TEPMETKO Film-coated tablet Ref.[49534] Active ingredients: Tepotinib

5.1 Interstitial Lung Disease (ILD)/Pneumonitis

ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 2.2% patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death. Four patients (0.9%) discontinued TEPMETKO due to ILD/pneumonitis.

Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3)].

5.2 Hepatotoxicity

Hepatotoxicity occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 13% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.2% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). Three patients (0.7%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 30 days (range 1 to 178).

Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.3)].

5.3 Embryo-Fetal Toxicity

Based on findings in animal studies and its mechanism of action TEPMETKO can cause fetal harm when administered to a pregnant woman. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose [See Use in Specific Populations (8.1, 8.3)].

The following adverse reactions are described in greater detail elsewhere in the labeling:

• Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to TEPMETKO in 448 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at a dose of 450 mg once daily. This included 255 patients with NSCLC positive for METex14 skipping alterations, who received TEPMETKO in VISION. Among 448 patients who received TEPMETKO, 32% were exposed for 6 months or longer, and 12% were exposed for greater than one year.

The data described below reflect exposure to TEPMETKO 450 mg once daily in 255 patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations in VISION [see Clinical Studies (14)].

Serious adverse reactions occurred in 45% of patients who received TEPMETKO. Serious adverse reactions in >2% of patients included pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), and musculoskeletal pain (2%). Fatal adverse reactions occurred in one patient (0.4%) due to pneumonitis, one patient (0.4%) due to hepatic failure, and one patient (0.4%) due to dyspnea from fluid overload.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received TEPMETKO. The most frequent adverse reactions (>1%) leading to permanent discontinuations of TEPMETKO were edema (5%), pleural effusion (2%), dyspnea (1.6%), general health deterioration (1.6%), and pneumonitis (1.2%).

Dosage interruptions due to an adverse reaction occurred in 44% of patients who received TEPMETKO. Adverse reactions which required dosage interruption in >2% of patients who received TEPMETKO included edema (23%), increased blood creatinine (6%), pleural effusion (4.3%), increased ALT (3.1%), and pneumonia (2.4%).

Dose reductions due to an adverse reaction occurred in 30% of patients who received TEPMETKO. Adverse reactions which required dose reductions in >2% of patients who received TEPMETKO included edema (19%), pleural effusion (2.7%), and increased blood creatinine (2.7%).

The most common adverse reactions (≥20%) in patients who received TEPMETKO were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin.

Table 2 summarizes the adverse reactions in VISION.

Table 2. Adverse Reactions in ≥10% of Patients with NSCLC with METex14 Skipping Alterations Who Received TEPMETKO in VISION:

^* Edema includes eye edema, face edema, generalized edema, localized edema, edema, genital edema, peripheral edema, peripheral swelling, periorbital edema, and scrotal edema.
^† Fatigue includes asthenia and fatigue.
^‡ Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain, and hepatic pain.
^§ Vomiting includes retching and vomiting.
^¶ Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, non-cardiac chest pain, pain in extremity, and spinal pain.
^# Dyspnea includes dyspnea, dyspnea at rest, and dyspnea exertional.
^Þ Cough includes cough, and productive cough.
^ß Pneumonia includes pneumonia, pneumonia aspiration, and pneumonia bacterial.

Clinically relevant adverse reactions in <10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache.

Table 3 summarizes the laboratory abnormalities observed in VISION.

Table 3. Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients Who Received TEPMETKO in VISION:

^* The denominator used to calculate the rate varied from 207 to 246 based on the number of patients with a baseline value and at least one post-treatment value.

A clinically relevant laboratory abnormality in <20% of patients who received TEPMETKO was increased lipase in 18% of patients, including 3.7% Grades 3 to 4.

Increased Creatinine

A median increase in serum creatinine of 31% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion.

7.1 Effects of Other Drugs on TEPMETKO

Dual Strong CYP3A Inhibitors and P-gp Inhibitors

The effect of strong CYP3A inhibitors or P-gp inhibitors on TEPMETKO has not been studied clinically. However, metabolism and in vitro data suggest concomitant use of drugs that are strong CYP3A inhibitors and P-gp inhibitors may increase tepotinib exposure [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of TEPMETKO. Avoid concomitant use of TEPMETKO with dual strong CYP3A inhibitors and P-gp inhibitors.

Strong CYP3A Inducers

The effect of strong CYP3A inducers on TEPMETKO has not been studied clinically. However, metabolism and in vitro data suggest concomitant use may decrease tepotinib exposure [see Clinical Pharmacology (12.3)], which may reduce TEPMETKO efficacy. Avoid concomitant use of TEPMETKO with strong CYP3A inducers.

7.2 Effects of TEPMETKO on Other Drugs

Certain P-gp Substrates

Tepotinib is a P-gp inhibitor. Concomitant use of TEPMETKO increases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of these substrates. Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

Risk Summary

Based on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], TEPMETKO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TEPMETKO in pregnant women. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at maternal exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In embryo-fetal development studies, pregnant rabbits received oral doses of 0.5, 5, 25, 50, 150, or 450 mg/kg tepotinib hydrochloride hydrate daily during organogenesis. Severe maternal toxicity occurred at the 450 mg/kg dose (approximately 0.75 times the human exposure at the 450 mg clinical dose). At 150 mg/kg (approximately 0.5 times the human exposure by AUC at the 450 mg clinical dose), two animals aborted and one animal died prematurely; mean fetal body weight was also decreased. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus, occurred at doses ≥5 mg/kg (approximately 0.003 times the human exposure by AUC at the 450 mg clinical dose); there was also an incidence of spina bifida at the 5 mg/kg dose level.

Risk Summary

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

Based on animal data, TEPMETKO can cause malformations at doses less than the human exposure based on AUC at the 450 mg clinical dose [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating TEPMETKO [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the final dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the final dose.

The safety and efficacy of TEPMETKO in pediatric patients have not been established.

Of 255 patients with METex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 43% were 75 years or older. No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

No dosage modification is recommended in patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].

No dosage modification is recommended in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied [see Clinical Pharmacology (12.3)].