Lenvima
Lenvatinib · Capsule · Oral
Uses
1 INDICATIONS AND USAGE LENVIMA is a kinase inhibitor that is indicated: Differentiated Thyroid Cancer (DTC) For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). ( 1.1 ) Renal Cell Carcinoma (RCC) In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC). ( 1.2 ) In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. ( 1.2 ) Hepatocellular Carcinoma (HCC) For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). ( 1.3 ) Endometrial Carcinoma (EC) In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. ( 1.4 , 2.1 ) 1.1 Differentiated Thyroid Cancer LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 1.2 Renal Cell Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). LENVIMA, in combination with everolimus, is indicated for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy. 1.3 Hepatocellular Carcinoma LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.4 Endometrial Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration ( 2.1 )] .
Dosage and administration
Single Agent Therapy: DTC: The recommended dosage is 24 mg orally once daily. ( 2.3 ) HCC: The recommended dosage is based on actual body weight: 12 mg orally once daily for patients greater than or equal to 60 kg or 8 mg orally once daily for patients less than 60 kg. ( 2.5 ) Combination Therapy: EC: The recommended dosage is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. ( 2.6 ) RCC: The recommended dosage is: 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. ( 2.4 ) 18 mg orally once daily with everolimus 5 mg orally once daily. ( 2.4 ) Modify the recommended daily dose for certain patients with renal or hepatic impairment. ( 2.8 , 2.9 ) 2.1 Patient Selection For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MMR or MSI status in tumor specimens [see Clinical Studies ( 14.4 )]. Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics . 2. 2 Important Dosage Information Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration ( 2.8 , 2.9 )] . Take LENVIMA once daily, with or without food, at the same time each day [see Clinical Pharmacology ( 12.3 )] . If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration. 2. 3 Recommended Dos ag e for Differentiated Thyroid Cancer (DTC) The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity. 2. 4 Recommended Dosage for Renal Cell Carcinoma (RCC) F irst- L ine Treatment of Patients with Advanced RCC The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. Previously Treated RCC The recommended dosage of LENVIMA is 18 mg in combination with 5 mg everolimus orally once daily until disease progression or until unacceptable toxicity. Refer to the everolimus prescribing information for recommended everolimus dosing information. 2. 5 Recommended Dosage for Hepatocellular Carcinoma (HCC) The recommended dosage of LENVIMA is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Take LENVIMA orally once daily until disease progression or until unacceptable toxicity. 2. 6 Recommended Dosage for Endometrial Carcinoma (EC) The recommended dosage of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression. Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. 2. 7 Dos age Modifications for Adverse Reactions Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of LENVIMA for adverse reactions. Table 1 : Recommended Dos ag e Modifications for LENVIMA for Adverse Reactions Adverse Reaction Severity a Dos ag e Modifications for LENVIMA Hypertension [see Warnings and Precautions ( 5.1 )] Grade 3 Withhold for Grade 3 that persists despite optimal antihypertensive therapy. Resume at reduced dose when hypertension is controlled at less than or equal to Grade 2. Grade 4 Permanently discontinue. Cardiac Dysfunction [see Warnings and Precautions ( 5.2 )] Grade 3 Withhold until improves to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Grade 4 Permanently discontinue. Arterial Thromboembolic Event [see Warnings and Precautions ( 5.3 )] Any Grade Permanently discontinue. Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Grade 3 or 4 Withhold until improves to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue depending on severity and persistence of hepatotoxicity. Permanently discontinue for hepatic failure. Renal Failure or Impairment [see Warnings and Precautions ( 5.5 )] Grade 3 or 4 Withhold until improves to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue depending on severity and persistence of renal impairment. Proteinuria [see Warnings and Precautions ( 5.6 )] 2 g or greater proteinuria in 24 hours Withhold until less than or equal to 2 grams of proteinuria per 24 hours. Resume at a reduced dose. Permanently discontinue for nephrotic syndrome. Gastrointestinal Perforation [see Warnings and Precautions ( 5.8 )] Any Grade Permanently discontinue. Fistula Formation [see Warnings and Precautions ( 5.8 )] Grade 3 or 4 Permanently discontinue. QT Prolongation [see Warnings and Precautions ( 5.9 )] Greater than 500 ms or greater than 60 ms increase from baseline Withhold until improves to less than or equal to 480 ms or baseline. Resume at a reduced dose. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions ( 5.11 )] Any Grade Withhold until fully resolved. Resume at a reduced dose or discontinue depending on severity and persistence of neurologic symptoms. Other Adverse Reactions [see Warnings and Precautions ( 5.7 , 5.10 , 5.12 )] Persistent or intolerable Grade 2 or 3 adverse reaction Grade 4 laboratory abnormality Withhold until improves to Grade 0 to 1 or baseline. Resume at reduced dose. Grade 4 adverse reaction Permanently discontinue. a.
