Tepotinib: Drug information

(For additional information see "Tepotinib: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)

Brand Names: US

Tepmetko

Brand Names: Canada

Tepmetko

Pharmacologic Category

Antineoplastic Agent, MET Inhibitor;
Antineoplastic Agent, Tyrosine Kinase Inhibitor

Dosing: Adult

Note: Select patients for treatment based on the presence of mesenchymal-epithelial transition (MET) exon 14 skipping alterations in tumor specimen (preferred) or plasma.

Non–small cell lung cancer, metastatic

Non–small cell lung cancer, metastatic: Oral: 450 mg once daily until disease progression or unacceptable toxicity.

Missed dose: If a dose is missed, do not make it up if it is within 8 hours of the next scheduled dose. If vomiting occurs after administering a dose, administer the next dose at the scheduled time.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Kidney function estimated by Cockcroft-Gault equation.

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: There is no dosage adjustment provided in the manufacturer's labeling (has not been established).

Dosing: Hepatic Impairment: Adult

Hepatic impairment at treatment initiation:

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

Severe impairment (Child-Pugh class C): There is no dosage adjustment provided in the manufacturer's labeling (has not been established).

Hepatotoxicity during treatment:

The recommended tepotinib dose reduction for adverse reactions is 225 mg once daily.

**Recommended Tepotinib Dosage Modification for Hepatotoxicity**
Adverse reaction	Severity	Tepotinib dose modification
Increased ALT and/or AST without increased total bilirubin	Grade 3	Withhold tepotinib until recovery to baseline ALT and/or AST. If recovered to baseline within 7 days, then resume tepotinib at the same dose; otherwise resume tepotinib at a reduced dose.
	Grade 4	Permanently discontinue tepotinib.
Increased ALT and/or AST with increased total bilirubin (in the absence of cholestasis or hemolysis)	ALT and/or AST >3 times ULN with total bilirubin >2 times ULN	Permanently discontinue tepotinib.
Increased total bilirubin without concurrent increased ALT and/or AST	Grade 3	Withhold tepotinib until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume tepotinib at a reduced dose; otherwise permanently discontinue tepotinib.
	Grade 4	Permanently discontinue tepotinib.

Dosing: Adjustment for Toxicity: Adult

**Recommended Tepotinib Dosage Reduction Level**
Initial (usual) dose	450 mg once daily
First dose reduction level	225 mg once daily
Permanently discontinue tepotinib if unable to tolerate 225 mg once daily.

**Recommended Tepotinib Dosage Modification for Adverse Reactions**
Adverse reaction	Severity	Tepotinib dose modification
Interstitial lung disease (ILD)/pneumonitis	Any	Withhold tepotinib if ILD is suspected. Permanently discontinue tepotinib if ILD is confirmed.
Other adverse reactions	Grade 2	Maintain tepotinib dose level. If adverse reaction is intolerable, consider withholding tepotinib until adverse reaction is resolved, then resume tepotinib at a reduced dose.
	Grade 3	Withhold tepotinib until adverse reaction is resolved, then resume tepotinib at a reduced dose.
	Grade 4	Permanently discontinue tepotinib.

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions (Significant): Considerations

Hepatotoxicity

Hepatotoxicity, including increased serum alanine aminotransferase (ALT), and increased serum aspartate aminotransferase (AST), has commonly been reported (Ref). Hepatic failure has been reported rarely. Depending on severity, therapy interruption or dose modification may be warranted, including permanent drug discontinuation.

Onset: Varied; median time to onset of ≥ grade 3 elevated ALT/AST was 30 days (range: 1 to 178 days).

Peripheral edema

Peripheral edema is commonly observed, including ≥ grade 3 events. Depending on severity, therapy interruption or dose modification may be warranted, including permanent discontinuation (Ref).

Pulmonary toxicity

Interstitial pulmonary disease (ILD)/pneumonitis, potentially life-threatening, has occurred, including rare ≥ grade 3 events (Ref). Symptoms of ILD/pneumonitis typically present as cough, dyspnea, and fever; permanent discontinuation is warranted if ILD/pneumonitis is confirmed.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Cardiovascular: Edema (4% to 70%; including peripheral edema)

Endocrine & metabolic: Decreased serum albumin (76%), decreased serum sodium (31%), increased amylase (23%), increased gamma-glutamyl transferase (24%), increased serum potassium (25%)

Gastrointestinal: Abdominal pain (16%), constipation (16%), decreased appetite (16%), diarrhea (26%), increased serum lipase (18%), nausea (27%), vomiting (13%)

Hematologic & oncologic: Decreased hemoglobin (27%; grades 3/4: 2%), leukopenia (23%; grades 3/4: <1%), lymphocytopenia (48%; grades 3/4: 11%)

Hepatic: Increased serum alanine aminotransferase (44%), increased serum alkaline phosphatase (50%), increased serum aspartate aminotransferase (35%)

Nervous system: Fatigue (27%)

Neuromuscular & skeletal: Musculoskeletal pain (2% to 24%)

Renal: Increased serum creatinine (55%)

Respiratory: Cough (15%), dyspnea (4% to 20%), pleural effusion (7% to 13%), pneumonia (5% to 11%)

1% to 10%:

Cardiovascular: Pulmonary embolism (2%)

Dermatologic: Pruritus (<10%), skin rash (<10%)

Nervous system: Dizziness (<10%), headache (<10%)

Respiratory: Interstitial pulmonary disease (<10%), pneumonitis (<10%)

Miscellaneous: Fever (<10%), physical health deterioration (4%)

Frequency not defined: Hepatic: Hepatic failure

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to tepotinib or any component of the formulation.

