Gilteritinib
Indications
Gilteritinib is used for:
Acute Myeloid Leukemia
Adult Dose
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
Child Dose
Renal Dose
Renal 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
Administration
Contra Indications
Hypersensitivity to gilteritinib or any of the excipients
Precautions
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
Pregnancy-Lactation
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
Interactions
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
Side Effects
Side effects of Gilteritinib :
>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%)
Mode 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