ALILAROTINIB Larotrectinib Sulfate 100mg

I. Basic Drug Information

Generic Name: Larotrectinib

Brand Names: Vitrakvi, ALILAROTINIB

Dosage Form and Strength: 100 mg per capsule; 30 capsules per box

Manufacturer: Lao United Pharmaceutical Group Co., Ltd.

Lao National Drug Administration Approval No.: 11 L 1228/24

Storage Conditions: 20°C–25°C (excursions permitted between 15°C–30°C)

II. Mechanism of Action

Larotrectinib is a highly selective TRK tyrosine kinase inhibitor. It functions by inhibiting the abnormal proteins produced by *NTRK* gene fusions (including *NTRK1/2/3*), thereby blocking tumor proliferation signaling pathways and inducing apoptosis in cancer cells.

III. Indications and Patient Population

Key Criteria

*NTRK* gene fusion positivity must be confirmed via genetic testing (verified through DNA/RNA sequencing or FISH).

Tumor Type: Locally advanced or metastatic solid tumors for which no satisfactory alternative treatment options exist, or where prior treatments have failed.

17 Covered Solid Tumor Types

| Common Types                               | Rare Types

| Lung Cancer, Thyroid Cancer, Melanoma      | Infantile Fibrosarcoma, Congenital Mesoblastic Nephroma

| Gastrointestinal Cancer, Colon Cancer, Breast Cancer | Cancer of Unknown Primary, Appendix Cancer

| Soft Tissue Sarcoma, Osteosarcoma, Pancreatic Cancer | Salivary Gland Cancer, Cholangiocarcinoma

Note: Particularly significant efficacy has been observed in cases of infantile fibrosarcoma and pediatric osteosarcoma. IV. Dosage and Administration

Standard Dosing Regimen

| Patient Population                          | Dose                     | Frequency         | Administration Method

| Adults and Children (BSA ≥ 1.0 m²)  | 100 mg                  | Twice daily    | Swallow capsules whole; may be taken with or without food.

| Children (BSA < 1.0 m²)         | 100 mg/m² (Body Surface Area) | Twice daily    | Oral solution must be measured using a syringe.

Dose Adjustment (Based on Toxicity)

| Adverse Reaction Grade | Management Measures

| Grade 3 Adverse Reaction | Suspend treatment → Upon recovery to Grade 1, reduce dose to 75 mg (or 75 mg/m²) → Maintain new dose.

| Grade 4 Adverse Reaction | Suspend treatment → If recovery to Grade 1 does not occur within 4 weeks, permanently discontinue treatment; if recovery occurs, reduce dose to 50 mg (or 50 mg/m²).

V. Adverse Reactions and Risk Management

Common Adverse Reactions (≥ 20%)

Systemic: Fatigue (51%), Fever (44%).

Gastrointestinal: Nausea (34%), Vomiting (31%), Diarrhea (32%), Constipation (28%).

Nervous System: Dizziness (27%), Gait disturbance (10%).

Laboratory Abnormalities: Anemia, Neutropenia, Elevated liver enzymes (AST/ALT).

Serious Adverse Reactions (Requiring Urgent Intervention)

| Adverse Reaction Type | Incidence        | Intervention Measures

| Hepatotoxicity            | 10%–15%  | Monitor liver function regularly; suspend treatment and reduce dose if anorexia, jaundice, or right upper quadrant pain occurs.

| Neurotoxicity         | 5%–10%   | Permanently discontinue treatment if confusion, seizures, or ataxia occurs.

| QT Interval Prolongation    | <5%          | Monitor ECG at baseline and mid-cycle; suspend treatment if QTc > 500 ms. VI. Contraindications and Precautions

1. Contraindications:

- Patients with hypersensitivity to larotrectinib or to any of the excipients.

2. Key Warnings:

Hepatotoxicity: Monitor liver function prior to treatment and every 4 weeks thereafter; dose adjustment is required for patients with moderate to severe hepatic impairment. 

Embryo-fetal Toxicity: Contraindicated in pregnant women (animal studies have demonstrated teratogenicity); patients of reproductive potential must use effective contraception during treatment and for 1 week following the last dose. 

Lactation: Breastfeeding is prohibited during treatment and for 1 week following the last dose.

3. Drug Interactions:

Strong CYP3A4 Inhibitors (e.g., ketoconazole): ↑ Larotrectinib plasma concentrations → Avoid co-administration or reduce dose. 

Strong CYP3A4 Inducers (e.g., rifampin): ↓ Larotrectinib efficacy → Co-administration is contraindicated.

VII. Use in Specific Populations

Pediatric Patients: Safety and efficacy have been established (including infants ≥1 month of age); dosage must be adjusted based on body surface area.

Geriatric Patients (≥65 years): No dose adjustment is required; however, enhanced monitoring of liver function and neurological status is recommended.

Hepatic/Renal Impairment:

- Mild Hepatic Impairment (Child-Pugh A): No dose adjustment is required.

- Moderate to Severe Hepatic Impairment (Child-Pugh B/C) or Renal Impairment: Data are limited; use with caution.

Summary and Key Points

1. Genetic Testing is a Prerequisite: Indicated only for solid tumors harboring an *NTRK* gene fusion; confirmation via molecular testing is mandatory prior to treatment initiation.

2. Significant Benefits in Pediatric Patients: Demonstrates high response rates in pediatric tumors (e.g., infantile fibrosarcoma); the oral solution formulation facilitates administration in younger patients.

3. Long-term Safety Management: Focus on monitoring for hepatotoxicity and neurotoxicity; conduct periodic assessments of liver function, ECGs, and neurological symptoms.