3x ULN

Increase ALP and GGT

  • ALP >2x ULN with GGT >2x ULN
    • Permanently discontinue
    • Monitor liver tests twice weekly until ALP ≤5x ULN, then weekly until ≤2x ULN

Increased bilirubin

  • Total bilirubin (TB) >ULN to <2x ULN or direct bilirubin (DB) >ULN and <1.5x ULN
    • Withhold and monitor liver tests twice weekly
    • If an alternate cause for increased bilirubin confirmed and bilirubin
    • If bilirubin is not
  • TB ≥2x ULN or DB >1.5x ULN
    • Permanently discontinue
    • Monitor liver tests twice weekly until bilirubin ≤ULN

Other severe/intolerable adverse effects or laboratory abnormalities

  • Withhold until improvement or resolution
  • Resume at reduced dose upon improvement or resolution

Coadministration with strong CYP3A or UGT inhibitors

  • Avoid coadministration
  • If unable to avoid concomitant use, reduce pexidartinib (see following)
  • If strong CYP3A or UGT inhibitor discontinued, increase pexidartinib dose (after 3 plasma half-lives of the strong CYP3A or UGT inhibitor) to the dose that was used before starting the inhibitor
  • Dose adjustment with strong CYP3A or UGT inhibitors
    • Planned total daily dose of 800 mg: Modify to 200 mg BID
    • Planned total daily dose of 600 mg: Modify to 200 mg BID
    • Planned total daily dose of 400 mg: Modify to 200 mg qDay

Concomitant use of acid-reducing agents

  • Avoid coadministration of proton pump inhibitors (PPIs)
  • Alternatives to PPI
    • Locally acting antacid: Administer pexidartinib at least 2 hr before or 2 hr after
    • H2-receptor antagonist: Administer pexidartinib at least 2 hr before or 10 hr after

Renal impairment

  • Mild-to-severe (CrCl 15-89 mL/min): 200 mg in AM and 400 mg in evening

Hepatic impairment

  • Mild (TB ULN or TB >1-1.5x ULN with any AST): No dosage adjustment required
  • Moderate or severe: Not established; see Warnings

Dosing Considerations

Monitor liver tests before initiating and at specified intervals during treatment

Safety and efficacy not established

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Interactions

Interaction Checker

and pexidartinib

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            All grades of severity listed unless otherwise indicated

            >10%

            Increased LDH (92%)

            Hair color changes (67%)

            Fatigue (64%)

            Increased AST, Grade 1 (61%)

            Increased cholesterol (44%)

            Decreased neutrophils (44%)

            Decreased lymphocytes (38%)

            Increased ALT (31%)

            Increased ALP (31%)

            Eye edema (30%)

            Decreased hemoglobin (30%)

            Rash (28%)

            Dysgeusia (26%)

            Peripheral edema (20%)

            Vomiting (20%)

            Pruritus (18%)

            Decreased appetite (16%)

            Decreased platelets (15%)

            Increased AST, Grade 2 (15%)

            Hypertension (15%)

            Increased ALT, Grade 2 (13%)

            Constipation (12%)

            Blurred vision (>10%)

            >10% (Grade ≥3)

            Increased ALT (20%)

            Increased AST (12%)

            1-10%

            Neuropathy (10%)

            Photophobia (<10%)

            Diplopia (<10%)

            Reduced visual acuity (<10%)

            Dry mouth (<10%)

            Stomatitis (<10%)

            Mouth ulceration (<10%)

            Pyrexia (<10%)

            Cholangitis (<10%)

            Hepatotoxicity (<10%)

            Liver disorder (<10%)

            Cognitive disorders (eg, memory impairment, amnesia, confusional state, disturbance in attention, attention-deficit/hyperactivity disorder) (<10%)

            Alopecia (<10%)

            Skin pigment changes (hypopigmentation, depigmentation, discoloration, hyperpigmentation) (<10%)

            Increased cholesterol (4.9%)

            Decreased phosphate (3.3%)

            Increased ALP, Grade 2 (3.3%)

            Increased bilirubin, Grade 1-2 (3.3%)

            1-10% (Grade ≥3)

            Hypertension (4.9%)

            Increased ALP (4.9%)

            Decreased neutrophils (3.3%)

            Increased bilirubin (3.3%)

            Rash (1.6%)

            Eye edema (1.6%)

            Vomiting (1.6%)

            Decreased lymphocytes (1.6%)

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            Warnings

            Black Box Warnings

            Hepatotoxicity

            • Serious and potentially fatal liver injury may occur
            • Monitor liver tests before initiating treatment and periodically during treatment
            • Withhold and dose reduce or permanently discontinue based on severity of hepatotoxicity
            • Available only through a restricted program called the Turalio Risk Evaluation and Mitigation Strategy (REMS)

            Contraindications

            None

            Cautions

            Based on animal studies and its mechanism of action, fetal harm may occur when administered to a pregnant woman

