I. Drug Name

Generic Name: Repotrectinib Capsules

Other Names: Repotrectinib Capsules

English Name: Repotrectinib

Brand Names: Augtyro, Repodx

Dosage Form: Capsules

Specification: 40 mg per capsule; 60 capsules per box

Manufacturer: Laos Big Bear Pharmaceutical Co., Ltd.

Regulatory Approval Number: 09L1203/24

II. Pharmacological Action

Pharmacological Classification: Tyrosine Kinase Inhibitor (TKI)

Mechanism of Action: Repotrectinib is a new-generation, potent, and selective inhibitor of ROS1 and TRK (tropomyosin receptor kinase).

Its molecular structure has been optimized to be smaller in size, enabling it to bind more effectively to the ROS1 or NTRK kinase domains—even in the presence of certain resistance mutations (such as ROS1 G2032R and SOL-1) that confer resistance to older-generation TKIs.

By inhibiting the activity of ROS1 or NTRK kinases, it blocks their downstream signaling pathways, thereby inhibiting tumor cell growth and inducing apoptosis.

Consequently, it has demonstrated superior efficacy in both TKI-naïve patients and patients who have previously received treatment and developed resistance.

III. Indications

Repotrectinib is indicated for the treatment of the following tumors in adult patients:

1. ROS1-positive Non-Small Cell Lung Cancer (NSCLC):

Indicated for the treatment of locally advanced or metastatic ROS1-positive non-small cell lung cancer.

2. NTRK Gene Fusion-positive Solid Tumors:

Indicated for the treatment of advanced or metastatic NTRK gene fusion-positive solid tumors in patients who meet the following criteria:

Disease progression following prior treatment with a TRK inhibitor; and

No satisfactory alternative treatment options are available.

IV. Dosage and Administration

Recommended Dosage: 160 mg, once daily, administered orally, for 14 consecutive days.

Subsequently: Starting from Day 15, the dosage is increased to 160 mg, twice daily (approximately every 12 hours). Administration:

Swallow the capsule/tablet whole; do not chew, crush, or dissolve it.

May be taken with or without food.

If a dose is missed, take it as soon as possible unless less than 8 hours remain before the next scheduled dose (for a twice-daily regimen) or 10 hours (for a once-daily regimen). Do not take a double dose to make up for a missed dose.

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

V. Contraindications

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

VI. Warnings and Precautions

1. Central Nervous System (CNS) Effects:

Repotrectinib may cause a wide range of CNS adverse reactions.

These include: dizziness (very common; may be severe), ataxia (lack of physical coordination), cognitive impairment, confusional state, sleep disorders, mood disorders, speech disorders, peripheral neuropathy, and paresthesia.

Patients are advised not to drive, operate hazardous machinery, or engage in any activities requiring mental alertness while undergoing treatment until they understand how repotrectinib affects them.

Depending on the severity of the CNS effects, treatment may require interruption, dose reduction, or permanent discontinuation.

2. Interstitial Lung Disease (ILD)/Pneumonitis:

Severe, and potentially fatal, ILD/pneumonitis may occur.

In patients presenting with symptoms suggestive of ILD/pneumonitis (e.g., dyspnea, cough, fever, hypoxemia), treatment should be immediately interrupted and an evaluation performed. If confirmed, repotrectinib must be permanently discontinued.

3. Hepatotoxicity:

May cause elevations in ALT (alanine aminotransferase) and AST (aspartate aminotransferase).

Monitor liver function prior to initiating treatment, every 2 weeks during the first 2 months of treatment, monthly thereafter, and as clinically indicated.

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

4. Creatine Phosphokinase (CPK) Elevation:

May lead to elevated CPK levels, indicative of muscle injury.

Monitor CPK levels prior to initiating treatment and periodically during treatment. Depending on the degree of elevation, it may be necessary to suspend the medication or reduce the dosage.

5. Hyperuricemia:

May cause elevated serum uric acid levels.

Monitor uric acid levels prior to initiating treatment and periodically throughout the course of treatment. Treat according to clinical indications, such as by administering uric acid-lowering agents.

