Gilternib

Approved indications

• Acute Myeloid Leukemia (AML) with FLT3 mutation: Indicated for adult patients with relapsed or refractory AML harboring FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations.
• Targeted therapy: Specifically for patients whose leukemia exhibits FLT3 gene alterations, which are associated with a poorer prognosis.

Off-label / clinically accepted uses

• Combination therapy with chemotherapy or other targeted agents in investigational protocols for FLT3-positive AML.
• Salvage therapy for patients ineligible for intensive chemotherapy.

Adults

• Standard dose: 120 mg orally once daily.
• Route: Oral; tablets should be swallowed whole with or without food.
• Duration: Continued until disease progression or unacceptable toxicity occurs.

Dose adjustments

• Hepatic impairment: Moderate impairment (Child-Pugh B) – use with caution; severe impairment not recommended.
• Renal impairment: Mild-to-moderate – no adjustment; severe (eGFR <30 mL/min/1.73 m²) – monitor closely.
• Hematologic toxicity: Dose interruption or reduction may be required for severe neutropenia or thrombocytopenia.

Pediatrics

• Safety and efficacy not established; use only in clinical trial settings.

Elderly

• Standard adult dosing is applicable; monitor for toxicity and comorbid conditions.

Gilteritinib fumarate is a selective FLT3 tyrosine kinase inhibitor. It binds to the FLT3 receptor’s ATP-binding domain, inhibiting its kinase activity, which blocks downstream signaling pathways responsible for leukemic cell proliferation and survival. By selectively targeting FLT3-mutated leukemic cells, gilteritinib reduces tumor burden while sparing most normal hematopoietic cells, leading to apoptosis and suppression of disease progression.

• Absorption: Rapid oral absorption with peak plasma concentration within 4–6 hours.
• Bioavailability: Not significantly affected by food; administration with or without meals is acceptable.
• Distribution: Extensive tissue distribution; high plasma protein binding (~94%).
• Metabolism: Predominantly via CYP3A4 in the liver; minor contribution by CYP2C8.
• Elimination: Primarily excreted via feces (~64%) and urine (~16%).
• Half-life: Approximately 113 hours, allowing once-daily dosing.
• Steady state: Achieved within 15 days of continuous dosing.

• Pregnancy: Category D; potential teratogenicity observed in animal studies. Avoid use in pregnancy.
• Breastfeeding: Unknown if excreted in human milk; breastfeeding is not recommended during treatment.
• Caution: Women of childbearing potential should use effective contraception during treatment and for at least 2 months after discontinuation.

• Primary class: Antineoplastic agent
• Subclass: FLT3 tyrosine kinase inhibitor; targeted therapy for AML

• Known hypersensitivity to gilteritinib fumarate or any excipients in the tablet formulation.
• Concomitant use with strong CYP3A4 inhibitors is not recommended without dose adjustment.
• Severe hepatic impairment (Child-Pugh C).

• High-risk patient groups: Patients with pre-existing cardiac conditions or QT prolongation.
• QT prolongation: ECG monitoring is recommended; correct electrolyte imbalances.
• Hepatotoxicity: Monitor liver function tests; discontinue or reduce dose if severe elevations occur.
• Differentiation syndrome: Rare but potentially fatal; monitor for fever, weight gain, dyspnea, hypotension.
• Myelosuppression: Monitor CBC regularly; dose interruptions may be necessary.
• Infections: Increased risk due to neutropenia; implement infection prevention strategies.

Common

• Fatigue, headache
• Fever
• Nausea, vomiting, diarrhea
• Elevated liver enzymes (AST, ALT)
• Constipation
• Myalgia or arthralgia

Serious / rare

• QT prolongation and arrhythmias
• Differentiation syndrome
• Severe hepatotoxicity
• Sepsis and opportunistic infections due to neutropenia
• Tumor lysis syndrome (rare)

Onset: Adverse effects may appear within the first weeks of therapy; monitoring throughout treatment is recommended.

• CYP3A4 inhibitors (e.g., ketoconazole): Increase gilteritinib plasma levels; dose adjustment recommended.
• CYP3A4 inducers (e.g., rifampin): Reduce plasma concentration; avoid or adjust dose.
• QT-prolonging drugs: Concurrent use increases risk of arrhythmias; ECG monitoring required.
• Grapefruit juice: Avoid, as it may increase gilteritinib exposure.

• 2024 guideline update: Gilteritinib remains first-line targeted therapy for relapsed/refractory FLT3-mutated AML in adults.
• Combination trials: Ongoing studies evaluate efficacy in combination with venetoclax or chemotherapy.
• Safety monitoring emphasis: Enhanced monitoring for QT prolongation, differentiation syndrome, and hepatotoxicity is now recommended in clinical practice guidelines.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture, heat, and light.
• Keep in original container with tightly closed cap.
• Do not freeze.
• Keep out of reach of children and pets.