lenvatinib (Rx)

>10%

Percentages are for all grades of adverse effects unless otherwise noted

Hypertension (73%)

Diarrhea (67%)

Fatigue (67%)

Arthralgia/myalgia (62%)

Decreased appetite (54%)

Weight decreased (51%)

Nausea (47%)

Hypertension, grades 3-4 (44%)

Stomatitis (41%)

Headache (38%)

Vomiting (36%)

Proteinuria (34%)

Palmar-plantar erythrodysesthesia (32%)

Abdominal pain (31%)

Dysphonia (31%)

Constipation (29%)

Oral pain (25%)

Cough (24%)

Peripheral edema (21%)

Rash (21%)

Dysgeusia (18%)

Dry mouth (17%)

Dizziness (15%)

Dyspepsia (13%)

Alopecia (12%)

Epistaxis (12%)

Insomnia (12%)

Urinary tract infection (11%)

1-10%

Percentages are for all grades of adverse effects unless otherwise noted

Dental infections (10%)

Hypotension (9%)

Diarrhea, grades 3-4 (9%)

Dehydration (9%)

Prolonged QT interval (9%)

Hypocalcemia (9%)

Decreased appetite, grades 3-4 (7%)

Hyperkeratosis (7%)

Hypokalemia (6%)

AST increased (5%)

ALT increased (4%)

Lipase increased (4%)

Creatinine increased (3%)

Nausea, grades 3-4 (2%)

Platelet count decreased (2%)

Postmarketing Reports

Pancreatitis

Amylase increased

Cholecystitis

Impaired wound healing

Fistula

Aortic dissection

Nephrotic syndrome

Contraindications

None

Cautions

NOTE: Please refer to Dose Section (Dosage Modifications) for information on withholding and/or reducing dose, and for information regarding discontinuing the drug

Hypertension reported in 73% of lenvatinib-treated patients in clinical trials (grade 3 hypertension was 44%); control blood pressure prior to treatment; monitor blood pressure after 1 week, then q2weeks for the first 2 months, and then at least monthly thereafter; withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue therapy based on severity

Serious complications of poorly controlled hypertension reported

Cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of treated patients; monitor for clinical symptoms or signs of cardiac decompensation; monitor patients for clinical symptoms or signs of cardiac dysfunction; withhold and resume at a reduced dose upon recovery or permanently discontinue therapy based on severity

Arterial thromboembolic events reported in 5% of treated patients; discontinue drug following a thromboembolic event; permanently discontinue therapy following an arterial thrombotic event (see Dosage Modifications)

Serious hepatic adverse reactions reported; 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 therapy based on severity; increased ALT and/or AST observed; rare reports of hepatic failure, including fatalities, were also reported

Proteinuria reported in 34% of lenvatinib-treated patients in clinical trials (grade 3 proteinuria was 11%); monitor for proteinuria before initiation of, and periodically throughout, 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 therapy on severity

Serious including fatal renal failure or impairment can occur with therapy; initiate prompt management of diarrhea or dehydration/hypovolemia; withhold and resume at a reduced dose upon recovery or permanently discontinue therapy for renal failure or impairment based on severity; renal failure and impairment reported in 14% (grade ≥3 [3%]); the primary risk factor for severe renal impairment was dehydration/hypovolemia due to diarrhea and vomiting; initiate active management of diarrhea and any other gastrointestinal symptoms Grade 1 events

Diarrhea may occur; initiate prompt medical management for diarrhea; monitor for dehydration; interrupt therapy for Grade 3 or 4 diarrhea; for Grade 3 diarrhea, resume at reduced dose when diarrhea resolves to Grade 1 or baseline; permanently discontinue therapy for Grade 4 diarrhea despite medical management; withhold and resume at a reduced dose upon recovery or permanently discontinue therapy

Gastrointestinal (GI) perforation or fistula reported (2%); discontinue if patient develops a GI perforation or life-threatening fistula; permanently discontinue therapy in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula

QT prolongation reported (9%); monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including class Ia and III antiarrhythmics; monitor and correct electrolyte abnormalities in all patients; monitor electrocardiograms in patients with congenital long QT syndrome; congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong QT interval, including Class Ia and III antiarrhythmics; withhold therapy for development of QTc interval prolongation >500 ms; resume therapy at reduced dose when QTc prolongation resolves to baseline

Hypocalcemia reported (Grade ≥3 [9%]); monitor blood calcium levels at least monthly and replace calcium as necessary during treatment; withhold and resume at reduced dose upon recovery or permanently discontinue therapy depending on severity

Reversible posterior leukoencephalopathy syndrome (RPLS) reported rarely; confirm diagnosis of RPLS with magnetic resonance imaging; withhold and resume at a reduced dose upon recovery or permanently discontinue therapy depending on severity and persistence of neurologic symptoms

Hemorrhagic events occurred in 35% of treated patients; consider 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 therapy based on the severity

Impairs exogenous thyroid suppression; monitor TSH levels monthly and adjust thyroid replacement medication as needed; monitor thyroid function prior to initiating therapy and at least monthly during treatment; treat hypothyroidism according to standard medical practice

Based on its mechanism of action and data from animal reproduction studies, lenvatinib can cause fetal harm when administered to a pregnant woman (see Pregnancy)

Wound healing complications, including fistula formation and wound dehiscence, can occur; withhold lenvatinib for at least 6 days prior to scheduled surgery; resumed treatment after surgery based on clinical judgment of adequate wound healing; permanently discontinue drug in patients with wound healing complications

Drug interactions overview

• Avoid coadministration of lenvatinib with drugs known to prolong QT/QTc interval

Pregnancy

Based on its mechanism of action and data from animal reproduction studies, lenvatinib can cause fetal harm when administered to a pregnant woman; verify the pregnancy status of females of reproductive potential prior to initiating

In animal reproduction studies, oral administration during organogenesis at doses below the recommended human dose (approximately 0.14 times the recommended human dose based on body surface area) resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits

There are no available human data informing the drug-associated risk

Advise pregnant women of the potential risk to a fetus

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after last dose

Infertility

• Females: May result in reduced fertility in females of reproductive potential
• Males: May result in damage to male reproductive tissues, leading to reduced fertility of unknown duration

Lactation

Unknown if distributed in human breast milk; because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose

Lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma (~2 times higher [based on AUC]) in milk compared with maternal plasma

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4)

Also inhibits other RTKs 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; the platelet-derived growth factor receptor alpha (PDGFR-alpha), KIT, and RET

Absorption

Peak plasma time: 1-4 hr after PO administration

Administration with food does not affect the extent of absorption but can delay the mean peak plasma time from 2 hr to 4 hr

Distribution

Protein bound: 98-99%

Substrate of P-gp and BCRP

Metabolism

Metabolized by the CYP3A enzymes and aldehyde oxidase

Elimination

Half-life: 28 hr

Excretion (10 days after single dose): 64% feces; 25% urine

Oral Administration

Swallow capsule whole

May take with or without food

Take at the same time each day

Missed dose: If a dose is missed and cannot be taken within 12 hr, skip that dose and take the next dose at the usual time of administration

If unable to swallow capsule

• Capsules can be dissolved in a small glass of liquid
• Measure 1 tablespoon of water or apple juice and put the capsules into the liquid without breaking or crushing them
• Leave the capsules in the liquid for at least 10 minutes
• Stir for at least 3 minutes, and then drink the mixture
• After drinking, add the same amount (1 tablespoon) of water or apple juice to the glass; swirl the contents a few times and swallow the additional liquid

Storage

Store at room temperature, between 68-77°F (20-25°C)