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Lenvatinib

Class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- VEGF Receptor Inhibitors
- VEGFR Inhibitors
- Vascular Endothelial Growth Factor Receptor Inhibitors
VA Class: AN900
Chemical Name: 4-[3-Chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-6-quinolinecarboxamide
Molecular Formula: C21H19ClN4O4C21H19ClN4O4•CH4O3S
CAS Number: 417716-92-8
Brands: Lenvima

Medically reviewed by Drugs.com on Dec 13, 2021. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.

Uses for Lenvatinib

Differentiated Thyroid Cancer

Treatment of locally recurrent or metastatic, progressive, radioactive iodine (iodine-131)-refractory differentiated thyroid cancer (designated an orphan drug by FDA for this cancer).

Renal Cell Carcinoma

In combination with pembrolizumab for initial treatment of advanced renal cell carcinoma.

In combination with everolimus for the treatment of advanced renal cell carcinoma following therapy with an anti-angiogenic agent.

Some experts recommend combination regimens with certain immune checkpoint inhibitors and tyrosine kinase inhibitors (e.g., lenvatinib and pembrolizumab, nivolumab and cabozantinib, pembrolizumab and axitinib) for the treatment of clear-cell metastatic renal cell carcinoma (RCC) in patients who are treatment-naive.

Some experts state that subsequent monotherapy with a tyrosine kinase inhibitor may be offered to patients who experience a treatment-limiting immune-mediated adverse effect following combination therapy with an immune checkpoint inhibitor.

Hepatocellular Carcinoma

First-line treatment for unresectable hepatocellular carcinoma (designated an orphan drug by FDA for this cancer).

American Society of Clinical Oncology (ASCO) guideline on systemic therapy for advanced hepatocellular carcinoma states that lenvatinib may be offered as first-line therapy for patients with advanced hepatocellular carcinoma, Child-Pugh class A, and an ECOG performance status of 0 or 1 if therapy with atezolizumab and/or bevacizumab is contraindicated.

ASCO also states that tyrosine kinase inhibitors (i.e., cabozantinib, lenvatinib, regorafenib, sorafenib) may be used as second-line therapy following therapy with atezolizumab in combination with bevacizumab.

Endometrial Carcinoma

In combination with pembrolizumab for the treatment of advanced endometrial carcinoma without microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) that progressed following prior systemic therapy in patients who are not candidates for curative surgery or radiation.

Lenvatinib Dosage and Administration

General

Pretreatment Screening

  • BP; control BP prior to initiating therapy.

  • Proteinuria on urine dipstick.

  • Thyroid function prior to initiating therapy.

  • Liver function prior to initiating therapy.

  • Serum electrolytes; correct electrolyte abnormalities prior to initiating therapy.

  • Oral examination.

  • Pregnancy test in females of reproductive potential.

Patient Monitoring

  • Monitor BP following 1 week of therapy, every 2 weeks for the first 2 months of therapy, and then at least monthly thereafter.

  • Monitor liver function every 2 weeks for the first 2 months, and at least monthly thereafter during treatment.

  • Monitor for proteinuria with dipstick urinalysis periodically during therapy.

  • Monitor patients for clinical symptoms or signs of cardiac dysfunction.

  • Monitor ECGs in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval.

  • Monitor serum calcium concentrations at least monthly during therapy.

  • Monitor thyroid function at least monthly during therapy.

  • Assess serum electrolytes periodically during therapy.

  • Oral examination periodically during therapy.

  • In patients with hepatocellular carcinoma (HCC): Closely monitor for signs of hepatic failure, including hepatic encephalopathy.

Other General Considerations

  • Clinicians should consult published protocols for information on the dosage, method of administration, and administration sequence of other antineoplastic agents used in combination regimens with lenvatinib.

  • Withhold therapy for at least 1 week prior to elective surgery. Do not administer for ≥2 weeks following major surgery and until adequate wound healing has occurred.

Administration

Oral Administration

Administer orally once daily without regard to meals. Take at the same time each day.

