b'T:7.875"S:6.875"LENVIMA (lenvatinib) BRIEF SUMMARYSee package insert for full prescribing information. CONTRAINDICATIONS None.66 INDICATIONS AND USAGE WARNINGS AND PRECAUTIONSIMPORTANT SAFETY INFORMATION of bisphosphonate treatment may reduce the risk of ONJ.Hepatocellular Carcinoma LENVIMA is indicated for the first-line treatment of patients with unresectableHypertension Hypertension occurred in 73% of patients in SELECT (differentiated thyroid cancer or DTC) hepatocellular carcinoma (HCC). receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg Warnings and Precautions (contd)Withhold LENVIMA if ONJ develops and restart based on clinical judgementor 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT of adequate resolution. DOSAGE AND ADMINISTRATION and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Hypocalcemia (cont\'d). Monitor blood calcium levels at least monthly Important Dosage Information Grade 4 hypertension occurred 1% in SELECT and Grade 4 hypertension was not reported in REFLECT.and replace calcium as necessary during treatment. Withhold and resume atEmbryo-Fetal Toxicity. Based on its mechanism of action and data from Reduce the dose for certain patients with renal or hepatic impairment In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205 (renal cell carcinoma Take LENVIMA once daily, with or without food, at the same time each day. If a dose is missed reduced dose upon recovery or permanently discontinue depending on severity. animal reproduction studies, LENVIMA can cause fetal harm when and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time or RCC) hypertension was reported in 42% of patients and the median time to onset of new or worsening administered to pregnant women. In animal reproduction studies, oral of administration hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients. Systolic blood pressure 160 Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across administration of lenvatinib during organogenesis at doses below the Recommended Dosage for Hepatocellular Carcinoma (HCC) The recommended dosage of LENVIMA mmHg occurred in 29% of patients and diastolic blood pressure 100 mmHg occurred in 21%.clinical studies of 1823 patients who received LENVIMA as a single agent, recommended clinical doses resulted in embryotoxicity, fetotoxicity, and is based on actual body weight: Serious complications of poorly controlled hypertension have been reported. RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and 12 mg orally once daily for patients greater than or equal to 60 kg or Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks teratogenicity in rats and rabbits. Advise pregnant women of the potential for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at aresume at reduced dose upon recovery or permanently discontinue risk to a fetus and advise females of reproductive potential to use effective 8 mg orally once daily for patients less than 60 kg reduced dose when hypertension is controlled or permanently discontinue LENVIMA based on severity.depending on severity and persistence of neurologic symptoms. contraception during treatment with LENVIMA and for at least 30 days after Take LENVIMA orally once daily until disease progression or until unacceptable toxicity. Cardiac Dysfunction Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in Dosage Modifications for Adverse Reactions Recommendations for LENVIMA dose interruption,799 patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including cardiomyopathy, left or right Hemorrhagic Events. Serious including fatal hemorrhagic events can the last dose. reduction and discontinuation for adverse reactions are listed in Table 1. Table 2 lists the recommended ventricular dysfunction, congestive heart failure, cardiac failure, ventricular hypokinesia, or decrease in left oroccur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic Adverse Reactions dosage reductions of LENVIMA for adverse reactions. right ventricular ejection fraction of more than 20% from baseline) occurred in 3% of LENVIMA-treated patients.events, of any grade, occurred in 29% of the 799 patients treated with Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose LENVIMA as a single agent or in combination with everolimus. The most In HCC, the most common adverse reactions (20%) observed in LENVIMA-a Dosage Modifications upon recovery or permanently discontinue LENVIMA based on severity.treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), Adverse Reaction Severity Arterial Thromboembolic Events Among patients receiving LENVIMA or LENVIMA with everolimus, arterial frequently reported hemorrhagic events (all grades and occurring in at least decreased appetite (34%), arthralgia/myalgia (31%), decreased weight for LENVIMA thromboembolic events of any severity occurred in 2% of patients in Study 205 (RCC), 2% of patients in REFLECT Withhold for Grade 3(HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5 arterial thromboembolic events ranged from 2% to 3% 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome that persists despite across all clinical trials.(27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), optimal antihypertensive Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in intracranial hemorrhage among 16 patients who received LENVIMA and had hypothyroidism (21%), and nausea (20%). The most common serious Grade 3 therapy.5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% adverse reactions (2%) were hepatic encephalopathy (5%), hepatic failure Hypertension Resume at reduced dose Permanently discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA of LENVIMA + everolimustreated patients, including 1 fatal cerebral when hypertension is after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to controlled at less than or who have had an arterial thromboembolic event within the previous 6 months.hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-dose reductions or interruption in 62% of patients. The most common equal to Grade 2. Hepatotoxicity Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies othertreated patients, including 7 fatal hemorrhagic events. Serious tumor-adverse reactions (5%) resulting in dose reductions were fatigue (9%), Grade 4 Permanently discontinue. than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients.treated patients in clinical trials and in the postmarketing setting. In Withhold until improves In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolicpostmarketing surveillance, serious and fatal carotid artery hemorrhages (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment to Grade 0 to 1 or baseline.encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated discontinuation due to an adverse reaction occurred in 20% of patients. Resume at a reduced dose patients. Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of were seen more frequently in patients with anaplastic thyroid carcinoma The most common adverse reactions (1%) resulting in discontinuation Cardiac Dysfunction Grade 3 or discontinue depending on sorafenib-treated patients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3%(ATC) than other tumors. Safety and effectiveness of LENVIMA in patients of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), the severity and persistence of sorafenib-treated patients; 2% of patients discontinued LENVIMA and 0.2% discontinued sorafenib due to with ATC have not been demonstrated in clinical trials.of adverse reaction. hepatic encephalopathy, and 1% of patients discontinued lenvatinib or sorafenib due to hepatic failure.hyperbilirubinemia (1%), and hepatic failure (1%). Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2 months, and at least Consider the risk of severe or fatal hemorrhage associated with tumor Grade 4 Permanently discontinue. monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including invasion or infiltration of major blood vessels (eg, carotid artery). Withhold Use in Specific Populations Arterial Thromboembolic Event Any Grade Permanently discontinue. hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue Because of the potential for serious adverse reactions in breastfed infants, Withhold until improves to LENVIMA based on severity.and resume at reduced dose upon recovery or permanently discontinue Renal Failure or Impairment Serious including fatal renal failure or impairment can occur with LENVIMA. advise women to discontinue breastfeeding during treatment and for at Grade 0 to 1 or baseline.based on severity. least 1 week after the last dose. LENVIMA may impair fertility in males and Either resume at a reducedRenal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patientsdose or discontinue depending receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% Impairment of Thyroid Stimulating Hormone Suppression/Thyroid females of reproductive potential. Hepatotoxicity Grade 3 or 4 on severity and persistence (HCC) of patients, including 1 fatality in each study.Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, of hepatotoxicity. In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with No dose adjustment is recommended for patients with mild (CLcr 60-89 everolimus, including Grade 3 in 10% of patients.Permanently discontinue for88% of patients had baseline thyroid stimulating hormone (TSH) level mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA hepatic failure. Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at a reduced S:10" T:10.5"0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level Withhold until improves to dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity.concentrations may increase in patients with DTC, RCC, or EC (endometrial 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated carcinoma) and severe (CLcr 15-29 mL/min) renal impairment. Reduce theGrade 0 to 1 or baseline. Proteinuria Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of Renal Failure or Impairment Grade 3 or 4 Resume at a reduced dose LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT anddose for patients with DTC, RCC, or EC and severe renal impairment. or discontinue depending onLENVIMA + everolimustreated patients and 21% of LENVIMA-treated severity and persistence of REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMAThere is no recommended dose for patients with HCC and severe renalwith everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients patients, respectively. In patients with normal or low TSH at baseline, impairment. LENVIMA has not been studied in patients with end-stagerenal impairment. receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus.elevation of TSH was observed post baseline in 70% of LENVIMA-treated renal disease. Withhold until less than or Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If urine dipstickpatients in HCC and 60% of LENVIMA + everolimustreated patients equal to 2 grams of proteinuriaproteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a No dose adjustment is recommended for patients with HCC and mild Proteinuria2 g or greater proteinuriaper 24 hours. reduced dose upon recovery or permanently discontinue LENVIMA based on severity.in RCC.in 24 hours Resume at a reduced dose.hepatic impairment (Child-Pugh A). There is no recommended dose for Discontinue for nephrotic Diarrhea Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred inMonitor thyroid function prior to initiation and at least monthly during patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) syndrome. 49% of patients, including Grade 3 diarrhea in 6%.treatment. Treat hypothyroidism according to standard medical practice. In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, includinghepatic impairment. No dose adjustment is recommended for patients withGastrointestinal Perforation Any Grade Permanently discontinue. Grade 3 in 19%. Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred Impaired Wound Healing. Impaired wound healing has been reported in DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMAFistula Formation Grade 3 or 4 Permanently discontinue. despite dose reduction. concentrations may increase in patients with DTC, RCC, or EC and severePromptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently patients who received LENVIMA. Withhold LENVIMA for at least 1 week Greater than 500 ms ordiscontinue LENVIMA based on severity.Withhold until improves toprior to elective surgery. Do not administer for at least 2 weeks following hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC andQT Prolongation greater than 60 ms increaseless than or equal to 480 ms Fistula Formation and Gastrointestinal Perforation Of 799 patients treated with LENVIMA or severe hepatic impairment. from baseline or baseline. LENVIMA with everolimus in SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal major surgery and until adequate wound healing. The safety of resumption Resume at a reduced dose.of LENVIMA after resolution of wound healing complications has not perforation occurred in 2%.Withhold until fully resolved. Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of any severity or been established. Reversible PosteriorResume at a reduced dose or Grade 3 or 4 fistula. Please see Brief Summary of Prescribing Information on theLeukoencephalopathyAny Grade discontinue depending on QT Interval Prolongation In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA- Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients following pages. Syndrome severity and persistence of treated patients and QT interval prolongation of 500 ms occurred in 2%. In Study 205 (RCC), QTc interval receiving LENVIMA. Concomitant exposure to other risk factors, such as neurologic symptoms. increases of 60 ms occurred in 11% of patients receiving LENVIMA with everolimus and QTc interval500 ms occurred in 6%. In REFLECT (HCC), QTc interval increases of 60 ms occurred in 8% of LENVIMA-bisphosphonates, denosumab, dental disease, or invasive dental References: 1. LENVIMA [package insert]. Woodcliff Lake, NJ: Eisai Inc. 2. Kudo M, Finn RS, Qin S, Persistent or intolerable Withhold until improves to treated patients and QTc interval 500 ms occurred in 2%.Grade 2 or 3 adverse reaction Grade 0 to 1 or baseline.procedures, may increase the risk of ONJ.et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular Other Adverse Reactions Resume at reduced dose. Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. MonitorPerform an oral examination prior to treatment with LENVIMA and carcinoma: a randomised phase 3 non-inferiority trial [published online February 9, 2018]. Grade 4 laboratory abnormality electrocardiograms in patients with congenital long QT syndrome, congestive heart failure,Lancet. 2018. doi:10.1016/S0140-6736(18)30207-1. 3. Lencioni R, et al. Independent imaging Grade 4 adverse reaction Permanently discontinue. bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia andperiodically during LENVIMA treatment. Advise patients regarding good oral review (IIR) results in a phase 3 trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment ofa National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.III antiarrhythmics. Withhold and resume at reduced dose of LENVIMA upon recovery based on severity.hygiene practices and to consider having preventive dentistry performed patients (pts) with unresectable hepatocellular carcinoma (uHCC). Abstract presented at: 2018 Hypocalcemia In SELECT (DTC), Grade 3 to 4 hypocalcemia occurred in 9% of patients receiving LENVIMA.prior to treatment with LENVIMA and throughout treatment with LENVIMA. Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 345.Table 2: Recommended Dosage Reductions of LENVIMA for Adverse Reactions In 65% of cases, hypocalcemia improved or resolved following calcium supplementation, with or withoutdose interruption or dose reduction.Avoid invasive dental procedures, if possible, while on LENVIMA treatment, Indication First Dosage Second DosageThird Dosage In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated with LENVIMA with particularly in patients at higher risk. Withhold LENVIMA for at least 1 Reduction To Reduction To Reduction To everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients.week prior to scheduled dental surgery or invasive dental procedures, if HCC 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.possible. For patients requiring invasive dental procedures, discontinuation Actual weight 60 kgReversible Posterior Leukoencephalopathy Syndrome (RPLS) Across clinical studies of 1823 patientsor greater 8 mg once daily 4 mg once daily 4 mg every other day who received LENVIMA as a single agent, reversible posterior leukoencephalopathy syndrome (RPLS) occurredActual weight less in 0.3%. than 60 kg 4 mg once daily 4 mg every other day Discontinue Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a reduced doseupon recovery or permanently discontinue LENVIMA depending on severity and persistence of neurologic Preparation and Administration LENVIMA capsules can be swallowed whole or dissolved in a smallsymptoms.glass of liquid. To dissolve in liquid, put capsules into 1 tablespoon of water or apple juice without breaking orHemorrhagic Events Serious including fatal hemorrhagic events can occur with LENVIMA. Acrosscrushing the capsules. Leave the capsules in the water or apple juice for at least 10 minutes. Stir for at least 3SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurred in 29% of minutes. After drinking the mixture, add 1 tablespoon of water or apple juice to the glass, swirl the contents athe 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most few times and swallow the water or apple juice. frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxisDOSAGE FORMS AND STRENGTHS and hematuria.LENVIMAis a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. Capsules: 2021 Eisai Inc.All rights reserved.Printed in USA/September 2021LENV-US6742 4 mg: yellowish-red body and yellowish-red cap, marked in black ink withon cap and LENV 4 mg on body.10 mg: yellow body and yellowish-red cap, marked in black ink withon cap and LENV 10 mg on body.84724_A-SIZE_PB.indd 3-4 9/24/21 1:15 PMLHCC21HSAW0697_M3_LENVIMA_Brief_Summary_Asize_ Printed At NoneSaved at 9-16-2021 4:22 PM from US3LINM0FQ35HMD by Suke Yawata / kwalshJob info ImagesFonts & ColorsClient Code None None ColorsClient Eisai/LenvimaBlackLive 6.875" x 10" FontsOverall Trim 7.875" x 10.5" Univers LT Std (67 Bold Condensed, 47 Light Con-Bleed None densed, 57 Condensed, 47 Light Condensed Oblique), Myriad Pro (Regular)# of Colors 1/0Notes Lenvima Brief Summary A size'