LENVIMA

a kinase inhibitor, is the mesylate salt of lenvatinib.

Its chemical name is 4-[3-chloro-4-( N ’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate.

The molecular formula is

C 21 H 19 ClN 4 O 4.

• CH 4 O 3 S, and the molecular weight of the mesylate salt is 522.96.

The chemical structure of lenvatinib mesylate is: Lenvatinib mesylate is a white to pale reddish yellow powder.

It is slightly soluble in water and practically insoluble in ethanol (dehydrated).

The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.3.

LENVIMA capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively.

The inactive ingredients are: calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and talc.

In addition, the capsule shell contains ferric oxide red, ferric oxide yellow, hypromellose, and titanium dioxide.

The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.

The chemical structure of lenvatinib mesylate is LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib.

Its chemical name is 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6 carboxamide methanesulfonate.

• CH4O3S, and the molecular weight of the mesylate salt is 522.96.

is a kinase inhibitor that is indicated: Differentiated Thyroid Cancer (DTC) For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Carcinoma (RCC) In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC).

In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy.

Carcinoma (HCC) For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

Carcinoma (EC) In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. 1.1 Differentiated Thyroid Cancer LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 1.2 Renal Cell Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

LENVIMA, in combination with everolimus, is indicated for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy. 1.3 Hepatocellular Carcinoma LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.4 Endometrial Carcinoma LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4).

Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRA), KIT, and RET.

Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 alpha (FRS2) phosphorylation.

In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone. 12.2 Pharmacodynamics Exposure-Response Relationships In a multicenter randomized (1:1) double blind trial of 152 patients with radioactive iodine (RAI)-refractory DTC, a 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. A 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.

In patients with solid tumors administered single and multiple doses of LENVIMA once daily, the maximum lenvatinib plasma concentration (C max ) 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 a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).

Geometric mean C max and AUC values at steady state for RCC, DTC and HCC are summarized in the Table 13.

Table 13: Lenvatinib C max and AUC in Patients with Solid Tumors a Tumor Type Dose Parameter N Geometric Mean %CV RCC 18 mg C max (ng/mL) 350 267 36.7 AUC (ng∙h/mL) 350 3148 42.5 20 mg C max (ng/mL) 346 275 32.6 AUC (ng∙h/mL) 346 3135 41.3 DTC 24 mg C max (ng/mL) 251 323 33.3 AUC (ng∙h/mL) 251 3483 34.7 HCC (body weight < 60 kg) 8 mg C max (ng/mL) 150 154 25.4 AUC (ng∙h/mL) 150 1835 34.0 HCC (body weight ≥ 60 kg) 12 mg C max (ng/mL) 318 172 23.1 AUC (ng∙h/mL) 318 2013 29.3 a Model-predicted steady-state pharmacokinetic parameters are presented.

The time to peak plasma concentration (T max ) typically occurred from to 4 hours post-dose.

Administration with a 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 T max from 2 hours to 4 hours.

Model-predicted geometric mean steady state volume of distribution is 97 L (%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 μg/mL in vitro.

The terminal elimination half-life of lenvatinib was approximately 28 hours.

The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.

Ten days after a single administration of radiolabeled lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Age (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 a significant effect on apparent oral clearance (CL/F).

Subjects with end stage renal disease were not studied.

The pharmacokinetics of lenvatinib following a single 10 mg dose were evaluated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

The pharmacokinetics of a single 5 mg dose were evaluated in subjects with severe (Child-Pugh C) hepatic impairment.

Compared to subjects with normal hepatic function, the dose-adjusted AUC 0-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 Weight Lenvatinib exposures in patients with HCC in REFLECT were comparable between those weighing <60 kg who received a starting dose of 8 mg and those ≥60 kg who received a starting dose of 12 mg. Drug Interaction Studies Effect of Other D rugs on L envatinib CYP3A, P-gp, and BCRP Inhibitor s: Ketoconazole (400 mg daily for 18 days) increased lenvatinib (administered as a single 5 mg dose on Day 5) AUC by 15% and C max by 19%.

Rifampicin (600 mg as a single dose) increased lenvatinib (24 mg as a single dose) AUC by 31% and C max by 33%.

CYP3A and P-gp Inducers: Rifampicin (600 mg daily for 21 days) decreased lenvatinib (24 mg as a single dose on Day 15) AUC by 18%.