If lenvatinib capsules cannot be swallowed whole, dissolve intact capsule in 1 tablespoon of water or apple juice in a small glass; do not break or crush the capsule. Allow the capsule to sit in the liquid for ≥10 minutes, and then stir for ≥3 minutes. After the mixture has been consumed, add 1 tablespoon of water or apple juice to the glass and swallow the rinse to ensure that the entire dose is consumed.

If a dose of lenvatinib is missed, do not take the missed dose within 12 hours of the next dose.

If lenvatinib is used immediately following sorafenib or other antineoplastic agents, potential risk for additive toxicities unless there is an adequate washout period between treatments. In clinical trials, the minimum washout period was 4 weeks.

Dosage

Available as lenvatinib mesylate; dosage expressed in terms of lenvatinib.

Adults

Differentiated Thyroid Cancer
Oral

24 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Renal Cell Carcinoma
First-line treatment of Advanced Renal Cell Carcinoma
Oral

20 mg once daily in combination with pembrolizumab 200 mg by IV infusion over 30 minutes every 3 weeks.

Continue lenvatinib in combination with pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity occurs. Following completion of 2 years of combination therapy, may continue lenvatinib as a single agent until disease progression or unacceptable toxicity occurs.

Consult prescribing information for pembrolizumab for detailed information on dosage modifications for this drug. If adverse effects occur, modify the dosage of lenvatinib and/or pembrolizumab as appropriate.

Previously Treated Advanced Renal Cell Carcinoma
Oral

18 mg once daily in combination with everolimus 5 mg orally once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Consult prescribing information for everolimus for detailed information on dosage modifications for this drug. If adverse effects associated with both lenvatinib and everolimus occur during combination therapy, withhold lenvatinib therapy or reduce the dosage of lenvatinib first, and then reduce the dosage of everolimus.

Hepatocellular Carcinoma
Oral

Dosage based on actual body weight.

In patients weighing ≥60 kg: 12 mg once daily.

In patients weighing <60 kg: 8 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Endometrial Carcinoma
Oral

20 mg once daily in combination with pembrolizumab 200 mg by IV infusion over 30 minutes every 3 weeks.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

If adverse effects occur during lenvatinib therapy, temporarily interrupt therapy, reduce dosage, and/or permanently discontinue drug. If dosage modification is required, reduce lenvatinib dosage as described in Table 1 in patients with differentiated thyroid cancer, renal cell carcinoma, or endometrial carcinoma and in Table 2 in patients with hepatocellular carcinoma.

Table 1. Recommended Dosage Reduction for Lenvatinib Toxicity in Patients with Differentiated Thyroid Cancer, Renal Cell Carcinoma, or Endometrial Carcinoma.1

Dosage Reduction Level

Differentiated Thyroid Cancer

(Starting Dosage = 24 mg daily)

Renal Cell Carcinoma

(Starting Dosage = 20 mg daily in combination with pembrolizumab or 18 mg in combination with everolimus)

Endometrial Carcinoma

(Starting Dosage = 20 mg daily)

First

Restart at 20 mg once daily

Restart at 14 mg once daily

Restart at 14 mg once daily

Second

Restart at 14 mg once daily

Restart at 10 mg once daily

Restart at 10 mg once daily

Third

Restart at 10 mg once daily

Restart at 8 mg once daily

Restart at 8 mg once daily

Table 2. Recommended Dosage Reduction for Lenvatinib Toxicity in Patients with Hepatocellular Carcinoma.1

Dosage Reduction Level

Patients Weighing ≥60 kg

(Starting Dosage = 12 mg daily)

Patients Weighing <60 kg

(Starting Dosage = 8 mg daily)

First

Restart at 8 mg once daily

Restart at 4 mg once daily

Second

Restart at 4 mg once daily

Restart at 4 mg every other day

Third

Restart at 4 mg every other day

Discontinue therapy

Temporarily interrupt therapy, reduce dosage, and/or permanently discontinue lenvatinib therapy in patients experiencing certain adverse effects (see Table 3).

