ALITEPOTNIB Tepotinib Hydrochloride

I. Basic Drug Information

Generic Name: Tepotinib Hydrochloride Tablets

Other Names: Tuodekang, TEPMETKO, ALITEPOTNIB

English Name: Tepotinib Hydrochloride

Specification: 225 mg/tablet; 60 tablets/bottle

Manufacturer: Lao United Pharmaceutical Group Co., Ltd.

Approval Number (National Drug Administration of Laos): 09 L 1387/25

Drug Category: c-Met (Mesenchymal-Epithelial Transition Factor) Tyrosine Kinase Inhibitor

II. Mechanism of Action

Tepotinib is a highly selective and potent c-Met inhibitor.

1.  Target: c-Met (also known as Hepatocyte Growth Factor Receptor, HGFR).

2.  Signaling Pathway: The c-Met signaling pathway plays a crucial role in normal cell growth, differentiation, and tissue repair. However, when this pathway is abnormally activated—such as through *MET* exon 14 skipping mutations or *MET* gene amplification—it drives tumor cell proliferation, survival, invasion, metastasis, and angiogenesis.

3.  Action of Tepotinib: By inhibiting the phosphorylation of c-Met, Tepotinib blocks its downstream signaling (e.g., via the MAPK, PI3K/AKT, and STAT pathways), thereby inhibiting the growth of tumor cells harboring *MET* gene abnormalities and inducing their apoptosis.

III. Indications

Tepotinib has been approved in numerous countries and regions worldwide for the treatment of the following types of cancer (please refer to the approvals issued by local drug regulatory authorities for specific indications):

Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with *MET* Exon 14 Skipping Mutations:

Indicated for the treatment of adult patients with advanced or metastatic NSCLC harboring *MET* exon 14 skipping mutations.

Key Prerequisite: Prior to initiating treatment with Tepotinib, the presence of *MET* exon 14 skipping mutations must be confirmed in tumor tissue or plasma using a validated testing method. If the plasma specimen tests negative, a tumor tissue biopsy is recommended for confirmation.

IV. Dosage and Administration

Route of Administration: Oral. Recommended Dosage: 450 mg (two 225 mg tablets), once daily.

Administration:

Swallow tablets whole; do not chew, crush, or break them.

Should be taken with food. This significantly increases drug absorption and improves bioavailability.

If a dose is missed, take the missed dose as soon as possible on the same day. If the entire day has passed, skip the missed dose and take the next dose at the regularly scheduled time the following day. Do not take a double dose to make up for a missed dose.

Treatment Duration: Continue treatment until disease progression or the occurrence of intolerable toxicity.

V. Dosage Adjustment 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: 450 mg, once daily, taken with food.

Dose Reduction Levels:

First reduction: 225 mg, once daily.

Second reduction: 150 mg, once daily (typically prepared using non-commercial formulations).

If the patient is unable to tolerate the 150 mg once-daily dosage, treatment should be permanently discontinued.

Specific dosage adjustments must strictly adhere to medical advice, particularly regarding the specific toxicities mentioned in the [Warnings and Precautions] section below.

VI. Contraindications

Contraindicated in patients with a history of severe hypersensitivity reactions to tepotinib or to any of the excipients.

VII. Warnings and Precautions

1. Interstitial Lung Disease (ILD)/Pneumonitis:

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

The incidence rate is approximately 4.5%.

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

2. Hepatotoxicity:

Tepotinib may cause elevations in liver enzymes.

Liver function (transaminases and bilirubin) should be monitored prior to treatment and periodically throughout the course of treatment.

Depending on the severity of the hepatotoxicity, it may be necessary to temporarily withhold the drug, reduce the dosage, or permanently discontinue treatment.

3. Peripheral Edema:

This is a very common adverse reaction associated with tepotinib. It may manifest as peripheral edema (leg swelling), facial edema, or generalized edema.

Most cases are Grade 1 or 2; however, severe Grade 3 events have also been reported.

Edema symptoms require close monitoring, and management—based on severity—may involve symptomatic treatment, temporary interruption of the drug, dose reduction, or permanent discontinuation.

4.  Embryo-Fetal Toxicity:

Based on data from animal studies, tepotinib may cause harm to the fetus.

Females of reproductive potential must use effective contraception during treatment and for at least 1 week following the last dose. Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 1 week following the last dose.

VIII. Adverse Reactions

In clinical studies, common adverse reactions included:

Very Common (≥20%) Adverse Reactions:

General Disorders: Peripheral edema, fatigue. 

Musculoskeletal: Musculoskeletal pain, arthralgia. 

Gastrointestinal: Nausea, diarrhea. 

Laboratory Abnormalities: Increased blood creatinine, decreased albumin, lymphopenia, increased alkaline phosphatase, increased lipase, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased amylase, increased blood glucose.

Common (<20%) but Important Adverse Reactions:

Dyspnea, constipation, vomiting, decreased appetite, rash, pruritus, etc.

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

Interstitial Lung Disease (ILD)/Pneumonitis

Hepatotoxicity

Severe Peripheral Edema

IX. Drug Interactions

Tepotinib is primarily metabolized by the enzyme CYP3A4 and transported by the transporter P-glycoprotein (P-gp).

1.  Strong CYP3A Inducers:

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

Effect: May significantly decrease tepotinib plasma concentrations, potentially leading to a loss of efficacy. 

Recommendation: Concomitant use should be avoided.

2.  P-glycoprotein (P-gp) Substrates:

Examples: Digoxin, dabigatran etexilate. **Impact:** Tepotinib may inhibit P-gp, thereby increasing the plasma concentrations of these substrate drugs and increasing the risk of associated adverse reactions. 

**Recommendation:** When co-administered with P-gp substrates with a narrow therapeutic window (e.g., digoxin), adverse reactions associated with these substrate drugs should be closely monitored, and a reduction in their dosage should be considered.

**X. Use in Specific Populations**

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

**Lactating Women:** It is not known whether tepotinib is excreted in human milk. Given the potential for serious adverse reactions in nursing infants, women should not breastfeed during treatment and for at least 1 week after the last dose.

**Pediatric Patients:** The safety and efficacy in pediatric patients 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 Hepatic Impairment:** No dosage adjustment is required. 

**Moderate or Severe Hepatic Impairment:** Use is not recommended. 

**Mild or Moderate Renal Impairment:** No dosage adjustment is required. 

**Severe Renal Impairment:** Use is not recommended.

**XI. Overdosage**

There is currently no specific antidote available.

Overdosage may exacerbate adverse reactions, particularly hepatotoxicity and edema.

In the event of an overdose, administration of the drug should be suspended immediately, and supportive care and symptomatic treatment should be initiated, including close monitoring of liver function and the presence of edema.

**XII. Storage**

Store below 30°C.

Store in the original packaging to protect from moisture.

Keep out of the reach of children.

**Final Emphasis:** This document 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 you experience—particularly difficulty breathing, severe swelling of the legs or face, or any other unusual symptoms.