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