Table 3. Recommended Dosage Modification for Lenvatinib Toxicity.1

Adverse Reaction and Severity

Modification

Hypertension

Grade 3 (despite optimal antihypertensive therapy)

Withhold therapy; when toxicity improves to ≤ grade 2, resume at reduced dosage (see Table 1)

Grade 4

Permanently discontinue therapy

Cardiac Dysfunction

Grade 3

Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of the toxicity

Grade 4

Permanently discontinue therapy

Arterial Thromboembolic Events

Any grade

Permanently discontinue therapy

Hepatotoxicity

Grade 3 or 4

Withhold therapy; when toxicity until resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of hepatotoxicity

Hepatic Failure

Permanently discontinue therapy

Nephrotoxicity

Grade 3 or 4 (including renal failure)

Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of renal impairment

Proteinuria

≥2 g proteinuria per 24 hours

Withhold therapy; when proteinuria improves to ≤2 g per 24 hours, resume at reduced dosage (see Table 1)

Nephrotic syndrome

Permanently discontinue therapy

GI Perforation

Any grade

Permanently discontinue therapy

Fistula Formation

Grade 3 or 4

Permanently discontinue therapy

QT Prolongation

>500 msec or >60 msec increase from baseline

Withhold therapy; when toxicity resolves or improves to ≤480 msec, resume at a reduced dosage (see Table 1)

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Any grade

Withhold therapy; when RPLS fully resolves, resume at reduced dosage (see Table 1) or discontinue therapy depending on severity and persistence of neurologic symptoms

Other Adverse Effects

Grade 2 or 3 (persistent or intolerable)

Withhold therapy; when toxicity resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1)

Grade 4 adverse effect

Permanently discontinue therapy

Grade 4 laboratory abnormality

Withhold therapy; when the laboratory abnormality resolves or improves to grade 0 or 1, resume at reduced dosage (see Table 1)

Special Populations

Hepatic Impairment

Pre-existing mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.

Pre-existing moderate hepatic impairment (Child-Pugh class B): No specific dosage recommendations.

Pre-existing severe hepatic impairment (Child-Pugh class C): Reduce dosage as described in Table 4.

Table 4. Recommended Dosage Modifications for Pre-existing Severe Hepatic Impairment.1

Indication

Reduced Initial Dosage

Differentiated thyroid cancer

14 mg once daily

Renal cell carcinoma

10 mg once daily

Endometrial carcinoma

10 mg once daily

Hepatocellular carcinoma

No specific recommendations

Renal Impairment

Pre-existing mild or moderate renal impairment (Clcr 30–89 mL/minute): No dosage adjustment required.

End-stage renal disease: Not studied; no specific dosage recommendations.

Pre-existing severe renal impairment (Clcr <30 mL/minute): Reduce dosage as described in Table 5.

Table 5. Recommended Dosage Modifications for Pre-existing Severe Renal Impairment.1

Indication

Reduced Initial Dosage

Differentiated thyroid cancer

14 mg once daily

Renal cell carcinoma

10 mg once daily

Endometrial carcinoma

10 mg once daily

Hepatocellular carcinoma

No specific recommendations

Geriatric Patients

No specific dosage recommendations.

Cautions for Lenvatinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Hypertension

Hypertension, mostly of grade 3 severity, occurs frequently in lenvatinib-treated patients. Usually develops early during therapy; median time to onset of new or worsening hypertension ranges from 16–35 days following initiation of therapy.

Assess and control BP prior to initiating and during lenvatinib therapy. Monitor BP following 1 week of therapy, every 2 weeks for the first 2 months, and then at least monthly thereafter. Manage hypertension medically (i.e., with antihypertensive therapy) as needed during therapy. Withhold and resume lenvatinib at a reduced dosage when BP is controlled or permanently discontinue, depending upon severity.

Cardiac Dysfunction

Lenvatinib may cause serious and fatal cardiac dysfunction. In clinical trials, grade 3 or higher cardiac dysfunction (i.e., cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, ventricular hypokinesia, decrease in left or right ventricular ejection fraction of >20% from baseline) occurred in 3% of lenvatinib-treated patients.

Monitor for clinical manifestations of cardiac dysfunction. Withhold therapy and resume at a reduced dosage upon recovery or permanently discontinue, depending upon severity.

Arterial Thromboembolic Events

Arterial thromboembolic events reported in lenvatinib-treated patients.

Permanently discontinue lenvatinib if an arterial thromboembolic event occurs. Safety of resuming lenvatinib following such an event not established. Not evaluated in patients who had an arterial thromboembolic event within the previous 6 months.

