CRIZNDR Crizotinib

I. Basic Drug Information

Generic Name: Crizotinib

Brand Names: XALKORI

English Name: Crizotinib

Dosage Form and Strength: Capsules (250 mg per capsule; 60 capsules per box)

Active Ingredient: Crizotinib (Chemical Name: (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyrimidin-2-amine)

Excipients: Silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, etc.

Storage: Store below 30°C; protect from light and moisture.

Manufacturer: INDAR Pharmaceutical Co., Ltd

II. Mechanism of Action

Crizotinib is a multi-target tyrosine kinase inhibitor that blocks tumor cell proliferation and survival signaling pathways by selectively inhibiting the phosphorylation of ALK (Anaplastic Lymphoma Kinase), ROS1, and c-Met. In tumors harboring ALK or ROS1 gene rearrangements/mutations, Crizotinib inhibits cancer cell growth through a "synthetic lethality" effect.

III. Indications

1. Non-Small Cell Lung Cancer (NSCLC):

ALK-positive locally advanced or metastatic NSCLC (Adults)

ROS1-positive advanced NSCLC (Adults)

2. Lymphomas and Soft Tissue Tumors:

ALK-positive systemic Anaplastic Large-Cell Lymphoma (ALCL) in patients aged 1 year and older

ALK-positive unresectable/recurrent Inflammatory Myofibroblastic Tumor (IMT) in patients aged 1 year and older

Prerequisite for Use: ALK/ROS1 positivity must be confirmed via authoritative testing (e.g., NGS or FISH).

IV. Dosage and Administration

1. Standard Dosing Regimen

Adults: 250 mg orally, twice daily (approximately every 12 hours); may be taken with or without food. Children (≥1 year of age): Dosage is calculated based on Body Surface Area (BSA), typically 280 mg/m² administered twice daily (see Table 1).

Table 1: Dosage Adjustments for Children Based on Body Surface Area (BSA)

| BSA (m²) | Single Dose | Total Daily Dose

| ≥1.70    | 500 mg      | 1000 mg

| 1.52–1.69| 450 mg      | 900 mg

| 0.38–0.46| 120 mg      | 240 mg

2. Dosage Adjustments for Special Populations

Patients with Hepatic Impairment:

Moderate (Total bilirubin > 1.5 to 3 times the ULN): 200 mg twice daily.

Severe (Total bilirubin > 3 times the ULN): 250 mg once daily.

Patients with Renal Impairment:

Severe Renal Impairment (Creatinine clearance < 30 mL/min): 250 mg once daily.

Concomitant use of strong CYP3A inhibitors (e.g., ketoconazole): Reduce dose to 250 mg once daily.

3. Management of Missed Doses/Vomiting

Missed Dose: If ≥6 hours remain before the next scheduled dose, take the missed dose immediately; otherwise, skip it.

Vomiting: Do not take a replacement dose; continue with the next scheduled dose as originally planned.

V. Adverse Reactions

Common Adverse Reactions (≥25%)

Visual Abnormalities: Blurred vision, photopsia (62%; occurs predominantly during the initial phase of treatment).

Gastrointestinal Reactions: Nausea (50%), vomiting (45%), diarrhea (40%), constipation (35%).

Systemic Reactions: Edema (35%), fatigue (30%).

Laboratory Abnormalities: Elevated transaminases (ALT/AST > 5 times the ULN: 11%), neutropenia (11%).

Serious Adverse Reactions (Requiring Emergency Intervention)

Hepatotoxicity: 0.1% fatality rate; 9.2% incidence of ALT > 5 times the ULN. Interstitial Lung Disease/Pneumonitis: Incidence of 2.9%; 0.5% were fatal cases. Most cases occur within 3 months of treatment initiation.

Cardiotoxicity:

QTc interval prolongation (2.7%; 1.4% of cases involved QTc ≥ 500 ms).

Symptomatic bradycardia (11%; heart rate < 50 beats/min).

Severe vision loss: Rare, but requires permanent discontinuation of the drug.

