Lenvatinib Mesylate (Monograph)

Brand name: Lenvima
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jul 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.

Uses for Lenvatinib Mesylate

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 (RCC).

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

For patients with intermediate- or poor-risk metastatic RCC who require systemic therapy in the first-line setting, the American Society of Clinical Oncology (ASCO) recommends offering combination treatment with 2 immune checkpoint inhibitors (i.e., ipilimumab and nivolumab) or an immune checkpoint inhibitor in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (e.g., pembrolizumab plus axitinib, nivolumab plus cabozantinib, avelumab plus axitinib, pembrolizumab plus lenvatinib). Patients with favorable-risk disease who require systemic therapy may be offered an immune checkpoint inhibitor in combination with a VEGFR tyrosine kinase inhibitor.

Hepatocellular Carcinoma

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

ASCO guideline states that lenvatinib may be offered as first-line therapy for patients with advanced HCC, Child-Pugh class A, and ECOG performance status of 0 or 1 if therapy with atezolizumab plus bevacizumab or durvalumab plus tremelimumab is contraindicated.

ASCO also states that tyrosine kinase inhibitors (i.e., cabozantinib, lenvatinib, regorafenib, sorafenib) may be used as second-line therapy^{† [off-label]} following therapy with atezolizumab plus bevacizumab or durvalumab plus tremelimumab.

Guideline recommendations from the American Gastroenterological Association (AGA) and the American Association for the Study of Liver Diseases (AASLD) are generally similar to ASCO recommendations.

Endometrial Carcinoma

In combination with pembrolizumab for the treatment of advanced endometrial carcinoma that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), in patients who have disease progression following prior systemic therapy and who are not candidates for curative surgery or radiation.

Some international experts recommend pembrolizumab plus lenvatinib for the second-line treatment of patients with pMMR or microsatellite stable advanced or recurrent endometrial cancer.

Lenvatinib Mesylate Dosage and Administration

General

Pretreatment Screening

Obtain BP; control BP prior to initiating therapy.
Evaluate proteinuria on urine dipstick.
Assess thyroid and liver function.
Assess serum electrolytes; correct electrolyte abnormalities prior to initiating therapy.
Perform dental examination.
Perform pregnancy test in females of reproductive potential.
For advanced endometrial carcinoma, select patients for treatment based on mismatch repair (MMR) or MSI status in tumor specimens. See information on FDA-approved tests for patient selection at [Web]. FDA-approved test for MSI-H not currently available.

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, CHF, bradyarrhythmias, or those 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.
Perform dental 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.

Swallow capsules whole; do not crush or chew. If lenvatinib capsules cannot be swallowed whole, dissolve intact capsules (maximum of 5) in 3 mL of water or apple juice in a small container or oral syringe (20 mL capacity); do not break or crush the capsules. For doses that require 6 capsules, prepare 3 capsules at a time according to instructions. Allow capsules to sit in the liquid for ≥10 minutes to allow the capsule shell to disintegrate, and then stir or shake for ≥3 minutes. After the mixture has been consumed, add 2 mL of water or apple juice to the container or oral syringe, swirl and shake, then administer. Repeat this step at least once and until no residue is visible to ensure all of the dose is consumed.

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

Feeding Tube Administration

For preparation of lenvatinib for feeding tube administration, dissolve intact capsules (maximum of 5) in 3 mL of water in a small container or oral syringe (20 mL capacity); do not break or crush the capsules. For doses that require 6 capsules, prepare 3 capsules at a time according to instructions. Allow the capsules to sit in the liquid for ≥10 minutes to allow the capsule shell to disintegrate, and then stir or shake for ≥3 minutes. After the mixture has been administered, add 2 mL of water to the container or syringe, swirl and shake, then administer. Repeat this step at least once and until no residue is visible to ensure all of the dose is consumed.

Lenvatinib suspension is compatible with polypropylene syringes, with polyvinyl chloride (PVC) and polyurethane feeding tubes of at least 5 French diameter, and with silicone feeding tubes of at least 6 French diameter.

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 DTC, RCC, or endometrial carcinoma and in Table 2 in patients with HCC.

Table 1. Recommended Dosage Reduction for Lenvatinib Toxicity in Patients with DTC, RCC, or Endometrial Carcinoma.1
Dosage Reduction Level	DTC (Starting Dosage = 24 mg daily)	RCC (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 HCC.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 or severe hepatic impairment (Child-Pugh class B) in patients with HCC: No specific dosage recommendations.

Pre-existing moderate hepatic impairment in patients with DTC, RCC, or endometrial carcinoma: No dosage adjustment required.

