Tepotinib Hydrochloride (Monograph)

Brand name: Tepmetko
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor.

Uses for Tepotinib Hydrochloride

Non-small Cell Lung Cancer (NSCLC)

Treatment of adult patients with metastatic NSCLC harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations (designated an orphan drug by FDA).

Recent ASCO update on advanced NSCLC with driver alterations states that clinicians may offer capmatinib or tepotinib as first-line treatment option in patients with MET exon 14 skipping mutation. Either agent may be offered second-line to these patients who have not received MET-targeted therapy prior.

Tepotinib Hydrochloride Dosage and Administration

General

Pretreatment Screening

• Confirm presence of mesenchymal-epithelial transition (MET) exon 14 skipping alteration in tumor specimens prior to initiating therapy. Use plasma specimens only if a tumor biopsy cannot be obtained; if MET exon 14 skipping alteration is not detected in plasma, reassess feasibility of tumor biopsy.

• Serum AST, ALT, and bilirubin concentrations.

• Monitor amylase and lipase levels.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor for symptoms of interstitial lung disease or pneumonitis (e.g., dyspnea, cough, fever).

• Serum AST, ALT, and bilirubin concentrations every 2 weeks for the first 3 months of therapy, then monthly or as clinically indicated. More frequent monitoring may be necessary if hepatotoxicity occurs.

• Monitor amylase and lipase levels regularly during treatment.

Administration

Oral Administration

Administer orally once daily with food at the same time of day. Swallow tablets whole; do not chew, crush, or split.

If a dose is missed, take as soon as remembered, but not within 8 hours of the next scheduled dose. If a dose is vomited, do not take extra doses. Administer the next dose at the regularly scheduled time.

If patient has difficulty swallowing solids, place tepotinib tablet(s) in a glass containing 30 mL (1 ounce) of non-carbonated water. Stir the tablets, without crushing, until tablets are dispersed into small pieces. Drink the tablet dispersion immediately or within 1 hour. Do not chew tablet pieces in the dispersion. Rinse glass with an additional 30 mL and drink immediately ensuring no residue remains in the glass and the full dose administered.

If NG (at least 8 French gauge) administration is required, disperse tepotinib tablet(s) in 30 mL of non-carbonated water as noted above. Administer immediately or within 1 hour as per NG tube manufacturer's instructions. Immediately rinse twice with 30 mL each time to ensure that no residue remains and full dose administered.

Dosage

Available as tepotinib hydrochloride; dosage expressed in terms of tepotinib.

Adults

NSCLC

Oral

450 mg once daily. Continue until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or discontinuance of the drug may be necessary for adverse reactions.

If dosage modification is necessary, reduce dosage to 225 mg once daily.

Dosage <225 mg once daily not recommended; permanently discontinue drug if 225 mg daily dosage not tolerated.

Pulmonary Toxicity

Oral

If interstitial lung disease or pneumonitis of any grade is suspected, temporarily interrupt tepotinib therapy.

If interstitial lung disease or pneumonitis is confirmed, permanently discontinue tepotinib.

Hepatotoxicity

Oral

If grade 3 elevations in ALT or AST concentrations occur in the absence of elevated total bilirubin concentrations, temporarily interrupt tepotinib therapy until serum ALT and AST concentrations return to baseline values. If recovery occurs within 7 days, resume tepotinib at the same dosage. If recovery is delayed beyond 7 days, resume therapy at a reduced dosage.

If grade 4 elevations in ALT or AST concentrations occur in the absence of elevated total bilirubin concentrations, permanently discontinue tepotinib.

If elevations in ALT or AST concentrations >3 times the ULN with concurrent total bilirubin concentrations >2 times the ULN occur in the absence of cholestasis or hemolysis, permanently discontinue tepotinib.

If grade 3 elevations in total bilirubin concentrations occur in the absence of elevated ALT and/or AST concentrations, temporarily interrupt tepotinib therapy until total bilirubin concentrations return to baseline values. If recovery occurs within 7 days, resume tepotinib at the recommended reduced dosage. If recovery is delayed beyond 7 days, permanently discontinue tepotinib.

If grade 4 elevations in total bilirubin concentrations occur in the absence of elevated ALT and/or AST concentrations, permanently discontinue tepotinib.

