ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS 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 )] 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.. 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) 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). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 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 randomized, placebo-controlled trial (SELECT). The median duration of exposure to LENVIMA across these five studies ranged from 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 presents adverse reactions occurring at 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 Between-Group Difference of >=5% in All Grades or >=2% in Grades and in SELECT (DTC)Adverse ReactionLENVIMA 24 mgN=261PlaceboN=131All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Vascular Hypertensiona 7344164Hypotension9220Gastrointestinal Diarrhea679170Nausea472251Stomatitisb 41580Vomiting362150Abdominal painc 312111Constipation290.4151Oral paind 25120Dry mouth170.480Dyspepsia130.440General Fatiguee 6711354Edema peripheral210.480Musculoskeletal and Connective Tissue Arthralgia/Myalgiaf 625283Metabolism and Nutrition Decreased appetite547181Decreased weight5113151Dehydration9221Nervous System Headache383111Dysgeusia18030Dizziness150.490Renal and Urinary Proteinuria341130Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia32310Rashg 210.430Alopecia12050Hyperkeratosis7020Respiratory, Thoracic and Mediastinal Dysphonia31150Cough240180Epistaxis12010Psychiatric Insomnia12030Infections Urinary tract infection11150Dental and oral infectionsh 10110Cardiac Electrocardiogram QT prolonged9220a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammationc Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain Includes oral pain, glossodynia, and oropharyngeal paine Includes asthenia, fatigue, and malaisef Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia Includes macular rash, maculo-papular rash, generalized rash, and rash Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infectionClinically important adverse reactions occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% were pulmonary embolism (3%, including fatal reports vs 2%, respectively) and osteonecrosis of the jaw (0.4% vs 0%, respectively).Laboratory abnormalities with difference of >=2% in Grade - events and at higher incidence in the LENVIMA arm are presented in Table 4.Table 4: Laboratory Abnormalities with Difference of >=2% in Grade - Events and at Higher Incidence in the LENVIMA Arma, in SELECT (DTC)Laboratory Abnormality LENVIMA 24 mgPlaceboGrades 3-4(%)Grades 3-4(%)ChemistryHypocalcemia92Hypokalemia61Increased aspartate aminotransferase (AST) 50Increased alanine aminotransferase (ALT) 40Increased lipase41Increased creatinine 30HematologyThrombocytopenia20a With at least 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 253 to 258), Placebo (n 129 to 131) The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at 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.First-Line Treatment of Renal Cell Carcinoma in Combination with Pembrolizumab (CLEAR)The safety of LENVIMA in combination with pembrolizumab was investigated in CLEAR [see Clinical Studies 14.2 )]. Patients received LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every weeks (n=352), or LENVIMA 18 mg orally once daily in combination with everolimus mg orally once daily (n=355), or sunitinib 50 mg orally once daily for weeks then off treatment for weeks (n=340). The median duration of exposure to the combination therapy of LENVIMA and pembrolizumab was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage.Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in >=2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (>=2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (>=5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).Tables and summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in >=20% of patients treated with LENVIMA and pembrolizumab in CLEAR.Table 5: Adverse Reactions in >=20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200mg N=352Sunitinib 50 mg N=340Adverse ReactionsAll Grades(%)Grade 3-4(%)All Grades(%)Grade 3-4(%)GeneralFatiguea 639568GastrointestinalDiarrheab 6210506Stomatitisc 432432Nausea363331Abdominal paind 272181Vomiting263201Constipation251190Musculoskeletal and connective tissueMusculoskeletal paine 584413EndocrineHypothyroidismf 571320VascularHypertensiong 56294320Hemorrhagic eventsh 275264MetabolismDecreased appetitei 414311Skin and subcutaneous tissueRashj 375171Palmar-plantar erythrodysaesthesia syndromek 294384Respiratory, thoracic, and mediastinalDysphonia30040Renal and urinaryProteinurial 308133Acute kidney injurym 215162InvestigationsWeight decreased30890Hepatobiliary Hepatotoxicityn 259215Nervous systemHeadache231161a Includes asthenia, fatigue, lethargy and malaiseb Includes diarrhea and gastroenteritisc Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitisd Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, and upper abdominal paine Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and pain in jawf Includes hypothyroidism, increased blood thyroid stimulating hormone and secondary hypothyroidismg Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressureh Includes all hemorrhage terms. Hemorrhage terms that occurred in or more subjects in either treatment group include: Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis hematoma hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, and upper gastrointestinal hemorrhagei Includes decreased appetite and early satietyj Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustulark Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema Includes hemoglobinuria, nephrotic syndrome, and proteinuriam Includes acute kidney injury, azotaemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininaemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxicn Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, and gamma-glutamyltransferase increasedClinically relevant adverse reactions (<20%) that occurred in patients receiving LENVIMA/pembrolizumab were myocardial infarction (3%) and angina pectoris (1%). Table 6: Laboratory Abnormalities in >=20% (All Grades) of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC)LENVIMA 20 mg in combination withPembrolizumab 200 mgSunitinib 50 mgLaboratory AbnormalityaAll Grades%bGrades 3-4%bAll Grades%bGrade 3-4%bChemistryHypertriglyceridemia80157115Hypercholesterolemia645431Increased lipase61345928Increased creatinine615612Increased amylase5917419Increased aspartate aminotransferase (AST)587573Hyperglycemia557483Increased alanine aminotransferase (ALT)527494Hyperkalemia449286Hypoglycemia442271Hyponatremia4112289Decreased albumin340.3220Increased alkaline phosphatase324321Hypocalcemia302221Hypophosphatemia297508Hypomagnesemia252153Increased creatine phosphokinase246365Hypermagnesemia232223Hypercalcemia211111HematologyLymphopenia5496615Thrombocytopenia3927313Anemia383668Leukopenia341778Neutropenia3147216a With at least 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/pembrolizumab (n= 343 to 349) and sunitinib (n= 329 to 335).Grade and increased ALT or AST was seen in 9% of patients. Grade >=2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received >=40 mg daily oral prednisone equivalent. Recurrence of Grade >=2 increased ALT or AST was observed in patients on rechallenge in patients receiving LENVIMA and 10 patients receiving both LENVIMA and pembrolizumab. Previously Treated Renal Cell Carcinoma in Combination with Everolimus (Study 205)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 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 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus arm. Study 205 was not designed to demonstrate 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 7.Table 7: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC) LENVIMA 18 mg with Everolimus mg N=62Everolimus 10 mg N=50Adverse ReactionsGrade 1-4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Endocrine Hypothyroidism24020Gastrointestinal Diarrhea8119342Vomiting487120Nausea455160Stomatitis/Oral inflammationa 442504Abdominal painb 37380Oral painc 23240Dyspepsia/Gastro-esophageal reflux210120Constipation160180General Fatigued 7318402Peripheral edema422200Pyrexia/Increased body temperature212102Metabolism and Nutrition Decreased appetite535180Decreased weight 34380Musculoskeletal and Connective Tissue Arthralgia/Myalgiae 555320Musculoskeletal chest pain18240Nervous System Headache192102Psychiatric Insomnia16220Renal and Urinary Proteinuria/Urine protein present318142Renal failure eventf 1810122Respiratory, Thoracic and Mediastinal Cough370300Dyspnea/Exertional dyspnea355288Dysphonia18040Skin and Subcutaneous Tissue Rashg 350400Vascular Hypertension/Increased blood pressure4213102Hemorrhagic eventsh 326262a Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulcerationb Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain Includes gingival pain, glossodynia, and oropharyngeal paind Includes asthenia, fatigue, lethargy and malaise Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgiaf Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic, renal failure, renal failure acute, and renal impairment Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash, and septic rash Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip hemorrhage, renal hematoma, and scrotal hematocele In Table 8, Grade 3-4 laboratory abnormalities occurring in >=3% of patients in the LENVIMA with everolimus arm are presented.Table 8: 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 mgwith Everolimus mgEverolimus 10 mgGrades 3-4(%)Grades 3-4(%)ChemistryHypertriglyceridemia1818Increased lipase 1312Hypercholesterolemia110Hyponatremia116Hypophosphatemia116Hyperkalemia62Hypocalcemia62Hypokalemia62Increased aspartate aminotransferase (AST) 30Increased alanine aminotransferase (ALT) 32Increased alkaline phosphatase 30Hyperglycemia316Increased creatine kinase 34HematologyLymphopenia1020Anemia816Thrombocytopenia50a With at least 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 baseline body weight of >=60 kg and mg orally once daily for patients with 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 summarizes the adverse reactions that occurred in >=10% of patients receiving LENVIMA in REFLECT. REFLECT was not designed to demonstrate statistically significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 9.Table 9: Adverse Reactions Occurring in >=10% of Patients in the LENVIMA Arm in REFLECT (HCC) Adverse ReactionLENVIMA mg/12 mg N=476 Sorafenib 800 mgN=475Grade 1-4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Endocrine Hypothyroidisma 210 30Gastrointestinal Diarrhea394464Abdominal painb 303284Nausea201141Vomiting16181Constipation161110Ascitesc 154113Stomatitisd 110.4141General Fatiguee 447366Pyrexiaf 150140.2Peripheral edema14170.2Metabolism and Nutrition Decreased appetite345271Decreased weight318223Musculoskeletal and Connective Tissue Arthralgia/Myalgiag 311202Nervous System Headache10180Renal and Urinary Proteinuriah 266122Respiratory, Thoracic and Mediastinal Dysphonia240.2120Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome2735211Rashi 140242Vascular Hypertensionj 45243115Hemorrhagic eventsk 234154a Includes hypothyroidism, blood thyroid stimulating hormone increased.b Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain Includes ascites and malignant ascitesd Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, and stomatitise Includes asthenia, fatigue, lethargy and malaisef Includes increased body temperature, pyrexiag Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, and myalgiah Includes proteinuria, increased urine protein, protein urine presenti Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash and rashj Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertensionk Includes all hemorrhage terms. Hemorrhage terms that occurred in 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 10, Grade 3-4 laboratory abnormalities occurring in >=2% of patients in the LENVIMA arm in REFLECT (HCC) are presented.Table 10: 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 creatinine22HematologyThrombocytopenia108Lymphopenia89Neutropenia73Anemia45a With at least grade increase from baselineb 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 in combination with pembrolizumab was investigated in Study 309, multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies 14.4 )]. Patients with endometrial carcinoma that are not MSI-H or dMMR received LENVIMA 20 mg orally once daily with pembrolizumab 200 mg intravenously every weeks (n=342); or received doxorubicin or paclitaxel (n= 325). For patients with not MSI-H or dMMR status, the median duration of study treatment was 7.2 months (range day to 26.8 months) and the median duration of exposure to LENVIMA was 6.7 months (range: day to 26.8 months). Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including cases of pneumonia, and case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency >=3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (>=1 %) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (>=5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%).Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (>=2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in patients receiving LENVIMA in Study 309.Table 11: Adverse Reactions in >=20% of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC) Endometrial Carcinoma (not MSI-H or dMMR)LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342Doxorubicin orPaclitaxelN=325Adverse ReactionAll Gradesa(%)Grades 3-4(%)All Gradesa(%)Grades 3-4(%)EndocrineHypothyroidismb 670.90.90VascularHypertensionc 673962.5Hemorrhagic eventsd 252.6150.9GeneralFatiguee 5811546GastrointestinalDiarrheaf 558202.8Nausea492.9471.5Vomiting372.3212.2Stomatitisg 352.6261.2Abdominal painh 342.6211.2Constipation270250.6Musculoskeletal and Connective TissueMusculoskeletal disordersi 535270.6MetabolismDecreased appetitej 447210InvestigationsDecreased weight341060.3Renal and UrinaryProteinuriak 2963.40.3InfectionsUrinary tract infectionl 315131.2Nervous SystemHeadache260.690.3Respiratory, Thoracic and MediastinalDysphonia2200.60Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesiam 232.90.90Rashn 202.34.90a Graded per NCI CTCAE v4.03 Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism, and secondary hypothyroidism Includes hypertension, blood pressure increased, hypertensive crisis, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, and blood pressure fluctuation Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, injection site hemorrhage, melena, purpura, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, coital bleeding, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, and vessel puncture site bruise Includes fatigue, asthenia, malaise, and lethargy Includes diarrhea and gastroenteritis Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, and tongue ulceration Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, and epigastric discomfort Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw Includes decreased appetite and early satiety Includes proteinuria, protein urine present, hemoglobinuria Includes urinary tract infection, cystitis, and pyelonephritis Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema, and skin reaction Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, and application site rashTable 12: Laboratory Abnormalities Worsened from Baselinea Occurring in >=20% (All Grades) or >=3% (Grades 3-4) of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC)Endometrial Carcinoma (not MSI-H or dMMR)LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342Doxorubicin orPaclitaxelN=325Laboratory TestbAll Gradesc(%)Grades 3-4(%)All Gradesc(%)Grades 3-4(%)ChemistryHypertriglyceridemia706451.7Hypoalbuminemia602.7421.6Increased aspartate aminotransferase589231.6Hyperglycemia588454.4Hypomagnesemia536323.8Increased alanine aminotransferase559211.2Hypercholesteremia533.2230.7Hyponatremia4615287Increased alkaline phosphatase434.7180.9Hypocalcemia404.7211.7Increased lipase3614133.9Increased creatinine354.7181.9Hypokalemia3410245Hypophosphatemia268173.2Increased amylase25781Hyperkalemia232.4121.2Increased creatine kinase193.770Increased bilirubin183.661.6HematologyLymphopenia50166520Thrombocytopenia508304.7Anemia4988414Leukopenia433.58343Neutropenia3167658a With at least 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/pembrolizumab (range: 312 to 404 patients) and doxorubicin or paclitaxel (280 to 380). Graded per NCI CTCAE v4.03. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of LENVIMA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Gastrointestinal: pancreatitis, increased amylaseGeneral: impaired wound healingHepatobiliary: cholecystitisRenal and Urinary: nephrotic syndromeVascular: arterial (including aortic) aneurysms, dissections, and rupture.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 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 randomized, placebo-controlled trial (SELECT). The median duration of exposure to LENVIMA across these five studies ranged from 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 presents adverse reactions occurring at 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 Between-Group Difference of >=5% in All Grades or >=2% in Grades and in SELECT (DTC)Adverse ReactionLENVIMA 24 mgN=261PlaceboN=131All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Vascular Hypertensiona 7344164Hypotension9220Gastrointestinal Diarrhea679170Nausea472251Stomatitisb 41580Vomiting362150Abdominal painc 312111Constipation290.4151Oral paind 25120Dry mouth170.480Dyspepsia130.440General Fatiguee 6711354Edema peripheral210.480Musculoskeletal and Connective Tissue Arthralgia/Myalgiaf 625283Metabolism and Nutrition Decreased appetite547181Decreased weight5113151Dehydration9221Nervous System Headache383111Dysgeusia18030Dizziness150.490Renal and Urinary Proteinuria341130Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia32310Rashg 210.430Alopecia12050Hyperkeratosis7020Respiratory, Thoracic and Mediastinal Dysphonia31150Cough240180Epistaxis12010Psychiatric Insomnia12030Infections Urinary tract infection11150Dental and oral infectionsh 10110Cardiac Electrocardiogram QT prolonged9220a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammationc Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain Includes oral pain, glossodynia, and oropharyngeal paine Includes asthenia, fatigue, and malaisef Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia Includes macular rash, maculo-papular rash, generalized rash, and rash Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infectionClinically important adverse reactions occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% were pulmonary embolism (3%, including fatal reports vs 2%, respectively) and osteonecrosis of the jaw (0.4% vs 0%, respectively).Laboratory abnormalities with difference of >=2% in Grade - events and at higher incidence in the LENVIMA arm are presented in Table 4.Table 4: Laboratory Abnormalities with Difference of >=2% in Grade - Events and at Higher Incidence in the LENVIMA Arma, in SELECT (DTC)Laboratory Abnormality LENVIMA 24 mgPlaceboGrades 3-4(%)Grades 3-4(%)ChemistryHypocalcemia92Hypokalemia61Increased aspartate aminotransferase (AST) 50Increased alanine aminotransferase (ALT) 40Increased lipase41Increased creatinine 30HematologyThrombocytopenia20a With at least 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 253 to 258), Placebo (n 129 to 131) The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at 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.First-Line Treatment of Renal Cell Carcinoma in Combination with Pembrolizumab (CLEAR)The safety of LENVIMA in combination with pembrolizumab was investigated in CLEAR [see Clinical Studies 14.2 )]. Patients received LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every weeks (n=352), or LENVIMA 18 mg orally once daily in combination with everolimus mg orally once daily (n=355), or sunitinib 50 mg orally once daily for weeks then off treatment for weeks (n=340). The median duration of exposure to the combination therapy of LENVIMA and pembrolizumab was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage.Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in >=2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (>=2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (>=5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).Tables and summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in >=20% of patients treated with LENVIMA and pembrolizumab in CLEAR.Table 5: Adverse Reactions in >=20% of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC) LENVIMA 20 mg in combination with Pembrolizumab 200mg N=352Sunitinib 50 mg N=340Adverse ReactionsAll Grades(%)Grade 3-4(%)All Grades(%)Grade 3-4(%)GeneralFatiguea 639568GastrointestinalDiarrheab 6210506Stomatitisc 432432Nausea363331Abdominal paind 272181Vomiting263201Constipation251190Musculoskeletal and connective tissueMusculoskeletal paine 584413EndocrineHypothyroidismf 571320VascularHypertensiong 56294320Hemorrhagic eventsh 275264MetabolismDecreased appetitei 414311Skin and subcutaneous tissueRashj 375171Palmar-plantar erythrodysaesthesia syndromek 294384Respiratory, thoracic, and mediastinalDysphonia30040Renal and urinaryProteinurial 308133Acute kidney injurym 215162InvestigationsWeight decreased30890Hepatobiliary Hepatotoxicityn 259215Nervous systemHeadache231161a Includes asthenia, fatigue, lethargy and malaiseb Includes diarrhea and gastroenteritisc Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitisd Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, and upper abdominal paine Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and pain in jawf Includes hypothyroidism, increased blood thyroid stimulating hormone and secondary hypothyroidismg Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressureh Includes all hemorrhage terms. Hemorrhage terms that occurred in or more subjects in either treatment group include: Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis hematoma hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, and upper gastrointestinal hemorrhagei Includes decreased appetite and early satietyj Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustulark Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema Includes hemoglobinuria, nephrotic syndrome, and proteinuriam Includes acute kidney injury, azotaemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininaemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxicn Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, and gamma-glutamyltransferase increasedClinically relevant adverse reactions (<20%) that occurred in patients receiving LENVIMA/pembrolizumab were myocardial infarction (3%) and angina pectoris (1%). Table 6: Laboratory Abnormalities in >=20% (All Grades) of Patients on LENVIMA plus Pembrolizumab in CLEAR (RCC)LENVIMA 20 mg in combination withPembrolizumab 200 mgSunitinib 50 mgLaboratory AbnormalityaAll Grades%bGrades 3-4%bAll Grades%bGrade 3-4%bChemistryHypertriglyceridemia80157115Hypercholesterolemia645431Increased lipase61345928Increased creatinine615612Increased amylase5917419Increased aspartate aminotransferase (AST)587573Hyperglycemia557483Increased alanine aminotransferase (ALT)527494Hyperkalemia449286Hypoglycemia442271Hyponatremia4112289Decreased albumin340.3220Increased alkaline phosphatase324321Hypocalcemia302221Hypophosphatemia297508Hypomagnesemia252153Increased creatine phosphokinase246365Hypermagnesemia232223Hypercalcemia211111HematologyLymphopenia5496615Thrombocytopenia3927313Anemia383668Leukopenia341778Neutropenia3147216a With at least 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/pembrolizumab (n= 343 to 349) and sunitinib (n= 329 to 335).Grade and increased ALT or AST was seen in 9% of patients. Grade >=2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received >=40 mg daily oral prednisone equivalent. Recurrence of Grade >=2 increased ALT or AST was observed in patients on rechallenge in patients receiving LENVIMA and 10 patients receiving both LENVIMA and pembrolizumab. Previously Treated Renal Cell Carcinoma in Combination with Everolimus (Study 205)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 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 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus arm. Study 205 was not designed to demonstrate 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 7.Table 7: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with Everolimus Arm in Study 205 (RCC) LENVIMA 18 mg with Everolimus mg N=62Everolimus 10 mg N=50Adverse ReactionsGrade 1-4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Endocrine Hypothyroidism24020Gastrointestinal Diarrhea8119342Vomiting487120Nausea455160Stomatitis/Oral inflammationa 442504Abdominal painb 37380Oral painc 23240Dyspepsia/Gastro-esophageal reflux210120Constipation160180General Fatigued 7318402Peripheral edema422200Pyrexia/Increased body temperature212102Metabolism and Nutrition Decreased appetite535180Decreased weight 34380Musculoskeletal and Connective Tissue Arthralgia/Myalgiae 555320Musculoskeletal chest pain18240Nervous System Headache192102Psychiatric Insomnia16220Renal and Urinary Proteinuria/Urine protein present318142Renal failure eventf 1810122Respiratory, Thoracic and Mediastinal Cough370300Dyspnea/Exertional dyspnea355288Dysphonia18040Skin and Subcutaneous Tissue Rashg 350400Vascular Hypertension/Increased blood pressure4213102Hemorrhagic eventsh 326262a Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulcerationb Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain Includes gingival pain, glossodynia, and oropharyngeal paind Includes asthenia, fatigue, lethargy and malaise Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgiaf Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic, renal failure, renal failure acute, and renal impairment Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash, and septic rash Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip hemorrhage, renal hematoma, and scrotal hematocele In Table 8, Grade 3-4 laboratory abnormalities occurring in >=3% of patients in the LENVIMA with everolimus arm are presented.Table 8: 