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Lenvatinib

Pronunciation

(len VA ti nib)

Index Terms

  • E7080
  • Lenvatinib Mesylate
  • Lenvima

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Therapy Pack, Oral:

Lenvima 10 MG Daily Dose: 10 mg (30 ea)

Lenvima 14 MG Daily Dose: 10 mg & 4 mg (60 ea)

Lenvima 18 MG Daily Dose: 10 mg & 2x4 mg (15 ea, 90 ea)

Lenvima 20 MG Daily Dose: 2x10 mg (60 ea)

Lenvima 24 MG Daily Dose: 2x10 mg & 4 mg (90 ea)

Lenvima 8 MG Daily Dose: 2x4 mg (10 ea, 60 ea)

Brand Names: U.S.

  • Lenvima 10 MG Daily Dose
  • Lenvima 14 MG Daily Dose
  • Lenvima 18 MG Daily Dose
  • Lenvima 20 MG Daily Dose
  • Lenvima 24 MG Daily Dose
  • Lenvima 8 MG Daily Dose

Pharmacologic Category

  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Lenvatinib is a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Inhibition of these receptor tyrosine kinases leads to decreased tumor growth and slowing of cancer progression. Combining lenvatinib with everolimus has demonstrated increased antiangiogenic and antitumor activity by decreasing human endothelial cell proliferation, tube formation, and VEGF signaling (in vitro) compared to either drug alone.

Metabolism

Primarily enzymatic through CYP3A and aldehyde oxidase; nonenzymatic metabolism also occurs

Excretion

Feces (~64%); urine (~25%)

Time to Peak

1 to 4 hours

Half-Life Elimination

~28 hours

Protein Binding

98% to 99%

Special Populations: Hepatic Function Impairment

In a single dose study of lenvatinib in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, the dose-adjusted AUC of lenvatinib was 119%, 107%, and 180%, respectively, as compared to patients with normal hepatic function.

Use: Labeled Indications

Renal cell carcinoma, advanced: Treatment of advanced renal cell carcinoma (in combination with everolimus) following one prior anti-angiogenic therapy.

Thyroid cancer, differentiated: Treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Note: Lenvatinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Renal cell carcinoma, advanced: Oral: 18 mg once daily (in combination with everolimus), continue until disease progression or unacceptable toxicity (Motzer 2015)

Thyroid cancer, differentiated: Oral: 24 mg once daily until disease progression or unacceptable toxicity (Schlumberger 2015)

Missed doses: Do not take a missed dose within 12 hours of the next dose (if within 12 hours, skip the missed dose and return to regular administration time).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Preexisting renal impairment:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute:

Renal cell cancer, advanced: 10 mg once daily

Thyroid cancer, differentiated: 14 mg once daily

End-stage renal disease (ESRD): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hemodialysis: Lenvatinib is not expected to be dialyzable (due to high protein binding).

Renal toxicity during treatment: Interrupt therapy or discontinue if grade 3 or 4 renal failure or impairment develops. Consider resuming at a reduced dose if resolves to ≤ grade 1 or baseline (depending on severity and persistence of toxicity).

Dosing: Hepatic Impairment

Preexisting hepatic impairment:

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C):

Renal cell cancer, advanced: 10 mg once daily

Thyroid cancer, differentiated: 14 mg once daily

Hepatotoxicity during treatment: Interrupt therapy if grade 3 or 4 hepatotoxicity develops. When improved to ≤ grade 1 or baseline, may either resume at a reduced dose or discontinue, depending on severity and persistence of toxicity. Discontinue for hepatic failure; do not resume.

Dosing: Adjustment for Toxicity

Recommended dose modifications for persistent and intolerable grade 2 or grade 3 adverse reactions or grade 4 laboratory abnormalities:

Renal cell cancer, advanced:

First occurrence: Interrupt therapy until resolved to ≤ grade 1 or baseline, then resume dosing at 14 mg once daily

Second occurrence (same or different toxicity): Interrupt therapy until resolved to ≤ grade 1 or baseline, then resume dosing at 10 mg once daily.

Third occurrence (same or different toxicity): Interrupt therapy until resolved to ≤ grade 1 or baseline, then resume dosing at 8 mg once daily.

Note: For toxicities related only to everolimus, reduce frequency to every other day or interrupt or discontinue everolimus (refer to everolimus monograph for dosage adjustment for toxicity). For toxicities related to both lenvatinib and everolimus, first reduce lenvatinib, and then everolimus.

