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. |
| Molecular Weight | 463.52 |
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 | There are no adequate and well-controlled studies in pregnant women. Based on its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. |
| 2nd trimester | There are no adequate and well-controlled studies in pregnant women. Based on its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. |
| 3rd trimester | There are no adequate and well-controlled studies in pregnant women. Based on its mechanism of action, TEPMETKO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. |
Clinical note
Comprehensive clinical and safety monograph for TEPMETKO (TEPMETKO).
| Placental transfer | Tepotinib is likely to cross the placenta based on its molecular weight (below 500 Da) and pharmacokinetic properties. However, specific data on placental transfer are not available. |
| Breastfeeding |
■ FDA Black Box Warning
None.
| Serious Effects |
None
| 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. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and may increase tepotinib levels. No other significant food interactions. TEPMETKO can be taken with or without food. |
| Clinical Pearls |
Loading safety data…
| There are no data on the presence of tepotinib in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with TEPMETKO and for at least 1 week after the last dose. |
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
| TEPMETKO (tepotinib) is a MET inhibitor indicated for metastatic NSCLC with METex14 skipping alterations. Monitor for hepatotoxicity, interstitial lung disease (ILD), and peripheral edema. Dose adjustments required for severe hepatic impairment (Child-Pugh C). Avoid concurrent use with strong CYP3A4 inducers (e.g., rifampin, phenytoin). |
| Patient Advice | Take TEPMETKO exactly as prescribed, with or without food. Swallow tablets whole; do not crush or chew. · Report new or worsening shortness of breath, cough, or fever immediately, as these may indicate ILD. · Watch for signs of liver injury: yellowing of skin/eyes, dark urine, nausea/vomiting, or right upper quadrant pain. · Notify your doctor if you experience significant swelling in legs or feet (peripheral edema). · Avoid grapefruit, grapefruit juice, and St. John's wort while on TEPMETKO due to potential interactions. · Inform all healthcare providers of your TEPMETKO use, especially before any new medications or surgeries. |