I. Basic Drug Information

Generic Name: Repotrectinib Capsules

Other Names: Repotrectinib, Repotinib, Lopotinib, Augtyro, ALIOLAPARIB

English Name: Repotrectinib

Specification: 40 mg/capsule; 60 capsules/bottle

Manufacturer: Lao United Pharmaceutical Group Co., Ltd.

Approval Number (Lao National Drug Administration): 09 L 1388/25

Drug Category: Tyrosine Kinase Inhibitor (targeting ROS1, TRK, and ALK)

II. Mechanism of Action

Repotrectinib is a new-generation, potent tyrosine kinase inhibitor.

1. Targets: It primarily acts upon the following targets:

ROS1: A driver gene that undergoes fusion with other genes in certain cases of non-small cell lung cancer (NSCLC).

NTRK1/2/3: Neurotrophic tyrosine receptor kinases, which undergo fusion in various solid tumors.

ALK: Anaplastic lymphoma kinase, which undergoes fusion in certain cases of NSCLC.

2. Key Characteristics:

High Potency: It exhibits very strong binding affinity for kinases, demonstrating higher potency than certain earlier-generation TKIs.

Compact Macrocyclic Structure: Its unique, compact three-dimensional molecular structure enables it to bind more tightly to the ATP-binding pocket—even in the presence of certain common resistance mutations.

Overcoming Resistance: This is one of its most significant features. For ROS1-positive NSCLC, it effectively targets the most common resistance mutation, ROS1 G2032R. For NTRK-positive solid tumors, it is also effective against a variety of NTRK resistance mutations.

III. Indications

Repotrectinib has been approved in certain countries and regions for the treatment of the following cancers (please refer to the specific approvals issued by local drug regulatory authorities):

1. Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer (NSCLC):

For First-Line Treatment: Indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC who have not previously received treatment with a ROS1 TKI.

For Subsequent Treatment: Indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC who have previously received one ROS1 TKI and have not received platinum-based chemotherapy.

2. NTRK Gene Fusion-Positive Solid Tumors:

Indicated for the treatment of adult and pediatric patients aged 12 years and older with locally advanced or metastatic NTRK gene fusion-positive solid tumors who have progressed following prior TRK inhibitor therapy or who have no satisfactory alternative treatment options.

Key Prerequisite: Prior to initiating treatment with Repotrectinib, the presence of a ROS1 fusion or NTRK gene fusion must be confirmed using an FDA-approved test method.

IV. Dosage and Administration

Route of Administration: Oral.

Recommended Dosage:

Standard Adult Dosage: 160 mg orally once daily for 14 consecutive days; subsequently, increase to 160 mg orally twice daily.

Weight-Based Pediatric Dosage (Applicable to NTRK-Positive Solid Tumors): For pediatric patients with a body surface area (BSA) greater than 1.5 m², the recommended dosage is the same as for adults. For pediatric patients with a smaller BSA, the dosage must be calculated based on BSA; please strictly follow the physician's instructions.

Administration Instructions:

Swallow capsules whole; do not chew, crush, or open the capsules.

May be taken with or without food.

If a dose is missed, do not take the missed dose unless more than 10 hours remain before the next scheduled dose. Do not take a double dose to make up for a missed dose.

Treatment Duration: Continue treatment until disease progression or until intolerable toxicity occurs.

V. Dosage Adjustments and Management

In the event of adverse reactions, the physician may recommend temporarily withholding the drug, reducing the dosage, or permanently discontinuing treatment, depending on the severity of the reaction.

Starting Dose: 160 mg orally once daily (loading phase, for 14 days).

Maintenance Dose: 160 mg orally twice daily.

Dose Reduction Levels:

First Dose Reduction: 120 mg orally twice daily.

Second Dose Reduction: 80 mg orally twice daily.

Third Dose Reduction: 40 mg orally twice daily (if 80 mg twice daily is not tolerated).

* If further dose reduction is required, treatment should be permanently discontinued. Specific dose adjustments (e.g., for central nervous system adverse reactions, hepatotoxicity, etc.) must strictly adhere to medical advice.

VI. Contraindications

Repotrectinib is contraindicated in patients with a history of severe hypersensitivity reactions to Repotrectinib or to any of its excipients.

VII. Warnings and Precautions

1. Central Nervous System (CNS) Effects:

Repotrectinib may cause dizziness and ataxia, which occur at a relatively high incidence.

Most events are Grade 1 or 2; however, Grade 3 events may also occur.

Patient Information: Patients should avoid driving or operating hazardous machinery until they understand how the drug affects their nervous system. Patients should avoid sudden changes in posture if dizziness occurs.

2. Interstitial Lung Disease (ILD)/Pneumonitis:

Potentially fatal cases of ILD/pneumonitis have been reported in patients treated with Repotrectinib.

Patients who develop new or worsening respiratory symptoms (e.g., dyspnea, cough, fever) should immediately suspend treatment and seek medical attention. If treatment-related ILD/pneumonitis is confirmed, Repotrectinib should be permanently discontinued.