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 mgwith Everolimus mgEverolimus 10 mgGrades 3-4(%)Grades 3-4(%)ChemistryHypertriglyceridemia1818Increased lipase 1312Hypercholesterolemia110Hyponatremia116Hypophosphatemia116Hyperkalemia62Hypocalcemia62Hypokalemia62Increased aspartate aminotransferase (AST) 30Increased alanine aminotransferase (ALT) 32Increased alkaline phosphatase 30Hyperglycemia316Increased creatine kinase 34HematologyLymphopenia1020Anemia816Thrombocytopenia50a With at least 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 baseline body weight of >=60 kg and mg orally once daily for patients with 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 summarizes the adverse reactions that occurred in >=10% of patients receiving LENVIMA in REFLECT. REFLECT was not designed to demonstrate statistically significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 9.Table 9: Adverse Reactions Occurring in >=10% of Patients in the LENVIMA Arm in REFLECT (HCC) Adverse ReactionLENVIMA mg/12 mg N=476 Sorafenib 800 mgN=475Grade 1-4(%)Grade 3-4(%)Grade 1-4(%)Grade 3-4(%)Endocrine Hypothyroidisma 210 30Gastrointestinal Diarrhea394464Abdominal painb 303284Nausea201141Vomiting16181Constipation161110Ascitesc 154113Stomatitisd 110.4141General Fatiguee 447366Pyrexiaf 150140.2Peripheral edema14170.2Metabolism and Nutrition Decreased appetite345271Decreased weight318223Musculoskeletal and Connective Tissue Arthralgia/Myalgiag 311202Nervous System Headache10180Renal and Urinary Proteinuriah 266122Respiratory, Thoracic and Mediastinal Dysphonia240.2120Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome2735211Rashi 140242Vascular Hypertensionj 45243115Hemorrhagic eventsk 234154a Includes hypothyroidism, blood thyroid stimulating hormone increased.b Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain Includes ascites and malignant ascitesd Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, and stomatitise Includes asthenia, fatigue, lethargy and malaisef Includes increased body temperature, pyrexiag Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, and myalgiah Includes proteinuria, increased urine protein, protein urine presenti Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash, pustular rash and rashj Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertensionk Includes all hemorrhage terms. Hemorrhage terms that occurred in 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 10, Grade 3-4 laboratory abnormalities occurring in >=2% of patients in the LENVIMA arm in REFLECT (HCC) are presented.Table 10: 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 creatinine22HematologyThrombocytopenia108Lymphopenia89Neutropenia73Anemia45a With at least grade increase from baselineb 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 in combination with pembrolizumab was investigated in Study 309, multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies 14.4 )]. Patients with endometrial carcinoma that are not MSI-H or dMMR received LENVIMA 20 mg orally once daily with pembrolizumab 200 mg intravenously every weeks (n=342); or received doxorubicin or paclitaxel (n= 325). For patients with not MSI-H or dMMR status, the median duration of study treatment was 7.2 months (range day to 26.8 months) and the median duration of exposure to LENVIMA was 6.7 months (range: day to 26.8 months). Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including cases of pneumonia, and case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency >=3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (>=1 %) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (>=5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%).Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (>=2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in patients receiving LENVIMA in Study 309.Table 11: Adverse Reactions in >=20% of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC) Endometrial Carcinoma (not MSI-H or dMMR)LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342Doxorubicin orPaclitaxelN=325Adverse ReactionAll Gradesa(%)Grades 3-4(%)All Gradesa(%)Grades 3-4(%)EndocrineHypothyroidismb 670.90.90VascularHypertensionc 673962.5Hemorrhagic eventsd 252.6150.9GeneralFatiguee 5811546GastrointestinalDiarrheaf 558202.8Nausea492.9471.5Vomiting372.3212.2Stomatitisg 352.6261.2Abdominal painh 342.6211.2Constipation270250.6Musculoskeletal and Connective TissueMusculoskeletal disordersi 535270.6MetabolismDecreased appetitej 447210InvestigationsDecreased weight341060.3Renal and UrinaryProteinuriak 2963.40.3InfectionsUrinary tract infectionl 315131.2Nervous SystemHeadache260.690.3Respiratory, Thoracic and MediastinalDysphonia2200.60Skin and Subcutaneous TissuePalmar-plantar erythrodysesthesiam 232.90.90Rashn 202.34.90a Graded per NCI CTCAE v4.03 Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism, and secondary hypothyroidism Includes hypertension, blood pressure increased, hypertensive crisis, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, and blood pressure fluctuation Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, injection site hemorrhage, melena, purpura, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, coital bleeding, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, and vessel puncture site bruise Includes fatigue, asthenia, malaise, and lethargy Includes diarrhea and gastroenteritis Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, and tongue ulceration Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, and epigastric discomfort Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw Includes decreased appetite and early satiety Includes proteinuria, protein urine present, hemoglobinuria Includes urinary tract infection, cystitis, and pyelonephritis Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema, and skin reaction Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, and application site rashTable 12: Laboratory Abnormalities Worsened from Baselinea Occurring in >=20% (All Grades) or >=3% (Grades 3-4) of Patients Receiving LENVIMA plus Pembrolizumab in Study 309 (EC)Endometrial Carcinoma (not MSI-H or dMMR)LENVIMA 20 mg in combination with Pembrolizumab 200 mg N=342Doxorubicin orPaclitaxelN=325Laboratory TestbAll Gradesc(%)Grades 3-4(%)All Gradesc(%)Grades 3-4(%)ChemistryHypertriglyceridemia706451.7Hypoalbuminemia602.7421.6Increased aspartate aminotransferase589231.6Hyperglycemia588454.4Hypomagnesemia536323.8Increased alanine aminotransferase559211.2Hypercholesteremia533.2230.7Hyponatremia4615287Increased alkaline phosphatase434.7180.9Hypocalcemia404.7211.7Increased lipase3614133.9Increased creatinine354.7181.9Hypokalemia3410245Hypophosphatemia268173.2Increased amylase25781Hyperkalemia232.4121.2Increased creatine kinase193.770Increased bilirubin183.661.6HematologyLymphopenia50166520Thrombocytopenia508304.7Anemia4988414Leukopenia433.58343Neutropenia3167658a With at least 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/pembrolizumab (range: 312 to 404 patients) and doxorubicin or paclitaxel (280 to 380). Graded per NCI CTCAE v4.03.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Capsules: mg: yellowish-red body and yellowish-red cap, marked in black ink with on cap and LENV mg on body. 10 mg: yellow body and yellowish-red cap, marked in black ink with on cap and LENV 10 mg on body.. mg: yellowish-red body and yellowish-red cap, marked in black ink with on cap and LENV mg on body. 10 mg: yellow body and yellowish-red cap, marked in black ink with on cap and LENV 10 mg on body.. Capsules: mg and 10 mg. (3).

DRUG INTERACTIONS SECTION.

7 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 known potential to prolong the QT/QTc interval see Warnings and Precaution ( 5.9 ].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Pregnancy 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 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 )].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of ertility Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the AUC at the recommended clinical dose of 24 mg once daily. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the AUC at the recommended clinical dose of 24 mg once daily, respectively. In addition, in monkeys, decreased incidence of menstruation was reported at lenvatinib exposures lower than those observed in humans at the recommended clinical dose of 24 mg once daily.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lenvatinib is 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 (PDGFR), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate (FRS2) phosphorylation. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic 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. 12.2 Pharmacodynamics Exposure-Response RelationshipsIn multicenter randomized (1:1) double blind trial of 152 patients with radioactive iodine (RAI)-refractory DTC, dose-response relationship for overall response rate (ORR) was observed over the dose range of 18 mg (0.75 times the recommended dose of 24 mg) and 24 mg. higher ORR was observed at the recommended lenvatinib dose.No dose-response relationships for adverse reactions, serious adverse reactions, adverse reactions leading to study drug discontinuation, and adverse reactions leading to study drug interruption were observed over the same dose range.. 12.3 Pharmacokinetics In patients with solid tumors administered single and multiple doses of LENVIMA once daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 mg (0.1 times the recommended clinical dose of 24 mg) to 32 mg (1.33 times the recommended clinical dose of 24 mg) with median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg). Geometric mean Cmax and AUC values at steady state for RCC, DTC and HCC are summarized in the Table 13.Table 13: Lenvatinib Cmax and AUC in Patients with Solid TumorsaTumor TypeDoseParameterNGeometric Mean%CVRCC 18 mgCmax (ng/mL)35026736.7AUC (ngh/mL)350314842.5 20 mgCmax (ng/mL)34627532.6AUC (ngh/mL)346313541.3DTC 24 mgCmax (ng/mL)25132333.3AUC (ngh/mL)251348334.7HCC (body weight 60 kg) mgCmax (ng/mL)15015425.4AUC (ngh/mL)150183534.0HCC (body weight >= 60 kg) 12 mgCmax (ng/mL)31817223.1AUC (ngh/mL)318201329.3a Model-predicted steady-state pharmacokinetic parameters are presented. AbsorptionThe time to peak plasma concentration (Tmax) typically occurred from to hours post-dose. Food EffectAdministration with high fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from hours to hours. DistributionModel-predicted geometric mean steady state volume of distribution is 97 (%CV, 30.2%). Protein binding of lenvatinib is 97% to 99%, which is independent of concentration, and is not impacted by hepatic or renal function. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 ug/mL in vitro. EliminationThe terminal elimination half-life of lenvatinib was approximately 28 hours. MetabolismThe main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. ExcretionTen days after single administration of radiolabeled lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively. Specific PopulationsAge (18 to 92 years), sex, race/ethnicity (White, Black and Asian), tumor types (DTC, RCC, HCC and other tumor types) and renal impairment (creatinine clearance: 15-89 mL/min) did not have significant effect on apparent oral clearance (CL/F). Subjects with end stage renal disease were not studied. Patients with Hepatic ImpairmentThe pharmacokinetics of lenvatinib following single 10 mg dose were evaluated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of single mg dose were evaluated in subjects with severe (Child-Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively. Apparent oral clearance of lenvatinib in patients with HCC and mild hepatic impairment was similar to patients with HCC and moderate hepatic impairment.Body WeightLenvatinib exposures in patients with HCC in REFLECT were comparable between those weighing <60 kg who received starting dose of mg and those >=60 kg who received starting dose of 12 mg.Drug Interaction StudiesEffect of Other Drugs on LenvatinibCYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg daily for 18 days) increased lenvatinib (administered as single mg dose on Day 5) AUC by 15% and Cmax by 19%. P-gp Inhibitor: Rifampicin (600 mg as single dose) increased lenvatinib (24 mg as single dose) AUC by 31% and Cmax by 33%. CYP3A and P-gp Inducers: Rifampicin (600 mg daily for 21 days) decreased lenvatinib (24 mg as single dose on Day 15) AUC by 18%. The Cmax was unchanged.Population pharmacokinetic analysis demonstrated that neither everolimus nor pembrolizumab meaningfully affect the pharmacokinetics of lenvatinib.In Vitro Studies with Transporters: Lenvatinib is substrate of P-gp and BCRP but not substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, MATE2-K, or the bile salt export pump (BSEP). Effect of Lenvatinib on Other DrugsCYP2C8 Substrate: There is no projected significant drug-drug interaction risk between lenvatinib and repaglinide.CYP3A4 Substrate: Co-administration of lenvatinib with midazolam had no effect on the pharmacokinetics of midazolam. Population pharmacokinetic analysis demonstrated that lenvatinib does not meaningfully affect the pharmacokinetics of either everolimus or pembrolizumab.In Vitro Studies with Substrates of CYP or UDP-glucuronosyltransferase (UGT): Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Lenvatinib does not inhibit CYP2A6 and CYP2E1. Lenvatinib induces CYP3A, but it does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme in tissues. Lenvatinib does not inhibit UGT1A6, UGT2B7 or aldehyde oxidase. Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7. In Vitro Studies with Substrates of Transporters: Lenvatinib does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. 14.1 Differentiated Thyroid ancer A multicenter, randomized (2:1), double-blind, placebo-controlled study (SELECT; NCT01321554) was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review. Radioactive iodine (RAI)-refractory was defined as or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity >600 mCi (22 GBq) with the last dose administered at least months prior to study entry. Patients were randomized to receive LENVIMA 24 mg once daily (n=261) or placebo (n=131) until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age. The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Independent review confirmation of disease progression was required prior to discontinuing patients from the randomization phase of the study. Other efficacy outcome measures included objective response rate (ORR) and overall survival (OS). Patients in the placebo arm could receive lenvatinib following independent review confirmation of disease progression.Of the 392 patients randomized, 51% were male, the median age was 63 years, 40% were 65 years or older, 79% were White, 54% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, and 24% had received prior VEGF/VEGFR-targeted therapy. Metastases were present in 99% of the patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. The histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had Hurthle cell and 11% had clear cell subtypes. In the LENVIMA arm, 67% of patients did not demonstrate iodine uptake on any RAI scan compared to 77% in the placebo arm. Additionally, 59% of patients on the LENVIMA arm and 61% of patients on placebo arm progressed, according to RECIST 1.1, within 12 months of prior 131 therapy; 19.2% of patients on the LENVIMA arm and 17.6% of patients on placebo arm received prior cumulative activity of >600 mCi or 22 GBq 131, with the last dose administered at least months prior to study entry. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq). statistically significant prolongation in PFS was demonstrated in LENVIMA-treated patients compared to those receiving placebo (Table 14 and Figure 1). Upon confirmation of progression, 83% of patients that were randomly assigned to placebo crossed over to receive open-label LENVIMA.Table 14: Efficacy Results in Differentiated Thyroid Cancer in SELECT LENVIMAN=261PlaceboN=131Progression-Free Survival (PFS)aNumber of events (%)107 (41)113 (86) Progressive disease93 (36)109 (83) Death14 (5)4 (3)Median PFS in months (95% CI)18.3 (15.1, NE)3.6 (2.2, 3.7)Hazard ratio (95% CI)b 0.21 (0.16, 0.28)P-valuec <0.001Objective Response RateaObjective response rate 65%2%(95% CI)(59%, 71%)(0%, 4%)Complete response 2%0%Partial response 63%2%P-valued <0.001Overall Survival (OS)eNumber of deaths (%)71 (27)47 (36)Median OS in months (95% CI)NE (22.1, NE)NE (20.3, NE)Hazard ratio (95% CI)b 0.73 (0.50, 1.07)P-valueb 0.10a Independent radiologic reviewb Estimated with Cox proportional hazard model stratified by region (Europe vs North America vs other), age group (<=65 years vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1)c Log-rank test stratified by region (Europe vs North America vs other), age group (<=65 years vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1)d Cochran-Mantel-Haenszel chi-square teste NE Not estimableFigure 1: Kaplan-Meier Curves for Progression-Free Survival in SELECT 14.2 Renal Cell Carcinoma First-Line Treatment of Patients with RCC in Combination with Pembrolizumab (CLEAR)The efficacy of LENVIMA in combination with pembrolizumab was investigated in CLEAR (NCT02811861), multicenter, open-label, randomized trial that enrolled 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America and Western Europe versus Rest of the World) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable, intermediate and poor risk).Patients were randomized (1:1:1) to one of the following treatment arms:LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every weeks up to 24 months. LENVIMA 18 mg orally once daily in combination with everolimus mg orally once daily. Sunitinib 50 mg orally once daily for weeks then off treatment for weeks.Treatment continued until unacceptable toxicity or disease progression. Administration of LENVIMA with pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Pembrolizumab dosing was continued for maximum of 24 months; however, treatment with LENVIMA could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every weeks.The study population characteristics were: median age of 62 years (range: 29 to 88 years); 42% age 65 or older, 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. LENVIMA in combination with pembrolizumab demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. Table 15 and Figures and summarize the efficacy results for CLEAR. Table 15: Efficacy Results in Renal Cell Carcinoma Per IRC in CLEARLENVIMA20 mg with Pembrolizumab 200mg N=355Sunitinib 50mgN=357Progression-Free Survival (PFS)Number of events, (%)160 (45%)205 (57%)Progressive disease145 (41%)196 (55%)Death15 (4%)9 (3%)Median PFS in months (95% CI)23.9 (20.8, 27.7)9.2 (6.0, 11.0)Hazard Ratioa (95% CI)0.39 (0.32, 0.49)p-valueb <0.0001Overall Survival (OS)Number of deaths, (%)80 (23%)101 (28%)Median OS in months (95% CI)NR (33.6, NE)NR (NE, NE)Hazard Ratioa (95% CI)0.66 (0.49, 0.88)p-valueb 0.0049Objective Response Rate (Confirmed)Objective response rate, (%)252 (71%)129 (36%)(95% CI)(66, 76)(31, 41) Complete response rate 16%4% Partial responses rate 55%32%p-valuec <0.0001Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR.Data cutoff date 28 Aug 2020CI confidence interval; NE= Not estimable; NR= Not reacheda Hazard ratio is based on Cox Proportional Hazards Model, stratified by geographic region and MSKCC prognostic groups. Two-sided p-value based on stratified log-rank test.c Two-sided p-value based upon CMH test. Figure 2: Kaplan-Meier Curves for Progression-Free Survival in CLEARL+P Lenvatinib Pembrolizumab; = Sunitinib.Figure 3: Kaplan-Meier Curves for Overall Survival in CLEAR L+P Lenvatinib Pembrolizumab; = Sunitinib.Previously Treated RCC in Combination with Everolimus (Study 205)The efficacy was evaluated in multicenter, randomized (1:1:1) study (Study 205: NCT01136733), in which 153 patients with advanced or metastatic renal cell carcinoma who have previously received anti-angiogenic therapy received LENVIMA 18 mg orally once daily with everolimus mg orally once daily, LENVIMA 24 mg orally once daily, or everolimus 10 mg orally once daily. Patients were required to have histological confirmation of clear cell RCC and ECOG PS of or 1. Patients were stratified by hemoglobin level (<= or >13 g/dL for males and <= or >11.5 g/dL for females) and corrected serum calcium (>=10 mg/dL vs. <10 mg/dL). The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST 1.1. Of the 101 patients randomized to the LENVIMA with everolimus arm or everolimus arm, 72% were male, the median age was 60 years, 31% were older than 65 years, and 96% were White. Metastases were present in 95% of the patients and unresectable advanced disease was present in 5%. All patients had baseline ECOG PS of either (54%) or (46%) with similar distribution across these two treatment arms. MSKCC favorable, intermediate, and poor risk categories were observed respectively, in 24%, 37%, and 39% of patients in the LENVIMA with everolimus arm, and 24%, 38%, and 38% of patients in the everolimus arm. Efficacy results from Study 205 are summarized in Table 16 and Figures and 5. The treatment effect of the combination on PFS was supported by retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.43 (95% CI: 0.24, 0.75) compared with the everolimus arm.Table 16: Efficacy Results in Renal Cell Carcinoma Per Investigator Assessment in Study 205 LENVIMA 18 mg with Everolimus mgN=51Everolimus 10 mgN=50Progression-Free Survival (PFS)aNumber of events, (%)26 (51)37 (74) Progressive disease21 (41)35 (70) Death5 (10)2 (4)Median PFS in months (95% CI)14.6 (5.9, 20.1)5.5 (3.5, 7.1)Hazard Ratio (95% CI)b LENVIMA with Everolimus vs Everolimus0.37 (0.22, 0.62) -Overall Survival (OS)cNumber of deaths, (%)32 (63)37 (74)Median OS in months (95% CI)25.5 (16.4, 32.1)15.4 (11.8, 20.6)Hazard Ratio (95% CI)b LENVIMA with Everolimus vs Everolimus0.67 (0.42, 1.08) -Objective Response Rate (Confirmed)Objective response rate, (%)19 (37)3 (6) (95% CI)(24, 52)(1, 17)Number of complete responses, (%)1 (2)0Number of partial responses (%)18 (35)3 (6)Tumor assessments were based on RECIST v1.1 criteria for progression but only confirmed responses are included for ORR. Data cutoff date 13 Jun 2014CI confidence intervala Point estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation.b Hazard ratio is based on stratified Cox regression model including treatment as covariate factor and hemoglobin and corrected serum calcium as strata. Data cutoff date 31 Jul 2015Figure 4: Kaplan-Meier Curves for Progression-Free Survival in Study 205 Figure 5: Kaplan-Meier Curves for Overall Survival in Study 205 LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every weeks up to 24 months. LENVIMA 18 mg orally once daily in combination with everolimus mg orally once daily. Sunitinib 50 mg orally once daily for weeks then off treatment for weeks.. 14.3 Hepatocellular Carcinoma. The efficacy of LENVIMA was evaluated in randomized, open-label, multicenter, international study (REFLECT; NCT01761266) conducted in patients with previously untreated unresectable hepatocellular carcinoma (HCC). The study enrolled adults with Child-Pugh and Barcelona Clinic Liver Cancer (BCLC) Stage or HCC who were ineligible for local liver-directed therapy; had an ECOG PS of or 1; had received no prior systemic therapy for HCC; and had at least one measurable target lesion according to modified RECIST for HCC.Patients were randomized (1:1) to receive LENVIMA (12 mg for baseline body weight >=60 kg or mg for baseline body weight <60 kg) orally once daily or sorafenib 400 mg orally twice daily until radiological disease progression or unacceptable toxicity. Randomization was stratified by region (Western vs Asia Pacific), presence of macroscopic portal vein invasion or extrahepatic spread (yes vs no), ECOG PS (0 vs 1), and body weight (<60 kg vs >=60 kg). The major efficacy outcome measure was overall survival (OS). REFLECT was designed to show the non-inferiority of LENVIMA to sorafenib for OS. Additional efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR) according to modified RECIST for HCC. total of 954 patients were randomized, 478 to the LENVIMA arm and 476 to the sorafenib arm. The demographics of the study population were: median age of 62 years (range: 20 to 88 years); 84% male; 69% Asian and 29% White; 63% ECOG PS of 0; and 69% weighed >=60 kg. Of the 590 (62%) patients with at least one site of documented distant metastatic disease, 52% had lung metastasis, 45% had lymph node metastasis, and 16% had bone metastasis.Macroscopic portal vein invasion, extra-hepatic spread, or both were present in 70% of patients. HCC was categorized as Child-Pugh and BCLC Stage in 79% and Child-Pugh and BCLC Stage in 21% of patients. Seventy-five percent (75%) of patients had radiographic evidence of cirrhosis at baseline. Investigator-documented primary risk factors for the development of HCC were hepatitis (50%), hepatitis (23%), alcohol use (6%), other (7%), and unknown (14%). REFLECT demonstrated that LENVIMA was non-inferior to sorafenib for OS. REFLECT did not demonstrate statistically significant improvement in OS for patients randomized to LENVIMA as compared to those in the sorafenib arm. LENVIMA was statistically significantly superior to sorafenib for PFS and ORR. Efficacy results are summarized in Table 17 and Figure 6.Table 17: Efficacy Results in Hepatocellular Carcinoma in REFLECT LENVIMA N= 478SorafenibN=476Overall Survival Number of deaths (%)351 (73)350 (74)Median OS in months (95% CI)13.6 (12.1, 14.9)12.3 (10.4, 13.9)Hazard Ratio (95% CI)a 0.92 (0.79, 1.06)Progression-Free Survivalb (mRECIST)Number of Events (%)311 (65)323 (68)Median PFS in months (95% CI)7.3 (5.6, 7.5)3.6 (3.6, 3.7)Hazard Ratio (95% CI)0.64 (0.55, 0.75)P-value<0.001Objective Response Rateb (mRECIST)Objective response rate 41%12%Complete responses, (%)10 (2.1)4 (0.8)Partial responses, (%)184 (38.5)55 (11.6)95% CI(36%, 45%)(10%, 16%)P-value<0.001Progression-Free Survivalb (RECIST 1.1)Number of Events (%)307 (64)320 (67)Median PFS in months (95% CI)7.3 (5.6, 7.5)3.6 (3.6, 3.9)Hazard Ratio (95% CI)0.65 (0.56, 0.77)Objective Response Rateb (RECIST 1.1)Objective response rate 19%7%Complete responses, (%)2 (0.4)1 (0.2)Partial responses, (%)88 (18.4)30 (6.3)95% CI(15%, 22%)(4%, 9%)CI confidence interval; ECOG PS Eastern Cooperative Oncology Group Performance Status; HR hazard ratio; OS overall survival.a Based on stratified Cox-model. Non-inferiority margin for HR (lenvatinib vs sorafenib) is 1.08.b Per independent radiology review. Figure 6: Kaplan-Meier Curves for Overall Survival in REFLECT 14.4 Endometrial Carcinoma (EC). The efficacy of LENVIMA in combination with pembrolizumab was investigated in Study 309 (NCT03517449), multicenter, open-label, randomized, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were not MSI-H or dMMR were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomized (1:1) to one of the following treatment arms:LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every weeks. Investigators choice consisting of either doxorubicin 60 mg/m2 every weeks, or paclitaxel 80 mg/m2 given weekly, weeks on/1 week off.Treatment with LENVIMA and pembrolizumab continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for pembrolizumab, maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated. Assessment of tumor status was performed every weeks. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ. Additional efficacy outcome measures included ORR and DOR, as assessed by BICR.Among the 697 not MSI-H or dMMR patients, 346 patients were randomized to LENVIMA in combination with pembrolizumab, and 351 patients were randomized to investigators choice of doxorubicin (n=254) or paclitaxel (n=97). The population characteristics of these patients were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy.Efficacy results for these patients are summarized in Table 18 and Figures and 8.Table 18: Efficacy Results in Endometrial Carcinoma in Study 309Endometrial Carcinoma (not MSI-H or dMMR)EndpointLENVIMA with pembrolizumabN=346Doxorubicin or PaclitaxelN=351OSNumber (%) of patients with event 165 (48%)203 (58%)Median in months (95% CI)17.4 (14.2, 19.9)12.0 (10.8, 13.3)Hazard ratioa (95% CI)0.68 (0.56, 0.84)p-Valueb 0.0001PFScNumber (%) of patients with event 247 (71%)238 (68%)Median in months (95% CI)6.6 (5.6, 7.4)3.8 (3.6, 5.0)Hazard ratioa (95% CI)0.60 (0.50, 0.72)p-Valueb <0.0001Objective Response RateORRc (95% CI)30% (26, 36)15% (12,19)Complete response5%3%Partial response25%13%p-Valued <0.0001Duration of ResponseN=105N=53Median in months (range)9.2 (1.6+, 23.7+)5.7 (0.0+, 24.2+) Based on the stratified Cox regression model Based on stratified log-rank test Per independent radiology review Based on Miettinen and Nurminen method stratified by ECOG performance status, geographic region, and history of pelvic radiationFigure 7: Kaplan-Meier Curves for Overall Survival in Study 309(not MSI-H or dMMR)Figure 8: Kaplan-Meier Curves for Progression-Free Survival in Study 309(not MSI-H or dMMR). LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every weeks. Investigators choice consisting of either doxorubicin 60 mg/m2 every weeks, or paclitaxel 80 mg/m2 given weekly, weeks on/1 week off.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION LENVIMA, 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. The chemical structure of lenvatinib mesylate is:Lenvatinib mesylate is 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 25C. The partition coefficient (log value) is 3.3.LENVIMA capsules for oral administration contain 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, 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Single Agent Therapy:DTC: The recommended dosage is 24 mg orally once daily. (2.2) 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 mg orally once daily for patients less than 60 kg. (2.4)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 weeks. (2.5) RCC: The recommended dosage is: 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every weeks. (2.3) 18 mg orally once daily with everolimus mg orally once daily. (2.3) Modify the recommended daily dose for certain patients with renal or hepatic impairment. (2.7, 2.8). DTC: The recommended dosage is 24 mg orally once daily. (2.2) 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 mg orally once daily for patients less than 60 kg. (2.4). 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 weeks. (2.5) RCC: The recommended dosage is: 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every weeks. (2.3) 18 mg orally once daily with everolimus mg orally once daily. (2.3) 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every weeks. (2.3) 18 mg orally once daily with everolimus mg orally once daily. (2.3). 2.1 Important Dosage Information Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration 2.7 2.8 )]. Take LENVIMA once daily, with or without food, at the same time each day [see Clinical Pharmacology 12.3 )]. If dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.. Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration 2.7 2.8 )]. Take LENVIMA once daily, with or without food, at the same time each day [see Clinical Pharmacology 12.3 )]. If dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.. 2.2 Recommended Dos ag for Differentiated Thyroid Cancer (DTC) The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity. 2.3 Recommended Dosage for Renal Cell Carcinoma (RCC). First-Line Treatment of Patients with Advanced RCCThe 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 weeks until disease progression or until unacceptable toxicity or up to years. After completing years of combination therapy, LENVIMA may be administered as single agent until disease progression or until unacceptable toxicity.Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.Previously Treated RCCThe recommended dosage of LENVIMA is 18 mg in combination with mg everolimus orally once daily until disease progression or until unacceptable toxicity.Refer to the everolimus prescribing information for recommended everolimus dosing information.. 2.4 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 mg for patients less than 60 kg. Take LENVIMA orally once daily until disease progression or until unacceptable toxicity.. 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. 2.5 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 weeks, until unacceptable toxicity or disease progression.Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.. 2.6 Dos age Modifications for Adverse Reactions Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1. Table lists the recommended dosage reductions of LENVIMA for adverse reactions.Table 1: Recommended Dosage Modifications for LENVIMA for Adverse ReactionsAdverse ReactionSeverity aDosage Modifications for LENVIMAHypertension [see Warnings and Precautions 5.1 )] Grade 3Withhold for Grade 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 to or baseline. Resume at 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 or 4Withhold until improves to Grade to or baseline. Either resume at 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 or 4Withhold until improves to Grade to or baseline. Resume at reduced dose or discontinue depending on severity and persistence of renal impairment. Proteinuria [see Warnings and Precautions 5.6 )] g or greater proteinuria in 24 hoursWithhold until less than or equal to grams of proteinuria per 24 hours. Resume at 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 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 reduced dose.Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions 5.11 )] Any GradeWithhold until fully resolved. Resume at 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 or adverse reactionGrade laboratory abnormalityWithhold until improves to Grade to or baseline. Resume at reduced dose. Grade adverse reaction Permanently discontinue.a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.Table 2: Recommended Dosage Reductions of LENVIMA for Adverse ReactionsIndicationFirst Dosage Reduction ToSecond Dosage Reduction ToThird Dosage Reduction ToDTC20 mg once daily 14 mg once daily 10 mgonce dailyRCC14 mg once daily 10 mgonce daily8 mgonce dailyEndometrial Carcinoma14 mg once daily 10 mgonce daily8 mgonce dailyHCCActual weight 60 kg or greater8 mg once daily mg once daily4 mg every other dayActual weight less than 60 kg4 mg once daily4 mg every other day DiscontinueRecommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with PembrolizumabWhen administering LENVIMA in combination with pembrolizumab, modify the dosage of one or both drugs as appropriate. Withhold, dose reduce, or discontinue LENVIMA as shown in Table 1. Refer to pembrolizumab prescribing information for additional dose modification information.Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with EverolimusWhen administering LENVIMA in combination with everolimus, withhold or reduce the LENVIMA dose first and then the everolimus dose for adverse reactions of both LENVIMA and everolimus. Refer to the everolimus prescribing information for additional dose modification information.. Withhold for Grade that persists despite optimal antihypertensive therapy. Resume at reduced dose when hypertension is controlled at less than or equal to Grade 2.. Permanently discontinue.. Withhold until improves to Grade to or baseline. Resume at reduced dose or discontinue depending on the severity and persistence of adverse reaction.. Permanently discontinue.. Permanently discontinue.. Withhold until improves to Grade to or baseline. Either resume at reduced dose or discontinue depending on severity and persistence of hepatotoxicity. Permanently discontinue for hepatic failure.. Withhold until improves to Grade to or baseline. Resume at reduced dose or discontinue depending on severity and persistence of renal impairment. Withhold until less than or equal to grams of proteinuria per 24 hours. Resume at reduced dose. Permanently discontinue for nephrotic syndrome.. Permanently discontinue.. Permanently discontinue.. Withhold until improves to less than or equal to 480 ms or baseline. Resume at reduced dose.. Withhold until fully resolved. Resume at reduced dose or discontinue depending on severity and persistence of neurologic symptoms.. Withhold until improves to Grade to or baseline. Resume at reduced dose. Permanently discontinue.. Actual weight 60 kg or greater. Actual weight less than 60 kg. 2.7 Dos ag Modifications for Severe Renal Impairment The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is [s ee Warnings and Precautions 5.5 ), Use in Specific Populations 8.6 )]:Differentiated thyroid cancer: 14 mg orally once daily Renal cell carcinoma: 10 mg orally once daily Endometrial carcinoma: 10 mg orally once daily. Differentiated thyroid cancer: 14 mg orally once daily Renal cell carcinoma: 10 mg orally once daily Endometrial carcinoma: 10 mg orally once daily. 2.8 Dos ag Modifications for Severe Hepatic Impairment The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is [s ee Warnings and Precautions 5.4 ), Use in Specific Populations 8.7 ]:Differentiated thyroid cancer: 14 mg taken orally once daily Renal cell carcinoma: 10 mg taken orally once daily Endometrial carcinoma: 10 mg orally once daily. Differentiated thyroid cancer: 14 mg taken orally once daily Renal cell carcinoma: 10 mg taken orally once daily Endometrial carcinoma: 10 mg orally once daily. 2.9 Preparation and Administration LENVIMA capsules can be swallowed whole or dissolved in small glass of liquid. To dissolve in liquid, put capsules into tablespoon of water or apple juice without breaking or crushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least minutes. After drinking the mixture, add tablespoon of water or apple juice to the glass, swirl the contents few times and swallow the water or apple juice.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING LENVIMA mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with on the cap and LENV 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 on the cap and LENV 10 mg on the body. LENVIMA capsules are supplied in cartons of cards. Each card is 5-day blister card as follows:NDC 62856-724-30: 24 mg, carton with cards NDC 62856-724-05 (ten 10 mg capsules and five mg capsules per card). NDC 62856-720-30: 20 mg, carton with cards NDC 62856-720-05 (ten 10 mg capsules per card). NDC 62856-718-30: 18 mg, carton with cards NDC 62856-718-05 (five 10 mg capsules and ten mg capsules per card). NDC 62856-714-30: 14 mg, carton with cards NDC 62856-714-05 (five 10 mg capsules and five mg capsules per card). NDC 62856-712-30: 12 mg, carton with cards NDC 62856-712-05 (fifteen mg capsules per card). NDC 62856-710-30: 10 mg, carton with cards NDC 62856-710-05 (five 10 mg capsules per card). NDC 62856-708-30: mg, carton with cards NDC 62856-708-05 (ten mg capsules per card). NDC 62856-704-30: mg, carton with cards NDC 62856-704-05 (five mg capsules per card).Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].. NDC 62856-724-30: 24 mg, carton with cards NDC 62856-724-05 (ten 10 mg capsules and five mg capsules per card). NDC 62856-720-30: 20 mg, carton with cards NDC 62856-720-05 (ten 10 mg capsules per card). NDC 62856-718-30: 18 mg, carton with cards NDC 62856-718-05 (five 10 mg capsules and ten mg capsules per card). NDC 62856-714-30: 14 mg, carton with cards NDC 62856-714-05 (five 10 mg capsules and five mg capsules per card). NDC 62856-712-30: 12 mg, carton with cards NDC 62856-712-05 (fifteen mg capsules per card). NDC 62856-710-30: 10 mg, carton with cards NDC 62856-710-05 (five 10 mg capsules per card). NDC 62856-708-30: mg, carton with cards NDC 62856-708-05 (ten mg capsules per card). NDC 62856-704-30: mg, carton with cards NDC 62856-704-05 (five mg capsules per card).