Thyroid cancer, differentiated:

First occurrence: Interrupt therapy until resolved to ≤ grade 1 or baseline, then resume dosing at 20 mg once daily

Second occurrence (same or different toxicity): Interrupt therapy until resolved to ≤ grade 1 or baseline, then resume dosing at 14 mg once daily

Third occurrence (same or different toxicity): Interrupt therapy until resolved to ≤ grade 1 or baseline, then resume dosing at 10 mg once daily

Note: There are currently no recommendations for resuming therapy in patients who experience grade 4 clinical adverse reactions that resolve.

Arterial thrombotic event: Discontinue therapy; do not resume.

Cardiac:

Cardiac dysfunction: Temporarily interrupt therapy for a grade 3 event until improved to ≤ grade 1 or baseline; depending on severity and persistence of toxicity, may either resume therapy at a reduced dose or discontinue treatment. Discontinue for a grade 4 event; do not resume.

Hypertension: Monitor blood pressure prior to and throughout therapy; initiate or adjust antihypertensive medication to control blood pressure. Temporarily interrupt therapy for grade 3 hypertension that persists despite optimal medical management. When hypertension is ≤ grade 2, resume therapy at a reduced dose. Discontinue therapy for life-threatening hypertension; do not resume.

QT prolongation: Temporarily interrupt therapy for ≥ grade 3 QT prolongation (>500 msec). When improved to ≤ grade 1 (<480 msec) or baseline, resume therapy at a reduced dose.

Gastrointestinal toxicity:

Nausea, vomiting, or diarrhea:

Grade 3: Initiate prompt medical management prior to interrupting therapy (or reducing dose) until resolves to ≤ grade 1 or baseline; then resume (may require dose reduction).

Grade 4 vomiting or diarrhea despite optimal medical management: Discontinue therapy; do not resume.

Perforation (any grade) or fistula formation (grade 3 or 4; life-threatening): Discontinue therapy; do not resume.

Hemorrhage: Temporarily interrupt therapy for a grade 3 event until improved to ≤ grade 1 or baseline; depending on severity and persistence of toxicity, may either resume therapy at a reduced dose or discontinue treatment. Discontinue for a grade 4 event; do not resume.

Hypocalcemia: Administer calcium replacement therapy as necessary; may require treatment interruption or dose reduction depending on the severity, presence of ECG changes, and persistence of hypocalcemia.

Nephrotic syndrome: Discontinue therapy; do not resume.

Proteinuria: Temporarily interrupt therapy for ≥2 g proteinuria/24 hours; resume therapy at a reduced dose when improved to <2 g proteinuria/24 hours.

Reversible posterior leukoencephalopathy syndrome (RPLS): Interrupt or discontinue therapy until fully resolved; consider resuming at a reduced dose if resolves to ≤ grade 1, depending on severity and persistence of neurologic symptoms.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH, 2014).

An oral solution may be prepared in a glass. Measure 15 mL of water or apple juice into a glass; add whole capsule and leave in liquid for at least 10 minutes, then stir for at least 3 minutes. Administer liquid, then add 15 mL of additional water or apple juice to glass, swirl a few times and then swallow additional liquid.

Lenvima (lenvatinib) [prescribing information]. Woodcliff Lake, NJ: Eisai Inc.; May 2016.

Administration

Lenvatinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting.

Oral: Administer orally at the same time each day (administer lenvatinib and everolimus at the same time each day when used for the treatment of renal cell cancer). May be administered without regards to meals.

Capsules should be swallowed whole, however, if unable to swallow whole, the capsules may be dissolved in a small glass of liquid. Measure 15 mL of water or apple juice into a glass; add whole capsule and leave in liquid for at least 10 minutes, then stir for at least 3 minutes. Administer liquid, then add 15 mL of additional water or apple juice to glass, swirl a few times and then swallow additional liquid.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single-gloving for administration of an intact capsule. If it is necessary to prepare an oral solution, NIOSH recommends to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (73%; grades 3/4: ≤44%), peripheral edema (21%; grades 3/4: <1%)

Central nervous system: Fatigue (67%; grades 3/4: 11%), headache (38%; grades 3/4: 3%), voice disorder (31%; grades 3/4: 1%), mouth pain (25%; grades 3/4: 1%), dizziness (15%; grades 3/4: <1%), insomnia (12%)

Dermatologic: Palmar-plantar erythrodysesthesia (32%; grades 3/4: 3%), skin rash (21%; grades 3/4: <1%), alopecia (12%)

Endocrine & metabolic: Increased thyroid stimulating hormone level (57%), weight loss (51%; grades 3/4: 13%)

