Lenvatinib is a kinase inhibitor indicated for:

• Differentiated Thyroid Cancer: Lenvatinib is used for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
• Renal Cell Carcinoma: Lenvatinib, in combination with Everolimus, is indicated for patients with advanced renal cell carcinoma (RCC) after one prior anti-angiogenic therapy.
• Hepatocellular Carcinoma: Lenvatinib is indicated as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC).
• Endometrial Carcinoma: Lenvatinib, in combination with Pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have progressed after prior systemic therapy and are not eligible for curative surgery or radiation.

Lenvatinib is a kinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It also inhibits other kinases involved in tumor angiogenesis and progression, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFRα); KIT; and RET. Additionally, Lenvatinib has shown antiproliferative effects in hepatocellular carcinoma cell lines through inhibition of FGFR signaling and FRS2 phosphorylation.
 

Absorption: Peak plasma concentration (Tmax) is usually reached within 1 to 4 hours after dosing. A high-fat meal (about 900 calories with ~55% fat, 15% protein, and 30% carbohydrates) does not change the extent of absorption but reduces the absorption rate and delays Tmax from about 2 hours to 4 hours.
 

Distribution: In vitro studies show that Lenvatinib is highly bound (98%–99%) to human plasma proteins at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranges from 0.59 to 0.61.
 

Metabolism: Lenvatinib is metabolized through enzymatic pathways (CYP3A and aldehyde oxidase) as well as non-enzymatic processes. After administration of a radiolabeled dose, about 64% and 25% of the dose are excreted in feces and urine, respectively.
 

Elimination: The terminal elimination half-life of Lenvatinib is approximately 28 hours.

Important Dosage Information: The dose reduction is needed for certain patients with renal or hepatic impairment. Lenvatinib should be taken once daily, with or without food, at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dosage for Differentiated Thyroid Cancer (DTC): The recommended dosage of Lenvatinib is 24 mg orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Renal Cell Carcinoma (RCC): The recommended dosage of Lenvatinib is 18 mg in combination with 5 mg Everolimus orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma (HCC): The recommended dosage of Lenvatinib is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Lenvatinib should be taken orally once daily until disease progression or until unacceptable toxicity.

Recommended Dosage for Endometrial Carcinoma: The recommended dosage of Lenvatinib is 20 mg orally once daily, in combination with Pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Administration

Lenvatinib capsules may be taken whole or dissolved in a small amount of liquid. To dissolve, place the capsules in 1 tablespoon of water or apple juice without crushing or breaking them. Let them sit for at least 10 minutes, then stir for at least 3 minutes. After drinking, add another tablespoon of water or apple juice to the glass, swirl, and drink the remaining contents.

Drugs That Prolong the QT Interval: Lenvatinib may prolong the QT/QTc interval. Avoid coadministration with drugs known to prolong the QT/QTc interval.

It is contraindicated in patients with known hypersensitivity to Lenvatinib or any component of the formulation.

Hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure and impairment, proteinuria, diarrhea, fistula formation, gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, thyroid dysfunction (including suppression of thyroid stimulating hormone), and complications in wound healing have been reported.

Use in Pregnancy: Based on its mechanism of action, Lenvatinib may cause embryo-fetal harm when administered during pregnancy. Pregnant women should be informed about the potential risk to the fetus. Women of reproductive potential should use effective contraception during treatment and for at least 30 days after the last dose.

Use in Lactation: It is not known whether Lenvatinib is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment and for at least 1 week after the final dose.

Hypertension: Control blood pressure prior to starting Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and periodically thereafter. Withhold and resume at a reduced dose or permanently discontinue Lenvatinib based on severity.

Cardiac Dysfunction: Serious and potentially fatal cardiac dysfunction may occur. Monitor for signs or symptoms. Withhold and resume at a reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming treatment after such events has not been established.

Hepatotoxicity: Monitor liver function tests prior to initiation, every 2 weeks for the first 2 months, and periodically thereafter. In patients with HCC, monitor for signs of hepatic failure. Withhold and resume at a reduced dose upon recovery or discontinue permanently depending on severity.

Renal Failure or Impairment: Withhold and resume at a reduced dose upon recovery or discontinue permanently based on severity.

Proteinuria: Monitor for proteinuria before initiation and periodically during treatment. If ≥2+ proteinuria is detected, obtain a 24-hour urine protein test. Withhold and resume at a reduced dose upon recovery or discontinue permanently depending on severity.

Diarrhea: Diarrhea may occur frequently and can be severe. Promptly initiate management. Withhold and resume at a reduced dose upon recovery or discontinue permanently based on severity.

Fistula Formation and Gastrointestinal Perforation: Permanently discontinue Lenvatinib in patients who develop gastrointestinal perforation or any grade 3 or 4 fistula.

QT Interval Prolongation: Monitor ECG and electrolytes at baseline and periodically during treatment. Monitor closely in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those receiving QT-prolonging drugs. Withhold and resume at a reduced dose upon recovery or discontinue permanently depending on severity.

Hypocalcemia: Monitor and correct calcium levels as needed, with or without dose interruption or reduction.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold and resume at a reduced dose upon recovery or discontinue permanently depending on the severity and persistence of neurologic symptoms.

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage, including tumor invasion into major blood vessels. Withhold and resume at a reduced dose upon recovery or discontinue permanently based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction: Monitor thyroid function before initiation and at least monthly during treatment. Treat hypothyroidism according to standard practice.

Wound Healing Complications: Wound healing complications, including fistula formation and wound dehiscence, may occur. Withhold Lenvatinib at least 6 days prior to scheduled surgery. Resume after surgery based on adequate wound healing and clinical judgment. Permanently discontinue in patients with severe wound healing complications.

Dosage Modifications for Severe Renal Impairment: The recommended dose of Lenvatinib for patients with differentiated thyroid cancer (DTC), renal cell carcinoma (RCC), or endometrial carcinoma and severe renal impairment (creatinine clearance <30 mL/min using Cockcroft-Gault equation with actual body weight) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily

Dosage Modifications for Severe Hepatic Impairment: The recommended dose of Lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is:

• Differentiated thyroid cancer: 14 mg orally once daily
• Renal cell carcinoma: 10 mg orally once daily
• Endometrial carcinoma: 10 mg orally once daily or as directed by a registered physician

Pediatric Use: The safety and effectiveness of Lenvatinib in pediatric patients have not been established.

Due to high plasma protein binding, Lenvatinib is not expected to be removed by dialysis. A fatal case of multiorgan dysfunction has been reported following a single oral dose of 120 mg.

Cytotoxic Chemotherapy.

Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.