Dosage forms and strengths
Capsules: 4 mg: yellowish-red body and yellowish-red cap, marked in black ink with “Є” on cap and “LENV 4 mg” on body. 10 mg: yellow body and yellowish-red cap, marked in black ink with “Є” on cap and “LENV 10 mg” on body. Capsules: 4 mg and 10 mg. ( 3 )
Contraindications
None. None. ( 4 )
Warnings and precautions
Hypertension : Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade 3 hypertension despite optimal antihypertensive therapy. Discontinue for Grade 4 hypertension. ( 2.7 , 5.1 ) Cardiac Dysfunction : Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold or discontinue for Grade 3 cardiac dysfunction. Discontinue for Grade 4 cardiac dysfunction. ( 2.7 , 5.2 ) Arterial Thromboembolic Events : Discontinue following an arterial thromboembolic event. ( 2.7 , 5.3 ) Hepatotoxicity : Monitor liver function prior to treatment and periodically during treatment. Withhold or discontinue for Grade 3 or 4 hepatotoxicity. Discontinue for hepatic failure. ( 2.7 , 5.4 ) Renal Failure or Impairment : Withhold or discontinue for Grade 3 or 4 renal failure or impairment. ( 2.7 , 5.5 ) Proteinuria : Monitor for proteinuria prior to treatment and periodically during treatment. Withhold for 2 or more grams of proteinuria per 24 hours. Discontinue for nephrotic syndrome. ( 2.7 , 5.6 ) Diarrhea : May be severe and recurrent. Promptly initiate management for severe diarrhea. Withhold or discontinue based on severity. ( 2.7 , 5.7 ) Fistula Formation and Gastrointestinal Perforation : Discontinue in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation. ( 2.7 , 5.8 ) QT Interval Prolongation : Monitor and correct electrolyte abnormalities. Withhold for QT interval greater than 500 ms or for 60 ms or greater increase in baseline QT interval. ( 2.7 , 5.9 ) Hypocalcemia : Monitor blood calcium levels at least monthly and replace calcium as necessary. Withhold or discontinue based on severity. ( 2.7 , 5.10 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : Withhold for RPLS until fully resolved or discontinue. ( 2.7 , 5.11 ) Hemorrha gic Events : Withhold or discontinue based on severity. ( 2.7 , 5.12 ) Impairment of Thyroid Stimulating Hormone Suppression /Thyroid Dysfunction : Monitor thyroid function prior to treatment and monthly during treatment. ( 5.13 ) Impaired Wound Healing : Withhold LENVIMA for at least 1 week before elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established. ( 5.14 ) Osteonecrosis of the Jaw : Consider preventive dentistry prior to treatment with LENVIMA. Avoid invasive dental procedures, if possible, particularly in patients at higher risk. ( 5.15 ) Embryo -F etal T oxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.16 , 8.1 , 8.3 ) 5.1 Hypertension Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in SELECT and Grade 4 hypertension was not reported in REFLECT. In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205 (RCC), hypertension was reported in 42% of patients and the median time to onset of new or worsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients. Systolic blood pressure ≥160 mmHg occurred in 29% of patients and diastolic blood pressure ≥100 mmHg occurred in 21% [see Adverse Reactions ( 6.1 )] . Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue LENVIMA based on severity [ see Dosage and Administration ( 2.7 ) ] . 5.2 Cardiac Dysfunction Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, cardiac failure, ventricular hypokinesia, or decrease in left or right ventricular ejection fraction of more than 20% from baseline) occurred in 3% of LENVIMA-treated patients. Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [ see Dosage and Administration ( 2.7 ) ] . 5.3 Arterial Thromboembolic Events Among patients receiving LENVIMA or LENVIMA with everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in Study 205 (RCC), 2% of patients in REFLECT (HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials [see Adverse Reactions ( 6.1 )] . Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%). Permanently discontinue LENVIMA following an arterial thrombotic event [ see Dosage and Administration ( 2.7 ) ] . The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 5.4 Hepatotoxicity Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients.
