gilteritinib (Rx)

Brand and Other Names:Xospata
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 40mg

Acute Myeloid Leukemia

Indicated for treatment of patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation

120 mg PO qDay

Response may be delayed

Continue for at least 6 months for a clinical response or until disease progression or unacceptable toxicity

Dosage Modifications

Dosage modifications for adverse reactions

  • Posterior reversible encephalopathy syndrome (PRES): Discontinue treatment
  • QTc interval >500 msec: Interrupt treatment; resume at 80 mg when QTc interval returns to within 30 msec of baseline or ≤480 msec
  • QTc interval increased by >30 msec on ECG on Day 8 of Cycle 1: Confirm ECG on Day 9; if confirmed, consider reducing dose to 80 mg
  • Pancreatitis: Interrupt treatment until pancreatitis resolved; resume at 80 mg
  • Other Grade ≥3 drug-related toxicity: Interrupt until toxicity resolves or improves to Grade 1; resume at 80 mg

Renal or hepatic impairment

  • Mild or moderate ([CrCl 30-80 mL/min] or [Child-Pugh Class A or B]): No clinically meaningful effects on the pharmacokinetics of gilteritinib
  • Severe ([CrCl <30 mL/min] or [Child-Pugh C]): Unknown

Dosing Considerations

Assess blood counts and chemistries before initiating, at least once weekly for the first month, once every other week for the second month, and once monthly thereafter

Perform ECG prior to initiation of treatment, on Days 8 and 15 of Cycle 1, and prior to the next 2 subsequent cycles

Patient selection

  • Select patients based on presence of FLT3 mutation in blood or bone marrow
  • Information on FDA-approved tests for FLT3 mutation detection in AML is available at http://www.fda.gov/CompanionDiagnostics

Safey and efficacy not established

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Interactions

Interaction Checker

and gilteritinib

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Myalgia/arthralgia (42%)

            Increased transaminases (41%)

            Fatigue/malaise (40%)

            Fever (35%)

            Dyspnea (34%)

            Edema (34%)

            Noninfectious diarrhea (34%)

            Rash (30%)

            Pneumonia (30%)

            Constipation (27%)

            Nausea (27%)

            Stomatitis (26%)

            Cough (25%)

            Pneumonia, Grade 3 or 4 (23%)

            Hypotension (21%)

            Headache (21%)

            Dizziness (20%)

            Vomiting (20%)

            Renal impairment (19%)

            Abdominal pain (17%)

            Increased transaminases, Grade 3 or 4 (16%)

            Decreased appetite (15%)

            Sepsis (15%)

            Insomnia (14%)

            Sepsis, Grade 3 or 4 (14%)

            Dyspnea, Grade 3 or 4 (12%)

            Dysgeusia (11%)

            Increased bilirubin (11%)

            1-10%

            Hypertension (10%)

            Hypotension, Grade 3 or 4 (7%)

            Hypertension, Grade 3 or 4 (6%)

            Myalgia/arthralgia, Grade 3 or 4 (5%)

            Increased bilirubin, Grade 3 or 4 (5%)

            Fever, Grade 3 or 4 (5%)

            Fatigue/malaise, Grade 3 or 4 (5%)

            Renal impairment, Grade 3 or 4 (4%)

            Stomatitis, Grade 3 or 4 (4%)

            Noninfectious diarrhea, Grade 3 or 4 (3%)

            Rash, Grade 3 or 4 (3%)

            Edema, Grade 3 or 4 (2%)

            Decreased appetite, Grade 3 or 4 (2%)

            Abdominal pain, Grade 3 or 4 (2%)

            Headache, Grade 3 or 4 (1%)

            Nausea, Grade 3 or 4 (1%)

            <1%

            Constipation, Grade 3 or 4

            Insomnia, Grade 3 or 4

            Dizziness, Grade 3 or 4

            Cough, Grade 3 or 4

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            Warnings

            Contraindications

            Hypersensitivity to gilteritinib or any of the excipients

            Cautions

            Rare reports of posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status

            Associated with prolonged QT interval cardiac ventricular repolarization; in clinical trials, 1.4% were found to have a QTc interval >500 msec and 7% of patients had an increase from baseline QTc >60 msec