Pre-existing severe hepatic impairment (Child-Pugh class C) in patients with DTC, RCC, or endometrial carcinoma: Reduce dosage as described in Table 4.

Table 4. Recommended Dosage Modifications for Pre-existing Severe Hepatic Impairment in Patients with DTC, RCC, or Endometrial Carcinoma.1
Indication	Reduced Initial Dosage
DTC	14 mg once daily
RCC	10 mg once daily
Endometrial carcinoma	10 mg once daily

Renal Impairment

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

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

Pre-existing severe renal impairment in patients with HCC: no specific dosage recommendations.

Pre-existing severe renal impairment (Cl_cr <30 mL/minute) in patients with DTC, RCC, or endometrial carcinoma: Reduce dosage as described in Table 5.

Table 5. Recommended Dosage Modifications for Pre-existing Severe Renal Impairment in Patients with DTC, RCC, or Endometrial Carcinoma.1
Indication	Reduced Initial Dosage
DTC	14 mg once daily
RCC	10 mg once daily
Endometrial carcinoma	10 mg once daily
HCC	No specific recommendations

Geriatric Patients

No specific dosage recommendations.

Cautions for Lenvatinib Mesylate

Contraindications

None.

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 16–26 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.

Hepatotoxicity

Serious hepatic adverse effects, sometimes fatal, reported rarely 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.

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 or 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.

Fistula Formation and GI Perforation

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.

QT Interval Prolongation

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 in clinical trials. 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.

Hemorrhagic Events

Hemorrhagic events, most commonly epistaxis, reported. Fatal hemorrhagic events have occurred. 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/Thyroid Dysfunction

Lenvatinib impairs exogenous thyroid suppression.

An increase in TSH levels from normal or low at baseline observed in lenvatinib-treated patients.

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. Verify pregnancy status of females of reproductive potential before initiating lenvatinib. 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.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status of females of reproductive potential before initiating lenvatinib. If used during pregnancy or if pregnancy occurs while receiving the drug, apprise patient of the potential fetal hazard.

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.

Females and Males of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraceptive methods during lenvatinib therapy and for 30 days 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.

Safety and efficacy of lenvatinib investigated but not established in pediatric patients 2 to <17 years of age with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma; hypothyroidism and pneumothorax occurred at a higher rate in pediatric patients compared to adult patients.

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 DTC, RCC, 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 DTC, RCC, or endometrial carcinoma and pre-existing severe hepatic impairment; 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 DTC, RCC, 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 DTC 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 RCC 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 RCC 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 HCC 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.

Drug Interactions

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/QT_c 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 Mesylate 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

Age, sex, race/ethnicity, and tumor type do not have a substantial effect on apparent clearance.

Stability

Storage

Oral

Capsules

Store capsules at 20–25°C (excursions permitted between 15–30°C).

If capsules are used to prepare a suspension, store suspension under refrigeration (2–8ºC) for 24 hours in a covered container. After 24 hours, discard any remaining suspension.

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

Advise 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, advise patients to skip that dose and take the next dose at the regularly scheduled time.
Risk of hypertension developing or worsening during therapy. Stress importance of regular monitoring of BP during treatment and informing clinician if hypertension occurs.
Risk of cardiac dysfunction. Stress importance of immediately informing clinician if symptoms of cardiac dysfunction (e.g., shortness of breath, peripheral edema) occur.
Risk of arterial thromboembolic events. Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with MI 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. Stress importance of liver function test monitoring before and during lenvatinib therapy and 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. Advise 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. Stress importance of seeking immediate medical attention if severe abdominal pain occurs.
Increased risk of hemorrhagic events. Advise patients to contact their clinician if bleeding or symptoms of severe bleeding occur.
Risk of QT-interval prolongation. Inform patients that ECGs and/or serum electrolytes may be monitored during lenvatinib therapy.
Risk of hypocalcemia. Stress importance of monitoring calcium concentrations during therapy.
Risk of reversible posterior leukoencephalopathy syndrome (RPLS). Stress 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 that 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. Stress importance of monitoring thyroid-stimulating hormone (TSH) during therapy.
Risk of fetal harm. Advise women of childbearing potential to avoid pregnancy and to use an effective method of contraception during therapy and for 30 days after the last dose. Advise women to inform their clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Advise women to avoid breast-feeding during lenvatinib therapy and for at least 1 week after the last dose. Advise women to inform their clinicians if they are or plan to breast-feed.
Advise patients to inform their 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]).
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Lenvatinib is obtained through designated specialty pharmacies. Contact the manufacturer or consult the Lenvima website for specific availability information.