TEPMETKO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TEPMETKO (TEPMETKO).
Tepotinib is a highly selective, ATP-competitive inhibitor of the mesenchymal-epithelial transition (MET) receptor tyrosine kinase, including the MET exon 14 skipping variant. It inhibits MET phosphorylation and downstream signaling pathways, thereby reducing tumor cell proliferation and migration.
| Metabolism | Primarily metabolized by CYP3A4 (major) and CYP2C8 (minor). Tepotinib is also a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily fecal (≥80% of absorbed dose), with renal excretion accounting for <5% as unchanged drug. |
| Half-life | Terminal elimination half-life approximately 12-15 hours in patients, supporting twice-daily dosing. |
| Protein binding | ≥99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Steady-state volume of distribution ~100 L (approximately 1.4 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability approximately 70% under fasting conditions; absorption is reduced by high-fat meals. |
| Onset of Action | Time to clinical effect (tumor response) varies; median time to response ~2 months with continuous oral dosing. |
| Duration of Action | Duration of action is sustained with continuous dosing; clinical effect lasts as long as therapeutic plasma concentrations are maintained, with median progression-free survival ~9 months in METex14 NSCLC. |
450 mg orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min) or ESRD. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Not recommended for moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment as safety and efficacy not established. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no dosing recommendations available. |
| Geriatric use | No specific dose adjustment recommended. Clinical studies included patients ≥65 years; no overall differences in safety or efficacy observed. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TEPMETKO (TEPMETKO).
| Breastfeeding | There are no data on the presence of tepotinib or its metabolites in human milk, the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TEPMETKO and for 1 week after the last dose. M/P ratio unknown. |
| Teratogenic Risk | Based on its mechanism of action (MET inhibitor) and animal studies, TEPMETKO (tepotinib) is expected to cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, administration of tepotinib to pregnant rats during organogenesis resulted in embryofetal mortality, reduced fetal body weight, and fetal skeletal variations at maternal exposures below the human exposure at the recommended dose. Advise pregnant women of the potential risk to a fetus. First trimester: highest risk of major malformations; second and third trimesters: risk of fetotoxicity and impaired growth. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None known (no absolute contraindications listed). Use caution in severe hepatic impairment and with strong CYP3A4 inducers/inhibitors."]
| Precautions | ["Interstitial lung disease/pneumonitis: Monitor for pulmonary symptoms; discontinue if confirmed.","Hepatotoxicity: Monitor liver function tests; dose adjustment or discontinuation may be required.","Peripheral edema: Manage with standard interventions; severe cases may require dose modification.","Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception."] |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) prior to initiation, every 2 weeks during the first 3 months, then monthly or as clinically indicated. Monitor for interstitial lung disease/pneumonitis; suspend and evaluate if symptoms occur. Monitor renal function and electrolytes. Monitor for pleural effusion, peripheral edema, and other fluid retention events. In pregnant patients, perform fetal ultrasound to assess growth and amniotic fluid volume. |
| Fertility Effects | Based on animal studies, TEPMETKO may impair female fertility. In female rats, tepotinib caused disruption of estrous cycles and reduced fertility at exposures approximately 0.3 times the human exposure. No dedicated studies on male fertility; however, testicular toxicity was observed in animal studies (degeneration of seminiferous tubules). Advise patients of potential impact on fertility. |