Hepatic Toxicity

Serious hepatic adverse effects, sometimes fatal, reported rarely (1.4%) in lenvatinib-treated patients with malignancies other than hepatocellular carcinoma.

Perform liver function tests prior to initiation of therapy, every 2 weeks for the first 2 months of therapy, and then at least monthly thereafter during therapy.

Closely monitor patients with hepatocellular carcinoma for signs of hepatic failure. Withhold therapy and resume at a reduced dosage upon recovery or permanently discontinue, depending upon severity.

Proteinuria

Proteinuria reported. Usually occurs early during therapy.

Monitor for proteinuria prior to initiation of lenvatinib and periodically during therapy. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold therapy and resume at a reduced dosage upon recovery or permanently discontinue, depending upon severity.

Renal Failure and Impairment

Renal impairment, sometimes severe, and renal failure reported.

Promptly manage diarrhea or dehydration/hypovolemia. Withhold therapy and resume at a reduced dosage upon recovery or permanently discontinue, depending upon severity.

Diarrhea

Diarrhea occurs frequently. Diarrhea is the most frequent cause of dose interruption or reduction. Diarrhea has recurred despite dosage reduction.

Promptly manage diarrhea. Withhold therapy and resume at a reduced dosage upon recovery or permanently discontinue, depending upon severity.

GI Perforation and Fistula Formation

GI perforation and fistula formation reported in patients receiving lenvatinib or other tyrosine kinase inhibitors.

Permanently discontinue lenvatinib if GI perforation of any severity or grade 3 or 4 fistula occurs.

Prolongation of QT Interval

Prolongation of QT interval reported.

Monitor serum electrolyte concentrations (i.e., potassium, magnesium, calcium) at baseline and periodically during therapy in all patients; correct any electrolyte abnormalities.

Monitor ECGs in patients with congenital long QT syndrome, CHF, or bradyarrhythmias, and in those receiving other drugs known to prolong the QT interval.

If QT-interval prolongation occurs, temporary interruption of therapy followed by dosage reduction may be necessary.

Hypocalcemia

Hypocalcemia requiring calcium replacement and temporary interruption of therapy and dosage reduction reported.

Monitor blood calcium concentrations at least monthly during therapy; replace calcium as necessary.

If hypocalcemia occurs, interrupt therapy and then reduce dosage or discontinue therapy depending on the presence of ECG changes and severity and persistence of the hypocalcemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS reported in 3 lenvatinib-treated patients (0.3%) in clinical trials. RPLS is a neurologic disorder that may manifest with severe headache, seizures, weakness, confusion, blindness, or other visual disturbances; hypertension also may be present. Magnetic resonance imaging (MRI) is necessary to confirm diagnosis.

If RPLS occurs, interrupt therapy until fully resolved. Upon resolution, may resume therapy at a reduced dosage or discontinue therapy, depending on the severity and persistence of the neurologic manifestations.

Hemorrhage

Hemorrhagic events, most commonly epistaxis, reported in 35% of lenvatinib-treated patients in the SELECT, REFLECT, and Study 205 trials. Fatal hemorrhagic events reported. In postmarketing surveillance, serious and fatal carotid artery hemorrhagic events occurred more frequently in patients with anaplastic thyroid carcinoma than in other tumor types. Safety and efficacy of lenvatinib in patients with anaplastic thyroid carcinoma not established.

Consider the risk of severe or fatal hemorrhagic events associated with tumor invasion or infiltration of major blood vessels during lenvatinib therapy. Withhold therapy and resume at a reduced dosage upon recovery or permanently discontinue, depending upon severity.

Impairment of Thyroid-stimulating Hormone Suppression

Lenvatinib impairs exogenous thyroid suppression.

An increase in TSH levels from normal or low at baseline was observed in 70% and 60% of lenvatinib-treated patients in REFLECT and Study 205.

Monitor thyroid function prior to initiation and at least monthly during therapy; adjust or treat with thyroid replacement therapy as needed.

Impaired Wound Healing

May impair wound healing.

Withhold therapy for at least 1 week prior to an elective surgery and do not administer for at least 2 weeks following major surgery and until adequate wound healing occurs.

