I. Drug Name

Generic Name: Brigatinib Tablets

English Name: Brigatinib Tablets

Brand Names: Alunbrig, Anburui, BRIGADX

Dosage Form: Oral Film-Coated Tablets

Specification: 90 mg per tablet; 180 mg per tablet; 21 tablets per box

Manufacturer: Laos Da Xiong Pharmaceutical Co., Ltd.

Regulatory Approval Numbers: 12 L1271/24; 12 L1270/24

II. Pharmacological Actions

Pharmacological Classification: Receptor Tyrosine Kinase Inhibitor

Mechanism of Action: Brigatinib is a potent, selective, and orally active second-generation Anaplastic Lymphoma Kinase (ALK) inhibitor.

In ALK-positive non-small cell lung cancer (NSCLC), ALK gene rearrangements lead to the production of abnormal fusion proteins, which constitutively activate signaling pathways that drive tumor growth.

Brigatinib inhibits tumor cell proliferation by suppressing ALK autophosphorylation and the activation of downstream signaling proteins mediated by ALK.

It is active against various ALK mutations (including G1202R) that confer resistance to first-generation ALK inhibitors (such as Crizotinib).

Additionally, it effectively inhibits EGFR mutations and possesses excellent blood-brain barrier penetration capabilities, demonstrating high potency against brain metastases.

III. Indications

Brigatinib is indicated for the treatment of adult patients with ALK-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).

IV. Dosage and Administration

Recommended Dosage and Administration Schedule:

First 7 Days: 90 mg once daily, orally.

After 7 Days: If the 90 mg dose was well tolerated during the first 7 days, increase the dose to 180 mg once daily.

Note: This "90 mg lead-in period" regimen is designed to reduce the risk of early-onset pulmonary adverse reactions.

Method of Administration:

Swallow the tablets whole; they may be taken with or without food.

If a dose is missed, take the missed dose immediately, unless the time remaining before the next scheduled dose is less than 12 hours. Do not take a double dose to make up for a missed dose.

If vomiting occurs after taking the medication, do not take a replacement dose; instead, wait until the next scheduled time to take the regular dose.

V. Contraindications

Patients with a history of severe hypersensitivity to brigatinib or to any of the excipients.

VI. Warnings and Precautions

1. Early-onset Pulmonary Events:

Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis may occur within the first week of treatment.

The incidence is approximately 3%–9%, particularly during the dose escalation phase.

For patients presenting with new or worsening respiratory symptoms (e.g., dyspnea, cough, hypoxia, etc.), treatment should be immediately interrupted, and an urgent assessment for ILD/pneumonitis should be performed. If confirmed, brigatinib must be permanently discontinued.

2. Hypertension:

Hypertension may occur.

Blood pressure should be controlled prior to initiating treatment and monitored approximately every two weeks during treatment. For patients developing Grade 3 hypertension, the medication should be temporarily withheld; for Grade 4 hypertension or hypertensive crisis, the medication must be permanently discontinued.

3. Bradycardia:

Symptomatic bradycardia (abnormally low heart rate) may occur.

Heart rate and blood pressure should be monitored regularly during treatment. Avoid concomitant use with medications known to cause bradycardia. Depending on the severity, withhold the medication, reduce the dose, or permanently discontinue treatment.

4. Creatine Phosphokinase (CPK) Elevation:

Significant elevations in CPK levels may occur, potentially leading to muscle pain, tenderness, or weakness.

CPK levels should be monitored prior to initiating treatment and periodically during treatment. Depending on the degree of elevation, withhold the medication or reduce the dose.

5. Pancreatic Enzyme Elevation:

Elevations in amylase and lipase levels may occur, increasing the risk of pancreatitis.

Pancreatic enzyme levels should be monitored prior to initiating treatment and periodically during treatment. Depending on the degree of elevation, withhold the medication or reduce the dose.

6. Hyperglycemia:

New-onset hyperglycemia or worsening of pre-existing diabetes may occur.

Blood glucose levels should be monitored prior to initiating treatment and periodically during treatment. Initiate or optimize anti-hyperglycemic medications as needed. 7. Embryo-Fetal Toxicity:

Based on its mechanism of action, Brigatinib may cause fetal harm when administered to pregnant women.

Females of reproductive potential should use effective contraception during treatment and for at least 4 months following the last dose.

Male patients should use condoms during treatment and for at least 3 months following the last dose.

VII. Adverse Reactions

Very Common (>10%) Serious and/or Major Adverse Reactions:

Gastrointestinal: Nausea, diarrhea, vomiting, constipation, abdominal pain.

