Tepotinib Hydrochloride

Tepotinib hydrochloride, a kinase inhibitor, is an antineoplastic agent.

Class: 10:00 • Antineoplastic Agents (AHFS primary) Brands: Tepmetko®
Uses
Tepotinib hydrochloride has the following uses:
⦁ Tepotinib hydrochloride is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
⦁ This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in con- firmatory trials.

Dosage and Administration
General. Tepotinib hydrochloride is available in the fol- lowing dosage form(s) and strength(s): Tablets: 225 mg.
Dosage. It is essential that the manufacturer’s la- beling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults.
Dosage and Administration.
⦁ Select patients for treatment with tepotinib hydrochloride on the presence of METex14 skipping.
⦁ Recommended dosage: 450 mg orally once daily with food until disease progression or unacceptable toxicity.

Cautions
Contraindications. None.
Warnings/Precautions.
Interstitial Lung Disease (ILD)/Pneumonitis. ILD/pneu- monitis, which can be fatal, occurred in patients treated with tepotinib hydrochloride. ILD/pneumonitis occurred in 2.2% patients treated with tepotinib hydrochloride, with one pa- tient experiencing a grade 3 or higher event; this event resulted in death. Four patients (0.9%) discontinued tepotinib hydro- chloride due to ILD/pneumonitis.
Monitor patients for new or worsening pulmonary symp- toms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold tepotinib hydrochloride in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified.

Hepatotoxicity. Hepatotoxicity occurred in patients treated with tepotinib hydrochloride. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 13% of patients treated with tepotinib hydrochloride. 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%) discon- tinued tepotinib hydrochloride 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 tepotinib hydrochloride, 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 aminotransferases or bili- rubin. Based on the severity of the adverse reaction, with- hold, dose reduce, or permanently discontinue tepotinib hydrochloride.
Embryofetal Toxicity. Based on findings in animal studies and its mechanism of action, tepotinib hydrochloride 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 (terato- genicity) 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 ef- fective contraception during treatment with tepotinib hydro- chloride and for one week after the final dose.
Specific Populations.

Pregnancy. Risk Summary: Based on findings in animal studies and the mechanism of action, tepotinib hydro- chloride can cause fetal harm when administered to a pregnant woman. There are no available data on the use of tepotinib hydrochloride in pregnant women. Oral admin- istration 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. 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 recog- nized pregnancies is 2% to 4% and 15% to 20%, respectively. Animal Data: In embryofetal 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

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also decreased. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with con- comitant 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.
Lactation. 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 tepotinib hydrochloride and for one week after the final dose.
Females and Males of Reproductive Potential. Based on animal data, tepotinib hydrochloride can cause malforma- tions at doses less than the human exposure based on AUC at the 450 mg clinical dose.
Verify pregnancy status in females of reproductive poten- tial prior to initiating tepotinib hydrochloride.
Advise females of reproductive potential to use effective contraception during tepotinib hydrochloride treatment and for one week after the final dose.
Advise male patients with female partners of repro- ductive potential to use effective contraception during tepotinib hydrochloride treatment and for one week after the final dose.

Pediatric Use. The safety and efficacy of tepotinib hydro- chloride in pediatric patients have not been established.
Geriatric Use. Of 255 patients with METex14 skipping alterations in the VISION study who received 450 mg of tepotinib hydrochloride 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 pa- tients aged 65 years or older and younger patients.

Renal Impairment. No dosage modification is recom- mended in patients with mild or moderate renal impair- ment (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)
Hepatic Impairment. No dosage modification is recom- mended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokin- etics and safety of tepotinib in patients with severe hepatic im- pairment (Child-Pugh Class C) have not been studied.
Common Adverse Effects. Most common adverse reactions (≥20%) 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, in- creased gamma-glutamyltransferase, increased amylase, in- creased ALT, increased AST, and decreased hemoglobin.
Interactions

Specific Drugs. It is essential that the manufacturer’s labeling be consulted for more detailed information on interactions with this drug, including possible dosage ad- justments. Interaction highlights:
⦁ Dual strong CYP3A inhibitors and P-gp inhibitors: Avoid concomitant use.
⦁ Strong CYP3A inducers: Avoid concomitant use.
⦁ Certain P-gp substrates: Avoid coadministration of tepotinib hydrochloride with P-gp substrates where minimal con- centration changes may lead to serious or life-threatening toxicities.

Actions
Mechanism of Action.
⦁ Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib in- hibits hepatocyte growth factor (HGF)-dependent and
-independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.
⦁ In vitro, tepotinib inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET- dependent tumor cells. In mice implanted with tumor cell lines with oncogenic activation of MET, including METex14 skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphor- ylation, and, in one model, decreased the formation of metastases.

Advice to Patients
⦁ Advise the patient to read the FDA-approved patient la- beling (Patient Information).
⦁ Inform patients of the risk of severe or fatal ILD/pneumon- itis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.
⦁ Inform patients that they will need to undergo lab tests to monitor liver function. Advise patients to immediately
contact their healthcare provider for signs and symptoms of liver dysfunction.
⦁ Advise males and females of reproductive potential that tepotinib hydrochloride can cause fetal harm.
⦁ Advise females of reproductive potential to use effective contraception during and for one week after the final dose of tepotinib hydrochloride.
⦁ Advise male patients with female partners of reproductive potential to use effective contraception during treatment

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with tepotinib hydrochloride and for one week after the final dose of tepotinib hydrochloride.
⦁ Advise women not to breastfeed during treatment with tepotinib hydrochloride and for one week after the final dose.
⦁ Advise patients to inform their healthcare provider of all concomitant medications, including prescription medi- cines, over-the-counter drugs and herbal products.
⦁ Instruct patients to take 450 mg tepotinib hydrochloride once daily with food.
⦁ Advise patients that a missed dose of tepotinib hydro- chloride can be taken as soon as remembered on the same day, unless the next dose is due within 8 hours. If vomiting occurs after taking a dose of tepotinib hydro- chloride, advise patients to take the next dose at the scheduled time.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in Tepotinib some individuals; consult specific product labeling for details.

Tepotinib
Hydrochloride Oral
Tablets, film-coated
225 mg (of tepotinib)
Tepmetko®, EMD Serono

© Copyright, March 8, 2021, American Society of Health-System Pharmacists, Inc.

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