ALIGIRITINIB Gilteritinib Fumarate 40mg

I. Basic Drug Information

Generic Name: Gilteritinib Fumarate

Brand Names: Shijiatan, Xospata, ALIGIRITINIB

Dosage Form and Strength: 40 mg Tablets; 90 tablets per box

Manufacturer: Lao United Pharmaceutical Group Co., Ltd.

Approval Number (Lao National Drug Administration): 07 L 1130/24

II. Mechanism of Action

Gilteritinib is a highly selective, second-generation FLT3 tyrosine kinase inhibitor that exerts its anti-leukemic effects through the following mechanisms:

1. Targeted Inhibition of FLT3 Mutations: Including FLT3-ITD (internal tandem duplication mutations) and FLT3-TKD (tyrosine kinase domain mutations, such as D835Y).

2. Blockade of Signaling Pathways: Inhibits FLT3 receptor phosphorylation, blocks downstream proliferative signals, and induces apoptosis in leukemia cells.

III. Indications

Patient Population: Adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) confirmed to harbor FLT3 mutations, as detected by FDA/NMPA-approved diagnostic methods.

Key Limitation: Indicated only for patients with FLT3-positive mutations; mutation status must be verified using peripheral blood or bone marrow samples.

IV. Dosage and Administration

Standard Dosing Regimen

| Item             | Description

| Recommended Dose | 120 mg (3 x 40 mg tablets), once daily; swallow tablets whole (do not crush or chew).

| Administration Time | Take at a fixed time each day; may be taken with or without food.

| Duration of Treatment | Continue treatment for ≥6 months (unless disease progression or intolerable toxicity occurs).

| Missed Dose Management | ≤12 hours: Take the missed dose as soon as possible; >12 hours: Skip the missed dose and take the next scheduled dose at the regular time (do not take a double dose). Dose Modification (Based on Toxicity)

| Type of Adverse Reaction | Management Measures

| Differentiation Syndrome | Suspend administration → Administer IV dexamethasone (10 mg every 12 hours) → Resume treatment once symptoms resolve.

| QTc Interval > 500 ms | Suspend administration → Correct electrolyte abnormalities → Resume treatment at a reduced dose of 80 mg/day.

| Pancreatitis | Suspend administration → Resume treatment at a reduced dose of 80 mg/day once symptoms resolve.

| Posterior Reversible Encephalopathy Syndrome (PRES) | Permanently discontinue treatment (symptoms include seizures, confusion, and visual disturbances).

V. Adverse Reactions

Common Adverse Reactions (Incidence ≥ 20%)

Hematologic: Anemia, thrombocytopenia, febrile neutropenia;

Systemic: Fatigue (52%), fever (44%), edema (33%);

Gastrointestinal: Nausea (34%), diarrhea (32%), stomatitis (28%);

Other: Elevated transaminases (45%), dyspnea (38%), rash (35%), headache (27%).

Serious Adverse Reactions (Requiring Urgent Intervention)

Differentiation Syndrome (3%–8%): Manifests as fever accompanied by dyspnea/hypoxia/pleural effusion/rapid weight gain; associated with a very high mortality rate;

Cardiotoxicity: QT interval prolongation (7% with QTc increase > 60 ms; 1% with QTc > 500 ms);

PRES (1%): Seizures, altered mental status;

Pancreatitis (4%–5%).

Table: Summary of Management for Key Safety Events with Gilteritinib

> | Adverse Event | Incidence | Intervention Measures

> | Differentiation Syndrome | 3%–8% | Corticosteroids + Hemodynamic monitoring; suspend treatment in severe cases. > | QT Interval Prolongation | 7%         | ECG monitoring (at baseline, on Days 8 and 15 of Cycle 1, and prior to subsequent cycles); suspend treatment and reduce dose if QTc > 500 ms.

> | Pancreatitis             | 4%-5%   | Suspend treatment + monitor amylase/lipase levels; reduce dose upon recovery.

> | PRES                     | 1%         | Permanently discontinue treatment + confirm via neuroimaging (MRI).

VI. Contraindications and Precautions

1. Contraindications:

- Hypersensitivity to gilteritinib or any of its excipients.

2. Core Warnings:

Embryo-fetal toxicity: Contraindicated in pregnant women (animal studies have demonstrated teratogenicity). Patients of reproductive potential must use effective contraception during treatment and for 6 months (for females) or 4 months (for males) following the last dose.

Lactation: Breastfeeding is prohibited during treatment and for 2 months following the last dose.

3. Pre-treatment Monitoring:

Laboratory tests: Complete blood count (CBC), electrolytes (potassium/magnesium), liver and renal function, creatine phosphokinase (CPK).

ECG: At baseline, on Days 8 and 15 of Cycle 1, and prior to subsequent cycles.

VII. Drug Interactions

| Concomitant Medication Type                               | Impact and Recommendations

| Strong CYP3A4 Inhibitors (e.g., Itraconazole) | ↑ Gilteritinib plasma concentration (AUC ↑ 120%) → Switch to an alternative medication or monitor closely for toxicity.

| Strong CYP3A4 Inducers (e.g., Rifampin)    | ↓ Gilteritinib efficacy (AUC ↓ 70%) → Concomitant use is prohibited.

| 5-HT2B/σ Receptor Antagonists (e.g., SSRI antidepressants) | ↓ Antidepressant efficacy → Avoid concomitant use.

| P-gp/BCRP Substrates (e.g., Dabigatran)       | ↑ Substrate drug concentration → Reduce the dose of the concomitant medication. VIII. Use in Special Populations

Hepatic/Renal Impairment: No definitive dosage adjustment recommendations have been established; close monitoring is required.

Pediatric Patients: Safety and efficacy have not been established.

Geriatric Patients (≥65 years): No dosage adjustment is required; however, enhanced monitoring for toxicity is necessary.

Summary

As a targeted therapy for FLT3-mutated Relapsed/Refractory AML, Gilteritinib significantly prolongs patient survival (as confirmed by the Phase III ADMIRAL trial). However, strict adherence to the following principles is essential:

1. Test for FLT3 mutations prior to administration to avoid off-label use;

2. Closely monitor for differentiation syndrome and cardiac toxicity, and intervene promptly if necessary;

3. Avoid concomitant use with strong CYP3A4 modulators to minimize pharmacokinetic risks.