b'T:7.875" T:7.875"S:6.875" S:6.875"WARNINGS AND PRECAUTIONS (cont\'d) Table 3: Adverse Reactions Occurring in 10% of Patients in the LENVIMA Arm in REFLECT (HCC) DRUG INTERACTIONSHemorrhagic Events (cont\'d) In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receivingLENVIMA 8 mg/12 mg Sorafenib 800 mg Drugs That Prolong the QT Interval LENVIMA has been reported to prolong the QT/QTc interval. Avoid69LENVIMA, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and hadN=476 N=475 coadministration of LENVIMA with medicinal products with a known potential to prolong the QT/QTc interval.CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients receivingAdverse Reaction Grade 1-4 Grade 3-4Grade 1-4Grade 3-4USE IN SPECIFIC POPULATIONSLENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA, including 7 fatal hemorrhagic events. (%) (%) (%) (%) PregnancySerious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treated withEndocrine Risk Summary LENVIMA in clinical trials and in the post-marketing setting. In post-marketing surveillance, serious and fatalHypothyroidisma 21 0 3 0 Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC)Gastrointestinal when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib than in other tumor types. The safety and effectiveness of LENVIMA in patients with ATC have not beenDiarrhea 39 4 46 4 during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, demonstrated in clinical trials. Abdominal painb 30 3 28 4 and teratogenicity in rats and rabbits. There are no available human data informing the drug-associated risk. Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major bloodAdvise pregnant women of the potential risk to a fetus. vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinueNausea 20 1 14 1 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in LENVIMA based on the severity. Vomiting 16 1 8 1 clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction LENVIMA impairsConstipation 16 1 11 0 Dataexogenous thyroid suppression. In SELECT (DTC), 88% of all patients had a baseline thyroid stimulatingAscitesc 15 4 11 3 Animal Data hormone (TSH) level 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH levelStomatitisd 11 0.4 14 1 In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses 0.3 mg/kg 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. General [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA with everolimus in Study 205Fatiguee 44 7 36 6 pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or lowPyrexiaf 15 0 14 0.2 fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA invisceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205. Peripheral edema 14 1 7 0.2 (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment. TreatMetabolism and Nutrition Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal hypothyroidism according to standard medical practice. Decreased appetite 34 5 27 1 external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than Impaired Wound Healing Impaired wound healing has been reported in patients who received LENVIMA. Decreased weight 31 8 22 3 or equal to 0.03 mg/kg (approximately 0.03 times the recommended clinical dose of 24 mg based on BSA). At Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeksMusculoskeletal and Connective Tissue the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib following major surgery and until adequate wound healing. The safety of resumption of LENVIMA afterArthralgia/Myalgiag 31 1 20 2 was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated atresolution of wound healing complications has not been established. Nervous System a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on Osteonecrosis of the Jaw (ONJ) ONJ has been reported in patients receiving LENVIMA.ConcomitantHeadache 10 1 8 0 BSA).exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dentalRenal and Urinary Lactationprocedures, may increase the risk of ONJ. Proteinuriah 26 6 12 2 Risk Summary Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment.Respiratory, Thoracic and Mediastinal It is not known whether LENVIMA is present in human milk; however, lenvatinib and its metabolites are Advise patients regarding good oral hygiene practices. excreted in rat milk at concentrations higher than those in maternal plasma. Because of the potential for Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higherDysphonia 24 0.2 12 0 serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment risk.Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures,Skin and Subcutaneous Tissue with LENVIMA and for at least 1 week after the last dose.if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatmentPalmar-plantar erythrodysesthesia27 3 52 11 Datamay reduce the risk of ONJ. syndrome Animal Data Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. Rashi 14 0 24 2 Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related Embryo-Fetal Toxicity Based on its mechanism of action and data from animal reproduction studies,Vascular radioactivity was approximately 2 times higher [based on area under the curve (AUC)] in milk compared to LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies,Hypertensionj 45 24 31 15 maternal plasma.oral administration of lenvatinib during organogenesis at doses below the recommended clinical dosesHemorrhagic eventsk 23 4 15 4 Females and Males of Reproductive Potentialresulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits.a Pregnancy Testing Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to useb Includes hypothyroidism, blood thyroid stimulating hormone increasedVerify the pregnancy status of females of reproductive potential prior to initiating LENVIMA.Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal effective contraception during treatment with LENVIMA and for at least 30 days after the last dose. c pain, lower abdominal pain, and upper abdominal painContraception ADVERSE REACTIONS dBased on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman. Includes ascites and malignant ascites Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosalThe following adverse reactions are discussed elsewhere in the labeling: blistering, and stomatitis Females Hypertension QT Interval Prolongation e fAdvise females of reproductive potential to use effective contraception during treatment with LENVIMA and Includes asthenia, fatigue, lethargy and malaiseIncludes increased body temperature, pyrexia Cardiac Dysfunction Hypocalcemia g I for at least 30 days after the last dose. ncludes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort, Arterial Thromboembolic Events Reversible Posterior Leukoencephalopathy Syndrome musculoskeletal pain, and myalgia S:10" T:10.5" InfertilityS:10" T:10.5"Hepatotoxicity Hemorrhagic Events h Includes proteinuria, increased urine protein, protein urine presentRenal Failure and ImpairmentImpairment of Thyroid Stimulating Hormone i LENVIMA may impair fertility in males and females of reproductive potential.I ncludes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash,Suppression/Thyroid Dysfunction papular rash, pruritic rash, pustular rash and rash j Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established.Proteinuria Impaired Wound HealingIncludes increased diastolic blood pressure, increased blood pressure, hypertension and orthostaticJuvenile Animal Data Diarrhea hypertensionFistula Formation and Osteonecrosis of the Jaw k Includes all hemorrhage terms. Hemorrhage terms that occurred in 5 or more subjects in either treatment Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 group include: epistaxis, hematuria, gingival bleeding, hemoptysis, esophageal varices hemorrhage, (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body Gastrointestinal Perforation hemorrhoidal hemorrhage, mouth hemorrhage, rectal hemorrhage and upper gastrointestinal hemorrhage weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverseand secondary delays in physical development and reproductive organ immaturity at doses greater than or reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trialsIn Table 4, Grade 3-4 laboratory abnormalities occurring in 2% of patients in the LENVIMA arm in REFLECTequal to 2 mg/kg (approximately 1.2 to 5 times the human exposure based on AUC at the recommended of another drug and may not reflect the rates observed in practice. (HCC) are presented. clinical dose of 24 mg). Decreased length of the femur and tibia persisted following 4 weeks of recovery.In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities The data in the Warnings and Precautions reflect exposure to LENVIMA as a single agent in 261 patientsTable 4:Grade 3-4 Laboratory Abnormalities Occurring in 2% of Patients in the LENVIMAincluding broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 406 patientsArma,b in REFLECT (HCC) duodenal lesions) occurred at earlier treatment time-points in juvenile rats.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 withLaboratory Abnormality LenvatinibSorafenibGeriatric Use Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to(%) (%) SELECT, 45% were 65 years of age and 11% were 75 years of age. No overall differences in safety or further characterize the risks of serious adverse reactions. Among the 1823 patients who received LENVIMAChemistry effectiveness were observed between these subjects and younger subjects.as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily,Increased GGT 17 20 Of the 352 patients with renal cell carcinoma (RCC) who received LENVIMA with pembrolizumab in CLEAR, and the median duration of exposure was 5.6 months. 45% were 65 years of age and 13% were 75 years of age. No overall differences in safety or effectiveness The data below reflect exposure to LENVIMA in 1557 patients enrolled in randomized, active-controlled trialsHyponatremia 15 9 were observed between these elderly patients and younger patients.(REFLECT; Study 205; CLEAR; Study 309), and a randomized, placebo-controlled trial (SELECT). The medianHyperbilirubinemia 13 10 Of the 62 patients with RCC who received LENVIMA with everolimus in Study 205, 36% were 65 years of duration of exposure to LENVIMA across these five studies ranged from 6 to 16 months. The demographicIncreased aspartate aminotransferase (AST) 12 18 age. Conclusions are limited due to the small sample size, but there appeared to be no overall differences in and exposure data for each clinical trial population are described in the subsections below. Increased alanine aminotransferase (ALT) 8 9 safety or effectiveness between these subjects and younger subjects.Hepatocellular CarcinomaIncreased alkaline phosphatase 7 5 Of the 476 patients with hepatocellular carcinoma (HCC) who received LENVIMA in REFLECT, 44% were The safety of LENVIMA was evaluated in REFLECT, which randomized (1:1) patients with unresectableIncreased lipase 6 17 65 years of