Gilteritinib fumarate is indicated for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML) who have a FLT3 (FMS-like tyrosine kinase 3) gene mutation, confirmed by an FDA-approved diagnostic test.

Gilteritinib is a small-molecule inhibitor that targets multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). It has been shown to suppress FLT3 receptor signaling and cell proliferation in cells expressing FLT3 mutations, including FLT3-ITD, tyrosine kinase domain (TKD) mutations such as FLT3-D835Y and FLT3-ITD-D835Y. Additionally, it promotes apoptosis in leukemic cells that express FLT3-ITD mutations.

Pharmacodynamics: In patients with relapsed or refractory acute myeloid leukemia (AML) treated with Gilteritinib 120 mg, rapid (within 24 hours of the first dose) and sustained inhibition (>90%) of FLT3 phosphorylation has been observed, as measured by ex vivo plasma inhibitory activity (PIA) assay.

Patient Selection: Select patients for the treatment of AML with Gilteritinib based on the presence of FLT3 mutations in the blood or bone marrow. Information on FDA-approved tests for the detection of a FLT3 mutation in AML is available.

Recommended Dosage: The recommended starting dose of Gilteritinib is 120 mg orally once daily with or without food. Response may be delayed. In the absence of disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response. Do not break or crush Gilteritinib tablets. Administer Gilteritinib tablets orally about the same time each day. If a dose of Gilteritinib is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

Dose Modification: Assess blood counts and blood chemistries, including creatine phosphokinase, prior to the initiation of Gilteritinib, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Perform electrocardiogram (ECG) prior to initiation of treatment with Gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles.

Effect of Other Drugs on Gilteritinib: Concomitant use of Gilteritinib with combined P-gp and strong CYP3A inducers can reduce its plasma concentration, potentially decreasing its therapeutic effectiveness. Therefore, such combinations should be avoided.

Strong CYP3A Inhibitors: Co-administration with strong CYP3A inhibitors may increase Gilteritinib exposure. Alternative medications that are not strong CYP3A inhibitors should be considered. If use is unavoidable, patients should be closely monitored for adverse effects, and dose adjustment or interruption may be required in cases of severe toxicity.

Effect of Gilteritinib on Other Drugs: Gilteritinib may reduce the effectiveness of drugs acting on 5HT2B receptors or sigma nonspecific receptors (e.g., escitalopram, fluoxetine, sertraline). Concurrent use should generally be avoided unless deemed necessary for patient care.

Gilteritinib is contraindicated in patients with known hypersensitivity to the drug or any of its components. Anaphylactic reactions have been reported in clinical studies.

Common side effects reported with Gilteritinib include:

• Fever
• Dizziness or lightheadedness
• Cough
• Rapid weight gain
• Difficulty breathing
• Swelling of arms or legs
• Skin rash
• Decreased urine output

Pregnancy: Findings from animal studies and its mechanism of action suggest that Gilteritinib may cause fetal harm if administered during pregnancy. There are no adequate human data to determine drug-associated risks. In animal studies, exposure during organogenesis resulted in fetal toxicity and developmental abnormalities at exposures similar to or higher than those seen in humans at recommended doses. Women of reproductive potential should avoid pregnancy during treatment and use effective contraception during therapy and for at least 6 months after the last dose. The risk of congenital abnormalities or miscarriage in humans is unknown, though background risks exist in all pregnancies.

Lactation: It is not known whether Gilteritinib or its metabolites are excreted in human milk or what effects they may have on the breastfed infant or milk production. Due to the potential for serious adverse reactions, breastfeeding is not recommended during treatment and for at least 2 months after the final dose.

Differentiation Syndrome: In clinical studies, differentiation syndrome has been reported in patients treated with Gilteritinib and may be life-threatening if untreated. Symptoms may include fever, dyspnea, edema, pulmonary infiltrates, hypotension, and organ dysfunction. Prompt recognition and treatment with corticosteroids and supportive care are essential.

Posterior Reversible Encephalopathy Syndrome (PRES): Cases of PRES have been reported, presenting with seizures, altered mental status, and visual disturbances. If suspected, Gilteritinib should be discontinued.

Prolonged QT Interval: Gilteritinib may prolong QT interval. ECG monitoring is recommended before and during treatment, especially in patients with risk factors. Dose adjustment or interruption may be necessary if QT prolongation occurs.

Pancreatitis: Cases of pancreatitis have been reported; patients should be monitored for symptoms and treatment modified if necessary.

Embryo-Fetal Toxicity: Based on its mechanism, Gilteritinib may cause harm to the fetus. Effective contraception is required during and after treatment.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed in elderly patients compared to younger adults.

Cytotoxic Chemotherapy

Store below 30°C in a cool and dry place, protected from light. Keep out of the reach of children.