This information is not for clinical use. These highlights do not include all the information needed to use Lenvima safely and effectively. Before taking Lenvima please consult with your doctor. See full prescribing information for Lenvima.

Indications And Usage

1 INDICATIONS AND USAGELENVIMA is a kinase inhibitor that is indicated: For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). (1.1) In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy. (1.2) For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). (1.3) In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. (1.4)1.1 Differentiated Thyroid Cancer LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 1.2 Renal Cell Carcinoma LENVIMA is indicated in combination with everolimus for the treatment of patients with advanced renal cell carcinoma (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 CarcinomaLENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

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Dosage And Administration

Table 1. Recommended Dosage Modifications for LENVIMA for Adverse Reactions
Adverse ReactionSeverity aDosage Modifications for LENVIMA
Hypertension [see Warnings and Precautions (5.1)] Grade 3Withhold 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 4Permanently discontinue.
Cardiac Dysfunction [see Warnings and Precautions (5.2)] Grade 3Withhold 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 4Permanently discontinue.
Arterial Thromboembolic Event [see Warnings and Precautions (5.3)]Any GradePermanently discontinue.
Hepatotoxicity [see Warnings and Precautions (5.4)]Grade 3 or 4Withhold 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 4Withhold 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 hoursWithhold 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 GradePermanently discontinue.
Fistula Formation [see Warnings and Precautions (5.8)]Grade 3 or 4Permanently discontinue.
QT Prolongation [see Warnings and Precautions (5.9)]Greater than 500 ms or greater than 60 ms increase from baselineWithhold 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 GradeWithhold 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 abnormalityWithhold until improves to Grade 0 to 1 or baseline. Resume at reduced dose.
Grade 4 adverse reaction Permanently discontinue.
a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHSCapsules: 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

4 CONTRAINDICATIONSNone.None. (4)

Warning and Cautions

5 WARNINGS AND PRECAUTIONSHypertension: Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade 3 hypertension despite optimal antihypertensive therapy. Discontinue for Grade 4 hypertension. (2.6, 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. (2.6, 5.2) Arterial Thromboembolic Events: Discontinue following an arterial thromboembolic event. (2.6, 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. (2.6, 5.4) Renal Failure or Impairment: Withhold or discontinue for Grade 3 or 4 renal failure or impairment. (2.6, 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. (2.6, 5.6) Diarrhea: May be severe and recurrent. Promptly initiate management for severe diarrhea. Withhold or discontinue based on severity. (2.6, 5.7) Fistula Formation and Gastrointestinal Perforation: Discontinue in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation. (2.6, 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. (2.6, 5.9) Hypocalcemia: Monitor blood calcium levels at least monthly and replace calcium as necessary. Withhold or discontinue based on severity. (2.6, 5.10) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold for RPLS until fully resolved or discontinue. (2.6, 5.11) Hemorrhagic Events: Withhold or discontinue based on severity. (2.6, 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) Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.15, 8.1, 8.3)5.1 HypertensionHypertension 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 (2.6)].5.2 Cardiac DysfunctionSerious 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 (2.6)].5.3 Arterial Thromboembolic EventsAmong 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)]. Permanently discontinue LENVIMA following an arterial thrombotic event [see Dosage and Administration (2.6)]. 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 HepatotoxicityAcross 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. In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated patients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Two percent of patients discontinued LENVIMA and 0.2% discontinued sorafenib due to hepatic encephalopathy and 1% of patients discontinued lenvatinib or sorafenib due to hepatic failure [see Adverse Reactions (6.1)].Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.6)].5.5 Renal Failure or ImpairmentSerious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patients receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in each study.In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade 3 in 10% of patients [see Adverse Reactions (6.1)]. Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity [see Dosage and Administration (2.6)]. 5.6 ProteinuriaProteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMA with everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus [see Adverse Reactions (6.1)].Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.6)].5.7 DiarrheaOf the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred in 49% of patients, including Grade 3 in 6%.In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction [see Adverse Reactions (6.1)]. Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration (2.6)].5.8 Fistula Formation and Gastrointestinal PerforationOf 799 patients treated with LENVIMA or LENVIMA with everolimus in SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula [see Dosage and Administration (2.6)].5.9 QT Interval ProlongationIn SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In Study 205 (RCC), QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA with everolimus and QTc interval >500 ms occurred in 6%. In REFLECT (HCC), QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose of LENVIMA upon recovery based on severity [see Dosage and Administration (2.6)].5.10 HypocalcemiaIn SELECT (DTC), Grade 3 to 4 hypocalcemia occurred in 9% of patients receiving LENVIMA. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction. In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated with LENVIMA with everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients [see Adverse Reactions (6.1)].Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA depending on severity [see Dosage and Administration (2.6)].5.11 Reversible Posterior Leukoencephalopathy SyndromeAcross clinical studies of 1823 patients who received LENVIMA as a single agent [see Adverse Reaction (6.1)], reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 0.3%. Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA depending on severity and persistence of neurologic symptoms [see Dosage and Administration (2.6)].5.12 Hemorrhagic EventsSerious including fatal hemorrhagic events can occur with LENVIMA. Across SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients receiving LENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA, including 7 fatal hemorrhagic events [see Adverse Reactions (6.1)].Serious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treated with LENVIMA in clinical trials and in the post-marketing setting. In post-marketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA based on the severity [see Dosage and Administration (2.6)].5.13 Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction LENVIMA impairs exogenous thyroid suppression. In SELECT (DTC), 88% of all patients had a baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients.Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA with everolimus in Study 205 (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205 [see Adverse Reactions (6.1)]. Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.5.14 Impaired Wound Healing Impaired wound healing has been reported in patients who received LENVIMA [see Adverse Reactions (6.2)]. Withhold LENVIMA for at least 1 week prior to 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.5.15 Embryo-Fetal ToxicityBased on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

