Dosing and uses of Lenvima (lenvatinib)
Adult dosage forms and strengths
capsule
- 4mg
- 10mg
Thyroid Cancer (DTC)
Indicated for locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC
24 mg (two 10 mg capsules and one 4 mg capsule) PO qDay
Renal Cell Carcinoma (RCC)
Indicated in combination with everolimus for advanced RCC following 1 prior anti-angiogenic therapy
18 mg (one 10 mg capsule and two 4 mg capsules) plus everolimus 5 mg PO qDay
Continue until disease progression or until unacceptable toxicity
Dosage modifications
DTC dose reductions
- DTC dose reductions
- Interrupt until resolved to grade 0-1 or baseline
- Adjusted dose: 20 mg PO qDay
- Second occurrence
- Interrupt until resolved to grade 0-1 or baseline
- Adjusted dose: 14 mg PO qDay
- Third occurrence
- Interrupt until resolved to grade 0-1 or baseline
- Adjusted dose: 10 mg PO qDay
RCC dose reductions
- First occurrence
- Interrupt until resolved to grade 0-1 or baseline
- Adjusted dose: 14 mg PO qDay
- Second occurrence
- Interrupt until resolved to grade 0-1 or baseline
- Adjusted dose: 10 mg PO qDay
- Third occurrence
- Interrupt until resolved to grade 0-1 or baseline
- Adjusted dose: 8 mg PO qDay
- Dose modification of everolimus in RCC
- For toxicities thought to be related to everolimus alone, discontinue, interrupt, or use alternate day dosing
- For toxicities thought to be related to both lenvatinib and everolimus, first reduce lenvatinib and then everolimus
- Severe renal or hepatic impairment in RCC
- CrCl <30 mL/min or Child-Pugh C: 10 mg PO qDay
Hypertension or cardiac dysfunction
- Grade 3: Hold drug; may resume at reduced dose after resolution of adverse effects to grades 0, 1, or 2
- Grade 4: Discontinue, do not resume
Arterial thrombotic event
- Any grade: Discontinue, do not resume
Hepatic impairment
- Hepatotoxicity grade 3 or 4: Hold or discontinue; consider resuming at reduced dose if resolves to grade 0, 1, or baseline
- Hepatic failure grade 3 or 4: Discontinue, do not resume
Proteinuria
- ≥2 g/24 hr: Hold dose; may resume at reduced dose after resolution to <2 g/24 hr
Nephrotic syndrome
- Discontinue; do not resume
GI toxicity
- Nausea, vomiting, and diarrhea grade 3: Hold; may resume at reduced dose after resolution to grade 0, 1, or baseline
- Vomiting and diarrhea grade 4: Discontinue, do not resume
- GI perforation, any grade: Discontinue, do not resume
- GI fistula grade 3 or 4: Discontinue, do not resume
Renal failure or impairment
- Grade 3 or 4: Hold or discontinue; consider resuming at reduced dose if resolves to grade 0, 1, or baseline
QTc prolongation
- >500 ms: Hold; may resume at reduced dose after resolution to <480 ms or baseline
Reversible posterior leukoencephalopathy syndrome (RPLS)
- Any grade: Hold or discontinue; consider resuming at reduced dose if resolves to grade 0 to 1
Hemorrhage
- Grade 3: Hold; may resume at reduced dose after resolution to grade 0 to 1
- Grade 4: Discontinue, do not resume
Pediatric dosage forms and strengths
Safety and efficacy not established
Lenvima (lenvatinib) adverse (side) effects
>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%)
Warnings
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
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
Arterial thromboembolic events reported in 5% of treated patients; discontinue drug following a thromboembolic event (see Dosage modifications)
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
Renal failure and impairment reported in 14% (3% ≥grade 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
Gastrointestinal (GI) perforation or fistula reported (2%); discontinue if patient develops a GI perforation or life-threatening 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 (9% ≥grade 3); monitor blood calcium levels at least monthly and replace calcium as necessary during treatment
Reversible posterior leukoencephalopathy syndrome (RPLS) reported rarely
Hemorrhagic events occurred in 35% of treated patients
Impairs exogenous thyroid suppression; monitor TSH levels monthly and adjust thyroid replacement medication as needed
Based on its mechanism of action and data from animal reproduction studies, lenvatinib can cause fetal harm when administered to a pregnant woman
Pregnancy and lactation
Pregnancy
Based on its mechanism of action and data from animal reproduction studies, lenvatinib can cause fetal harm when administered to a pregnant woman
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 2 weeks following completion of therapy
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; advise women to discontinue breastfeeding during treatment because of the potential for serious adverse reactions in nursing infants
Lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma (approximately 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.
Pharmacology of Lenvima (lenvatinib)
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
Orally administered
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
Administration
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