3. Hepatotoxicity:

Repotrectinib may cause elevations in liver enzymes.

Liver function should be monitored prior to the initiation of treatment and periodically throughout the course of treatment.

Depending on the severity of the hepatotoxicity, treatment may require suspension, dose reduction, or permanent discontinuation.

4. Creatine Phosphokinase (CPK) Elevation:

Repotrectinib may lead to elevated CPK levels, which are associated with muscle injury.

CPK levels should be monitored periodically. If CPK levels become significantly elevated, treatment should be suspended and appropriate management initiated as directed by a physician.

5. Hyperuricemia:

Repotrectinib may cause elevated uric acid levels.

Serum uric acid levels should be monitored periodically, and uric acid-lowering therapy should be initiated when clinically indicated.

6. Embryo-Fetal Toxicity:

Based on data from animal studies, Repotrectinib may cause harm to a fetus.

Females of reproductive potential must use effective contraception during treatment and for at least 2 months following the last dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 4 months following the last dose. VIII. Adverse Reactions

In clinical studies, common adverse reactions included:

Very Common (≥20%) Adverse Reactions:

Nervous System: Dizziness, ataxia, dysgeusia (altered sense of taste), peripheral neuropathy.

Musculoskeletal: Myalgia, arthralgia.

Gastrointestinal: Constipation, dyspnea, nausea, abdominal pain.

Systemic Reactions: Fatigue.

Laboratory Abnormalities: Increased CPK, lymphopenia, increased uric acid, hypophosphatemia, neutropenia, decreased hemoglobin, increased AST/ALT.

Common (<20%) but Important Adverse Reactions:

Cognitive impairment, blurred vision, somnolence, headache, etc.

Important and Serious Adverse Reactions (See [Warnings and Precautions] for details):

Interstitial Lung Disease/Pneumonitis

Hepatotoxicity

Central Nervous System (CNS) Effects (severe dizziness/ataxia)

IX. Drug Interactions

Repotrectinib is a substrate of CYP3A4 and an inhibitor of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).

1. Strong CYP3A Inhibitors:

Examples: Clarithromycin, itraconazole, ketoconazole, ritonavir, conivaptan.

Effect: Significantly increases Repotrectinib plasma concentrations, increasing the risk of adverse reactions.

Recommendation: Concomitant use should be avoided. If concomitant use cannot be avoided, the dose of Repotrectinib should be reduced, and the patient should be closely monitored.

2. Strong CYP3A Inducers:

Examples: Rifampin, carbamazepine, St. John's wort, phenytoin.

Effect: Significantly decreases Repotrectinib plasma concentrations, potentially leading to a loss of efficacy.

Recommendation: Concomitant use should be avoided.

3. Effects of Repotrectinib as an Inhibitor:

Repotrectinib may increase the plasma concentrations of drugs that are substrates of P-gp and BCRP.

Examples of Affected Drugs: Digoxin, dabigatran etexilate, rosuvastatin. Recommendation: When used concomitantly, closely monitor for adverse reactions associated with these substrate medications, and consider reducing the dosages of these medications.

Before starting any new medication (including prescription drugs, over-the-counter drugs, and herbal products), be sure to inform your physician.

X. Use in Specific Populations

Pregnant Women: Based on its mechanism of action, Repotrectinib may cause harm to the fetus; therefore, it is contraindicated.

Lactating Women: It is not known whether Repotrectinib is excreted in human milk. Given the potential for serious adverse reactions in nursing infants, breastfeeding should be discontinued during treatment and for 10 days following the last dose.

Pediatric Patients: The safety and efficacy of Repotrectinib have been established in patients aged 12 years and older with solid tumors harboring *NTRK* gene fusions. The safety and efficacy in children under 12 years of age have not been established.

Geriatric Patients: In clinical studies, no overall differences in safety or efficacy were observed between patients aged 65 years and older and younger patients.

Hepatic/Renal Impairment:

Mild to Moderate Hepatic Impairment: No dosage adjustment is required.

Severe Hepatic Impairment: A recommended dosage has not been established; use with caution.

Mild to Moderate Renal Impairment: No dosage adjustment is required.

Severe Renal Impairment: A recommended dosage has not been established; use with caution.

XI. Overdosage

There is currently no specific antidote available.

Overdosage may exacerbate adverse reactions.

In the event of an overdose, discontinue the medication immediately and institute supportive care and symptomatic treatment.

XII. Storage

Store at 20°C to 25°C; excursions between 15°C and 30°C are permitted.

Keep in the original packaging to protect from moisture.

Keep out of reach of children.

Final Reminder: This content serves as an informational summary and is not a substitute for professional medical advice. Your treating physician is the most reliable and up-to-date source for information regarding your treatment. Please ensure you communicate closely with your healthcare team and report any discomfort or adverse effects you experience.