            Hypokalemia or hypomagnesemia may increase QT prolongation risk; correct electrolyte abnormalities before initiating and during administration

            In clinical trials, rare reports of pancreatitis noted

            Embryo-fetal harm may occur when administered to pregnant women (see Pregnancy)

            Drug interactions overview

            • Gilteritinib is a CYP3A and P-gp substrate; it potentially inhibits breast cancer resistance protein (BCRP) and organic cation transporter 1 (OCT1) transporter
            • Combined P-gp and strong CYP3A inducers
              • Coadministration with a combined P-gp and strong CYP3A inducer decreases gilteritinib exposure which may decrease efficacy
              • Avoid use with combined P-gp and strong CYP3A inducers
            • Strong CYP3A inhibitors
              • Coadministration with a strong CYP3A inhibitor increases gilteritinib exposure
              • Consider alternative therapies that are not strong CYP3A inhibitors; if concomitant use is necessary, closely monitor for adverse reactions of gilteritinib
              • Interrupt and reduce dose in patients with serious or life-threatening toxicity
            • Drugs that target 5HT2B receptor or sigma nonspecific receptor
              • Coadministration with drugs that target 5HT2B receptors or sigma nonspecific receptors (eg, escitalopram, fluoxetine, sertraline) may reduce effects of these drugs
              • Avoid use of these drugs unless clinically necessary
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            Pregnancy

            Pregnancy

            Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to pregnant women

            No data available on use in pregnant women to inform a drug-associated risk of adverse developmental outcomes

            Animal studies

            • In animal reproduction studies, administration to pregnant rats during organogenesis caused adverse developmental outcomes including embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures ~0.4 times the AUC in patients receiving the recommended dose
            • Advise pregnant women of potential fetal risks
            • Pregnancy testing recommended for females of reproductive potential within 7 days before initiating treatment

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for ≥6 months after last dose
            • Males: Males with partners of reproductive potential should use effective contraception during treatment and for ≥4 months

            Lactation

            No data on presence of gilteritinib and/or its metabolites in human milk, effects on the breastfed child, or effects on milk production

            Following administration to lactating rats, milk concentrations of radioactivity were higher than radioactivity in maternal plasma at 4 and 24 hr post-dose

            In animal studies, gilteritinib and/or its metabolite(s) were distributed to tissues in infant rats via the milk

            Advise lactating women not to breastfeed during treatment and for 2 months after last 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.

            more...
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            Pharmacology

            Mechanism of Action

            Small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3)

            Demonstrates ability to inhibit FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, tyrosine kinase domain mutations (TKD) FLT3-D835Y and FLT3-ITD-D835Y, and induces apoptosis in leukemic cells expressing FLT3-ITD

            Absorption

            Peak plasma concentration (steady-state): 374 ng/mL

            Peak plasma time (fasted state): 4-6 hr

            AUC: 6943 ng·hr/mL

            Steady-state plasma levels reached: Within 15 days

            Effect of food (single 40-mg dose in healthy adults)

            • Peak plasma concentration decreased by 26% and AUC decreased by <10% when coadministered with a high-fat meal compared to a fasted state
            • Median peak plasma time delayed by 2 hr when administered with a high-fat meal

            Distribution

            Vd: 1092 L (central); 1100 L (peripheral)

            Protein bound: ~94%

            Metabolism

            Primarily metabolized via CYP3A4

            At steady state, primary metabolites include M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N-dealkylation)

            None of these metabolites exceeded 10% of overall parent exposure

            Elimination

            Half-life: 113 hr

            Clearance: 14.85 L/hr

            Excretion (single dose): Feces (64.5%)

            Excretion (total dose): Urine (16.4% [unchanged drug and metabolites])

            Pharmacogenomics

            Patient selection are based on presence of FLT3 mutation in blood or bone marrow

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            Administration

            Oral Administration

            Administer with or without food

            Swallow whole; do not break or crush

            Administer at same time each day

            Missed dose

            • Administer as soon as possible on the same day, and at least 12 hr prior to next scheduled dose; resume normal schedule the following day
            • Do not administer 2 doses within 12 hr

            Storage

            Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

            Keep in original container

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            Formulary

            FormularyPatient Discounts

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            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
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the 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.