C max was unchanged.

Population pharmacokinetic analysis demonstrated that neither everolimus nor pembrolizumab meaningfully affect the pharmacokinetics of lenvatinib.

Lenvatinib is a substrate of P-gp and BCRP but not a 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 L envatinib on O ther D rugs CYP2C8 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

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.

UGT1A6, UGT2B7 or aldehyde oxidase.

Lenvatinib does not induce

In Vitro Studies with Substrates of Transporter s: Lenvatinib does not have the potential to inhibit MATE1, MATE2-K, OCT1, OCT2, OAT1, OAT3, BSEP, OATP1B1, or OATP1B3 in vivo.

The following adverse reactions are discussed elsewhere in the labeling: Hypertension Cardiac Dysfunction Arterial Thromboembolic Events Hepatotoxicity Renal Failure and Impairment Proteinuria Diarrhea Fistula Formation and Gastrointestinal Perforation QT Interval Prolongation Hypocalcemia Reversible Posterior Leukoencephalopathy Syndrome Hemorrhagic Events Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction Impaired Wound Healing Osteonecrosis of the Jaw (ONJ) 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.

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.

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.

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.

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.

To report SUSPECTED ADVERSE

REACTIONS, contact Eisai Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and Precautions reflect exposure to LENVIMA as a single agent in 261 patients with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 406 patients with endometrial carcinoma (Study 309), LENVIMA with everolimus in 62 patients with RCC (Study 205), and LENVIMA with pembrolizumab in 352 patients with RCC (CLEAR).

Safety data obtained in 1823 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions.

Among the 1823 patients who received LENVIMA as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily, and the median duration of exposure was 5.6 months.

The data below reflect exposure to

LENVIMA in 1557 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205; CLEAR; Study 309), and a randomized, placebo-controlled trial (SELECT).

The median duration of exposure to

LENVIMA across these five studies ranged from to 16 months.

The demographic and exposure data for each clinical trial population are described in the subsections below.

Differentiated Thyroid Cancer The safety of LENVIMA was evaluated in SELECT, in which patients with radioactive iodine-refractory differentiated thyroid cancer were randomized (2:1) to LENVIMA (n=261) or placebo (n=131) .

The median treatment duration was 16.1 months for LENVIMA.

Among 261 patients who received LENVIMA, median age was 64 years, 52% were females, 80% were White, 18% were Asian, and 2% were Black; and 4% were Hispanic/Latino.

The most common adverse reactions observed in LENVIMA-treated patients (≥30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia.

The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA; 18% of patients discontinued LENVIMA for adverse reactions.

The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

Table 3 presents adverse reactions occurring at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the study.

Table 3: Adverse Reactions Occurring in Patients with a Between-Group Difference of ≥5% in All Grades or ≥2% in Grades and 4 in SELECT (DTC) Adverse Reaction LENVIMA 24 mg N=261 Placebo N=131 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3.

• 4 (%) Vascular Hypertension a 73 44 16 4 Hypotension 9 2 2 0 Gastrointestinal Diarrhea 67 9 17 0 Nausea 47 2 25 1 Stomatitis b 41 5 8 0 Vomiting 36 2 15 0 Abdominal pain c 31 2 11 1 Constipation 29 0.4 15 1 Oral pain d 25 1 2 0 Dry mouth 17 0.4 8 0 Dyspepsia 13 0.4 4 0 General Fatigue e 67 11 35 4 Edema peripheral 21 0.4 8 0 Musculoskeletal and Connective Tissue Arthralgia/Myalgia f 62 5 28 3 Metabolism and Nutrition Decreased appetite 54 7 18 1 Decreased weight 51 13 15 1 Dehydration 9 2 2 1 Nervous System Headache 38 3 11 1 Dysgeusia 18 0 3 0 Dizziness 15 0.4 9 0 Renal and Urinary Proteinuria 34 11 3 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia 32 3 1 0 Rash g 21 0.4 3 0 Alopecia 12 0 5 0 Hyperkeratosis 7 0 2 0 Respiratory, Thoracic and Mediastinal Dysphonia 31 1 5 0 Cough 24 0 18 0 Epistaxis 12 0 1 0 Psychiatric Insomnia 12 0 3 0.

Infections Urinary tract infection 11 1 5 0 Dental and oral infections h 10 1 1 0 Cardiac Electrocardiogram QT prolonged 9 2 2 0 a.

