Class: Antineoplastic Agents
- Fms-like Tyrosine Kinase-3 Inhibitor
- Flt-3 Inhibitor
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical Name: 2-Pyrazinecarboxamide, 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]amino]-5-[(tetrahydro-2H-pyran-4-yl)amino]-, (2E)-2-butenedioate (2:1)
Molecular Formula: (C29H44N8O3)2•C4H4O4
CAS Number: 1254053-84-3
Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases including fms-like tyrosine kinase-3 (Flt-3).
Uses for Gilteritinib
Acute Myeloid Leukemia (AML)
For the treatment of relapsed or refractory AML harboring Flt-3 mutation (designated an orphan drug by FDA for this use).
FDA-approved companion diagnostic test (e.g., LeukoStrat CDx Flt-3 mutation assay) required to confirm presence of Flt-3 mutation prior to initiation of therapy.
Gilteritinib Dosage and Administration
Confirm presence of Flt-3 mutation (peripheral blood or bone marrow) prior to initiation of therapy for AML.
Monitor CBC counts and blood chemistries, including CK, prior to initiation of therapy and at least weekly for the first month of therapy, every other week for the following month of therapy, and then monthly thereafter.
Perform ECG prior to initiation of therapy, on days 8 and 15 of cycle 1, and prior to initiation of cycles 2 and 3. (See Prolongation of QT Interval under Cautions.)
Restricted Distribution Program
Obtain through specialty pharmacies and distributors.
Contact manufacturer at 844-632-9272 or consult the Xospata website ([Web]) for specific ordering and availability information.
Administer orally once daily without regard to meals. Take at approximately the same time each day.
Swallow tablets whole with water; do not chew, crush, or break.
Available as gilteritinib fumarate; dosage expressed in terms of gilteritinib.
120 mg once daily on days 1–28 of each 28-day cycle. Continue therapy for ≥6 months to allow time for response or until disease progression or unacceptable toxicity occurs.
Dosage Modification for Toxicity
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)Oral
If RPLS occurs, discontinue therapy.
Prolongation of QT IntervalOral
If corrected QT (QTc) interval >500 msec occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when QTc interval improves to ≤480 msec or ≤30 msec from baseline.
If QTc interval increase of >30 msec from baseline on days 8 and 9 of cycle 1 occurs, consider reduced dosage of 80 mg daily.
If pancreatitis occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when pancreatitis resolves.
If other grade 3 or 4 adverse reaction occurs, withhold gilteritinib therapy; resume therapy at reduced dosage of 80 mg daily when toxicity improves to grade 1 or less.
No special population dosage recommendations at this time.
Cautions for Gilteritinib
Hypersensitivity to gilteritinib or any ingredient in the formulation. (See Sensitivity Reactions under Cautions.)
Anaphylactic reactions reported in 1% of gilteritinib-treated patients in clinical trials.
RPLS reported rarely; may manifest as seizure and altered mental status. Brain imaging, preferably MRI, necessary to confirm diagnosis. Manifestations may resolve following discontinuance of therapy. If RPLS occurs, discontinue gilteritinib.
Prolongation of QT Interval
QTc interval prolongation reported.
Monitor ECG prior to initiation of gilteritinib, on days 8 and 15 of cycle 1, and prior to initiation of cycles 2 and 3.
Monitor serum electrolytes (e.g., potassium, magnesium) prior to initiation of gilteritinib therapy and at least weekly for the first month of therapy, every other week for the following month of therapy, and then monthly thereafter. Correct hypokalemia and hypomagnesemia prior to initiation of and during gilteritinib therapy.
If QTc interval prolongation occurs, temporary interruption and/or dosage reduction of gilteritinib may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)
Pancreatitis reported rarely. Evaluate patients who develop manifestations of pancreatitis (e.g., severe and persistent abdominal pain, which may be accompanied by nausea or vomiting). If pancreatitis occurs, temporary interruption followed by dosage reduction may be necessary. (See Dosage Modification for Toxicity under Dosage and Administration.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm based on mechanism of action and animal findings; embryofetal toxicity and teratogenicity demonstrated in animals.
Placental transfer of gilteritinib observed in rats.
Confirm pregnancy status within 7 days prior to initiating gilteritinib therapy. Avoid pregnancy during therapy. Advise women of reproductive potential to use effective methods of contraception while receiving the drug and for ≥6 months after the drug is discontinued. Advise men who are partners of such women to use effective methods of contraception while receiving the drug and for ≥4 months after drug is discontinued. If used during pregnancy, apprise of potential fetal hazard.