6. Embryo-Fetal Toxicity:

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

Females of reproductive potential should use effective contraception during treatment and for at least 2 months following the final dose.

Male patients with female partners who are pregnant or of reproductive potential should use effective condoms during treatment and for at least 1 month following the final dose.

VII. Adverse Reactions

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

Nervous System: Dizziness (most common), dysgeusia, peripheral neuropathy, ataxia, cognitive impairment, headache, paresthesia.

Gastrointestinal: Constipation, diarrhea, nausea.

General: Fatigue.

Musculoskeletal: Myalgia, arthralgia.

Laboratory Abnormalities: Elevated CPK, elevated ALT/AST, neutropenia, hypophosphatemia, hyperuricemia.

Common but Serious Adverse Reactions:

ILD/Pneumonitis, hepatotoxicity.

VIII. Drug Interactions

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

Co-administration significantly increases Repotrectinib plasma concentrations, thereby increasing the risk of adverse reactions (particularly CNS effects).

Avoid co-administration. If co-administration is unavoidable, closely monitor for adverse reactions and consider reducing the Repotrectinib dosage.

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

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

Avoid co-administration. CYP3A Substrates:

Repotrectinib is a moderate inducer of CYP3A; it may reduce the plasma concentrations of drugs metabolized by CYP3A (e.g., midazolam, certain statins, hormonal contraceptives), potentially leading to a loss of efficacy for these drugs.

When co-administered, the efficacy of these substrate drugs should be closely monitored, and consideration should be given to increasing their dosages or selecting alternative medications.

IX. Use in Specific Populations

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

Lactating Women: It is recommended to discontinue breastfeeding during treatment and for 10 days following the last dose.

Pediatric Patients: Safety and efficacy have not been established.

Geriatric Patients: In patients aged 65 years and older, no overall differences in safety were observed compared to younger patients.

Patients with Hepatic/Renal Impairment:

Hepatic Impairment: For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the recommended dosage is 160 mg once daily (no dose escalation is required). For patients with severe (Child-Pugh C) hepatic impairment, the recommended dosage is 80 mg once daily.

Renal Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (eGFR 30–89 mL/min/1.73 m²). For patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m²), the recommended dosage is 160 mg once daily. Data are limited for patients with end-stage renal disease; therefore, caution is advised.

X. Overdosage

Symptoms: Overdosage is expected to result in an exacerbation of adverse reactions, particularly central nervous system effects and hepatotoxicity.

Management: The drug should be immediately discontinued; supportive care and symptomatic treatment should be initiated, and vital signs and liver function should be closely monitored.

XI. Clinical Pharmacology

Pharmacokinetics: Following oral administration, repotrectinib is rapidly absorbed, reaching peak plasma concentrations in approximately 4 to 6 hours. High-fat meals significantly increase its exposure. In vivo, it is primarily metabolized via CYP3A4. Fecal excretion is the primary route of elimination. XII. Patient Information and Counseling

1. **Genetic Testing:** Understand that testing for *ROS1* or *NTRK* gene alterations is mandatory prior to initiating treatment.

2. **Central Nervous System (CNS) Effects:** Be aware of potential side effects such as dizziness and cognitive changes; avoid driving or engaging in hazardous activities, and promptly report any severe symptoms.

3. **Adherence to Prescribing Instructions:** Strictly follow your physician's instructions regarding the initial dosage and any subsequent dose escalations.

4. **Regular Monitoring:** Understand the importance of regular monitoring of liver function, CPK levels, and uric acid levels.

5. **Pulmonary Symptoms:** Immediately report any new onset or worsening of respiratory difficulties, coughing, fever, or similar symptoms.

6. **Contraception Requirements:** Patients with reproductive potential must understand and strictly adhere to contraception requirements, and should be aware that hormonal contraceptives may be less effective while taking this medication.

In conclusion, we emphasize once again: Please strictly follow the specific guidance provided by your treating physician and pharmacist. Should you experience any questions or discomfort during the course of treatment, please communicate immediately with your healthcare team.