Lenvacent

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.

Hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure and impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT Interval Prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, wound healing complications.

Due to the high plasma protein binding, Lenvatinib is not expected to be dialyzable. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvatinib 120 mg orally.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha (PDGFR ), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate 2 (FRS2 ) phosphorylation.

Absorption: The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with a high-fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

Distribution: In vitro binding of Lenvatinib to human plasma proteins ranged from 98% to 99% at concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

Metabolism: The main metabolic pathways for Lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. Excretion: Ten days after a single administration of radiolabeled Lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

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

Hypertension: Control blood pressure prior to initiating Lenvatinib. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue Lenvatinib is based on severity.

Cardiac Dysfunction: Serious and fatal cardiac dysfunction can occur with Lenvatinib. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Arterial Thromboembolic Events: Permanently discontinue Lenvatinib following an arterial thrombotic event. The safety of resuming Lenvatinib after an arterial thromboembolic event has not been established and Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity: Monitor liver function prior to initiating Lenvatinib, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

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

Proteinuria: Monitor for proteinuria prior to initiating Lenvatinib and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

Diarrhea: Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue Lenvatinib based on severity.

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

QT Interval Prolongation: Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at a reduced dose of Lenvatinib upon recovery based on severity.

Hypocalcemia: Hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction.

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

Hemorrhagic Events: Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue Lenvatinib based on the severity.

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

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