Impairment of Fertility
Animal studies suggest gilteritinib may impair male fertility.
May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Confirm pregnancy status prior to initiating gilteritinib therapy.
Gilteritinib and/or its metabolite(s) distribute into milk in rats. Not known whether the drug or its metabolites distribute into human milk or if drug affects milk production or the nursing infant. Advise women not to breast-feed during therapy and for ≥2 months following drug discontinuance.
Safety and efficacy not established.
In clinical trials in patients with relapsed or refractory AML, no overall differences in safety and efficacy relative to younger adults observed.
In a hepatic impairment study, systemic exposure of unbound gilteritinib not altered by mild or moderate hepatic impairment (Child-Pugh class A or B) in noncancer patients. (See Special Populations under Pharmacokinetics.)
Effects of severe hepatic impairment (Child-Pugh class C) on pharmacokinetics not established.
In a population pharmacokinetic analysis, systemic exposure not substantially altered by Scr concentrations in patients with relapsed or refractory AML.
Mild or moderate renal impairment (Clcr of 30–80 mL/minute) not expected to have clinically important effects on systemic exposure of the drug.
Effects of severe renal impairment (Clcr ≤29 mL/minute) on pharmacokinetics not established.
Common Adverse Effects
Relapsed or refractory AML: Myalgia/arthralgia, fatigue/malaise, pyrexia, dyspnea, edema, diarrhea without infectious etiology, rash, pneumonia, constipation, nausea, stomatitis, cough, headache, hypotension, dizziness, vomiting, renal impairment, abdominal pain, decreased appetite, sepsis, insomnia, dysgeusia, elevated bilirubin concentrations, hypertension, elevated Scr concentrations, hyperglycemia, hypertriglyceridemia, elevated alkaline phosphatase concentrations, hypocalcemia, hypoalbuminemia, elevated CK concentrations, hypophosphatemia, elevated ALT or AST concentrations, hypokalemia, hyponatremia.
Interactions for Gilteritinib
Principally metabolized by CYP3A4.
Weak inhibitor of CYP3A4.
Substrate of P-glycoprotein (P-gp). Potent inhibitor of multidrug and toxin extrusion (MATE) transporter 1 and organic cation transporter (OCT) 2; potential inhibitor of breast cancer resistance protein (BCRP) and organic cation transporter (OCT) 1.
Drugs Affecting Hepatic Microsomal Enzymes and/or Efflux Transport Systems
Potent CYP3A inhibitors: Possible increased gilteritinib exposure. Avoid concomitant use; consider alternative agent with less CYP3A inhibition potential. If concomitant use cannot be avoided, monitor frequently for signs of toxicity; may need to interrupt therapy and reduce dosage if serious or life-threatening adverse effects occur. (See Dosage Modification for Toxicity under Dosage and Administration.)
Combined P-gp and potent CYP3A inducers: Possible decreased gilteritinib exposure and reduced gilteritinib efficacy. Avoid concomitant use.
Drugs Metabolized by Hepatic Microsomal Enzymes
CYP3A substrates: Possible increased exposure of the CYP3A substrate.
Drugs Affected by Multidrug and Toxin Extrusion Transporter
MATE1 substrates: Possible decreased exposure of the MATE1 substrate.
Drugs that Interact with Serotonin Type 2B Receptor or Nonspecific σ-receptors
Possible pharmacokinetic interaction (reduced efficacy of drugs that bind to 5-HT2B or nonspecific σ-receptors). Avoid concomitant use unless such use is necessary.
Antidepressants, SSRIs (e.g., escitalopram, fluoxetine, sertraline)
Possible reduced efficacy of SSRI
Drugs that interact with 5-HT2B or nonspecific σ-receptors: Avoid concomitant use unless considered essential
Antifungals, azoles (e.g., fluconazole, itraconazole)
Fluconazole: Increased peak plasma concentrations and AUC of gilteritinib by approximately 16 and 40%, respectively
Itraconazole: Increased peak plasma concentrations and AUC of gilteritinib by approximately 20 and 120%, respectively
Potent CYP3A inhibitors (e.g., itraconazole): Consider alternative antifungal with less CYP3A inhibition potential; if concomitant use cannot be avoided, monitor frequently for toxicity and interrupt therapy and reduce dosage if serious or life-threatening toxicity occurs (see Dosage Modification for Toxicity under Dosage and Administration)
Decreased peak plasma concentrations and AUC of cephalexin by <10%
Increased peak plasma concentrations and AUC of midazolam by approximately 10%
Possible reduced gilteritinib efficacy
Decreased peak plasma concentrations and AUC of gilteritinib by approximately 30 and 70%, respectively
Avoid concomitant use
Peak plasma concentrations and AUC are dose proportional over the gilteritinib dosage range of 20–450 mg daily.