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b.

Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c.

Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d.

Includes oral pain, glossodynia, and oropharyngeal pain e.

Includes asthenia, fatigue, and malaise f.

Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g.

Includes macular rash, maculo-papular rash, generalized rash, and rash h.

Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection Clinically 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 a difference of ≥2% in Grade 3 – 4 events and at a higher incidence in the LENVIMA arm are presented in Table 4.

Table 4: Laboratory Abnormalities with a Difference of ≥2% in Grade 3.

• 4 Events and at a Higher Incidence in the LENVIMA Arm a, b in SELECT (DTC) Laboratory A bnormality LENVIMA 24 mg Placebo Grades 3-4 (%) Grades 3-4 (%) Chemistry Hypocalcemia 9 2 Hypokalemia 6 1 Increased aspartate aminotransferase (AST) 5 0 Increased alanine aminotransferase (ALT) 4 0 Increased lipase 4 1 Increased creatinine 3 0 Hematology Thrombocytopenia 2 0 a.

With at least 1 grade increase from baseline b.

Abnormality percentage is based on the number of patients who had both baseline and at least one post baseline laboratory measurement for each parameter.

LENVIMA (n = 253 to 258), Placebo (n = 129 to 131) The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

First-Line Treatment of Renal Cell Carcinoma in Combination with P embrolizumab (CLEAR) The safety of LENVIMA in combination with pembrolizumab was investigated in CLEAR [ s ee Clinical Studies.

Patients received

LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks (n=352), or LENVIMA 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 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 vo.

Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable.

Death due to multiorgan dysfunction occurred in a patient who received a single dose of LENVIMA 120 mg orally.

The recommended dosage is 24 mg orally once daily.

The recommended dosage is based on actual body weight: 12 mg orally once daily for patients greater than or equal to 60 kg or 8 mg orally once daily for patients less than 60 kg. Combination Therapy: EC: The recommended dosage is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.

The recommended dosage is: 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. 18 mg orally once daily with everolimus 5 mg orally once daily.

Modify the recommended daily dose for certain patients with renal or hepatic impairment. 2.1 Patient Selection For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MMR or MSI status in tumor specimens.

Information on

FDA-approved tests for patient selection is available at: . 2.

Reduce the dose for certain patients with renal or hepatic impairment.

LENVIMA once daily, with or without food, at the same time each day.

If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration. 2.

Recommended Dos ag e for Differentiated Thyroid Cancer (DTC) The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity. 2.

Carcinoma (RCC) F irst.

• L ine Treatment of Patients with Advanced RCC The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years.

After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity.

Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.

Previously Treated RCC The recommended dosage of LENVIMA is 18 mg in combination with 5 mg everolimus orally once daily until disease progression or until unacceptable toxicity.

Refer to the everolimus prescribing information for recommended everolimus dosing information. 2.

Carcinoma (HCC) The recommended dosage of LENVIMA is based on actual body weight: 12 mg for patients greater than or equal to 60 kg or 8 mg for patients less than 60 kg. Take LENVIMA orally once daily until disease progression or until unacceptable toxicity. 2.

Carcinoma (EC) The recommended dosage of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information. 2.

Dos age Modifications for Adverse Reactions Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1.

Table 2 lists the recommended dosage reductions of LENVIMA for adverse reactions.

Table 1: Recommended Dos ag e Modifications for LENVIMA for Adverse Reactions Adverse Reaction Severity a Dos ag e Modifications for LENVIMA Hypertension Grade 3 Withhold for Grade 3 that persists despite optimal antihypertensive therapy.

Resume at reduced dose when hypertension is controlled at less than or equal to Grade 2.

Grade 4 Permanently discontinue.

Grade 3 Withhold until improves to Grade to 1 or baseline.

Resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction.

Permanently discontinue.

Grade 3 or 4 Withhold until improves to Grade to 1 or baseline.

Either resume at a reduced dose or discontinue depending on severity and persistence of hepatotoxicity.

Permanently discontinue for hepatic failure.

Resume at a reduced dose or discontinue depending on severity and persistence of renal impairment.

Proteinuria 2 g or greater proteinuria in 24 hours Withhold until less than or equal to 2 grams of proteinuria per 24 hours.

Resume at a reduced dose.

Permanently discontinue for nephrotic syndrome.

