LENVATINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LENVATINIB (LENVATINIB).
Lenvatinib is a kinase inhibitor that inhibits the receptor tyrosine kinases (RTKs) including VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), FGFR1, FGFR2, FGFR3, FGFR4, PDGFRα, KIT, and RET. It also inhibits the kinase activities of other RTKs involved in tumor angiogenesis and tumor growth.
| Metabolism | Primarily metabolized by CYP3A4 and aldehyde oxidase (AO). Minor routes: CYP3A5, CYP2C9, CYP2C19, and CYP2D6. |
| Excretion | Fecal (approximately 64% of dose) and renal (approximately 25% of dose, with <2% as unchanged drug). |
| Half-life | Approximately 28 hours (range 22-35 hours); supports once-daily dosing with steady-state achieved in ~5-7 days. |
| Protein binding | 99.3% bound to plasma proteins (albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Approximately 4.2 L/kg (range 2.4-6.0 L/kg); suggests extensive tissue distribution. |
| Bioavailability | Approximately 85% after oral administration; absorption is not significantly affected by food. |
| Onset of Action | Clinical effect (e.g., tumor shrinkage) typically observed within weeks to months of continuous daily oral dosing; no rapid onset. |
| Duration of Action | Duration of therapeutic effect is continuous with daily dosing; elimination half-life of ~28 hours allows sustained exposure over 24-hour dosing interval. |
24 mg orally once daily for differentiated thyroid carcinoma; 8 mg twice daily or 12 mg once daily in combination with everolimus for renal cell carcinoma; 12 mg once daily in combination with pembrolizumab for advanced endometrial carcinoma.
| Dosage form | CAPSULE |
| Renal impairment | For CrCl ≥30 mL/min: no adjustment. For CrCl 15-29 mL/min: reduce dose by 50% (e.g., to 14 mg once daily for thyroid cancer). For CrCl <15 mL/min: not recommended due to lack of data. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce starting dose to 10 mg once daily for thyroid cancer; for other indications, reduce by 50%. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established; no approved pediatric dosing available. Clinical trial doses ranged from 8-24 mg/m² once daily based on body surface area, but not standard. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor renal function and manage dose according to renal and hepatic function; elderly patients may be more susceptible to adverse effects such as hypertension and fatigue. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LENVATINIB (LENVATINIB).
| Breastfeeding | No data on the presence of lenvatinib in human milk, its effects on the breastfed infant, or its effects on milk production. Due to the potential for serious adverse reactions in nursing infants from lenvatinib, breastfeeding is not recommended during treatment and for at least 1 month after the last dose. The M/P ratio is unknown. |
| Teratogenic Risk | Lenvatinib is embryotoxic and teratogenic in animals. In humans, based on its mechanism of action (VEGFR/FGFR/RET/PDGFR inhibition) and animal data, there is a potential risk of fetal harm if used during pregnancy. Specifically, there is a risk of major birth defects, including cardiovascular and skeletal malformations, and fetal loss. Use is contraindicated in pregnant women. Adequate contraception should be used during treatment and for at least 1 month after the last dose. |
■ FDA Black Box Warning
WARNING: HYPERTENSION, ARTERIAL THROMBOTIC EVENTS, HEPATOTOXICITY, HEMORRHAGE, PROTEINURIA, RENAL IMPAIRMENT AND FAILURE, CARDIAC DYSFUNCTION, and HYPOTHYROIDISM. Lenvatinib can cause severe and fatal hypertension, arterial thrombotic events (e.g., myocardial infarction, cerebrovascular accident), hepatotoxicity, hemorrhage, proteinuria, renal impairment and failure, cardiac dysfunction, and hypothyroidism.
| Serious Effects |
None.
| Precautions | ["Hypertension: Monitor blood pressure regularly; manage with antihypertensives; withhold or permanently discontinue for severe hypertension.","Arterial thrombotic events: Discontinue in patients who experience an arterial thrombotic event.","Hepatotoxicity: Monitor liver function; withhold or discontinue for severe hepatotoxicity.","Hemorrhage: Discontinue for severe bleeding.","Proteinuria: Monitor urine protein; withhold or discontinue for nephrotic syndrome or severe proteinuria.","Renal impairment: Monitor renal function; adjust dose for severe impairment.","Cardiac dysfunction: Monitor for signs of heart failure; discontinue for severe dysfunction.","Hypothyroidism: Monitor thyroid function before and during treatment; manage with thyroid hormone replacement.","Gastrointestinal perforation: Discontinue for perforation.","Fistula formation: Discontinue for fistula.","Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue if RPLS occurs.","QT interval prolongation: Monitor ECG in patients at risk; correct electrolyte abnormalities.","Diarrhea: Manage with antidiarrheals; interrupt or reduce dose for severe diarrhea.","Embryofetal toxicity: Can cause fetal harm; advise females of reproductive potential of potential risk and to use effective contraception."] |
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| Fetal Monitoring | Monitor pregnancy status in women of reproductive potential. Confirm negative pregnancy test before starting treatment. Monitor for signs of fetal distress using ultrasound if exposure occurs. Monitor maternal blood pressure (due to hypertension risk), liver and renal function, thyroid function, and cardiac function. Evaluate for proteinuria and bleeding. In case of inadvertent pregnancy, consider genetic counseling and serial ultrasounds for fetal anomalies. |
| Fertility Effects | Lenvatinib may impair fertility in both males and females. In animal studies, reduced fertility and implantations were observed. In humans, based on its antiangiogenic effects, it may affect ovarian function and spermatogenesis. Amenorrhea has been reported in women of reproductive potential. Effects may be reversible upon discontinuation. |