Pancreatic Toxicity

Oral

If grade 3 elevations in lipase or amylase, withhold tepotinib until levels return to ≤grade 2 or baseline. If recovery to baseline or ≤grade 2 occurs within 14 days, resume tepotinib at a reduced dose; otherwise, permanently discontinue.

If grade 4 elevations in lipase or amylase, permanently discontinue tepotinib.

If grade 3 or 4 pancreatitis, permanently discontinue tepotinib.

Other Toxicity

Oral

If grade 2 adverse reactions occur, continue tepotinib at the same dosage.

If intolerable grade 2 adverse reactions occurs, consider interruption of tepotinib therapy. When the toxicity resolves, resume tepotinib therapy at the recommended reduced dosage.

If grade 3 adverse reactions occur, temporarily interrupt tepotinib therapy. When the toxicity resolves, resume tepotinib therapy at the recommended reduced dosage.

If grade 4 adverse reactions occur, permanently discontinue tepotinib.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.

Severe hepatic impairment (Child-Pugh class C): Not studied; no specific dosage recommendations at this time.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): No specific dosage adjustment has been established.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Tepotinib Hydrochloride

Contraindications

• None.

Warnings/Precautions

Interstitial Lung Disease/Pneumonitis

Tepotinib can cause potentially fatal interstitial lung disease or pneumonitis. Discontinuance of tepotinib therapy was necessary because of interstitial lung disease or pneumonitis in 1% of patients receiving the drug.

Monitor patients receiving tepotinib for new or worsening pulmonary symptoms (e.g., dyspnea, cough, or fever). Tepotinib therapy should be withheld immediately in patients with suspected interstitial lung disease or pneumonitis. If no other etiology is identified, permanently discontinue tepotinib therapy.

Hepatotoxicity

Drug-induced hepatotoxicity reported, sometimes fatal. Median time to onset of grade 3 or greater elevations in ALT or AST concentrations is 47 days.

Monitor liver function tests (i.e., ALT, AST, total bilirubin concentrations) prior to initiating tepotinib therapy, every 2 weeks during the first 3 months of therapy, monthly thereafter or as clinically indicated. More frequent testing is necessary in patients who develop aminotransferase or bilirubin elevations during therapy. If hepatotoxicity occurs, temporary interruption, dosage reduction, or discontinuation of tepotinib may be necessary.

Pancreatic Toxicity

Elevations in amylase and lipase reported. Monitor amylase and lipase levels at baseline and periodically during treatment. Dependent upon severity, temporary interruption, dosage reduction, or discontinuation of tepotinib may be necessary.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.

Avoid pregnancy during tepotinib therapy. Verify pregnancy status in females of reproductive potential. Females of reproductive potential should use effective contraceptive methods while receiving the drug and for 1 week after the last dose; male partners of such females also should use effective contraceptive methods during therapy and for 1 week after the last dose. If the drug is used during pregnancy or if the patient or their partner becomes pregnant during therapy, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status before starting tepotinib in females of reproductive potential.

Lactation

Not known whether tepotinib or its major metabolite M506 are distributed into human milk, affects breast-fed infants, or affects milk production. Females should not breast-feed during therapy and for 1 week after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential. Females of reproductive potential should use effective contraceptive methods while receiving the drug and for 1 week after the last dose; male partners of such females also should use effective contraceptive methods during therapy and for 1 week after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In the principal efficacy study evaluating tepotinib in patients with metastatic NSCLC, 79% of patients were ≥65 years of age and 41% were ≥75 years of age. No overall differences in safety or efficacy in patients ≥65 years of age compared with younger adults.

Hepatic Impairment

Pharmacokinetics not substantially altered by mild to moderate hepatic impairment; no dosage adjustment required.

Not studied in severe hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered by mild to moderate renal impairment; no dosage adjustment required.

Not studied in severe renal impairment.

Common Adverse Effects

Advanced or metastatic NSCLC with MET exon 14 skipping alteration (≥20%): Edema, fatigue, nausea, diarrhea, musculoskeletal pain, decreased appetite, rash, dyspnea.

Grade 3 or 4 laboratory abnormalities (≥2%): Decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased lipase, increased AST, decreased hemoglobin.