Systemic: Fatigue.

Musculoskeletal: Myalgia (often associated with elevated CPK), arthralgia, back pain.

Respiratory: Cough, dyspnea.

Nervous System: Headache.

Laboratory Abnormalities: Elevated CPK, elevated lipase, elevated amylase, hyperglycemia, lymphopenia, hypophosphatemia, elevated ALT/AST.

Common but Serious Adverse Reactions:

Early-onset pulmonary events (ILD/pneumonitis), hypertension, bradycardia, pancreatitis.

VIII. Drug Interactions

Strong CYP3A Inhibitors (e.g., clarithromycin, itraconazole, ritonavir):

Co-administration significantly increases Brigatinib plasma concentrations, increasing the risk of adverse reactions.

Avoid co-administration. If co-administration is unavoidable, consider reducing the Brigatinib dosage by approximately 50% (e.g., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Strong CYP3A Inducers (e.g., rifampin, carbamazepine, St. John's wort):

Co-administration significantly decreases Brigatinib plasma concentrations, potentially compromising efficacy.

Avoid co-administration.

IX. Use in Specific Populations

Pregnant Women: May cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Lactation: Advise women to discontinue breastfeeding during treatment and for 1 week following the last dose.

Pediatric Use: Safety and efficacy have not been established.

Geriatric Use: No overall differences in safety were observed between patients aged 65 years and older and younger patients. Patients with Hepatic/Renal Impairment:

Hepatic Impairment: No dose adjustment is required for patients with mild hepatic impairment. For patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, the recommended dose is 60 mg once daily (during the induction phase); if tolerated, the dose may be increased to 120 mg once daily.

Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment. For patients with severe renal impairment or those requiring dialysis, the recommended dose is 60 mg once daily (during the induction phase); if tolerated, the dose may be increased to 120 mg once daily.

X. Overdosage

Symptoms: An exacerbation of adverse reactions is expected.

Management: The drug should be discontinued immediately; supportive care should be initiated, and symptomatic treatment provided.

XI. Clinical Pharmacology

Pharmacokinetics: Brigatinib is rapidly absorbed following oral administration, reaching peak plasma concentrations approximately 1 to 4 hours after dosing. High-fat meals result in a slight increase in exposure. *In vivo*, the drug is primarily metabolized via CYP2C8 and CYP3A4. Fecal excretion is the primary route of elimination.

XII. Patient Counseling Information

1. Genetic Testing: Understand that *ALK* gene testing must be performed prior to initiating treatment.

2. Strict Adherence to Dosing Regimen: Understand the importance of the 90 mg induction phase during the first 7 days, and do not increase the dose prematurely on your own initiative.

3. Early Pulmonary Symptoms: Be aware of the risk of ILD/pneumonitis, and seek immediate medical attention if any new or worsening respiratory symptoms occur during the early stages of treatment.

4. Regular Monitoring: Understand the importance of regular monitoring of blood pressure, heart rate, CPK, pancreatic enzymes, and blood glucose levels.

5. Muscular Symptoms: Report any unexplained muscle pain, tenderness, or weakness.

6. Contraception Requirements: Patients of reproductive potential must understand and strictly adhere to contraception requirements.

Final Reminder: Please strictly follow the specific instructions provided by your treating physician and pharmacist. If you have any questions or experience any discomfort during the course of treatment, please communicate immediately with your healthcare team. [Manufacturer Introduction]

Daxiong Pharmaceutical stands as one of Laos's officially recognized and legitimate chemical pharmaceutical enterprises. Following an extensive two-year site selection process—conducted under the guidance of investors and accompanied by the Laotian Minister of Health—the company ultimately established its manufacturing facility in Vientiane, the national capital of Laos. Preparations for the project commenced in 2020, culminating in the completion of the factory in 2021. The parent company invested substantial capital to implement industrial upgrades, thereby creating production workshops that meet advanced international manufacturing standards. Furthermore, the facility has made significant contributions toward alleviating the shortage of medical care and pharmaceutical supplies within Laos. Over the past two years, Daxiong Pharmaceutical has maintained a steadfast commitment to innovation and prudent management, achieving steady growth and continuously expanding its scope of operations. The company has sustained an exceptional performance record, with its key economic indicators consistently ranking at the forefront of the domestic pharmaceutical industry in Laos. This milestone marks the beginning of a new chapter for Daxiong Pharmaceutical as it sets out to build a modern pharmaceutical conglomerate that is both a domestic leader in Laos and a world-class enterprise.