Table 2: Dosage Adjustment Guidelines (Based on Severity of Adverse Reactions)

| Type of Adverse Reaction | Management Measures

| Grade 3 Hematologic Toxicity | Suspend dosing → Recover to ≤ Grade 2 → Resume at original dose

| Grade 4 Hematologic Toxicity | Suspend dosing → Recover to ≤ Grade 2 → Reduce dose by one level

| Hepatotoxicity (ALT > 5 × ULN) | Suspend dosing → Recover to ≤ 3 × ULN → Reduce dose by one level; Permanently discontinue if accompanied by elevated bilirubin

| Interstitial Lung Disease | Permanently discontinue at any grade

| Symptomatic Bradycardia | Suspend dosing → Resume once heart rate is ≥ 60 beats/min; Permanently discontinue in cases of recurrence or if emergency intervention is required

VI. Contraindications

1. Patients with hypersensitivity to crizotinib or any of its excipients.

2. Patients with severe hepatic impairment (total bilirubin > 3 times the ULN).

3. Pregnant women (risk of fetal malformation).

VII. Important Precautions

1. Monitoring for Hepatotoxicity:

During the first 2 months of treatment: Monitor ALT/AST/bilirubin weekly; thereafter, monitor once monthly.

2. Monitoring of Cardiopulmonary Function:

Perform baseline and periodic ECGs (to monitor for QTc prolongation and bradycardia).

Investigate for interstitial lung disease in the event of new-onset respiratory symptoms (e.g., cough, dyspnea).

3. Visual Assessment:

Perform an immediate ophthalmologic examination if symptoms such as flashes of light, floaters, or decreased vision occur. 4. Drug Interactions:

Avoid concomitant use with: Strong CYP3A inducers (e.g., rifampin, which reduces plasma drug concentrations by 87%), QTc-prolonging agents (e.g., amiodarone), and bradycardia-inducing agents (e.g., beta-blockers).

5. Reproductive Toxicity:

Patients of reproductive potential (including males) must use effective contraception during treatment and for 90 days following discontinuation of the drug.

VIII. Use in Specific Populations

Pediatric Patients: Approved for use in patients ≥1 year of age; dosage should be adjusted based on Body Surface Area (BSA). Long-term use requires monitoring for the risk of growth inhibition.

Geriatric Patients (≥65 years): No dosage adjustment is required; however, enhanced monitoring of cardiac function is recommended.

Lactating Women: The drug may be excreted into breast milk; it is recommended to either discontinue the drug or discontinue breastfeeding.

Important Safety Information

1. During treatment, if Interstitial Lung Disease (ILD), Grade 4 hepatotoxicity, or uncontrollable bradycardia is confirmed, the drug must be permanently discontinued.

2. This information does not substitute for medical advice; the drug must be administered under the guidance of a specialist in oncology, and the treatment regimen should be adjusted based on genetic testing results and individual tolerability.

Product Specifications

Product Name: Crizotinib Capsules 250 mg (60 capsules/box) — CRIZNDR Crizotinib

Common Name: Crizotinib Capsules

Active Ingredient: Crizotinib

Dosage Form: Capsule

Specification: 250 mg per capsule; 60 capsules per box

Manufacturer: INDAR Pharmaceutical Co., Ltd.

Indications: 1. Non-Small Cell Lung Cancer (NSCLC):

ALK-positive locally advanced or metastatic NSCLC (in adults)

ROS1-positive advanced NSCLC (in adults)

2. Lymphoma and Soft Tissue Tumors:

ALK-positive systemic Anaplastic Large-Cell Lymphoma (ALCL) in patients aged 1 year and older

ALK-positive unresectable/recurrent Inflammatory Myofibroblastic Tumor (IMT) in patients aged 1 year and older

Prerequisite for Use: Confirmation of ALK/ROS1 positivity via validated testing methods (e.g., NGS or FISH) is required. Dosage and Administration: Adults: 250 mg orally, twice daily (approximately 12 hours apart); may be taken on an empty stomach or with food.

Children (≥1 year): Dosage calculated based on Body Surface Area (BSA), typically 280 mg/m², twice daily.