Safety of resuming lenvatinib therapy after resolution of wound healing complications not established.

Osteonecrosis of the Jaw

May cause osteonecrosis of the jaw. Risk increases with concomitant exposure to other risk factors (e.g., bisphosphonate or denosumab therapy, dental disease, or invasive dental procedures).

Perform an oral examination prior to, and periodically during, therapy. Avoid invasive dental procedures, particularly in patients at higher risk for osteonecrosis of the jaw, during lenvatinib therapy, if possible. Withhold therapy for at least 1 week before a scheduled dental surgery or invasive dental procedure, if possible. In patients receiving concomitant bisphosphonate therapy, discontinue bisphosphonate therapy. Withhold therapy if osteonecrosis of the jaw occurs and resume based on clinical judgment of adequate resolution.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.

Avoid pregnancy during therapy. Females of reproductive potential should use an effective method of contraception while receiving lenvatinib and for 30 days after discontinuance of therapy. If used during pregnancy or if patient becomes pregnant while receiving the drug, apprise patients of potential fetal hazard.

Impairment of Fertility

Results of animal studies suggest that lenvatinib may impair male and female fertility. Effect on fertility in humans not known.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether lenvatinib is distributed into human milk; lenvatinib and its metabolites are distributed into milk in rats. Discontinue breast-feeding during therapy and for ≥1 week after the last dose.

Pediatric Use

Safety and efficacy not established.

Growth retardation (decreased weight gain, food consumption, and femur and tibia width and/or length), secondary delays in physical development, and reproductive organ immaturity observed in juvenile rats receiving daily oral administration of lenvatinib for 8 weeks.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.

Hepatic Impairment

Pre-existing mild or moderate hepatic impairment did not substantially affect systemic exposure of lenvatinib in patients with differentiated thyroid cancer, renal cell carcinoma, or endometrial carcinoma; dosage reduction not necessary. In patients with HCC and pre-existing mild hepatic impairment, dosage reduction not necessary; however, manufacturer makes no specific recommendations for patients with HCC and pre-existing moderate hepatic impairment.

Increased systemic exposure in patients with pre-existing severe hepatic impairment in patients with differentiated thyroid cancer, renal cell carcinoma, or endometrial carcinoma; dosage reduction recommended. No specific dosage recommendation for patients with HCC and pre-existing severe hepatic impairment.

Renal Impairment

Pre-existing mild or moderate renal impairment did not substantially affect systemic exposure of lenvatinib; dosage adjustment not necessary.

Increased systemic exposure in patients with pre-existing severe renal impairment; dosage reduction recommended in patients with differentiated thyroid cancer, renal cell carcinoma, or endometrial carcinoma. No specific dosage recommendation for patients with HCC and pre-existing severe renal impairment.

Not studied in patients with end-stage renal disease.

Common Adverse Effects

Adverse effects reported in ≥30% of patients receiving lenvatinib for the treatment of differentiated thyroid cancer include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite and weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia.

Adverse effects reported in ≥20% of patients receiving lenvatinib in combination with pembrolizumab for the treatment of renal cell carcinoma include fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, decreased weight, dysphonia, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, hemorrhagic events, vomiting, constipation, hepatotoxicity, headache, and acute kidney injury.

Adverse effects reported in ≥30% of patients receiving lenvatinib in combination with everolimus for the treatment of renal cell carcinoma include diarrhea, fatigue, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, decreased weight, hemorrhagic events, and proteinuria.

Adverse effects reported in ≥20% of patients receiving lenvatinib for the treatment of hepatocellular carcinoma include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite and weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.

Adverse effects reported in ≥20% of patients receiving lenvatinib for the treatment of endometrial carcinoma include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite and weight, vomiting, stomatitis, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia syndrome, dysphonia, and rash.

Interactions for Lenvatinib

Metabolized principally by CYP3A4.

Inhibits CYP isoenzymes 2C8, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A and also UGT 1A1, 1A4, and 1A9. Does not inhibit CYP isoenzymes 2A6 or 2E1 and also does not inhibit UGT1A6 or 2B7, or aldehyde oxidase.