Gastrointestinal: Diarrhea (67%; grades 3/4: 9%), decreased appetite (54%; grades 3/4: 7%), nausea (47%; grades 3/4: 2%), stomatitis (41%; grades 3/4: 5%), vomiting (36%; grades 3/4: 2%), abdominal pain (31%; grades 3/4: 2%), constipation (29%), dysgeusia (18%), xerostomia (17%; grades 3/4: <1%), dyspepsia (13%; grades 3/4: <1%), infection of mouth (10%; grades 3/4: 1%)

Genitourinary: Proteinuria (34%; grade 3: 11%), urinary tract infection (11%; grades 3/4: 1%)

Hematologic & oncologic: Hemorrhage (35%; grades ≥3: 2%)

Neuromuscular & skeletal: Arthralgia (≤62%; grades 3/4: ≤5%), myalgia (≤62%; grades 3/4: ≤5%)

Renal: Renal insufficiency (14%; grade 3 or higher: 3%)

Respiratory: Cough (24%), epistaxis (12%)

1% to 10%:

Cardiovascular: Hypotension (9%; grades 3/4: 2%), prolonged Q-T interval on ECG (9%; grades 3/4: 2%), thromboembolic complications (5%; grade 3 or higher: 3%; arterial events), pulmonary embolism (3%), reduced ejection fraction (2%; ejection fraction reduced by >20%)

Dermatologic: Hyperkeratosis (7%)

Endocrine & metabolic: Dehydration (9%; grades 3/4: 2%), hypocalcemia (grades 3/4: 9%), hypokalemia (grades 3/4: 6%), hypercalcemia (>5%), hypercholesterolemia (>5%), hyperkalemia (>5%), hypoalbuminemia (>5%), hypoglycemia (>5%), hypomagnesemia (>5%)

Gastrointestinal: Increased serum amylase (>5%), increased serum lipase (grades 3/4: 4%), gastrointestinal fistula (2%)

Hematologic & oncologic: Decreased platelet count (grades 3/4: 2%)

Hepatic: Hyperbilirubinemia (>5%), increased serum alkaline phosphatase (>5%), increased serum AST (grades 3 or higher: 5%), increased serum ALT (grades 3 or higher: 4%)

Renal: Increased serum creatinine (grades 3/4: 3%)

Respiratory: Pulmonary edema (7%; grade 3 or higher: 2%)

<1% (Limited to important or life-threatening): Reversible posterior leukoencephalopathy syndrome, tumor hemorrhage

Warnings/Precautions

Concerns related to adverse effects:

• Cardiac effects: Hypertension, including grade 3 and 4 toxicity, occurred in patients treated with lenvatinib in clinical trials; the median time to onset of new or worsening hypertension was 16 to 35 days. Blood pressure should be controlled prior to initiating therapy; monitor frequently throughout treatment. Other cardiac events, such as decreased left or right ventricular function, decreased ejection fraction (EF), cardiac failure, or pulmonary edema, were also reported, including grades 2, 3, and 4 events. In patients with thyroid cancer, decreased ejection fraction was the most commonly reported of these events; some patients experienced greater than 20% EF reduction. Monitor for signs/symptoms of cardiac decompensation. QT/QTc prolongation was also observed in lenvatinib-treated patients, including prolongation >500 msec and increases >60 msec from baseline. Monitor and correct electrolyte abnormalities in all patients; obtain electrocardiograms in patients with congenital long QT syndrome, heart failure, bradyarrhythmias, or in those on concomitant medications known to prolong the QT interval. Cardiac effects may require therapy interruption, dosage reduction, or discontinuation.

• Endocrine effects: Lenvatinib impairs exogenous thyroid suppression. In patients with differentiated thyroid cancer and a normal thyroid stimulating hormone (TSH) level at baseline, TSH elevations were observed in over half of lenvatinib-treated patients. Grades 1 and 2 hypothyroidism occurred in renal cell cancer patients receiving lenvatinib and everolimus; TSH elevations occurred in over half of in patients with a normal or low TSH at baseline. Monitor TSH levels at baseline and at least monthly; adjust thyroid hormone therapy or manage hypothyroidism as clinically necessary.

• Gastrointestinal perforation/fistula: Gastrointestinal perforation, fistula formation, or abscess were reported in a small percentage of patients in clinical trials. Discontinue use in patients who develop perforation or life-threatening fistula.