Side effects
The following adverse reactions are discussed elsewhere in the labeling: Hypertension [see Warnings and Precautions ( 5.1 )] Cardiac Dysfunction [see Warnings and Precautions ( 5.2 )] Arterial Thromboembolic Events [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Renal Failure and Impairment [see Warnings and Precautions ( 5.5 )] Proteinuria [see Warnings and Precautions ( 5.6 )] Diarrhea [see Warnings and Precautions ( 5.7 )] Fistula Formation and Gastrointestinal Perforation [see Warnings and Precautions ( 5.8 )] QT Interval Prolongation [see Warnings and Precautions ( 5.9 )] Hypocalcemia [see Warnings and Precautions ( 5.10 )] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions ( 5.11 )] Hemorrhagic Events [see Warnings and Precautions ( 5.12 )] Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction [see Warnings and Precautions ( 5.13 )] Impaired Wound Healing [see Warnings and Precautions ( 5.14 )] Osteonecrosis of the Jaw (ONJ) [see Warnings and Precautions ( 5.15 )] In DTC, the most common adverse reactions (incidence ≥30%) for LENVIMA are hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. ( 6.1 ) In RCC: The most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are 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. ( 6.1 ) The most common adverse reactions (incidence ≥30%) for LENVIMA and everolimus are diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and proteinuria. ( 6.1 ) In HCC, the most common adverse reactions (incidence ≥20%) for LENVIMA are hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. ( 6.1 ) In EC, the most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, decreased weight, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warnings and Precautions reflect exposure to LENVIMA as a single agent in 261 patients with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 406 patients with endometrial carcinoma (Study 309), LENVIMA with everolimus in 62 patients with RCC (Study 205), and LENVIMA with pembrolizumab in 352 patients with RCC (CLEAR). Safety data obtained in 1823 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions. Among the 1823 patients who received LENVIMA as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily, and the median duration of exposure was 5.6 months. The data below reflect exposure to LENVIMA in 1557 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205; CLEAR; Study 309), and a randomized, placebo-controlled trial (SELECT). The median duration of exposure to LENVIMA across these five studies ranged from 6 to 16 months. The demographic and exposure data for each clinical trial population are described in the subsections below. Differentiated Thyroid Cancer The safety of LENVIMA was evaluated in SELECT, in which patients with radioactive iodine-refractory differentiated thyroid cancer were randomized (2:1) to LENVIMA (n=261) or placebo (n=131) [ see Clinical Studies ( 14.1 ) ] . The median treatment duration was 16.1 months for LENVIMA. Among 261 patients who received LENVIMA, median age was 64 years, 52% were females, 80% were White, 18% were Asian, and 2% were Black; and 4% were Hispanic/Latino. The most common adverse reactions observed in LENVIMA-treated patients (≥30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA; 18% of patients discontinued LENVIMA for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). Table 3 presents adverse reactions occurring at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the study.
Drug interactions
7.1 Drugs That Prolong the QT Interval LENVIMA has been reported to prolong the QT/QTc interval. Avoid coadministration of LENVIMA with medicinal products with a known potential to prolong the QT/QTc interval [ see Warnings and Precaution s ( 5.9 ) ] .