Induces CYP3A; does not induce CYP isoenzymes 1A1, 1A2, 2B6, or 2C9, and UGT 1A1, 1A4, 1A6, 1A9, or 2B7.

In vitro, substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate for organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transport protein (OATP)1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, MATE2-K, or the bile salt export pump (BSEP). Does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo.

Drugs Affecting Hepatic Microsomal Enzymes and/or Efflux Transport Systems

CYP3A, P-gp, and BCRP inhibitors: Clinically important pharmacokinetic interactions unlikely.

CYP3A and P-gp inducers: Clinically important pharmacokinetic interactions unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Clinically important pharmacokinetic interactions not expected.

Substrates of CYP2C8: Clinically important pharmacokinetic interactions not expected.

Drugs that Prolong QT Interval

Potential pharmacologic interactions (additive effect on QT-interval prolongation). Avoid concurrent administration of lenvatinib with medicinal products that are known to prolong the QT/QTc interval. Monitor ECGs during concomitant use; also monitor for and correct any electrolyte abnormalities at baseline and periodically during treatment.

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmic agents, class IA (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol)

Possible additive effect on QT-interval prolongation

Periodically monitor ECGs; monitor for and correct electrolyte abnormalities at baseline and periodically during treatment

Ketoconazole

Ketoconazole increased peak concentrations and AUC of lenvatinib by 19 and 15%, respectively

Midazolam

Clinically important pharmacokinetic interaction unlikely

Repaglinide

Clinically important pharmacokinetic interaction unlikely

Rifampin

Rifampin (single dose) increased peak concentrations and AUC of lenvatinib by 33 and 31%, respectively

When administered once daily for 21 days with a single lenvatinib dose on day 15, rifampin decreased AUC of lenvatinib by 18%; peak plasma concentrations were unchanged

Lenvatinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations usually attained within 1–4 hours.

Systemic exposure and peak plasma concentrations appear to increase in a proportional manner following single or repeated administration of lenvatinib 3.2–32 mg once daily.

Food

Food decreases rate (time to peak concentration delayed by 2 hours) but does not substantially affect extent of absorption.

Special Populations

End-stage renal disease: Pharmacokinetics not studied.

Mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment: Dose-adjusted total exposure was 119, 107, or 180% higher, respectively, compared with individuals with normal hepatic function.

Distribution

Extent

Not known whether lenvatinib is distributed into human milk. Lenvatinib and its metabolites distribute into milk in rats at concentrations higher than maternal plasma.

Plasma Protein Binding

97–99%.

Elimination

Metabolism

Primarily metabolized by CYP3A4, aldehyde oxidase, and nonenzymatic processes.

Elimination Route

Eliminated in feces (approximately 64%) and urine (approximately 25%).

Half-life

Approximately 28 hours.

Special Populations

In a pharmacokinetic population analysis, age, sex, race/ethnicity, and tumor type did not have a substantial effect on apparent clearance.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

  • Inhibits multiple receptor tyrosine kinases (RTKs), which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis).

  • Inhibits kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR-1, VEGFR-2, and VEGFR-3.

  • Also inhibits other RTKs involved in pathogenic angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3, and FGFR4), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (c-Kit), and ret proto-oncogene (RET).

  • Demonstrates antiproliferative activity in hepatocellular carcinoma cell lines dependent on FGFR signaling with concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information before starting lenvatinib therapy and each time their prescription is refilled.

  • If a dose is missed by more than 12 hours, importance of advising patients to skip that dose and take the next dose at the regularly scheduled time.

  • Risk of hypertension developing or worsening during therapy. Importance of regular monitoring of blood pressure during treatment. Importance of informing clinician if hypertension occurs.

  • Risk of cardiac dysfunction. Importance of immediately informing clinician if symptoms of cardiac dysfunction (e.g., shortness of breath, peripheral edema) occur.

  • Risk of arterial thromboembolic events. Importance of advising patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke (e.g., severe chest pain or pressure, shortness of breath, unilateral numbness or weakness, difficulty talking, severe headache, vision changes, arm, back, neck, or jaw pain).