            Hepatoxicity

            • Hepatotoxicity with ductopenia and cholestasis occurred; mechanism of cholestatic hepatotoxicity is unknown and its occurrence cannot be predicted
            • It is unknown whether liver injury occurs in the absence of increased transaminases
            • Administration with food increases drug exposure by 100% and may increase risk of hepatotoxicity
            • Monitor liver tests before initiating treatment, weekly for the first 8 weeks, every 2 weeks for the next month, and every 3 months thereafter

            REMS program

            • Available only through a restricted program under a REMS, owing to the risk of hepatoxicity
            • Requirements of the program include the following:
            • Prescribers must be certified with the program by enrolling and completing training
            • Patients must complete and sign an enrollment form for inclusion in a patient registry
            • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive pexidartinib
            • Further information is available at www.turalioREMS.com or 1-833-887-2546

            Drug interaction overview

            • Pexidartinib is CYP3A4 and UGT1A4 substrate; also known to cause hepatoxicity
            • Hepatotoxic agents
              • Avoid coadministration of pexidartinib with other products known to cause hepatoxicity in patients with increased serum transaminases, total bilirubin, or direct bilirubin (>ULN) or active liver or biliary tract disease, owning to increased risk of hepatoxicity
            • Strong CYP3A inhibitors
              • Coadministration with a strong CYP3A inhibitor increases pexidartinib plasma concentrations and potentially increases the incidence and severity of adverse reactions
            • Strong CYP3A inducers
              • Avoid coadministration
              • Concomitant use of a strong CYP3A inducer with pexidartinib decreases pexidartinib plasma, which may decrease pexidartinib efficacy
            • UGT inhibitors
              • Concomitant use of a UGT inhibitor increases pexidartinib plasma concentrations and potentially increases the incidence and severity of adverse reactions
            • Acid-reducing agents
              • Avoid coadministration with proton pump inhibitors (PPIs)
              • Concomitant PPI decreases pexidartinib plasma concentrations, which may decrease pexidartinib efficacy
              • Alternatively, may use locally acting antacid or H2-receptor antagonist (see Dosage Modifications for dosing intervals)
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            Pregnancy & Lactation

            Pregnancy

            Based on findings from animal studies and its mechanism of action, embryofetal harm may occur when administered to a pregnant woman

            Available human data do not establish the presence or absence of major birth defects or miscarriage related to use in pregnant women

            Animal data

            • Oral administration of pexidartinib to pregnant animals during organogenesis resulted in malformations, postimplantation 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

            Pregnancy testing

            • Verify pregnancy status in females of reproductive potential before initiating treatment

            Contraception

            • Embryofetal harm may occur when administered to a pregnant woman
            • Females of reproductive potential: Use effective contraception during treatment and for 1 month after final dose
            • Males with female partners of reproductive potential: Use effective contraception during treatment and for 1 week after final dose

            Infertility

            • Based on findings from animal studies, treatment may impair both male and female fertility

            Lactation

            There are no data on presence of pexidartinib or its metabolites in either human or animal milk or its effects on a breastfed child or on milk production

            Owing to the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for at least 1 week after final dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Orally bioavailable inhibitor of colony-stimulator factor 1 receptor (CSF1R), a tyrosine kinase receptor; also elicits potential antineoplastic, macrophage checkpoint-inhibitory, and immunomodulating activities

            Targets and binds to CSF1R expressed on monocytes, macrophages, and osteoclasts, and inhibits the binding of the CSF1R ligands colony-stimulating factor-1 and interleukin-34, to CSF1R; this prevents CSF1R activation and CSF1R-mediated signaling in these cells

            The described actions block production of inflammatory mediators by macrophages and monocytes and reduce inflammation, thereby inhibiting immunomodulating activity by macrophages and enhancing T-cell infiltration and antitumor T-cell immune responses, which inhibits tumor cell proliferation

            Absorption

            Peak plasma time: 2.5 hr

            Peak plasma concentration: 8625 ng/mL

            AUC: 77,465 ng h/mL

            Time to steady-state: ~7 days

            Administration with food

            • High-fat meal
              • Increases peak plasma concentration and AUC by 100%
              • Delays peak plasma time by 2.5 hr

            Distribution

            Vd: 187 L

            Protein binding

            • >99%
            • Human serum albumin: 99.9%
            • Alpha-1 acid glycoprotein: 89.9%

            Metabolism

            Primary pathway

            • Oxidation: CYP3A4
            • Glucuronidation: UGT1A4

            N-glucuronide metabolite

            • Major inactive metabolite formed by UGT1A4
            • ~10% higher exposure than pexidartinib after single dose

            Elimination

            Half-life: 26.6 hr

            Clearance: 5.1 L/hr

            Excretion

            • Feces: 65% (44% unchanged)
            • Urine: 27% as metabolites (>/=10% as N-glucuronide)
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            Administration

            Oral Administration

            Administer on empty stomach, at least 1 hr before or 2 hr after a meal or snack

            Swallow capsule whole; do not open, break, or chew

            Missed or vomited dose: Instruct patient to take the next dose at its scheduled time

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Keep containers closed and do not remove desiccant from bottles

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            Images

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            Formulary

            FormularyPatient Discounts

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            • Compare formulary status to other drugs in the same class.
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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.