Use in specific populations
Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits ( see Data ) . There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% post-implantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the recommended clinical dose of 24 mg based on BSA). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). 8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk; however, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than those in maternal plasma ( see Data ) . Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment with LENVIMA and for 1 week after the last dose. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher [based on area under the curve (AUC)] in milk compared to maternal plasma. 8.3 Females and Males of Reproductive Potential Based on animal data and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating LENVIMA [see Use in Specific Populations ( 8.1 )]. Contraception Females Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with LENVIMA and for 30 days after the last dose. Infertility LENVIMA may impair fertility in males and females of reproductive potential [ see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established. The safety and efficacy of LENVIMA alone and in combination were investigated but not established in four open label studies (NCT02432274, NCT04154189, NCT04447755, NCT03245151) in 232 patients aged 2 to <17 years with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma. Hypothyroidism and pneumothorax were observed at a higher rate in pediatric patients compared to that of adult patients. The pharmacokinetics (PK) of lenvatinib in pediatric patients were within range of values previously observed in adults at the approved recommended dose of 24 mg. Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the human exposure based on AUC at the recommended clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats. 8.5 Geriatric Use Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in SELECT, 45% were ≥65 years of age and 11% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 352 patients with renal cell carcinoma (RCC) who received LENVIMA with pembrolizumab in CLEAR, 45% were ≥65 years of age and 13% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Of the 62 patients with RCC who received LENVIMA with everolimus in Study 205, 36% were ≥65 years of age. Conclusions are limited due to the small sample size, but there appeared to be no overall differences in safety or effectiveness between these subjects and younger subjects.
Pregnancy
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits ( see Data ) . There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% post-implantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the recommended clinical dose of 24 mg based on BSA). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established. The safety and efficacy of LENVIMA alone and in combination were investigated but not established in four open label studies (NCT02432274, NCT04154189, NCT04447755, NCT03245151) in 232 patients aged 2 to <17 years with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma. Hypothyroidism and pneumothorax were observed at a higher rate in pediatric patients compared to that of adult patients. The pharmacokinetics (PK) of lenvatinib in pediatric patients were within range of values previously observed in adults at the approved recommended dose of 24 mg. Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the human exposure based on AUC at the recommended clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.
Geriatric use
8.5 Geriatric Use Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in SELECT, 45% were ≥65 years of age and 11% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 352 patients with renal cell carcinoma (RCC) who received LENVIMA with pembrolizumab in CLEAR, 45% were ≥65 years of age and 13% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Of the 62 patients with RCC who received LENVIMA with everolimus in Study 205, 36% were ≥65 years of age. Conclusions are limited due to the small sample size, but there appeared to be no overall differences in safety or effectiveness between these subjects and younger subjects. Of the 476 patients with hepatocellular carcinoma (HCC) who received LENVIMA in REFLECT, 44% were ≥65 years of age and 12% were ≥75 years of age. No overall differences in safety or effectiveness were observed between patients ≥65 and younger subjects. Patients ≥75 years of age showed reduced tolerability to LENVIMA. Of 406 adult patients with endometrial carcinoma (EC) who were treated with LENVIMA in combination with pembrolizumab in Study 309, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Overdosage
Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable [see Clinical Pharmacology ( 12.3 )] . Death due to multiorgan dysfunction occurred in a patient who received a single dose of LENVIMA 120 mg orally.
Description
11 DESCRIPTION LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3-chloro-4-( N ’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula is C 21 H 19 ClN 4 O 4
• CH 4 O 3 S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is: Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.3. LENVIMA capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively. The inactive ingredients are: calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and talc. In addition, the capsule shell contains ferric oxide red, ferric oxide yellow, hypromellose, and titanium dioxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac. The chemical structure of lenvatinib mesylate is LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6 carboxamide methanesulfonate. The molecular formula is C21H19ClN4O4
• CH4O3S, and the molecular weight of the mesylate salt is 522.96.
Mechanism of action
12.1 Mechanism of Action Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRA), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 alpha (FRS2) phosphorylation. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone.
