Dosing & Uses
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
Differentiation syndrome
- If suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptoms resolve for at least 3 days
- Interrupt dose if severe signs and/or symptoms persist for >48 hr after initiation of corticosteroids
- Resume when signs and symptoms improve to Grade ≤2
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 cell counts and chemistries prior to initiation, at least qWeek 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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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
Postmarketing Reports
Differentiation syndrome
Warnings
Black Box Warnings
Differentiation syndrome
- Symptoms of differentiation syndrome may occur, which can be fatal or life-threatening
- Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction
- If differentiation syndrome suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution
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; symptoms resolved after discontinuing treatment; a diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI); discontinue therapy in patients who develop PRES
Associated with prolonged QT interval cardiac ventricular repolarization; in clinical trials, 1% were found to have a QTc interval >500 msec and 7% of patients had an increase from baseline QTc >60 msec; interrupt and reduce dosage in patients who have a QTcF >500 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; interrupt and reduce dose in patients who develop pancreatitis
Embryo-fetal harm may occur when administered to pregnant women (see Pregnancy)
Differentiation syndrome
- Differentiation syndrome reported (see Black Box Warnings)
- Associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated
- May occur as early as 1 day and up to 82 days after initiation of therapy and has been observed with or without concomitant leukocytosis
- If differentiation syndrome suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement
- Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days; symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment
- If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt therapy until signs and symptoms are no longer severe
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
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
Advise pregnant women of potential fetal risks
Pregnancy testing recommended for females of reproductive potential within 7 days before initiating treatment
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
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.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
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
Images
| BRAND | FORM. | UNIT PRICE | PILL IMAGE |
|---|---|---|---|
| Xospata oral - | 40 mg tablet |  |
Copyright © 2010 First DataBank, Inc.
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