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. |
| Molecular Weight | 426.85 |
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 | Avoid. Lenvatinib is teratogenic in animals; human data limited but contraindicated due to risk of fetal harm. |
| 2nd trimester | Avoid. Potential for fetal nephrotoxicity and other adverse effects; no safe dose established. |
| 3rd trimester | Avoid. Risk of fetal hemorrhage, impaired renal function, and potential for labor complications. |
Clinical note
Comprehensive clinical and safety monograph for LENVATINIB (LENVATINIB).
| Placental transfer | Expected to cross placenta based on molecular weight and animal studies demonstrating fetal exposure. |
| Breastfeeding | Excreted in animal milk; human data absent. Discontinue breastfeeding due to potential serious adverse reactions in nursing infants. |
| Lactation Rating |
■ 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 |
PregnancyBreastfeeding
| 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. |
Loading safety data…
| L5 (Contraindicated) |
| 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. |
| 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. |
| Food/Dietary | Lenvatinib can be taken with or without food. Avoid grapefruit and grapefruit juice as they may increase lenvatinib plasma concentrations via CYP3A4 inhibition. No other specific food restrictions. Ensure adequate hydration, especially if diarrhea occurs. |
| Clinical Pearls | Lenvatinib is a multikinase inhibitor targeting VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT. Monitor blood pressure closely; hypertension is a common adverse effect, often requiring antihypertensive therapy. Dose adjust for severe hepatic impairment (Child-Pugh B/C). Thyroid-stimulating hormone (TSH) levels should be monitored monthly due to risk of hypothyroidism. Lenvatinib has a long half-life (~28 hours); steady-state achieved in ~14 days. Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin) as they reduce exposure. For differentiated thyroid cancer, lenvatinib is indicated after radioactive iodine failure. In renal cell carcinoma, it is used in combination with everolimus after prior anti-angiogenic therapy. Hepatocellular carcinoma indication requires Child-Pugh A cirrhosis. |
| Patient Advice | Take lenvatinib exactly as prescribed, usually once daily with or without food. Swallow capsule whole; do not crush or open. · Do not skip doses or stop without your doctor's advice; dose adjustments may be needed for side effects. · Common side effects include high blood pressure, diarrhea, fatigue, decreased appetite, weight loss, nausea, and hand-foot skin reaction. Report severe symptoms. · Monitor your blood pressure at home and keep a log; report readings >140/90 mmHg immediately. · You may develop thyroid problems (hypothyroidism); you will need regular blood tests for thyroid function and may need thyroid hormone replacement. · Avoid grapefruit or grapefruit juice during treatment as it may increase side effects. · Tell your doctor about all medications you take, including over-the-counter drugs and supplements, especially St. John's wort, carbamazepine, phenytoin, rifampin, and HIV medications. · If you have diarrhea, drink plenty of fluids and consult your doctor if it persists or causes dehydration. · Women of childbearing age must use effective contraception during treatment and for at least 30 days after the last dose. Do not breastfeed during treatment. · May cause severe bleeding or perforation. Seek immediate medical help for: black/tarry stools, coughing up blood, unusual bruising, severe abdominal pain, or non-healing wounds. |