age and 12% were 75 years of age. No overall differences in safety or effectiveness were hepatocellular carcinoma (HCC) to LENVIMA (n=476) or sorafenib (n=475). The dose of LENVIMA was 12 mgHypokalemia 3 4 observed between patients 65 and younger subjects. Patients 75 years of age showed reduced tolerability orally once daily for patients with a baseline body weight of 60 kg and 8 mg orally once daily for patientsHyperkalemia 3 2 to LENVIMA.with a baseline body weight of 60 kg. The dose of sorafenib was 400 mg orally twice daily. Duration ofOf 406 adult patients with endometrial carcinoma (EC) who were treated with LENVIMA in combination treatment was 6 months in 49% and 32% of patients in the LENVIMA and sorafenib groups, respectively.Decreased albumin 3 1 with pembrolizumab in Study 309, 201 (50%) were 65 years and over. No overall differences in safety or Among the 476 patients who received LENVIMA in REFLECT, the median age was 63 years, 85% were men,Increased creatinine 2 2 effectiveness were observed between elderly patients and younger patients.28% were White and 70% were Asian. Hematology Renal Impairment No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or The most common adverse reactions observed in the LENVIMA-treated patients (20%) were, in order ofThrombocytopenia 10 8 moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase in patients with decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreasedLymphopenia 8 9 DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose of weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagicNeutropenia 7 3 lenvatinib for patients with RCC, DTC, or endometrial carcinoma and severe renal impairment. There is no events, hypothyroidism, and nausea.recommended dose of LENVIMA for patients with HCC and severe renal impairment. LENVIMA has not been The most common serious adverse reactions (2%) in LENVIMA-treated patients were hepatica Anemia 4 5 studied in patients with end stage renal disease. encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). bHepatic Impairment No dose adjustment is recommended for patients with HCC and mild hepatic impairment With at least 1 grade increase from baseline Laboratory Abnormality percentage is based on the number of patients who had both baseline and at leastAdverse reactions led to dose reduction or interruption in 62% of patients receiving LENVIMA. The mostone post baseline laboratory measurement for each parameter. LENVIMA (n=278 to 470) and sorafenib (Child-Pugh A). There is no recommended dose for patients with HCC with moderate or severe hepatic common adverse reactions (5%) resulting in dose reduction or interruption of LENVIMA were fatigue(n=260 to 473) impairment. (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantarPostmarketing Experience The following adverse reactions have been identified during post approval useNo dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or erythrodysesthesia syndrome (5%). of LENVIMA. Because these reactions are reported voluntarily from a population of uncertain size, it is notmoderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations may increase in patients with DTC, Treatment discontinuation due to adverse reactions occurred in 20% of patients in the LENVIMA-treatedalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure. RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C). Reduce the dose of lenvatinib for group. The most common adverse reactions (1%) resulting in discontinuation of LENVIMA were fatigueGastrointestinal: pancreatitis, increased amylase patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment.(1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). General: impaired wound healing OVERDOSAGETable 3 summarizes the adverse reactions that occurred in 10% of patients receiving LENVIMA in REFLECT.Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Death due to multiorgan REFLECT was not designed to demonstrate a statistically significant reduction in adverse reaction rates forHepatobiliary: cholecystitis dysfunction occurred in a patient who received a single dose of LENVIMA 120 mg orally.LENVIMA, as compared to sorafenib, for any specified adverse reaction listed in Table 3. Renal and Urinary: nephrotic syndromeVascular: arterial (including aortic) aneurysms, dissections, and ruptureLENVIMA is a registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. 2021 Eisai Inc. All rights reserved. Printed in USA/September 2021 LENV-US674084724_A-SIZE_PB.indd 5-6 9/24/21 1:15 PMLHCC21HSAW0697_M3_LENVIMA_Brief_Summary_Asize_ Printed At None LHCC21HSAW0697_M3_LENVIMA_Brief_Summary_Asize_ Printed At NoneSaved at 9-16-2021 4:22 PM from US3LINM0FQ35HMD by Suke Yawata / kwalsh Saved at 9-16-2021 4:22 PM from US3LINM0FQ35HMD by Suke Yawata / kwalshJob info ImagesFonts & Colors Job info ImagesFonts & ColorsClient Code None None Colors Client Code None Eisai_K.ai (3.6%) ColorsClient Eisai/LenvimaBlack Client Eisai/LenvimaBlackLive 6.875" x 10" Fonts Live 6.875" x 10" FontsOverall Trim 7.875" x 10.5" Univers LT Std (67 Bold Condensed, 47 Light Con- Overall Trim 7.875" x 10.5" Univers LT Std (67 Bold Condensed, 47 Light Con-Bleed None densed, 57 Condensed, 47 Light Condensed Oblique),Bleed None densed, 57 Condensed, 47 Light Condensed Oblique), Myriad Pro (Regular) Myriad Pro (Regular)# of Colors 1/0 # of Colors 1/0Notes Lenvima Brief Summary A size Notes Lenvima Brief Summary A size'