6 ADVERSE REACTIONSThe 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)]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 ≥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 Endometrial Carcinoma, the most common adverse reactions (incidence ≥20%) for LENVIMA and pembrolizumab are fatigue, hypertension, musculoskeletal pain, diarrhea, decreased appetite, hypothyroidism, nausea, stomatitis, vomiting, decreased weight, abdominal pain, headache, constipation, urinary tract infection, dysphonia, hemorrhagic events, hypomagnesemia, palmar-plantar erythrodysesthesia, dyspnea, cough, 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 ExperienceBecause 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 94 patients with endometrial carcinoma (Study 111), and LENVIMA with everolimus in 62 patients with RCC (Study 205). 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 893 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205), a randomized, placebo-controlled trial (SELECT) and a single arm trial (Study 111). The median duration of exposure to LENVIMA across these four 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 CancerThe 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.Table 3: Adverse Reactions Occurring in Patients with a Between-Group Difference of ≥5% in All Grades or ≥2% in Grades 3 and 4 in SELECT (DTC)Adverse ReactionLENVIMA 24 mg N=261Placebo N=131All Grades (%)Grades 3-4 (%)All Grades (%)Grades 3-4 (%)Vascular Hypertensiona7344164Hypotension9220Gastrointestinal Diarrhea679170Nausea472251Stomatitisb41580Vomiting362150Abdominal painc312111Constipation290.4151Oral paind25120Dry mouth170.480Dyspepsia130.440General Fatiguee6711354Edema peripheral210.480Musculoskeletal and Connective Tissue Arthralgia/Myalgiaf625283Metabolism and Nutrition Decreased appetite547181Decreased weight5113151Dehydration9221Nervous System Headache383111Dysgeusia18030Dizziness150.490Renal and Urinary Proteinuria341130Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia32310Rashg210.430Alopecia12050Hyperkeratosis7020Respiratory, Thoracic and Mediastinal Dysphonia31150Cough240180Epistaxis12010Psychiatric Insomnia12030Infections Urinary tract infection11150Dental and oral infectionsh10110Cardiac Electrocardiogram QT prolonged9220a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes macular rash, maculo-papular rash, generalized rash, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infectionA clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively).Laboratory abnormalities with a difference of ≥2% in Grade 3 – 4 events and at a higher incidence in the LENVIMA arm are presented in Table 4.Table 4: Laboratory Abnormalities with a Difference of ≥ 2% in Grade 3 - 4 Events and at a Higher Incidence in the LENVIMA Arma, b in SELECT (DTC)Laboratory Abnormality LENVIMA 24 mg Placebo Grades 3-4 (%)Grades 3-4 (%)ChemistryHypocalcemia92Hypokalemia61Increased aspartate aminotransferase (AST) 50Increased alanine aminotransferase (ALT) 40Increased lipase41Increased creatinine 30HematologyThrombocytopenia20a With at least 1 grade increase from baseline b Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA (n = 253 to 258), Placebo (n = 129 to 131) The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.Renal Cell Carcinoma The safety of LENVIMA was evaluated in Study 205, in which patients with unresectable advanced or metastatic renal cell carcinoma (RCC) were randomized (1:1:1) to LENVIMA 18 mg orally once daily with everolimus 5 mg orally once daily (n=51), LENVIMA 24 mg orally once daily (n=52), or everolimus 10 mg orally once daily (n=50) [see Clinical Studies (14.2)]. This data also includes patients on the dose escalation portion of the study who received LENVIMA with everolimus (n=11). The median treatment duration was 8.1 months for LENVIMA with everolimus. Among 62 patients who received LENVIMA with everolimus, the median age was 61 years, 71% were men, and 98% were White.The most common adverse reactions observed in the LENVIMA with everolimus-treated group (≥30%) were, in order of decreasing frequency, 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. The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA with everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA with everolimus-treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%).Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA with everolimus-treated group.Table 5 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus arm. Study 205 was not designed to demonstrate a statistically significant difference in adverse reaction rates for LENVIMA in combination with everolimus, as compared to everolimus for any specific adverse reaction listed in Table 5.Table 5: Adverse Reactions Occurring in > 15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC) LENVIMA 18 mg with Everolimus 5 mg N=62Everolimus 10 mg N=50Adverse ReactionsGrade 1-4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)Endocrine Hypothyroidism24020Gastrointestinal Diarrhea8119342Vomiting487120Nausea455160Stomatitis/Oral inflammationa442504Abdominal painb37380Oral painc23240Dyspepsia/Gastro-esophageal reflux210120Constipation160180General Fatigued7318402Peripheral edema422200Pyrexia/Increased body temperature212102Metabolism and Nutrition Decreased appetite535180Decreased weight 34380Musculoskeletal and Connective Tissue Arthralgia/Myalgiae555320Musculoskeletal chest pain18240Nervous System Headache192102Psychiatric Insomnia16220Renal and Urinary Proteinuria/Urine protein present318142Renal failure eventf1810122Respiratory, Thoracic and Mediastinal Cough370300Dyspnea/Exertional dyspnea355288Dysphonia18040Skin and Subcutaneous Tissue Rashg350400Vascular Hypertension/Increased blood pressure4213102Hemorrhagic eventsh326262a Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration b Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain c Includes gingival pain, glossodynia, and oropharyngeal pain d Includes asthenia, fatigue, lethargy and malaise e Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgia f Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic, renal failure, renal failure acute, and renal impairment g Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash, and septic rash h Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip hemorrhage, renal hematoma, and scrotal hematocele In Table 6, Grade 3-4 laboratory abnormalities occurring in ≥3% of patients in the LENVIMA with everolimus arm are presented. Table 6: Grade 3-4 Laboratory Abnormalities Occurring in ≥ 3% of Patients in the LENVIMA with Everolimus Arma,b in Study 205 (RCC)Laboratory Abnormality LENVIMA 18 mg with Everolimus 5 mg Everolimus 10 mg Grades 3-4 (%)Grades 3-4 (%)ChemistryHypertriglyceridemia1818Increased lipase 1312Hypercholesterolemia110Hyponatremia116Hypophosphatemia116Hyperkalemia62Hypocalcemia62Hypokalemia62Increased aspartate aminotransferase (AST) 30Increased alanine aminotransferase (ALT) 32Increased alkaline phosphatase 30Hyperglycemia316Increased creatine kinase 34HematologyLymphopenia1020Anemia816Thrombocytopenia50With at least 1 grade increase from baseline Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA with Everolimus (n = 62), Everolimus (n = 50).Hepatocellular CarcinomaThe safety of LENVIMA was evaluated in REFLECT, which randomized (1:1) patients with unresectable hepatocellular carcinoma (HCC) to LENVIMA (n=476) or sorafenib (n=475) [see Clinical Studies (14.3)]. The dose of LENVIMA was 12 mg orally once daily for patients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with a baseline body weight of <60 kg. The dose of sorafenib was 400 mg orally twice daily. Duration of treatment was ≥6 months in 49% and 32% of patients in the LENVIMA and sorafenib groups, respectively. Among the 476 patients who received LENVIMA in REFLECT, the median age was 63 years, 85% were men, 28% were White and 70% were Asian. The most common adverse reactions observed in the LENVIMA-treated patients (≥20%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. The most common serious adverse reactions (≥2%) in LENVIMA-treated patients were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%).Adverse reactions led to dose reduction or interruption in 62% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%).Treatment discontinuation due to adverse reactions occurred in 20% of patients in the LENVIMA-treated group. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). Table 7 summarizes the adverse reactions that occurred in ≥10% of patients receiving LENVIMA in REFLECT. REFLECT was not designed to demonstrate a statistically significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 7.Table 7: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in REFLECT (HCC) Adverse ReactionLENVIMA 8 mg/12 mg N=476Sorafenib 800 mg N=475Grade 1-4 (%)Grade 3-4 (%)Grade 1-4 (%)Grade 3-4 (%)Endocrine Hypothyroidisma210 30Gastrointestinal Diarrhea394464Abdominal painb303284Nausea201141Vomiting16181Constipation161110Ascitesc154113Stomatitisd110.4141General Fatiguee447366Pyrexiaf150140.2Peripheral edema14170.2Metabolism and Nutrition Decreased appetite345271Decreased weight318223Musculoskeletal and Connective Tissue Arthralgia/Myalgiag311202Nervous System Headache10180Renal and Urinary Proteinuriah266122Respiratory, Thoracic and Mediastinal Dysphonia240.2120Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome2735211Rashi140242Vascular Hypertensionj45243115Hemorrhagic eventsk234154Includes hypothyroidism, blood thyroid stimulating hormone increased. Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain Includes ascites and malignant ascites Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, and stomatitis Includes asthenia, fatigue, lethargy and malaise Includes increased body temperature, pyrexia Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, and myalgia Includes proteinuria, increased urine protein, protein urine present Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash and rash Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertension Includes all hemorrhage terms. Hemorrhage terms that occurred in 5 or more subjects in either treatment group include: epistaxis, hematuria, gingival bleeding, hemoptysis, esophageal varices hemorrhage, hemorrhoidal hemorrhage, mouth hemorrhage, rectal hemorrhage and upper gastrointestinal hemorrhageIn Table 8, Grade 3-4 laboratory abnormalities occurring in ≥2% of patients in the LENVIMA arm in REFLECT (HCC) are presented.Table 8: Grade 3-4 Laboratory Abnormalities Occurring in ≥2% of Patients in the LENVIMA Arma,b in REFLECT (HCC)Laboratory Abnormality Lenvatinib (%)Sorafenib (%)ChemistryIncreased GGT1720Hyponatremia159Hyperbilirubinemia1310Increased aspartate aminotransferase (AST)1218Increased alanine aminotransferase (ALT)89Increased alkaline phosphatase75Increased lipase617Hypokalemia34Hyperkalemia32Decreased albumin31Increased creatinine22HematologyThrombocytopenia108Lymphopenia89Neutropenia73Anemia45With at least 1 grade increase from baseline Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter. LENVIMA (n=278 to 470) and sorafenib (n=260 to 473)Endometrial CarcinomaThe safety of LENVIMA (20 mg orally once daily) in combination with pembrolizumab (200 mg intravenously every 3 weeks) was evaluated in Study 111, a single-arm, multicenter, open-label trial in 94 patients with endometrial carcinoma whose tumors had progressed following one line of systemic therapy and were not MSI-H or dMMR [see Clinical Studies (14.4)]. The median duration of study treatment was 7 months (range: 0.03 to 37.8 months). Pembrolizumab was continued for a maximum of 24 months; however, treatment with LENVIMA could be continued beyond 24 months.Fatal adverse reactions occurred in 3% of patients treated with LENVIMA and pembrolizumab, including gastrointestinal perforation, RPLS with intraventricular hemorrhage, and intracranial hemorrhage.Serious adverse reactions occurred in 52% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).Permanent discontinuation due to adverse reaction (Grade 1-4) occurred in 21% of patients who received LENVIMA and pembrolizumab. The most common adverse reactions (>2%) resulting in discontinuation of LENVIMA were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (2%).Adverse reactions led to dose reduction or interruption in 88% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (32%), hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%), hemorrhages (7%), renal impairment (6%), decreased weight (6%), rash (5%), headache (5%), increased lipase (5%), and proteinuria (5%).Table 9 presents the adverse reactions in ≥20% of patients with LENVIMA in combination with pembrolizumab.Table 9: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in Study 111 LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=94Adverse ReactionsAll Grades (%)Grade 3-4 (%)GeneralFatiguea6517Musculoskeletal and Connective TissueMusculoskeletal painb653Vascular Hypertensionc6538Hemorrhagic eventsd284GastrointestinalDiarrheae644Nausea485Stomatitisf430Vomiting390Abdominal paing336Constipation320MetabolismDecreased appetiteh520Hypomagnesaemia273EndocrineHypothyroidismi511InvestigationsDecreased weight363Nervous SystemHeadache331InfectionsUrinary tract infectionj314Respiratory, Thoracic and MediastinalDysphonia290Dyspneak242Cough210Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesia syndrome263Rashl213a Includes asthenia, fatigue, and malaise b Includes arthralgia, arthritis, back pain, breast pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity c Includes essential hypertension, hypertension, and hypertensive encephalopathy d Includes catheter site bruise, contusion, epistaxis, gastrointestinal hemorrhage, hematemesis, hematuria, hemorrhage intracranial, injection site hemorrhage, intraventricular hemorrhage, large intestinal hemorrhage, metrorrhagia, mouth hemorrhage, uterine hemorrhage, and vaginal hemorrhage e Includes diarrhea, gastroenteritis, gastrointestinal viral infection, and viral diarrhea f Includes glossitis, mouth ulceration, oral discomfort, oral mucosal blistering, oropharyngeal pain, and stomatitis g Includes abdominal discomfort, abdominal pain, lower abdominal pain, and upper abdominal pain h Includes decreased appetite and early satiety i Includes increased blood thyroid stimulating hormone and hypothyroidism j Includes cystitis and urinary tract infection k Includes dyspnea and exertional dyspnea l Includes rash, rash generalized, rash macular, and rash maculo-papularTable 10 presents, laboratory abnormalities in ≥20% (All Grades) or ≥3% (Grades 3-4) of patients with LENVIMA in combination with pembrolizumab. Table 10: Laboratory Abnormalities in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients on LENVIMA plus Pembrolizumab in Study 111LENVIMA 20 mg plus Pembrolizumab 200 mgLaboratory AbnormalityaAll Grades %bGrade 3-4 %bChemistryIncreased creatinine807Hypertriglyceridemia584Hyperglycemia 531Hypercholesteremia496Hypoalbuminemia480Hypomagnesemia472Increased aspartate aminotransferase434Hyponatremia4213Increased lipase4218Increased alanine aminotransferase353Increased alkaline phosphatase321Hypokalemia275Increased amylase 196Hypocalcemia143Hypermagnesemia43HematologyThrombocytopenia480Leukopenia382Lymphopenia367Anemia351Increased INR 213Neutropenia123a With at least 1 grade increase from baseline b Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter (range: 71 to 92 patients)6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of LENVIMA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Gastrointestinal: pancreatitis, increased amylaseGeneral: impaired wound healingHepatobiliary: cholecystitisRenal and Urinary: nephrotic syndromeVascular: arterial (including aortic) aneurysms, dissections, and rupture

Drug Interactions

7 DRUG INTERACTIONS7.1 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 Precautions (5.9)].

Use In Specific Populations

8 USE IN SPECIFIC POPULATIONSLactation: Advise not to breastfeed. (8.2)8.1 PregnancyRisk SummaryBased on its mechanism of action and data from animal reproduction studies, 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. DataAnimal DataIn 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% postimplantation 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 LactationRisk SummaryIt 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 infants, advise women to discontinue breastfeeding during treatment with LENVIMA and for at least 1 week after the last dose. DataAnimal DataFollowing 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 PotentialPregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating LENVIMA [see Use in Specific Populations (8.1)].ContraceptionBased on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. FemalesAdvise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.InfertilityLENVIMA may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].8.4 Pediatric UseThe safety and effectiveness of LENVIMA in pediatric patients have not been established.Juvenile Animal DataDaily 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 UseOf 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 62 patients with renal cell carcinoma (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.8.6 Renal ImpairmentNo dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose of lenvatinib for patients with RCC, DTC, or endometrial carcinoma and severe renal impairment [see Dosage and Administration (2.6)]. There is no recommended dose of LENVIMA for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].8.7 Hepatic ImpairmentNo dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate or severe hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C). Reduce the dose of lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].