TEPODX Tepotinib tablets

[Product Name] Tepotinib Tablets

[Other Names] Tepotinib / Tepmetko

[English Name] Tepotinib Tablets

[Specification] 225 mg × 60 tablets/box

[Manufacturer] Bigbear Pharmaceutical Laos

Tepotinib exerts its therapeutic effects by specifically binding to and inhibiting the activation of the MET receptor. Mutations in the MET receptor lead to abnormal signaling, which drives the growth and spread of tumor cells. By interfering with this abnormal MET signaling, the drug blocks the proliferation and migration of tumor cells, thereby inhibiting the progression of cancer.

[Indications]

Indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

[Storage]

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

[Dosage and Administration]

The recommended dosage is 450 mg taken orally once daily, with food, until disease progression or unacceptable toxicity occurs.

[Adverse Reactions]

Serious adverse reactions occurred in 45% of patients receiving Tepotinib treatment.

Common adverse reactions include edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were lymphopenia, hypoalbuminemia, hyponatremia, increased gamma-glutamyltransferase (GGT), increased amylase, increased ALT, increased lipase, increased AST, and decreased hemoglobin.

Serious adverse reactions included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general physical deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%).

[Monitoring for Serious Adverse Reactions]

1. Interstitial Lung Disease (ILD) / Pneumonitis

ILD/pneumonitis has occurred in patients treated with Tepotinib and may be fatal. ILD/pneumonitis occurred in 2.2% of patients treated with tepotinib; of these, one patient experienced a Grade 3 or higher event, which resulted in death. Four patients (0.9%) discontinued tepotinib due to ILD/pneumonitis.

Monitor patients for new or worsening pulmonary symptoms suggestive of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold tepotinib in patients with suspected ILD/pneumonitis, and permanently discontinue the drug if no other potential causes for the ILD/pneumonitis are identified.

2. Hepatotoxicity

Hepatotoxicity has occurred in patients treated with tepotinib. Elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels occurred in 13% of patients treated with tepotinib. Grade 3 or 4 ALT/AST elevations occurred in 4.2% of patients. One patient (0.2%) experienced a fatal adverse reaction of hepatic failure. Three patients (0.7%) discontinued tepotinib due to ALT/AST elevations. The median time to onset of Grade 3 or higher ALT/AST elevations was 30 days (range: 1 to 178 days).

Perform liver function tests (including ALT, AST, and total bilirubin) prior to initiating tepotinib, every 2 weeks during the first 3 months of treatment, and monthly thereafter or as clinically indicated; perform more frequent testing in patients who develop elevations in transaminases or bilirubin. Withhold, reduce the dose of, or permanently discontinue tepotinib based on the severity of the adverse reaction.

3. Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, tepotinib may cause fetal harm when administered to pregnant women. Oral administration of tepotinib to pregnant rabbits during organogenesis resulted in malformations (teratogenicity) and abnormalities at exposures lower than the human exposure based on Area Under the Curve (AUC) at the recommended clinical dose of 450 mg daily. Advise pregnant women of the potential risk to the fetus.

Advise females of reproductive potential, or male patients with female partners of reproductive potential, to use effective contraception during treatment with tepotinib and for 1 week after the final dose. [Dosage and Administration]

1. Patient Selection for MET Exon 14 Skipping Alterations

Select patients for treatment with tepotinib based on the presence of MET exon 14 skipping alterations in plasma or tumor specimens. Testing for MET exon 14 skipping alterations in plasma specimens is recommended only when a tumor biopsy cannot be obtained. If no alteration is detected in the plasma specimen, re-evaluate the feasibility of performing a tumor tissue biopsy for testing. Currently, there is no FDA-approved test for the detection of MET exon 14 skipping alterations in NSCLC (non-small cell lung cancer) to select patients for treatment with tepotinib.

2. Recommended Dosage

The recommended dosage of tepotinib is 450 mg orally once daily, taken with food, until disease progression or unacceptable toxicity occurs.

Instruct patients to take the dose of tepotinib at approximately the same time each day and to swallow the tablet whole. Do not chew, crush, or split the tablets.

Advise patients not to take a missed dose if less than 8 hours remain before the next scheduled dose.

If vomiting occurs after taking a dose of tepotinib, advise the patient to take the next dose at the scheduled time.

3. Administration for Patients with Difficulty Swallowing Solids

Place the tepotinib tablets in a glass containing 30 mL (1 ounce) of non-carbonated water. Do not use or add other liquids. Stir (do not crush) until the tablets disperse into small pieces (the tablets will not completely dissolve), and drink immediately or within 1 hour. Swallow the tablet dispersion. Do not chew the tablet fragments. Rinse the glass with an additional 30 mL of water and drink immediately to ensure that no residue remains in the glass and that the full dose is administered.

If administration via a nasogastric tube is required, disperse the tablets in 30 mL of non-carbonated water as described above. Administer the 30 mL of liquid immediately or within 1 hour, following the nasogastric tube manufacturer's instructions. Flush immediately twice with 30 mL of water each time to ensure that no residue remains in the glass or syringe and that the full dose is administered. [Dosage Adjustments for Adverse Reactions]

The recommended dose reduction of tepotinib for the management of adverse reactions is 225 mg orally once daily.

For patients unable to tolerate 225 mg orally once daily, permanently discontinue tepotinib.

Tepotinib may cause adverse reactions such as interstitial lung disease/pneumonitis, hepatotoxicity, peripheral edema, embryo-fetal toxicity, and nephrotoxicity; patients should undergo periodic monitoring of relevant parameters and follow their physician's guidance while taking the medication.

[Use in Specific Populations]

1. Pregnancy

Based on findings from animal studies and its mechanism of action, tepotinib may cause fetal harm when administered to pregnant women.

2. Lactation

There are no data regarding the presence of tepotinib or its metabolites in human milk, or regarding its effects on the breastfed infant or on milk production. Women are advised not to breastfeed during treatment with tepotinib and for one week after the final dose.

3. Females and Males of Reproductive Potential

Based on animal data, tepotinib may cause malformations at doses lower than the human exposure (based on AUC) at the clinical dose of 450 mg.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating tepotinib.

Contraception

Females

Females of reproductive potential are advised to use effective contraception during treatment with tepotinib and for one week after the final dose.

Males

Male patients with female partners of reproductive potential are advised to use effective contraception during treatment with tepotinib and for one week after the final dose.

4. Pediatric Use

The safety and effectiveness of tepotinib in pediatric patients have not been established.

5. Geriatric Use

Among the 255 patients with *MET* exon 14 skipping alterations who received 450 mg of tepotinib orally once daily, 79% were 65 years of age or older, and 43% were 75 years of age or older.

No clinically significant differences in safety or effectiveness were observed between patients aged 65 years or older and younger patients. 6. Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min, estimated using the Cockcroft-Gault formula). A recommended dose has not been established for patients with severe renal impairment (CLcr < 30 mL/min).

7. Hepatic Impairment

No dose adjustment is recommended for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).