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. LENVIMA is kinase inhibitor that is indicated: Differentiated Thyroid Cancer (DTC) For the treatment of 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 not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.4). For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). (1.1). 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). 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 (EC) that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (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, 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 not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING 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 EventsAdvise 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 )]. HepatotoxicityAdvise 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/ImpairmentAdvise 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 )]. DiarrheaAdvise 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 )]. Fistula Formation and Gastrointestinal PerforationAdvise 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 )]. QTc Interval ProlongationAdvise 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 )]. HypocalcemiaAdvise 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 Posterior Leukoencephalopathy Syndrome (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 EventsAdvise 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 DysfunctionAdvise 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 HealingAdvise 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-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider of 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 at least 30 days after the last dose [see Use in Specific Populations 8.3 )]. LactationAdvise women to discontinue breastfeeding during treatment with LENVIMA and for at least week after the last dose [see Use in Specific Populations 8.2 )]. Distributed by:Eisai Inc.Nutley, NJ 07110LENVIMA(R) is registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc.(C) 2015-2021 Eisai Inc.

LACTATION SECTION.

8.2 Lactation Risk 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 week after the last dose. DataAnimal DataFollowing administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately times higher [based on area under the curve (AUC)] in milk compared to maternal plasma.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Lenvatinib is 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 (PDGFR), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with concurrent inhibition of FGF-receptor substrate (FRS2) phosphorylation. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of ertility Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the AUC at the recommended clinical dose of 24 mg once daily. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the AUC at the recommended clinical dose of 24 mg once daily, respectively. In addition, in monkeys, decreased incidence of menstruation was reported at lenvatinib exposures lower than those observed in humans at the recommended clinical dose of 24 mg once daily.

OVERDOSAGE SECTION.

10 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 patient who received single dose of LENVIMA 120 mg orally.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 62856-704-30Lenvima(lenvatinib) capsules4 mg daily dose. NDC 62856-704-30Lenvima(lenvatinib) capsules4 mg daily dose.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established.Juvenile Animal DataDaily oral administration of lenvatinib mesylate to juvenile rats for weeks starting on postnatal day 21 (approximately equal to human pediatric age of 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 mg/kg (approximately 1.2 to times the human exposure based on AUC at the recommended clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Exposure-Response RelationshipsIn multicenter randomized (1:1) double blind trial of 152 patients with radioactive iodine (RAI)-refractory DTC, dose-response relationship for overall response rate (ORR) was observed over the dose range of 18 mg (0.75 times the recommended dose of 24 mg) and 24 mg. higher ORR was observed at the recommended lenvatinib dose.No dose-response relationships for adverse reactions, serious adverse reactions, adverse reactions leading to study drug discontinuation, and adverse reactions leading to study drug interruption were observed over the same dose range.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics In patients with solid tumors administered single and multiple doses of LENVIMA once daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 mg (0.1 times the recommended clinical dose of 24 mg) to 32 mg (1.33 times the recommended clinical dose of 24 mg) with median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg). Geometric mean Cmax and AUC values at steady state for RCC, DTC and HCC are summarized in the Table 13.Table 13: Lenvatinib Cmax and AUC in Patients with Solid TumorsaTumor TypeDoseParameterNGeometric Mean%CVRCC 18 mgCmax (ng/mL)35026736.7AUC (ngh/mL)350314842.5 20 mgCmax (ng/mL)34627532.6AUC (ngh/mL)346313541.3DTC 24 mgCmax (ng/mL)25132333.3AUC (ngh/mL)251348334.7HCC (body weight 60 kg) mgCmax (ng/mL)15015425.4AUC (ngh/mL)150183534.0HCC (body weight >= 60 kg) 12 mgCmax (ng/mL)31817223.1AUC (ngh/mL)318201329.3a Model-predicted steady-state pharmacokinetic parameters are presented. AbsorptionThe time to peak plasma concentration (Tmax) typically occurred from to hours post-dose. Food EffectAdministration with high fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from hours to hours. DistributionModel-predicted geometric mean steady state volume of distribution is 97 (%CV, 30.2%). Protein binding of lenvatinib is 97% to 99%, which is independent of concentration, and is not impacted by hepatic or renal function. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 ug/mL in vitro. EliminationThe terminal elimination half-life of lenvatinib was approximately 28 hours. MetabolismThe main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes. ExcretionTen days after single administration of radiolabeled lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively. Specific PopulationsAge (18 to 92 years), sex, race/ethnicity (White, Black and Asian), tumor types (DTC, RCC, HCC and other tumor types) and renal impairment (creatinine clearance: 15-89 mL/min) did not have significant effect on apparent oral clearance (CL/F). Subjects with end stage renal disease were not studied. Patients with Hepatic ImpairmentThe pharmacokinetics of lenvatinib following single 10 mg dose were evaluated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of single mg dose were evaluated in subjects with severe (Child-Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively. Apparent oral clearance of lenvatinib in patients with HCC and mild hepatic impairment was similar to patients with HCC and moderate hepatic impairment.Body WeightLenvatinib exposures in patients with HCC in REFLECT were comparable between those weighing <60 kg who received starting dose of mg and those >=60 kg who received starting dose of 12 mg.Drug Interaction StudiesEffect of Other Drugs on LenvatinibCYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg daily for 18 days) increased lenvatinib (administered as single mg dose on Day 5) AUC by 15% and Cmax by 19%. P-gp Inhibitor: Rifampicin (600 mg as single dose) increased lenvatinib (24 mg as single dose) AUC by 31% and Cmax by 33%. CYP3A and P-gp Inducers: Rifampicin (600 mg daily for 21 days) decreased lenvatinib (24 mg as single dose on Day 15) AUC by 18%. The Cmax was unchanged.Population pharmacokinetic analysis demonstrated that neither everolimus nor pembrolizumab meaningfully affect the pharmacokinetics of lenvatinib.In Vitro Studies with Transporters: Lenvatinib is substrate of P-gp and BCRP but not substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, MATE2-K, or the bile salt export pump (BSEP). Effect of Lenvatinib on Other DrugsCYP2C8 Substrate: There is no projected significant drug-drug interaction risk between lenvatinib and repaglinide.CYP3A4 Substrate: Co-administration of lenvatinib with midazolam had no effect on the pharmacokinetics of midazolam. Population pharmacokinetic analysis demonstrated that lenvatinib does not meaningfully affect the pharmacokinetics of either everolimus or pembrolizumab.In Vitro Studies with Substrates of CYP or UDP-glucuronosyltransferase (UGT): Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Lenvatinib does not inhibit CYP2A6 and CYP2E1. Lenvatinib induces CYP3A, but it does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme in tissues. Lenvatinib does not inhibit UGT1A6, UGT2B7 or aldehyde oxidase. Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7. In Vitro Studies with Substrates of Transporters: Lenvatinib does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of LENVIMA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Gastrointestinal: pancreatitis, increased amylaseGeneral: impaired wound healingHepatobiliary: cholecystitisRenal and Urinary: nephrotic syndromeVascular: arterial (including aortic) aneurysms, dissections, and rupture.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryBased on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to 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 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 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.2) 08/2021Indications and Usage (1.4) 07/2021Dosage and Administration (2.3, 2.6) 08/2021Warnings and Precautions (5.3) 08/2021Warnings and Precautions (5.15) 12/2020.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONLENVIMA(R) (lehn-veema)(lenvatinib)capsulesWhat is LENVIMALENVIMA is prescription medicine that is used to treat people with certain kinds of cancer.LENVIMA is used by itself to treat differentiated thyroid cancer (DTC), type of thyroid cancer that can no longer be treated with radioactive iodine and is progressing. LENVIMA is used to treat adults with type of kidney cancer called advanced renal cell carcinoma (RCC): along with the medicine pembrolizumab as your first treatment when your kidney cancer has spread or cannot be removed by surgery. along with the medicine everolimus after one course of treatment with another anti-cancer medicine. LENVIMA is used by itself as the first treatment for type of liver cancer called hepatocellular carcinoma (HCC) when it cannot be removed by surgery. LENVIMA is used along with another medicine called pembrolizumab to treat endometrial carcinoma, type of uterine cancer:when your tumor is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and you have received anti-cancer treatment, and it is no longer working, and your cancer cannot be cured by surgery or radiation (advanced endometrial carcinoma).It is not known if LENVIMA is safe and effective in children.Before you take LENVIMA, tell your healthcare provider about all of your medical conditions, including if you:have high blood pressure have heart problems have history of blood clots in your arteries (type of blood vessel), including stroke, heart attack, or change in vision have or have had liver or kidney problems have history of tear (perforation) in your stomach or intestine, or an abnormal connection between two or more body parts (fistula) have headaches, seizures, or vision problems have any bleeding problems plan to have surgery, dental procedure, or have had recent surgery. You should stop taking LENVIMA at least week before planned surgery. See What are the possible side effects of LENVIMA are pregnant or plan to become pregnant. LENVIMA can harm your unborn baby. Females who are able to become pregnant o Your healthcare provider should do pregnancy test before you start treatment with LENVIMA. You should use an effective method of birth control during treatment with LENVIMA and for at least 30 days after the last dose of LENVIMA. Talk with your healthcare provider about birth control methods you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LENVIMA.are breastfeeding or plan to breastfeed. It is not known if LENVIMA passes into your breast milk. Do not breastfeed during treatment with LENVIMA and for at least week after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Especially tell your healthcare provider if you are taking, or have taken, an osteoporosis medicine.Know the medicines you take. Keep list of your medicines to show to your healthcare provider and pharmacist when you get new medicine.How should take LENVIMATake LENVIMA exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much LENVIMA to take and when to take it. Your healthcare provider may change your dose during treatment, stop treatment for some time, or completely stop treatment with LENVIMA if you have side effects. Take LENVIMA time each day at the same time, with or without food. If you miss dose of LENVIMA, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take the next dose at your regular time. If you cannot swallow LENVIMA capsules whole:o Use medicine cup to measure about one tablespoon of water or apple juice and place into small glass.o Place the LENVIMA capsules into the small glass without breaking or crushing them.o Leave the capsules in the liquid for at least 10 minutes. Stir the contents of the glass for at least minutes.o Drink the mixture. After drinking, rinse the glass with small amount of additional water or apple juice and swallow the liquid. If you take too much LENVIMA, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of LENVIMALENVIMA may cause serious side effects, including:high blood pressure (hypertension). High blood pressure is common side effect of LENVIMA and can be serious. Your blood pressure should be well controlled before you start taking LENVIMA. Your healthcare provider should check your blood pressure regularly during treatment with LENVIMA. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. heart problems. LENVIMA can cause serious heart problems that may lead to death. Call your healthcare provider right away if you get symptoms of heart problems, such as shortness of breath or swelling of your ankles. problem with blood clots in your blood vessels (arteries). Get emergency medical help right away if you get any of the following symptoms: severe chest pain or pressure pain in your arms, back, neck or jaw shortness of breath numbness or weakness on one side of your bodytrouble talking sudden severe headache sudden vision changesliver problems. LENVIMA may cause liver problems that may lead to liver failure and death. Your healthcare provider will check your liver function before and during treatment with LENVIMA. Tell your healthcare provider right away if you have any of the following symptoms: your skin or the white part of your eyes turns yellow (jaundice) dark tea colored urine light-colored bowel movements (stools) feeling drowsy, confused or loss of consciousness kidney problems. Kidney failure, which can lead to death, has happened with LENVIMA treatment. Your healthcare provider should do regular blood tests to check your kidneys. increased protein in your urine (proteinuria). Proteinuria is common side effect of LENVIMA and can be serious. Your healthcare provider should check your urine for protein before and during your treatment with LENVIMA. diarrhea. Diarrhea is common side effect of LENVIMA and can be serious. If you get diarrhea, ask your healthcare provider about what medicines you can take to treat your diarrhea. It is important to drink more water when you get diarrhea. Tell your healthcare provider or go to the emergency room, if you are unable to drink enough liquids and your diarrhea is not able to be controlled.an opening in the wall of your stomach or intestines (perforation) or an abnormal connection between two or more body parts (fistula). Get emergency medical help right away if you have severe stomach (abdomen) pain. changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider will do blood tests before and during your treatment with LENVIMA to check the levels of potassium, magnesium, and calcium in your blood, and may check the electrical activity of your heart with an ECG. low levels of blood calcium (hypocalcemia). Your healthcare provider will check your blood calcium levels during treatment with LENVIMA and may tell you to take calcium supplement if your calcium levels are low. condition called Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Call your healthcare provider right away if you get severe headache, seizures, weakness, confusion, or blindness or change in vision. bleeding. LENVIMA may cause serious bleeding problems that may lead to death. Tell your healthcare provider if you have any signs or symptoms of bleeding during treatment with LENVIMA, including:severe and persistent nose bleeds vomiting blood red or black (looks like tar) stoolsblood in your urine coughing up blood or blood clots heavy or new onset vaginal bleedingchange in thyroid hormone levels. Your healthcare provider should check your thyroid hormone levels before starting and every month during treatment with LENVIMA.wound healing problems. Wound healing problems have happened in some people who take LENVIMA. Tell your healthcare provider if you plan to have any surgery before or during treatment with LENVIMA. You should stop taking LENVIMA at least week before planned surgery. Your healthcare provider should tell you when you may start taking LENVIMA again after surgery. severe jaw bone problems (osteonecrosis). Severe jaw bone problems have happened in some people who take LENVIMA. Certain risk factors such as taking bisphosphonate medicine or the medicine denosumab, having dental disease, or an invasive dental procedure may increase your risk of getting jaw bone problems. Your healthcare provider should examine your mouth before you start and during treatment with LENVIMA. Tell your dentist that you are taking LENVIMA. It is important for you to practice good mouth care during treatment with LENVIMA. Tell your healthcare provider right away if you get signs or symptoms of jaw bone problems during treatment with LENVIMA, including jaw pain, toothache, or sores on your gums. Tell your healthcare provider if you plan to have any dental procedures before or during treatment with LENVIMA. You should avoid having invasive dental procedures if possible, during treatment with LENVIMA. Stopping your bisphosphonate medicine before an invasive dental procedure may help decrease your risk of getting these jaw problems.o You should stop taking LENVIMA at least week before planned dental surgery or invasive dental procedures.o Your healthcare provider should tell you when you may start taking LENVIMA again after dental procedures. The most common side effects of LENVIMA in people treated for thyroid cancer include:tirednessjoint and muscle pain decreased appetite weight loss nausea mouth soresheadache vomiting rash, redness, itching, or peeling of your skin on your hands and feet stomach (abdomen) pain hoarsenessThe most common side effects of LENVIMA when given with everolimus include:tirednessjoint and muscle pain decreased appetite vomiting nausea mouth sores swelling in your arms and legscough stomach (abdomen) pain trouble breathing rash weight loss bleedingThe most common side effects of LENVIMA in people treated for liver cancer include:tiredness decreased appetite joint and muscle pain weight loss stomach (abdomen) painrash, redness, itching, or peeling of your skin on your hands and feet hoarseness bleeding change in thyroid hormone levels nauseaThe most common side effects of LENVIMA when given with pembrolizumab include:decrease in thyroid hormone levels increased blood pressure tiredness diarrhea joint and muscle pain nausea decreased appetite vomiting mouth soresweight loss stomach-area (abdomen) pain urinary tract infection protein in your urine constipation headache bleeding rash, redness, itching, or peeling of your skin on your hands and feet hoarseness rashLENVIMA may cause fertility problems in males and females. Talk to your healthcare provider if this is concern for you.Your healthcare provider may need to reduce your dose of LENVIMA, or delay or completely stop treatment, if you have certain side effects.These are not all the possible side effects of LENVIMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store LENVIMAStore LENVIMA at room temperature, between 68F to 77F (20C to 25C).Keep LENVIMA and all medicines out of the reach of children.General information about the safe and effective use of LENVIMA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use LENVIMA for condition for which it was not prescribed. Do not give LENVIMA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LENVIMA that is written for health professionals.What are the ingredients in LENVIMAActive ingredient: lenvatinib Inactive ingredients: calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropylcellulose, mannitol, microcrystalline cellulose, and talc. The capsule shell contains: hypromellose, titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol and shellac.Distributed by: Eisai Inc., Nutley, NJ 07110LENVIMA(R) is registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc.For more information, call 1-877-873-4724 or go to www.LENVIMA.com.(C) 2015-2021 Eisai Inc. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2021. LENVIMA is used by itself to treat differentiated thyroid cancer (DTC), type of thyroid cancer that can no longer be treated with radioactive iodine and is progressing. LENVIMA is used to treat adults with type of kidney cancer called advanced renal cell carcinoma (RCC): along with the medicine pembrolizumab as your first treatment when your kidney cancer has spread or cannot be removed by surgery. along with the medicine everolimus after one course of treatment with another anti-cancer medicine. along with the medicine pembrolizumab as your first treatment when your kidney cancer has spread or cannot be removed by surgery. along with the medicine everolimus after one course of treatment with another anti-cancer medicine.. LENVIMA is used by itself as the first treatment for type of liver cancer called hepatocellular carcinoma (HCC) when it cannot be removed by surgery. LENVIMA is used along with another medicine called pembrolizumab to treat endometrial carcinoma, type of uterine cancer:. when your tumor is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and you have received anti-cancer treatment, and it is no longer working, and your cancer cannot be cured by surgery or radiation (advanced endometrial carcinoma).. have high blood pressure have heart problems have history of blood clots in your arteries (type of blood vessel), including stroke, heart attack, or change in vision have or have had liver or kidney problems have history of tear (perforation) in your stomach or intestine, or an abnormal connection between two or more body parts (fistula) have headaches, seizures, or vision problems have any bleeding problems plan to have surgery, dental procedure, or have had recent surgery. You should stop taking LENVIMA at least week before planned surgery. See What are the possible side effects of LENVIMA are pregnant or plan to become pregnant. LENVIMA can harm your unborn baby. Females who are able to become pregnant o Your healthcare provider should do pregnancy test before you start treatment with LENVIMA. You should use an effective method of birth control during treatment with LENVIMA and for at least 30 days after the last dose of LENVIMA. Talk with your healthcare provider about birth control methods you can use during this time. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LENVIMA.. are breastfeeding or plan to breastfeed. It is not known if LENVIMA passes into your breast milk. Do not breastfeed during treatment with LENVIMA and for at least week after the last dose.. Take LENVIMA exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much LENVIMA to take and when to take it. Your healthcare provider may change your dose during treatment, stop treatment for some time, or completely stop treatment with LENVIMA if you have side effects. Take LENVIMA time each day at the same time, with or without food. If you miss dose of LENVIMA, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take the next dose at your regular time. If you cannot swallow LENVIMA capsules whole:. If you take too much LENVIMA, call your healthcare provider or go to the nearest hospital emergency room right away. high blood pressure (hypertension). High blood pressure is common side effect of LENVIMA and can be serious. Your blood pressure should be well controlled before you start taking LENVIMA. Your healthcare provider should check your blood pressure regularly during treatment with LENVIMA. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure. heart problems. LENVIMA can cause serious heart problems that may lead to death. Call your healthcare provider right away if you get symptoms of heart problems, such as shortness of breath or swelling of your ankles. problem with blood clots in your blood vessels (arteries). Get emergency medical help right away if you get any of the following symptoms: severe chest pain or pressure pain in your arms, back, neck or jaw shortness of breath numbness or weakness on one side of your body. trouble talking sudden severe headache sudden vision changes. liver problems. LENVIMA may cause liver problems that may lead to liver failure and death. Your healthcare provider will check your liver function before and during treatment with LENVIMA. Tell your healthcare provider right away if you have any of the following symptoms: your skin or the white part of your eyes turns yellow (jaundice) dark tea colored urine light-colored bowel movements (stools) feeling drowsy, confused or loss of consciousness your skin or the white part of your eyes turns yellow (jaundice) dark tea colored urine light-colored bowel movements (stools) feeling drowsy, confused or loss of consciousness. kidney problems. Kidney failure, which can lead to death, has happened with LENVIMA treatment. Your healthcare provider should do regular blood tests to check your kidneys. increased protein in your urine (proteinuria). Proteinuria is common side effect of LENVIMA and can be serious. Your healthcare provider should check your urine for protein before and during your treatment with LENVIMA. diarrhea. Diarrhea is common side effect of LENVIMA and can be serious. If you get diarrhea, ask your healthcare provider about what medicines you can take to treat your diarrhea. It is important to drink more water when you get diarrhea. Tell your healthcare provider or go to the emergency room, if you are unable to drink enough liquids and your diarrhea is not able to be controlled.. an opening in the wall of your stomach or intestines (perforation) or an abnormal connection between two or more body parts (fistula). Get emergency medical help right away if you have severe stomach (abdomen) pain. changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider will do blood tests before and during your treatment with LENVIMA to check the levels of potassium, magnesium, and calcium in your blood, and may check the electrical activity of your heart with an ECG. low levels of blood calcium (hypocalcemia). Your healthcare provider will check your blood calcium levels during treatment with LENVIMA and may tell you to take calcium supplement if your calcium levels are low. a condition called Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Call your healthcare provider right away if you get severe headache, seizures, weakness, confusion, or blindness or change in vision. bleeding. LENVIMA may cause serious bleeding problems that may lead to death. Tell your healthcare provider if you have any signs or symptoms of bleeding during treatment with LENVIMA, including:. severe and persistent nose bleeds vomiting blood red or black (looks like tar) stools. blood in your urine coughing up blood or blood clots heavy or new onset vaginal bleeding. change in thyroid hormone levels. Your healthcare provider should check your thyroid hormone levels before starting and every month during treatment with LENVIMA.. wound healing problems. Wound healing problems have happened in some people who take LENVIMA. Tell your healthcare provider if you plan to have any surgery before or during treatment with LENVIMA. You should stop taking LENVIMA at least week before planned surgery. Your healthcare provider should tell you when you may start taking LENVIMA again after surgery. You should stop taking LENVIMA at least week before planned surgery. Your healthcare provider should tell you when you may start taking LENVIMA again after surgery.. severe jaw bone problems (osteonecrosis). Severe jaw bone problems have happened in some people who take LENVIMA. Certain risk factors such as taking bisphosphonate medicine or the medicine denosumab, having dental disease, or an invasive dental procedure may increase your risk of getting jaw bone problems. Your healthcare provider should examine your mouth before you start and during treatment with LENVIMA. Tell your dentist that you are taking LENVIMA. It is important for you to practice good mouth care during treatment with LENVIMA. Tell your healthcare provider right away if you get signs or symptoms of jaw bone problems during treatment with LENVIMA, including jaw pain, toothache, or sores on your gums. Tell your healthcare provider if you plan to have any dental procedures before or during treatment with LENVIMA. You should avoid having invasive dental procedures if possible, during treatment with LENVIMA. Stopping your bisphosphonate medicine before an invasive dental procedure may help decrease your risk of getting these jaw problems.o You should stop taking LENVIMA at least week before planned dental surgery or invasive dental procedures.o Your healthcare provider should tell you when you may start taking LENVIMA again after dental procedures. tiredness. joint and muscle pain decreased appetite weight loss nausea mouth sores. headache vomiting rash, redness, itching, or peeling of your skin on your hands and feet stomach (abdomen) pain hoarseness. tiredness. joint and muscle pain decreased appetite vomiting nausea mouth sores swelling in your arms and legs. cough stomach (abdomen) pain trouble breathing rash weight loss bleeding. tiredness decreased appetite joint and muscle pain weight loss stomach (abdomen) pain. rash, redness, itching, or peeling of your skin on your hands and feet hoarseness bleeding change in thyroid hormone levels nausea. decrease in thyroid hormone levels increased blood pressure tiredness diarrhea joint and muscle pain nausea decreased appetite vomiting mouth sores. weight loss stomach-area (abdomen) pain urinary tract infection protein in your urine constipation headache bleeding rash, redness, itching, or peeling of your skin on your hands and feet hoarseness rash. Store LENVIMA at room temperature, between 68F to 77F (20C to 25C).

SPL UNCLASSIFIED SECTION.

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).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to 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 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 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at 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 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 week after the last dose. DataAnimal DataFollowing administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately times higher [based on area under the curve (AUC)] in milk compared to maternal plasma.. 8.3 Females and Males of Reproductive Potential Pregnancy 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 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 Use The safety and effectiveness of LENVIMA in pediatric patients have not been established.Juvenile Animal DataDaily oral administration of lenvatinib mesylate to juvenile rats for weeks starting on postnatal day 21 (approximately equal to human pediatric age of 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 mg/kg (approximately 1.2 to times the human exposure based on AUC at the recommended clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 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. 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.. 8.6 Renal Impairment No 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 Impairment No 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 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 ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Hypertension: Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade hypertension despite optimal antihypertensive therapy. Discontinue for Grade hypertension. (2.6, 5.1) Cardiac Dysfunction: Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold or discontinue for Grade cardiac dysfunction. Discontinue for Grade 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 or hepatotoxicity. Discontinue for hepatic failure. (2.6, 5.4) Renal Failure or Impairment: Withhold or discontinue for Grade or renal failure or impairment. (2.6, 5.5)Proteinuria: Monitor for proteinuria prior to treatment and periodically during treatment. Withhold for 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 or 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 week before elective surgery. Do not administer for at least 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-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception. (5.16, 8.1, 8.3). Hypertension: Control blood pressure prior to treatment and monitor during treatment. Withhold for Grade hypertension despite optimal antihypertensive therapy. Discontinue for Grade hypertension. (2.6, 5.1) Cardiac Dysfunction: Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold or discontinue for Grade cardiac dysfunction. Discontinue for Grade 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 or hepatotoxicity. Discontinue for hepatic failure. (2.6, 5.4) Renal Failure or Impairment: Withhold or discontinue for Grade or renal failure or impairment. (2.6, 5.5). Proteinuria: Monitor for proteinuria prior to treatment and periodically during treatment. Withhold for 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 or 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 week before elective surgery. Do not administer for at least 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-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of 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 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 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade hypertension occurred <1% in SELECT and Grade 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 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 week, then every weeks for the first months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue LENVIMA based on severity see Dosage and Administration 2.6 ].. 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 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 reduced dose upon recovery or permanently discontinue LENVIMA based on severity see Dosage and Administration 2.6 ].. 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 to 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 2.6 ]. 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 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. 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 to hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated patients. Grade to 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 weeks for the first 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 reduced dose upon recovery or permanently discontinue LENVIMA based on severity see Dosage and Administration 2.6 ].. 5.5 Renal Failure or Impairment Serious 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 to renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including fatality in each study.In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade in 10% of patients [see Adverse Reactions 6.1 )]. Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity see Dosage and Administration 2.6 ]. 5.6 Proteinuria Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 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 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 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA based on severity see Dosage and Administration 2.6 ].. 5.7 Diarrhea Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred in 49% of patients, including Grade in 6%.In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 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 reduced dose upon recovery or permanently discontinue LENVIMA based on severity see Dosage and Administration 2.6 ].. 5.8 Fistula Formation and Gastrointestinal Perforation Of 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 or fistula see Dosage and Administration 2.6 ].. 5.9 QT Interval Prolongation In 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 Hypocalcemia In SELECT (DTC), Grade to 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 to hypocalcemia occurred in 6% of patients treated with LENVIMA with everolimus. In REFLECT (HCC), Grade 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 Leukoe ncephalopathy Syndrome Across clinical studies of 1823 patients who received LENVIMA as 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 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 vents Serious 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 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 to hemorrhage occurred in 2% of patients receiving LENVIMA, including fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In Study 205, Grade to hemorrhage occurred in 8% of patients receiving LENVIMA with everolimus, including fatal cerebral hemorrhage. In REFLECT, Grade to hemorrhage occurred in 5% of patients receiving LENVIMA, including 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 baseline thyroid stimulating hormone (TSH) level <=0.5 mU/L. In those patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients.Grade or 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 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 week prior to elective surgery. Do not administer for at least 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 Osteonecrosis of the Jaw Osteonecrosis of the Jaw (ONJ) has been reported in patients receiving LENVIMA [see Adverse Reactions 6.1 )]. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. 5.16 Embryo -F etal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to 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 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 ].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment No 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 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 ].

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment No 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 ].