Warnings/Precautions

Other warnings/precautions:

• Mesenchymal-epithelial transition (MET) alterations: Select patients for treatment based on the presence of MET exon 14 skipping alterations in plasma or tumor specimens. Tumor biopsy is preferred; plasma specimen is recommended only when tumor biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

Tepmetko: 225 mg

Generic Equivalent Available: US

Pricing: US

Tablets (Tepmetko Oral)

225 mg (per each): $488.46

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Tepmetko: 225 mg

Administration: Adult

Oral: Administer with food at approximately the same time each day. Swallow whole; do not chew, crush, or split the tablets. Tablets may be dispersed in a glass of noncarbonated water (30 mL); do not use other liquids. Stir without crushing until tablet is in small pieces (tablet will not completely dissolve). Administer immediately or within 1 hour; do not chew tablet pieces. Rinse glass with an additional 30 mL and drink immediately to ensure remaining residue and full dose is administered.

NG tube: Tablets may be dispersed in a glass of noncarbonated water (30 mL); do not use other liquids. Stir without crushing until tablet is in small pieces (tablet will not completely dissolve). Administer immediately or within 1 hour via NG tube (≥8 French gauge); immediately rinse twice with 30 mL each time to ensure remaining residue and full dose is administered.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Tepotinib may cause teratogenicity and reproductive toxicity.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Use: Labeled Indications

Non–small cell lung cancer, metastatic: Treatment of metastatic non–small cell lung cancer in adults harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

Medication Safety Issues

Sound-alike/look-alike issues:

Tepotinib may be confused with capmatinib, crizotinib, ertlotinib, nilotinib, talazoparib, tofacitinib, trametinib, tucatinib.

Tepmetko may be confused with Tabrecta.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) included among its lists of drug classes that have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of CYP3A4 (minor), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits P-glycoprotein/ABCB1

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification

Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Risk C: Monitor therapy

Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Risk X: Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of CYP3A4 inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: Consider therapy modification

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy

Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Risk D: Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Risk C: Monitor therapy

Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Risk C: Monitor therapy

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor therapy

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy

Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Risk C: Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider therapy modification

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy

Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Risk C: Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination

Pralsetinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider therapy modification

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: Monitor therapy

Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification

Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification

Repotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Repotrectinib. Risk X: Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification

RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy

RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy

Saquinavir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy

Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification

Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination

Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy

Tegaserod (Withdrawn from US Market): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod (Withdrawn from US Market). Risk C: Monitor therapy

Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Risk C: Monitor therapy

Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who may become pregnant. Patients who may become pregnant should use effective contraception during therapy and for at least 1 week after the last dose of tepotinib. Patients with partners who may become pregnant should also use effective contraception during therapy and for 1 week after the last tepotinib dose.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to tepotinib may cause fetal harm.

Breastfeeding Considerations

It is not known if tepotinib is present in breast milk.

Breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last tepotinib dose.

Monitoring Parameters

Mesenchymal-epithelial transition (MET) exon 14 skipping alterations status (in tumor specimen [preferred] or plasma). Monitor LFTs (ALT, AST, and total bilirubin) at baseline, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated; monitor more frequently if transaminases or bilirubin are elevated. Evaluate pregnancy status prior to use in patients who may become pregnant. Monitor for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis (eg, dyspnea, cough, fever). Monitor adherence.

The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Tepotinib is a receptor tyrosine kinase inhibitor that selectively targets mesenchymal-epithelial transition (MET), including the mutant variant produced by exon 14 skipping (Paik 2020). Tepotinib inhibits hepatocyte growth factor–dependent and –independent MET phosphorylation as well as MET-dependent downstream signaling pathways, which inhibits tumor cell proliferation, anchorage-independent growth, and metastases of MET-dependent tumor cells.

Pharmacokinetics (Adult Data Unless Noted)

Absorption: The tepotinib mean AUC_0-inf and C_max increased by 1.6-fold and by 2-fold, respectively, after administration of a high-fat, high-calorie meal (~800 to 1,000 calories; 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat).

Distribution: V_d: 1,038 L.

Protein binding: 98%.

Metabolism: Primarily via CYP3A4 and CYP2C8; M506 is the major circulating metabolite.

Bioavailability: 71.6% (in a fed state).

Half-life elimination: 32 hours.

Time to peak: Median: 8 hours (range: 6 to 12 hours).

Excretion: Feces: ~85% (45% as unchanged drug); urine: ~14% (7% as unchanged drug).

Clearance: 23.8 L/hour.

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AR) Argentina: Tepmetko;
(AT) Austria: Tepmetko;
(BE) Belgium: Tepmetko;
(BR) Brazil: Tepmetko;
(CH) Switzerland: Tepmetko;
(CZ) Czech Republic: Tepmetko;
(ES) Spain: Tepmetko;
(FI) Finland: Tepmetko;
(GB) United Kingdom: Tepmetko;
(HK) Hong Kong: Tepmetko;
(IE) Ireland: Tepmetko;
(NL) Netherlands: Tepmetko;
(NO) Norway: Tepmetko;
(PL) Poland: Tepmetko;
(PR) Puerto Rico: Tepmetko;
(PT) Portugal: Tepmetko;
(SE) Sweden: Tepmetko;
(SG) Singapore: Tepmetko;
(TW) Taiwan: Tepmetko

<800> Hazardous Drugs–Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.
Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407 [PubMed 32469185]
Tepmetko (tepotinib) [prescribing information]. Rockland, MA: EMD Serono Inc; March 2023.
Tepmetko (tepotinib) [product monograph]. Mississauga, Ontario, Canada: EMD Serono; May 2021.
US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html. Updated September 2016. Accessed February 5, 2021.

Topic 130698 Version 46.0

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Tepotinib: Drug information