Median increase in S_cr concentration of 30% reported 21 days following initiation of tepotinib therapy and remained elevated until discontinuance of therapy.

Drug Interactions

Metabolized mainly by CYP3A4 and CYP2C8.

In vitro, tepotinib and its major metabolite (M506) do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP2E1 and do not induce CYP1A2 or CYP2B6 at clinically relevant concentrations. Physiologically based pharmacokinetic modeling suggests tepotinib does not result in clinically important inhibition of CYP2C9.

In vitro, tepotinib and M506 do not inhibit UDP-glucuronosyltransferase (UGT) 1A1, 1A9, 2B17, 1A3/4/6, or 2B7/15 at clinically relevant concentrations.

In vitro, tepotinib is a substrate and inhibitor of P-gp and may inhibit intestinal breast cancer resistance protein (BCRP). Does not inhibit bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1 or 1B3, or organic anion transporter (OAT) 1 or 3.

Drugs Affecting Hepatic Microsomal Enzymes

No clinically significant differences in the pharmacokinetics of tepotinib were observed when coadministered with a strong CYP3A and P-gp inhibitor or strong CYP3A inducer.

Drugs Affecting or Affected by Transport Systems

Substrates of P-gp: Possible increased plasma concentrations of the P-gp substrate and possible adverse events. Avoid concomitant use of tepotinib with P-gp substrates that have a narrow therapeutic index. If coadministration cannot be avoided, clinicians should consult the manufacturer's labeling of the P-gp substrate for dosage adjustment recommendations.

Drugs Affecting Gastric Acidity

No clinically important changes in tepotinib pharmacokinetics with concomitant use of a proton-pump inhibitor.

Specific Drugs

Tepotinib Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations attained in approximately 8 hours in the fed state.

Estimated absorption of a single 450-mg dose is >70% in fed state.

Systemic exposure increases in a dose-proportional manner over dosage range of 27–450 mg daily.

Food

High-fat, high calorie meal increased tepotinib AUC and peak plasma concentration by 1.6- and 2-fold, respectively; administer tepotinib with food.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) does not affect pharmacokinetics.

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics not studied.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute) does not affect pharmacokinetics.

Severe renal impairment (Cl_cr <30 mL/minute): Pharmacokinetics not studied.

Age, sex, race, and body weight do not affect pharmacokinetics.

Distribution

Extent

Crosses the blood-brain barrier.

Not known whether distributed into human milk.

Plasma Protein Binding

98%; independent of drug concentration.

Elimination

Metabolism

Metabolized mainly by CYP3A4 and CYP2C8 to major circulating metabolite M506.

Elimination Route

Eliminated in feces (85%) and urine (13.6%); unchanged drug accounted for 45% of dose recovered in feces and 7% of dose recovered in urine.

Major circulating metabolite M506 accounts for approximately 40% of the dose found in plasma.

Half-life

32 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30ºC). Dispense in original package.

Actions

• Selective type 1b inhibitor of mesenchymal-epithelial transition (MET) receptor tyrosine kinase.

• Inhibits off-target receptors melatonin 2 and imidazoline 1.

• Activation of MET tyrosine kinase, occurring through overexpression, MET amplification, or MET exon 14 skipping mutation, is thought to initiate a cascade of intracellular signaling events leading to cell proliferation and processes critical to cell survival and tumor progression (e.g., angiogenesis, apoptosis, metastasis).

• MET exon 14 skipping alterations identified in approximately 2–4% of patients with NSCLC.

• Inhibits MET phosphorylation caused by binding of hepatocyte growth factor or by MET amplification, resulting in downregulation or downstream MET signaling proteins and inhibition of proliferation and survival or MET-dependent tumor cells.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients that a missed dose of tepotinib 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, advise patients to take the next dose at the scheduled time.

• Advise patients who have difficulty swallowing solids that a dispersion of tepotinib tablets may be administered in order to deliver the full dose.

• Inform patients of the risk of severe or fatal interstitial lung disease/pneumonitis. 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.

• Inform patients that pancreatic function will be monitored during therapy. Advise patients to immediately contact their healthcare provider for signs and symptoms of pancreatitis.

• Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for one week after the final dose of tepotinib.

• Advise women not to breast-feed during treatment with tepotinib and for one week after the final dose.

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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