How supplied
4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on the body. LENVIMA 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on the body. LENVIMA capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows: NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card). NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card). NDC 62856-718-30: 18 mg, carton with 6 cards NDC 62856-718-05 (five 10 mg capsules and ten 4 mg capsules per card). NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card). NDC 62856-712-30: 12 mg, carton with 6 cards NDC 62856-712-05 (fifteen 4 mg capsules per card). NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card). NDC 62856-708-30: 8 mg, carton with 6 cards NDC 62856-708-05 (ten 4 mg capsules per card). NDC 62856-704-30: 4 mg, carton with 6 cards NDC 62856-704-05 (five 4 mg capsules per card). Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Hypertension Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated [see Warnings and Precautions ( 5.1 )] . Cardiac Dysfunction Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction [see Warnings and Precautions ( 5.2 )]. Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke [see Warnings and Precautions ( 5.3 )]. Hepatotoxicity Advise patients that they will need to undergo laboratory tests to monitor liver function and to report any new symptoms indicating hepatic toxicity or failure [see Warnings and Precautions ( 5.4 )]. Proteinuria and Renal Failure/Impairment Advise patients that they will need to undergo regular laboratory tests to monitor kidney function and protein in the urine [see Warnings and Precautions ( 5.5 , 5.6 )]. Diarrhea Advise patients when to start standard anti-diarrheal therapy and to maintain adequate hydration. Advise patients to contact their healthcare provider if they are unable to maintain adequate hydration [see Warnings and Precautions ( 5.7 )]. F istula F ormation and Gastrointestinal Perforation Advise patients that LENVIMA can increase the risk of fistula formation or gastrointestinal perforation and to seek immediate medical attention for severe abdominal pain [see Warnings and Precautions ( 5.8 )]. QT c Interval Prolongation Advise patients who are at risk for QTc prolongation that they will need to undergo regular ECGs. Advise all patients that they will need to undergo laboratory tests to monitor electrolytes [see Warnings and Precautions ( 5.9 )]. Hypocalcemia Advise patients of the risks of hypocalcemia, that they will need to undergo laboratory tests to monitor calcium levels, and the potential requirement for calcium supplementation [see Warnings and Precautions ( 5.10 )] . Reversible P osterior L eukoencephalopathy S yndrome (RPLS) Advise patients of the signs and symptoms of RPLS and to contact their healthcare provider for new onset or worsening neurological function [see Warnings and Precautions ( 5.11 )] . Hemorrhagic Events Advise patients that LENVIMA can increase the risk for bleeding and to contact their healthcare provider for bleeding or symptoms of severe bleeding [see Warnings and Precautions ( 5.12 )] . Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction Advise patients that LENVIMA can cause hypothyroidism and that their thyroid function should be monitored regularly during treatment [see Warnings and Precautions ( 5.13 )]. Impaired Wound Healing Advise patients that LENVIMA may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions ( 5.14 )]. Osteonecrosis of the Jaw (ONJ) Advise patients regarding good oral hygiene practices and to have preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA. Inform patients being treated with LENVIMA, particularly those who are at high risk for ONJ, to avoid invasive dental procedures, if possible, and to inform their healthcare provider of any planned dental procedures [see Warnings and Precautions ( 5.15 )]. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with ONJ. Embryo - F etal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.16 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose [see Use in Specific Populations ( 8.3 )]. Lactation Advise women to discontinue breastfeeding during treatment with LENVIMA and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )]. Distributed by: Eisai Inc. Nutley, NJ 07110 LENVIMA ® is a registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015-20XX Eisai Inc.
Label text from the FDA structured product label by Eisai Inc. (revised Jun 30, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Lenvatinib in 5 products
Lenvima NDC products (8)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 62856-704 | Lenvatinib 4 mg/1 Capsule | Eisai Inc. | NDA |
| 62856-708 | Lenvatinib 4 mg/1 Capsule | Eisai Inc. | NDA |
| 62856-710 | Lenvatinib 10 mg/1 Capsule | Eisai Inc. | NDA |
| 62856-712 | Lenvatinib 4 mg/1 Capsule | Eisai Inc. | NDA |
| 62856-714 | Kit | Eisai Inc. | NDA |
| 62856-718 | Kit | Eisai Inc. | NDA |
| 62856-720 | Lenvatinib 10 mg/1 Capsule | Eisai Inc. | NDA |
| 62856-724 | Kit | Eisai Inc. | NDA |
Frequently asked questions
What is Lenvima used for?
1 INDICATIONS AND USAGE LENVIMA is a kinase inhibitor that is indicated: Differentiated Thyroid Cancer (DTC) For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). ( 1.1 ) Renal Cell Carcinoma (RCC) In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal…
What are the side effects of Lenvima?
The following adverse reactions are discussed elsewhere in the labeling: Hypertension [see Warnings and Precautions ( 5.1 )] Cardiac Dysfunction [see Warnings and Precautions ( 5.2 )] Arterial Thromboembolic Events [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Renal Failure and Impairment [see Warnings and Precautions ( 5.5 )] Proteinuria [see… See the full label for the complete list.
Who makes Lenvima?
Lenvima is listed by 1 labeler in the FDA NDC directory, including Eisai Inc..