Dosing & Uses
Dosage Forms & Strengths
tablet
- 225mg
Non–Small Cell Lung Cancer
Indicated for metastatic non–small cell lung cancer (NSCLC) in adults harboring mesenchymal-epithelial transition (MET) exon 14 (ex14) skipping alterations
450 mg PO qDay
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Recommended dose reduction to manage adverse reactions: 225 mg PO qDay
Permanently discontinue if unable to tolerate 225 mg PO qDay
Interstitial lung disease (ILD)/ pneumonitis
- Suspected ILD (any grade): Withhold
- Confirmed ILD: Permanently discontinue
Increased AST/ALT and/or total bilirubin
-
Grade 3 increased AST/ALT without increased total bilirubin
- Withhold until recovery to baseline ALT/AST
- If recovered to baseline ≤7 days, resume at same dose; otherwise, resume at a reduced dose
-
Grade 3 increased total bilirubin without concurrent increased AST/ALT
- Withhold until recovery to baseline total bilirubin
- If recovered to baseline ≤7 days, resume at reduced dose; otherwise, permanently discontinue
-
Permanently discontinue
- Grade 4 increased ALT/AST without increased total bilirubin
- ALT/AST >3x ULN with total bilirubin >2x ULN without cholestasis or hemolysis
- Grade 4 increased total bilirubin without concurrent increased AST/ALT
Other adverse reactions
- Grade 2: Maintain dose; if intolerable, consider withholding until resolved, then resume at reduced dose
- Grade 3: Withhold until resolved, then resume at reduced dose
- Grade 4: Permanently discontinue
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): Recommended dose not established
Hepatic impairment
- Mild-to-moderate (Child-Pugh Class A or B): No dosage adjustment necessary
- Severe (Child-Pugh Class C): Pharmacokinetics and safety not studied
Dosing Considerations
Verify pregnancy status in females of reproductive potential before initiating
Patient selection
- Select patients for treatment based on presence of METex14 skipping alterations in tumor biopsy specimen or plasma (if tumor biopsy cannot be obtained)
- If alterations are undetected in plasma, re-evaluate the feasibility of tumor biopsy
- An FDA-approved test for detection of METex14 skipping alteration is not available
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
All grades
- Decreased albumin (76%)
- Edema (70%)
- Increased creatinine (55%)
- Increased alkaline phosphatase (50%)
- Decreased lymphocytes (48%)
- Increased ALT (44%)
- Increased AST (35%)
- Decreased sodium (31%)
- Fatigue (27%)
- Nausea (27%)
- Decreased hemoglobin (27%)
- Diarrhea (26%)
- Increased potassium (25%)
- Increased gamma-glutamyltransferase (24%)
- Musculoskeletal pain (24%)
- Increased amylase (23%)
- Decreased leukocytes (23%)
- Dyspnea (20%)
- Decreased appetite (16%)
- Cough (15%)
- Abdominal pain (16%)
- Constipation (16%)
- Vomiting (13%)
- Pleural effusion (13%)
- Pneumonia (11%)
Grade 3 to 4
- Decreased lymphocytes (11%)
1-10%
All grades
- ILD/pneumonitis (<10%)
- Rash (<10%)
- Fever (<10%)
- Dizziness (<10%)
- Pruritus (<10%)
- Headache (<10%)
Grade 3 to 4
- Decreased albumin (9%)
- Decreased sodium (8%)
- Pleural effusion (5%)
- Increased gamma-glutamyltransferase (5%)
- Increased amylase (4.6%)
- Increased ALT (4.1%)
- Pneumonia (3.9%)
- Increased AST (2.5%)
- Musculoskeletal pain (2.4%)
- Decreased hemoglobin (2%)
- Dyspnea (2%)
- Increased alkaline phosphatase (1.6%)
- Increased potassium (1.6%)
- Vomiting (1.2%)
- Decreased appetite (1.2%)
<1%
Grade 3 to 4
- Nausea (0.8%)
- Abdominal pain (0.8%)
- Decreased leukocytes (0.8%)
- Increased creatinine (0.4%)
- Diarrhea (0.4%)
- Cough (0.4%)
Warnings
Contraindications
None
Cautions