Following oral administration in fasted state, peak plasma gilteritinib concentrations attained in 4–6 hours.
Steady-state concentrations are achieved within 15 days of once-daily dosing with approximately tenfold accumulation.
Substantial inhibition of Flt-3 phosphorylation (>90%) within 24 hours of initial 120-mg dose.
Administration of a single 40-mg dose with a high-fat, high-calorie meal (800–1000 calories with 500–600 calories from fat) decreases gilteritinib peak plasma concentrations and AUC by 26 and <10%, respectively. Administration with a high-fat meal delays time to peak plasma concentration by 2 hours.
In a hepatic impairment study, mild or moderate hepatic impairment (Child-Pugh class A or B) did not alter systemic exposure in noncancer patients.
In a population pharmacokinetic analysis, Scr concentrations did not substantially alter systemic exposure in patients with relapsed or refractory AML.
Pharmacokinetics not substantially affected by age (20–87 years), gender, race, or ethnicity (Japanese versus non-Japanese).
Crosses placenta in rats; not known whether gilteritinib crosses placenta in humans.
Distributed into milk in rats; not known whether gilteritinib or its metabolites distribute into human milk.
Extensively distributes into tissues.
Plasma Protein Binding
Approximately 94% (mainly albumin).
Principally metabolized by CYP3A4, via N-dealkylation and oxidation to metabolites M17, M16, M10 (account for ≤10% of total drug exposure).
Eliminated in feces (64.5% of recovered dose) and urine (16.4% [≤10% as unchanged drug]).
20–25ºC (may be exposed to 15–30ºC). Store in original container.
Inhibits multiple receptor tyrosine kinases (e.g., Flt-3).
Inhibits wild-type and mutant (i.e., internal tandem duplications [ITD] and/or tyrosine kinase domain [TKD] point mutations in codon D835Y) Flt-3.
Inhibits AXL, an oncogenic tyrosine kinase that promotes Flt-3 signaling.
Induces apoptosis in leukemic cells expressing Flt-3-ITD mutations, in the presence or absence of TKD point mutations.
Inhibits anaplastic lymphoma kinase (ALK), leukocyte receptor tyrosine kinase (LTK), and stem cell factor receptor (c-Kit).
Advice to Patients
Importance of instructing patients to read the manufacturer’s patient information.
Importance of advising patients to swallow gilteritinib tablets whole with a cup of water and not to break, crush, or chew the tablets.
If a dose of gilteritinib is missed by ≤12 hours, importance of administering the missed dose on the same day as soon as it is remembered and taking the next dose at the regularly scheduled time on the following day. If a dose is missed by >12 hours, importance of administering the next dose at the regularly scheduled time; do not administer an additional dose to replace the missed dose. Advise patients not to take 2 doses within a 12-hour period.
Risk of RPLS. Importance of informing clinician immediately if manifestations of RPLS (e.g., seizure; altered mental status; rapidly worsening headache, decreased alertness, confusion, visual disturbances) occur.
Risk of QT interval prolongation. Importance of informing clinician immediately if an abnormal heartbeat, loss of consciousness, or feelings of dizziness, lightheadedness, or faintness occur. Importance of monitoring electrolytes in patients with a history of electrolyte abnormalities (i.e., hypokalemia, hypomagnesemia).
Risk of pancreatitis. Importance of informing clinician immediately if manifestations of pancreatitis (e.g., severe and persistent abdominal pain, with or without nausea and vomiting) occur.
Risk of fetal harm. Necessity of advising women of reproductive potential to use effective methods of contraception while receiving the drug and for ≥6 months after discontinuance of therapy; necessity of advising men who are partners of such women to use effective methods of contraception while receiving the drug and for ≥4 months after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to fetus.
Importance of advising women to avoid breast-feeding while receiving the drug and for ≥2 months after discontinuance of therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hypokalemia, hypomagnesemia).
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of gilteritinib is restricted. (See Restricted Distribution Program under Dosage and Administration.)
40 mg (of gilteritinib)
AHFS DI Essentials™. © Copyright 2022, Selected Revisions June 17, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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