  • Risk of hepatotoxicity. Importance of liver function test monitoring before and during lenvatinib therapy. Importance of immediately reporting any possible manifestations of hepatotoxicity (e.g., jaundice, dark or “tea-colored” urine, light-colored stools).

  • Risk of proteinuria and renal impairment or failure. Importance of advising patients that they will be monitored regularly for renal function and proteinuria during lenvatinib therapy.

  • Inform patients when to initiate anti-diarrheal medication and to maintain adequate hydration. Instruct patients to contact a clinician if they cannot maintain adequate hydration.

  • Increased risk of GI perforation or fistula formation. Importance of seeking immediate medical attention if severe abdominal pain occurs.

  • Increased risk of hemorrhagic events. Importance of advising patients to contact their clinician if bleeding or symptoms of severe bleeding occur.

  • Risk of QT-interval prolongation. Importance of informing patients that ECGs and/or serum electrolytes may be monitored during lenvatinib therapy.

  • Risk of hypocalcemia. Importance of monitoring calcium concentrations during therapy.

  • Risk of reversible posterior leukoencephalopathy syndrome (RPLS). Importance of contacting clinician promptly if severe headache, seizures, weakness, confusion, or visual disturbances occur during therapy.

  • Advise patients that lenvatinib therapy may cause hypothyroidism and regular monitoring of thyroid function during therapy may occur.

  • Instruct patients that lenvatinib therapy may impair wound healing and to inform a clinician of any planned surgical procedure.

  • Advise patients to employ good oral hygiene practices and attend regular dental checkups before and throughout treatment with lenvatinib. Instruct patients, particularly those at high risk for osteonecrosis of the jaw, to avoid invasive dental procedures, if possible. Advise patients to inform a clinician of any planned dental procedures and immediately contact a clinician if they have signs or symptoms of osteonecrosis of the jaw (e.g., pain or swelling in the mouth, loosening of teeth, poor healing or infection of the gums, or an area of exposed bone in the mouth).

  • Risk of impairment of exogenous thyroid suppression. Importance of monitoring thyroid-stimulating hormone (TSH) during therapy.

  • Risk of fetal harm. Necessity of advising women of childbearing potential to avoid pregnancy and to use an effective method of contraception during therapy and for at least 30 days after the last dose. Importance of women informing their clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

  • Importance of advising women to avoid breast-feeding during lenvatinib therapy and for at least 1 week after the last dose. Importance of women informing their clinicians if they are or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease [including congenital long QT syndrome]).

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of lenvatinib mesylate is restricted. Lenvatinib can only be obtained through designated specialty pharmacies. Contact the manufacturer or consult the Lenvima website for specific availability information.

Lenvatinib Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

4 mg (of lenvatinib)

Lenvima

Eisai

10 mg (of lenvatinib)

Lenvima

Eisai

Kits

5 Capsules, Lenvatinib mesylate 4 mg (of lenvatinib) (Lenvima)

Lenvima 4 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

10 Capsules, Lenvatinib mesylate 4 mg (of lenvatinib) (Lenvima)

Lenvima 8 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

5 Capsules, Lenvatinib mesylate 10 mg (of lenvatinib) (Lenvima)

Lenvima 10 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

15 Capsules, Lenvatinib mesylate 4 mg (of lenvatinib) (Lenvima)

Lenvima 12 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

5 Capsules, Lenvatinib mesylate 10 mg (of lenvatinib) (Lenvima)

5 Capsules, Lenvatinib mesylate 4 mg (of lenvatinib) (Lenvima)

Lenvima 14 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

10 Capsules, Lenvatinib mesylate 4 mg (of lenvatinib) (Lenvima)

5 Capsules, Lenvatinib mesylate 10 mg (of lenvatinib) (Lenvima)

Lenvima 18 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

10 Capsules, Lenvatinib mesylate 10 mg (of lenvatinib) (Lenvima)

Lenvima 20 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

10 Capsules, Lenvatinib mesylate 10 mg (of lenvatinib) (Lenvima)

5 Capsules, Lenvatinib mesylate 4 mg (of lenvatinib) (Lenvima)

Lenvima 24 mg Daily Dose (available in a package containing 6 blister cards)

Eisai

AHFS DI Essentials™. © Copyright 2022, Selected Revisions December 13, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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