ILD/pneumonitis, which can be fatal, occurred; monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever)
Fetal harm may occur when administered to pregnant females
Hepatoxicity
- Hepatoxicity reported
- Median time to onset of Grade ≥3 was 30 days
- Monitor liver function tests (eg, AST, ALT, total bilirubin) before initiation, q2weeks during the first 3 months, then monthly or as clinically indicated
- More frequent testing if increased AST/ALT or bilirubin develops
Drug interaction overview
Inhibits P-gp; substrate of CYP3A4, CYP2C8, and P-gp
Effects of strong CYP3A4 or P-gp inhibitors and CYP3A4 inducers on tepotinib have not been studied clinically
-
Dual strong CYP3A4 and P-gp inhibitors
- Avoid coadministration
- Data suggest drugs that strongly inhibit both CYP3A4 and P-gp may increase tepotinib exposure and risk of toxicities
-
Strong CYP3A4 inducers
- Avoid coadministration
- Data suggest drugs that are strong CYP3A4 inducers may decrease exposure and efficacy of tepotinib
-
Certain P-gp substrates
- Avoid coadministration with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities
- Tepotinib may increases concentration levels and risk of toxicities of P-gp substrates
Pregnancy & Lactation
Pregnancy
Based on animal studies and mechanism of action, fetal harm may occur when administered to pregnant females
Data are unavailable on use in pregnant females
Verify pregnancy status in females of reproductive potential before initiation
Animal data
- Oral administration to pregnant rabbits during organogenesis resulted in malformation (teratogenicity) and anomalies at maternal exposures less than human exposure based on AUC at 450 mg daily
- Advise pregnant females of potential risk to fetus
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 1 week after final dose
- Male partners with female partners of reproductive potential: Use effective contraception during treatment and for 1 week after final dose
Lactation
There are no data regarding tepotinib or its metabolites in human milk, its effects on breastfed infants, or milk production
Advise females not to breastfeed during treatment and for 1 week after final dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
MET tyrosine kinase inhibitor
Selectively binds to MET tyrosine kinase and disrupts MET and hepatocyte growth factor (HGF)–dependent signal transduction pathways, which may induce apoptosis in tumor cells overexpressing this kinase
Absorption
Peak plasma concentration (steady-state): 1,291 ng/mL
Peak plasma time: 8 hr
AUC: 27,438 ng⋅hr/mL
Absolute bioavailability: 71.6%
Effect of food
- Mean AUC increased by 1.6-fold and peak plasma concentration increased by 2-fold following a high-fat, high-calories meal (~800-1,000 calories, 150 calories [protein], 250 calories [carbohydrates], and 500-600 calories [fat])
- Median peak plasma time shifted from 12 hr to 8 hr
Distribution
Vd: 1,038 L
Protein bound: 98%
Metabolism
Primarily metabolized by CYP3A4 and CYP2C8
Major metabolite: M506
Elimination
Clearance: 23.8 L/hr
Half-life: 32 hr
Excretion
- Tepotinib: Feces (45% unchanged); urine (13.6% [7% unchanged])
- M506 (metabolite): 40.4% in plasma
Administration
Oral Administration
Take at same time every day with food
Swallow tablets whole; do not chew, crush, or split
Missed dose
- ≥8 hr from next scheduled dose: Take as soon as possible
- <8 hr from next scheduled dose: Skip dose and take next dose at regular scheduled time
- Vomited dose: Skip dose and take next dose at regular scheduled time
Storage
Store at 20-25ºC (68-77ºF); excursion permitted to 15-30ºC (59-86ºF)
Store in original package
Images
Patient Handout
Formulary
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