Grade 3 or 4 Permanently discontinue.

Greater than 500 ms or greater than 60 ms increase from baseline Withhold until improves to less than or equal to 480 ms or baseline.

Reversible Posterior Leukoencephalopathy Syndrome Any Grade Withhold until fully resolved.

Resume at a reduced dose or discontinue depending on severity and persistence of neurologic symptoms.

Other Adverse Reactions Persistent or intolerable Grade 2 or 3 adverse reaction Grade 4 laboratory abnormality Withhold until improves to Grade to 1 or baseline.

Resume at reduced dose.

Grade 4 adverse reaction Permanently discontinue. a.

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Table 2: Recommended Dosage Reductions of LENVIMA for Adverse Reactions Indication First Dosage Reduction To Second Dosage Reduction To Third Dosage Reduction To DTC 20 mg once daily 14 mg once daily 10 mg once daily RCC 14 mg once daily 10 mg once daily 8 mg once daily Endometrial Carcinoma 14 mg once daily 10 mg once daily 8 mg once daily HCC Actual weight 60 kg or greater 8 mg once daily 4 mg once daily 4 mg every other day Actual weight less than 60 kg 4 mg once daily 4 mg every other day Discontinue Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Pembrolizumab When 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 Everolimus When 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. 2.

Dosage 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, Use in Specific Populations ] : Differentiated thyroid cancer: 14 mg orally once daily Renal cell carcinoma: 10 mg orally once daily Endometrial carcinoma: 10 mg orally once daily 2.

Dosage 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, Use in Specific Populations ] : 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. 1 0 Capsule Administration and Preparation of Suspension for Administration Administration Oral: Capsule or Suspension Capsule Swallow LENVIMA capsules whole at the same time each day with or without food.

Do not crush or chew the

LENVIMA capsules.

Prepare oral suspension with water or apple juice and administer at the same time each day with or without food.

Prepare suspension for feeding tube administration with water and administer at the same time each day with or without food.

Place the required number of capsules, up to a maximum of 5, in a small container (approximately 20 mL capacity) or syringe (20 mL).

Do not break or crush capsules.

Add 3 mL of liquid to the container or syringe.

Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until capsules are fully disintegrated and administer the entire contents.

Next, add an additional 2 mL of liquid to the container or syringe using a second syringe or dropper, swirl or shake and administer.

Repeat this step at least once and until there is no visible residue to ensure all of the medication is taken.

If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time.

If LENVIMA suspension is not used at the time of preparation, LENVIMA suspension may be stored in a refrigerator at 36ºF to 46ºF (2ºC to 8ºC) for a maximum of 24 hours in a covered container.

If not administered within 24 hours, the suspension should be discarded.

Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube).

mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on the body.

LENVIMA 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on the body.

LENVIMA capsules are supplied in cartons of 6 cards.

Each card is a 5-day blister card as follows: NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card).

NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card).

NDC 62856-718-30: 18 mg, carton with 6 cards NDC 62856-718-05 (five 10 mg capsules and ten 4 mg capsules per card).

NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card).

NDC 62856-712-30: 12 mg, carton with 6 cards NDC 62856-712-05 (fifteen 4 mg capsules per card).

NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card).

NDC 62856-708-30: 8 mg, carton with 6 cards NDC 62856-708-05 (ten 4 mg capsules per card).

NDC 62856-704-30: 4 mg, carton with 6 cards NDC 62856-704-05 (five 4 mg capsules per card).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Based on findings from animal studies and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman.

In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits.

There are no available human data informing the drug-associated risk.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies.

Greater than 80% post-implantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the recommended clinical dose of 24 mg based on BSA).

At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed.

Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

The safety and effectiveness of

LENVIMA in pediatric patients have not been established.

The safety and efficacy of

LENVIMA alone and in combination were investigated but not established in four open label studies (NCT02432274, NCT04154189, NCT04447755, NCT03245151) in 232 patients aged to <17 years with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma.

Hypothyroidism and pneumothorax were observed at a higher rate in pediatric patients compared to that of adult patients.

The pharmacokinetics (PK) of lenvatinib in pediatric patients were within range of values previously observed in adults at the approved recommended dose of 24 mg. Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the human exposure based on AUC at the recommended clinical dose of 24 mg).

Decreased length of the femur and tibia persisted following 4 weeks of recovery.

In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.

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.