• Gastrointestinal toxicity: Lenvatinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting. Nausea, vomiting, and diarrhea were commonly observed. Initiate appropriate management prior to therapy interruption or dosage reduction; initiate active management of diarrhea and other gastrointestinal symptoms for grade 1 or higher events. Monitor closely for dehydration; dehydration or hypovolemia due to diarrhea and vomiting are risk factors for renal toxicity. Diarrhea may require treatment interruption, dose reduction, and or discontinuation. The incidence of diarrhea is higher in when lenvatinib is used in combination with everolimus; recurrent diarrhea occurred despite dose reduction. Diarrhea was the most common reason for dose reduction or treatment interruption in patients with renal cell cancer.

• Hemorrhage: Hemorrhagic events (most frequently epistaxis) occurred in over one-third of lenvatinib-treated patients. Serious tumor-related bleeding events (including cases of fatal hemorrhage) have been observed in clinical trials and postmarketing surveillance. Serious and fatal carotid artery hemorrhages were reported more frequently in patients with anaplastic thyroid carcinoma (ATC) than with other tumor types. Safety and efficacy of lenvatinib have not been established in the treatment of ATC. Consider the risk of hemorrhage associated with tumor infiltration/invasion into major blood vessels. Monitor for bleeding; may require therapy interruption, dosage reduction, or discontinuation.

• Hepatotoxicity: Elevations in transaminases (including grade 3 or greater events) were observed. There have been case reports of hepatic failure (some fatal) and acute hepatitis with single-agent lenvatinib. Monitor liver function tests at baseline and throughout therapy. May require therapy interruption, dosage reduction, or discontinuation. If hepatic failure occurs, discontinue treatment.

• Hypocalcemia: An increased incidence of hypocalcemia (including grade 3 events) was observed in lenvatinib-treated patients compared to the control group in clinical trials. Calcium replacement therapy and dosage interruption or reduction generally corrected hypocalcemia. Monitor serum calcium levels at least monthly; replace calcium as necessary. May require therapy interruption or dosage reduction.

• Palmar-plantar erythrodysesthesia: Palmar-plantar erythrodysesthesia (usually grades 1 to 2) was observed in nearly one-third of patients receiving lenvatinib.

• Renal toxicity: Proteinuria (including grade 3 toxicity) was commonly observed. Monitor for proteinuria at baseline and periodically throughout therapy. If urine dipstick for proteinuria is 2+, obtain a 24-hour urine protein. Withhold treatment for proteinuria ≥2 g/24 hours; resume at a reduced dose when proteinuria is <2 g/24 hours. Discontinue for nephrotic syndrome. Renal impairment may also occur (may be grade 3 or higher); a primary risk factor for severe renal impairment is dehydration or hypovolemia due to diarrhea and vomiting. Monitor renal function throughout treatment; may require therapy interruption, dosage reduction, or discontinuation.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred (rarely). If RPLS diagnosis is confirmed through MRI, interrupt treatment until fully resolved. Therapy may resume at a reduced dose or be discontinued, depending on the severity and persistence of neurologic symptoms.

• Thromboembolic events: Arterial thromboembolic events, including grade 3 or greater events, have been reported. Discontinue treatment if arterial thrombosis occurs; the safety of resuming therapy after such an event has not been established. Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the preceding 6 months.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

Liver function tests (at baseline, every 2 weeks for 2 months, and at least monthly thereafter); renal function; electrolytes; serum calcium at least monthly; TSH levels at baseline and monthly or as clinically indicated; monitor for proteinuria at baseline and periodically during treatment (urine dipstick; if 2+ then 24-hour urine protein); monitor blood pressure after 1 week, then every 2 weeks for 2 months, and at least monthly thereafter; electrocardiogram in select patients; monitor for signs/symptoms of cardiac decompensation, arterial thrombosis, reversible posterior leukoencephalopathy syndrome, signs/symptoms of gastrointestinal perforation/fistula, and hemorrhagic events

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, lenvatinib may cause fetal harm if administered in pregnancy. Females of reproductive potential should use effective contraception during lenvatinib treatment and for at least 2 weeks after completion of therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience change in taste, cough, constipation, lack of appetite, dry mouth, hair loss, heartburn, mouth pain, mouth sores, muscle pain, joint pain, nausea, vomiting, loss of strength and energy, insomnia, change in voice, or weight loss. Have patient report immediately to prescriber signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a heart attack (angina; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe bleeding or persistent bleeding), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, tachycardia, more thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), severe headache, signs of a low thyroid level (constipation; difficulty handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), severe diarrhea, vision changes, severe dizziness, passing out, tachycardia, abnormal heartbeat, redness or irritation of palms or soles of feet, severe abdominal pain, shortness of breath, excessive weight gain, swelling of arms or legs (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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